Infectious Diseases Ct Is &Ious D & 3 2011 Journal of Abstracts and Conference Reports from International Workshops on Infectious Diseases & Antiviral Therapy

Pneumonie.nl

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REVIEWSI in Antiviral Therapy N S

I E Reviews N S F A E E INFECTIOUS DISEASES CT IS &IOUS D & 3 2011 JOURNAL OF ABSTRACTS AND CONFERENCE REPORTS FROM INTERNATIONAL WORKSHOPS ON INFECTIOUS DISEASES & ANTIVIRAL THERAPY

Meeting report 6th International Workshop on HIV Transmission Principles of Intervention 14 - 15 July, 2011, Rome, Italy

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Prof. Dr. Marc Bonten Universitair Medisch Centrum Utrecht Prof. Dr. Han van den Bosch Vrije Universiteit Amsterdam Prof. Dr. Robert Sauerwein St. Radboud Universitair Medisch Centrum Nijmegen Prof. Dr. Ben van der Zeijst Leids Universitair Medisch Centrum, Leiden

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Ad Atripla.indd 1 19-01-11 12:12 Reviews in Antiviral Therapy &INFECTIOUS DISEASES Reviews in Antiviral Therapy & Infectious Diseases is the official journal of abstracts and conference reports from International Workshops on infectious diseases & antiviral therapy.

Reviews in Antiviral Therapy & Infectious Diseases publishes peer-reviewed articles relating to viral diseases including HIV, Hepatitis and emerging viruses. Featured topics include clinical management, drug resistance, diagnostic applications, pharmacology, transmission & prevention. Each edition will be dedicated to a specific aspect of viral infection, focusing on the presentations from the latest international meeting on the topic.

Reviews in Antiviral Therapy & Infectious Diseases aims at translating the latest key scientific and clinical findings in antiviral therapy into tangible and applicable knowledge to assist readers in routine clinical management.

Editors-in-chief: Charles A.B. Boucher, MD, PhD, Erasmus Medical Center Rotterdam, The Netherlands

Jonathan M. Schapiro, MD, Sheba Medical Center, Tel Aviv, Israel

Publisher: Virology Education, Biltstraat 106, 3572 BJ Utrecht, The Netherlands Phone: +31-30 2307140 Fax: +31-30 2307148 [email protected]; www.virology-education.com

ISSN: 1872-437X

Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permission of the publisher. © Virology Education.

Reprints: In order to acquire additional reprints of this volume, please contact Virology Education at [email protected]

Printed on woodfree coated paper Printed by Labor, Utrecht, The Netherlands (CU-COC-807561)

Disclaimer The information in this journal is those of the authors and not necessarily reflects the views of the board or the publisher. No responsibility is assumed by Virology Education for any injury and/or damage to persons or property as result of product liability, negligence or otherwise, or form any use or operation of any methods, products, instructions, or ideas contained in the material herein. All clinical diagnoses and drug regimens/dosages must be independently verified. A qualified healthcare professional should be consulted before using any therapeutic product discussed.

Reviews in Antiviral Therapy & Infectious Diseases - volume 1; 2011 - Supplement 1 open een wereld Nieuw! Viramune met Verlengde afgifte van nieuwe stabiele spiegels met eenmaal daags 1 tablet mogelijkheden

ISENTRESS, de eerste integraseremmer, nu geregistreerd voor zowel behandelingsnaïeve als eerder behandelde volwassenen met HIV in combinatie met andere antiretrovirale middelen. Dus kies vanaf het eerste begin ISENTRESS!

• het vertrouwde Viramune nu met verlengde afgifte 1 • eenmaaldaagse dosering van 400 mg 1 • goed bijwerkingenprofiel voor de lange termijn3,4,5,6 ISENTRESS is geïndiceerd in combinatie met andere antiretrovirale geneesmiddelen voor de behandeling van humaan-immunodeﬁ ciëntievirus (HIV-1)-infectie bij volwassen patiënten. 1. Samenvatting van de productkenmerken 2. Battegay et al. Clin ther. 2011; 33: 1308-1320 3. elzi et al. Raadpleeg de volledige productinformatie (SPC) inclusief dosering, contra-indicaties en arch intern med. 2010; 170(1): 57-65 4. reliquet et al. HiV lin tirals 2010; 170: 57-65 5. Vallicello et al. aidS waarschuwingen alvorens ISENTRESS voor te schrijven. research and human retroviruses. 2011; 27(10) 6. gathe et al. antiviral therapy 2011; 16: 759-69.

0910RTG09NL416J0909 Zie elders in dit blad voor de verkorte bijsluiter Voor productinformatie zie elders in dit blad.

ISENTRESS® en univadis zijn geregistreerde handelsmerken van MERCK & Co., Inc., Whitehouse Station, NJ, USA.

Postbus 581, 2003 PC Haarlem, www.msd.nl, www.univadis.nl Sterk op de lange termijn

ISE416J_Adv210x297sept'09.indd 1 05-11-2009 10:15:37 open een wereld Nieuw! Viramune met Verlengde afgifte van nieuwe stabiele spiegels met eenmaal daags 1 tablet mogelijkheden

0910RTG09NL416J0909 Zie elders in dit blad voor de verkorte bijsluiter Voor productinformatie zie elders in dit blad.

ISENTRESS® en univadis zijn geregistreerde handelsmerken van MERCK & Co., Inc., Whitehouse Station, NJ, USA.

Postbus 581, 2003 PC Haarlem, www.msd.nl, www.univadis.nl Sterk op de lange termijn

ISE416J_Adv210x297sept'09.indd 1 05-11-2009 10:15:37 VERKORTE PRODUCTINFORMATIE (bijvoorbeeld rifampicine). Rifampicine verlaagt de gedrag (vooral bij patiënten met een voorgeschiedenis van ‡ In klinisch onderzoek van eerder behandelde patiënten ISENTRESS 400 mg filmomhulde tabletten. plasmaconcentraties van raltegravir; de invloed daarvan psychische aandoeningen)‡‡. werd huiduitslag ongeacht causaliteit bij behandelingen Samenstelling op de werkzaamheid van raltegravir is onbekend. Maar als Zenuwstelselaandoeningen: vaak: duizeligheid, hoofdpijn, met ISENTRESS + darunavir vaker gezien dan bij die Filmomhulde tablet: 400 mg raltegravir (als kaliumzout). gelijktijdige toediening met rifampicine onontkoombaar is, soms: amnesie, carpaaltunnelsyndroom, cognitieve stoornis, met ISENTRESS zonder darunavir of darunavir zonder Indicaties kan verdubbeling van de dosis ISENTRESS worden aandachtsstoornis, duizeligheid bij houdingsverandering, ISENTRESS. Maar volgens de onderzoeker kwam ISENTRESS is geïndiceerd in combinatie met andere overwogen. Myopathie en rabdomyolyse zijn gemeld. dysgeusie, hypersomnie, hypo-esthesie, lethargie, geneesmiddelgerelateerde huiduitslag ongeveer even vaak antiretrovirale geneesmiddelen voor de behandeling Gebruik met voorzichtigheid bij patiënten die in het verleden geheugenstoornis, migraine, perifere neuropathie, voor. De voor blootstelling aangepaste frequenties van van humaan-immunodeficiëntievirus (hiv-1)-infectie bij myopathie of rabdomyolyse hebben gehad of anderszins paresthesie, slaperigheid, spanningshoofdpijn, tremoren. huiduitslag (alle oorzaken) waren resp. 10,9, 4,2 en 3,8 per volwassen patiënten. gepredisponeerd zijn. Oogaandoeningen: soms: visusverslechtering. 100 patiëntjaren (PYR) en voor geneesmiddelgerelateerde Deze indicatie is gebaseerd op gegevens over veiligheid en Huiduitslag kwam bij eerder behandelde patiënten die een Evenwichtsorgaan- en ooraandoeningen: vaak: vertigo, huiduitslag resp. 2,4, 1,1 en 2,3 per 100 PYR. Deze huiduitslag werkzaamheid uit twee dubbelblinde, placebogecontroleerde behandeling met ISENTRESS + darunavir kregen vaker soms: tinnitus. was licht tot matig-ernstig en leidde niet tot stopzetting van onderzoeken bij eerder behandelde patiënten en een voor dan bij patiënten die ISENTRESS zonder darunavir of Hartaandoeningen: soms: palpitaties, sinusbradycardie, de behandeling. dubbelblind, met werkzame stof gecontroleerd onderzoek bij darunavir zonder ISENTRESS kregen. ventriculaire extrasystoles. ‡‡ Deze bijwerking is vastgesteld in de periode sinds het niet eerder behandelde patiënten. ISENTRESS bevat lactose. Patiënten met zeldzame Bloedvataandoeningen: soms: opvliegers, hypertensie. geneesmiddel op de markt is, maar werd in gerandomiseerd Klinische ervaring erfelijke stoornissen als galactose-intolerantie, Lapp- Ademhalingsstelsel-, borstkas- en mediastinumaandoeningen: gecontroleerd klinisch fase III-onderzoek (protocols 018, Bewijs voor de effectiviteit van ISENTRESS is gebaseerd lactasedeficiëntie of glucose-galactosemalabsorptie mogen soms: dysfonie, epistaxis, neusverstopping. 019 en 021) niet gemeld als zijnde geneesmiddelgerelateerd. op analyses van 96-weeksdata uit twee lopende, dit geneesmiddel niet gebruiken. Maagdarmstelselaandoeningen: vaak: opgezwollen buik, De frequentiecategorie is gedefinieerd als “soms”, in gerandomiseerde, dubbelblinde, placebogecontroleerde Interacties buikpijn, diarree, winderigheid, misselijkheid, braken, soms: overeenstemming met de richtlijnen voor de samenvatting studies (BENCHMRK 1 en BENCHMRK 2, Protocols 018 en Uit in vitro-onderzoek blijkt dat raltegravir geen substraat van gastritis†, last van de buik, pijn in de bovenbuik, gevoeligheid van de productkenmerken (SmPC) (rev. 2 sept. 2009) 019) bij eerder met antiretrovirale middelen behandelde, met cytochroom P450 (CYP)-enzymen, is, CYP1A2, CYP2B6, van de buik, pijn in de anus of het rectum, obstipatie, droge op basis van een geschatte bovengrens van het hiv-1 geïnfecteerde volwassen patiënten, en analyse van CYP2C8, CYP2C9, CYP2C19, CYP2D6 of CYP3A niet remt geen mond, dyspepsie, pijn in de bovenbuik, erosieve duodenitis, 95 %-betrouwbaarheidsinterval voor 0 voorvallen en het 96-weeksdata uit een lopende, gerandomiseerde, dubbelblinde, inductie van CYP3A4 geeft en het door P-glycoproteïne oprispingen, gastro-oesofageale reflux, gingivitis, glossitis, aantal proefpersonen dat in het klinisch fase III-onderzoek met werkzame stof gecontroleerde studie (STARTMRK, gereguleerde transport niet remt. Op basis van deze gegevens odynofagie, acute pancreatitis, maagzweer, rectale bloeding. met ISENTRESS werd behandeld (n=743). Protocol 021) bij niet eerder met antiretrovirale middelen wordt niet verwacht dat ISENTRESS de farmacokinetiek Lever- en galaandoeningen: soms: hepatitis†, hepatische Patiënten die tevens geïnfecteerd zijn met het hepatitis B- en/ behandelde en met hiv-1 geïnfecteerde volwassen patiënten. beïnvloedt van geneesmiddelen die substraten zijn van deze steatose. of hepatitis C-virus Contra-indicaties enzymen of P-glycoproteïne. Huid- en onderhuidaandoeningen: vaak: huiduitslag‡, In fase III-onderzoeken mochten eerder behandelde patiënten Overgevoeligheid voor het werkzame bestanddeel of voor één Op basis van in vitro- en in-vivo-onderzoeken wordt soms: acne, alopecia, dermatitis acneiforme, droge huid, (N = 114/699 ofwel 16 %; HBV=6 %, HCV=9 %, HBV+HCV=1 %) van de hulpstoffen. raltegravir voornamelijk uitgescheiden door erytheem, ingevallen gezicht, hyperhidrose, verkregen en niet eerder behandelde patiënten (N = 34/563 of 6 %; Waarschuwingen en voorzorgen metabolisme via UGT1A1- geïnduceerde glucuronidatieroute. lipodystrofie, lipohypertrofie, nachtelijk zweten, prurigo, HBV=4 %, HCV=2 %, HBV+HCV=0,2 % met gelijktijdige In het algemeen werd in de farmacokinetiek van Hoewel uit in-vitro-onderzoek gebleken is dat raltegravir pruritus, gegeneraliseerde pruritus, maculaire uitslag, chronische (maar geen acute) infectie met hepatitis B en/of raltegravir aanzienlijke inter- en intra-individuele geen remmer is van de UDP-glucuronosyltransferases maculopapulaire uitslag, uitslag bij pruritus, huidlaesie, hepatitis C) meedoen op voorwaarde dat de leverfunctietests variabiliteit waargenomen. (UGTs) 1A1 en 2B7, doet één klinisch onderzoek op grond urticaria, xeroderma, Stevens Johnson syndroom‡‡. bij baseline niet hoger waren dan 5 keer de normale Raltegravir heeft een relatief lage genetische barrière van een waargenomen effect op de glucuronidatie Skeletspierstelsel- en bindweefselaandoeningen: soms: bovengrens. In het algemeen was het veiligheidsprofiel voor resistentie. Daarom moet raltegravir waar mogelijk van bilirubine vermoeden dat er in vivo enige remming artralgie, artritis, rugpijn, pijn in de flank, musculoskeletale van ISENTRESS bij patiënten met een gelijktijdige infectie gecombineerd worden met twee andere actieve ARTs van UGT1A1 kan voorkomen. Maar de omvang van het pijn, myalgie, nekpijn, osteopenie, pijn in de extremiteiten, met hepatitis B-en/of hepatitis C-virus gelijk aan die van om de kans op virologisch falen en het optreden van effect leidt waarschijnlijk niet tot klinisch belangrijke tendinitis, rabdomyolyse‡‡. patiënten zonder hepatitis B-en/of hepatitis C-virus, hoewel resistentie te beperken. geneesmiddelinteracties. Nier- en urinewegaandoeningen: soms: nierfalen†, nefritis, in beide behandelingsgroepen de frequentie van AST- en Bij niet eerder behandelde patiënten zijn de klinische Bijwerkingen nefrolithiase, nycturie, niercyste, nierfunctiestoornis, ALT-afwijkingen in de subgroep met gelijktijdige infectie met gegevens over gebruik van raltegravir beperkt tot Infecties en parasitaire aandoeningen: soms: genitale tubulo-interstitiële nefritis. hepatitis B en/of hepatitis C iets hoger was. gebruik in combinatie met twee nucleotide-reverse- herpes†, folliculitis, gastro-enteritis, herpes simplex, infectie Voortplantingsstelsel- en borstaandoeningen: soms: Farmacotherapeutische categorie transcriptaseremmers (NRTIs) (emtricitabine en met herpesvirus, herpes zoster, influenza, molluscum erectiestoornis, gynaecomastie, menopauzale verschijnselen. Antiviraal middel voor systemisch gebruik, Andere tenofovirdisoproxilfumaraat). contagiosum, nasofaryngitis, bovensteluchtweginfectie. Algemene aandoeningen en toedieningsplaatsstoornissen: antiretrovirale middelen, ATC-code: J05AX08 De veiligheid en werkzaamheid van ISENTRESS zijn niet Neoplasmata, benigne, maligne en niet-gespecificeerd vaak: asthenie, vermoeidheid, pyrexie, soms: pijn op de Afleverstatus vastgesteld bij patiënten met ernstige onderliggende (inclusief cysten en poliepen): soms: huidpapilloom. borst, rillingen, oedeem in het gezicht, meer vetweefsel, zich UR leveraandoeningen. Daarom moet ISENTRESS bij patiënten Bloed- en lymfestelselaandoeningen: soms: anemie†, anemie schrikachtig voelen, malaise, perifeer oedeem, pijn. Verpakking met een ernstige leverfunctiestoornis met voorzichtigheid wegens ijzergebrek, pijn in lymfeklieren, lymfadenopathie, Onderzoeken: vaak: verhoogd alanineaminotransferase, ISENTRESS 400 mg is verkrijgbaar in flesjes met 60 tabletten. worden toegepast. Patiënten met een al eerder bestaande neutropenie, trombocytopenie‡‡. atypische lymfocyten, verhoogd aspartaatamino-transferase, Vergoeding en prijzen leverfunctiestoornis waaronder chronische hepatitis hebben Immuunsysteemaandoeningen: soms: verhoogde triglyceriden in het bloed, verhoogde lipase, soms: ISENTRESS 400 mg wordt volledig vergoed. Voor prijzen: tijdens antiretrovirale combinatietherapie een verhoogde immuunreconstitutiesyndroom†, geneesmiddelen- verlaagde absolute neutrofielentelling, verhoogde alkalische zie ZI-index. frequentie van leverfunctiestoornissen gehad en moeten overgevoeligheid†, overgevoeligheid. fosfatase, verlaagd bloedalbumine, verhoogde bloedamylase, volgens de standaardpraktijk worden gecontroleerd. Voedings- en stofwisselingsstoornissen: soms: anorexia, verhoogd bloedbilirubine, verhoogd bloedcholesterol, Raadpleeg de volledige productinformatie (SPC) alvorens Er zijn zeer beperkte gegevens over het gebruik van cachexie, verminderde eetlust, diabetes mellitus, verhoogd bloedcreatinine, verhoogd bloedglucose, verhoogd ISENTRESS voor te schrijven. raltegravir bij patiënten die naast hiv ook geïnfecteerd dyslipidemie, hypercholesterolemie, hyperglykemie, BUN, verhoogde creatinefosfokinase, nuchter bloedglucose zijn met hepatitis B-virus (HBV) of hepatitis C-virus (HCV). hyperlipidemie, hyperfagie, meer eetlust, polydipsie. verhoogd, glucose aanwezig in urine, verhoogd HDL, verlaagd 31 augustus 2010. Patiënten met chronische hepatitis B of C die worden Psychische stoornissen: vaak: abnormaal dromen, LDL, verhoogd LDL, minder trombocyten, positief op rode behandeld met antiretrovirale combinatietherapie hebben een slapeloosheid, soms: psychische aandoening†, bloedcellen in urine, grotere tailleomtrek, gewichtstoename, Merck Sharp & Dohme BV hogere kans op ernstige en mogelijk fatale leverbijwerkingen. zelfmoordpoging†, angst, verwarring, neerslachtige minder witte bloedcellen. Waarderweg 39 Voorzichtigheid moet worden betracht bij gelijktijdige stemming, depressie, ernstige depressie, slapeloosheid in Letsels, intoxicaties en verrichtingscomplicaties: soms: 2031 BN Haarlem toediening van ISENTRESS met sterke inductoren van het midden van de nacht, wisselende stemming, nachtmerrie, onbedoelde overdosis†. Tel.: 023 - 5153 153 uridinedifosfaat-glucuronosyltransferase (UGT) 1A1 paniekaanval, slaapstoornis, suïcidale gedachten‡‡, suïcidaal † met minstens één ernstige bijwerking www.msd.nl

Verkorte 1b-tekst Viramune® 200 mg tabletten, Viramune® 400 mg tabletten met verlengde afgifte, Viramune® 100 mg tabletten met verlengde afgifte en Viramune® 50 mg/5 ml suspensie voor oraal gebruik

Farmacotherapeutische groep: antivirale middelen voor systemisch gebruik , ATC: J05AGO1. Samenstelling: 1 tablet Viramune 200 mg tabletten bevat 200 mg nevirapine-anhydraat (actieve stof). 1 tablet Viramune 400 mg tabletten met verlengde afgifte bevat 400 mg nevirapine-anhydraat. 1 tablet Viramune 100 mg tabletten met verlengde afgiftebevat 100 mg nevirapine-anhydraat. Suspensie voor oraal gebruik bevat 10 mg/ml nevirapine (actieve stof). Indicatie: Viramune is geïndiceerd in combinatie met andere antiretrovirale geneesmiddelen voor de behandeling van HIV-1 geïnfecteerde volwassenen en kinderen ongeacht de leeftijd. Dosering: Gewenningsdosering gedurende de eerste 2 weken: eenmaaldaags 200 mg nevirapine. Onderhoudsdosering: 400 mg per dag. Bij starten van Viramune behandeling dient altijd een gewenningsperiode van 2 weken in acht genomen te worden om de kans op huiduitslag te beperken. Deze gewenningsperiode geldt ook indien de behandeling langer dan 1 week onderbroken is. Bij patiënten die tijdens de 14-daagse gewenningsperiode huiduitslag ontwikkelen, mag de dosering niet worden verhoogd voordat de huiduitslag volledig verdwenen is. Alvorens te beginnen met de Viramune-therapie, en daarna met regelmatige tussenpozen tijdens de therapie, dient klinisch laboratoriumonderzoek waaronder leverfunctietesten, te worden uitgevoerd. Voor patiënten van 16 jaar en ouder, of met een gewicht van meer dan 50 kg of met een lichaamsoppervlak groter dan 1,25 m2, is de dosering gedurende de eerste 14 dagen 200 mg per dag. Na twee weken wordt de dosering verhoogd naar 400 mg per dag. Voor patiënten jonger dan 16 jaar die minder dan 50 kg wegen of minder dan 1,25 m2 lichaamsoppervlak hebben kan suspensie worden gegeven op basis van of het lichaamsgewicht of het lichaamsoppervlak (zie volledige 1b tekst). De dosering op basis van lichaamsgewicht is voor kinderen tot 8 jaar 4 mg/kg éénmaal daags gedurende twee weken, gevolgd door 7 mg/kg tweemaal daags. De aanbevolen dosering voor patiënten van 8 tot 16 jaar is 4 mg/kg éénmaal daags gedurende twee weken, gevolgd door 4 mg/kg tweemaal daags. De dosering op basis van lichaamsoppervlak (formule van Mosteller) is 150 mg/m2 eenmaal daags gedurende de eerste twee weken gevolgd door 150 mg/m2 tweemaal daags. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel nevirapine of voor één van de hulpstoffen. Kruidenpreparaten die sint-janskruid (Hypericum perforatum) bevatten dienen niet tegelijk met Viramune te worden gebruikt. Gelijktijdig gebruik van Viramune met rifampicine of ketoconazol wordt niet aanbevolen. Viramune dient niet opnieuw te worden toegediend aan patiënten bij wie de behandeling definitief moest worden gestaakt vanwege ernstige huiduitslag, huiduitslag gepaard gaande met constitutionele symptomen, overgevoeligheidsreacties, of klinische hepatitis ten gevolge van Viramune gebruik. Viramune dient niet te worden gebruikt bij patiënten met ernstig leverfalen. Indien AST of ALT tijdens de behandeling stijgt tot > 5 keer de bovengrens van de normaalwaarde dient Viramune direct te worden gestaakt. Wanneer AST en ALT genormaliseerd zijn en wanneer de patiënt geen klinische verschijnselen of symptomen heeft gehad van hepatitis, huiduitslag, constitutioneel eczeem of andere verschijnselen die wijzen op een gestoorde orgaanfunctie, dan is het mogelijk Viramune te herintroduceren, per geval beoordeeld, met een startdosering van 200 mg per dag gedurende 14 dagen gevolgd door 400 mg per dag. In deze gevallen is een meer frequente levercontrole vereist. Als de leverfunctie-afwijkingen terugkeren, dient Viramune definitief te worden gestaakt. Waarschuwingen en voorzorgen: De eerste 18 weken van de behandeling met Viramune is een kritische periode, die een nauwkeurige controle van de patiënt vereist om het mogelijk optreden van ernstige en levensbedreigende huidreacties of ernstige hepatitis of leverfalen uit te sluiten. Het hoogste risico op leveraandoeningen en huidreacties bestaat gedurende de eerste 6 weken van de therapie. Bij patiënten met een detecteerbare plasma HIV-1 viral load (≥50 kopieën/ml) zijn vrouwelijk geslacht en hogere uitgangswaarden van CD4+ cellen bij het begin van de therapie risicofactoren voor levercomplicaties. Mannen met meer dan 400 CD4+ cellen/mm3 en vrouwen met meer dan 250 CD4+ cellen/mm3 die een detecteerbare viral load hebben bij aanvang van de behandeling, dienen alleen te starten met Viramune behandeling als de voordelen opwegen tegen het risico. Huidreacties: Er zijn ernstige, levensbedreigende en zelfs fatale, huidreacties opgetreden bij patiënten die behandeld werden met Viramune. Hieronder waren gevallen van het Stevens-Johnson syndroom (SJS), toxische epidermale necrolyse (TEN) en overgevoeligheidsreacties gekenmerkt door huiduitslag, constitutionele verschijnselen en verminderd functioneren van inwendige organen. De behandeling met Viramune moet gestaakt worden bij patiënten die ernstige huiduitslag ontwikkelen, of huiduitslag vergezeld van constitutionele symptomen, zoals koorts, blaarvorming, orale laesies, conjunctivitis, oedeem in het gezicht, zwellingen, spier- of gewrichtspijn of algehele onbehaaglijkheid. Vrouw en blijken een hoger risico te hebben op het ontwikkelen van huiduitslag dan mannen, ongeacht het gebruik van Viramune. De patiënt dient er nadrukkelijk op te worden gewezen dat huiduitslag de belangrijkste bijwerking van Viramune is en moet geadviseerd worden huiduitslag onmiddellijk aan de arts te melden. Huiduitslag die samenhangt met het gebruik van Viramune treedt meestal op in de eerste 6 weken na aanvang van de therapie. Daarom dienen patiënten tijdens deze periode zorgvuldig gecontroleerd te worden op het optreden van huiduitslag. Hepatische reacties: Bij patiënten die worden behandeld met Viramune is ernstige en levensbedreigende hepatotoxiciteit, met inbegrip van fatale hepatische necrose, voorgekomen. Er is melding gemaakt van afwijkende leverfunctietests tijdens gebruik van Viramune, ook in de eerste weken van de therapie. Omdat er in enkele gevallen, gedurende de eerste weken na aanvang van de therapie met Viramune, melding is gemaakt van klinische hepatitis dient bepaling van ALT en AST de eerste twee maanden van de behandeling elke twee weken plaats te vinden. In de derde maand dient de controle van de leverfunctie éénmaal, en vervolgens regelmatig plaats te vinden. Overig: Voorzichtigheid is geboden wanneer Viramune wordt voorgeschreven aan zwangere vrouwen. Viramune kan de plasmaconcentraties van hormonale anticonceptiva doen afnemen. De patiënt dient geadviseerd te worden om naast een hormonaal anticonceptivum ook altijd een ander voorbehoedsmiddel te gebruiken. Nevirapine induceert het leverenzym CYP3A en mogelijk 2B6. Middelen die door CYP3A en/of CYP2B6 worden gemetaboliseerd kunnen verlaagd zijn als ze samen met Viramune worden gebruikt. Bij gelijktijdig gebruik van Viramune met fluconazol, warfarine, methadon of claritromycine dient de patiënt nauwkeurig te worden gecontroleerd. Bijwerkingen: De meest frequent gerapporteerde bijwerkingen van Viramune zijn huiduitslag, allergische reacties, hepatitis, afwijkende leverfunctie testen, misselijkheid, braken, diarree, buikpijn, vermoeidheid, koorts, hoofdpijn en spierpijn. De meest voorkomende bijwerking van Viramune is huiduitslag. De huiduitslag bestaat gewoonlijk uit milde tot matig-ernstige, maculopapuleuze, erythemateuze huiduitslag, met of zonder jeuk, op de romp, het gezicht en de armen en benen. Ernstige en levensbedreigende huidreacties, waaronder het Stevens-Johnson syndroom (SJS) en toxische epidermale necrolyse (TEN) zijn opgetreden. Bij patiënten die lever en/of huidreacties ondervinden ten gevolge van Viramune gebruik is rhabdomyolyse waargenomen. Distributie: UR. Vergoeding: Viramune wordt volledig vergoed binnen het GVS. Nadere informatie: de volledige 1b-tekst, productinformatie en publicaties zijn verkrijgbaar bij Boehringer Ingelheim bv, Comeniusstraat 6, 1817 MS Alkmaar, telefoon 0800-2255889. Datum laatste herziening: september 2011. Report

6th Workshop on HIV Transmission Principles of Intervention

14-15 July 2011 in Rome, Italy Report

Report on 6th Workshop on HIV Transmission

J. Albert1, C. Boucher2, M. Cohen3, W. Heneine4, E. Hunter5, P. Kanki6, B. Mathieson7, G. Scarlatti8, R. Swanstrom9, M. Wainberg10, A. Wensing11

1Karolinska Institute, Stockholm, Sweden; 2Erasmus University Rotterdam, The Netherlands; 3University of North Carolina, Chapel Hill, NC, USA; 4Division of HIV/AIDS Prevention, CDC, Atlanta, GA, USA; 5Emory University, Atlanta, GA, USA; 6Harvard School of Public Health, Boston, MA, USA; 7Office of AIDS Research at the National Institutes of Health,Bethesda, MD, USA; 8San Raffaele Scientific Institute in Milan, Italy;9 University of North Carolina, Chapel Hill, NC, USA; 10McGill University, Montreal, Canada; 11University Medical Center Utrecht, The Netherlands

Written by Wendy Smith on behalf of the Organizng Committee

HIV Transmission – Human Biology

Cell biology of HIV sexual transmission Dr Hope (Northwestern University, USA) addressed the topic of the cell biology of sexual transmission, especially the movement of the virus from the lumen of the female genital tract to the target cells, such as T cells and dendritic cells in the sub basal layer of the epithelium1. The process is very rapid: in macaque models, simian immunodeficiency virus (SIV) infections can be established within 30-60 minutes of vaginal challenge. Using virus carrying a photoactivatable GFP fused to Vpr, it has been possible to visualise the virus moving through the vaginal epithelium of explant cultures. Considerable variation was observed in the rate of movement of the viruses from the lumen through the epithelium: most of the viral particles only penetrate a short distance while some are able to penetrate ~50 microns. HIV is able to breach the columnar epithelium of the vagina and access the underlying target cells. Virus often becomes trapped in the mucus that lines the vaginal epithelium and protects the endocervix from infection. When neuraminidase was used to cleave sugars from mucus, HIV was able to penetrate the endocervix more easily. HIV penetrates between the cell junctions of the epithelium (i.e. interstitial diffusion) rather than directly entering the cells. If EDTA is applied to break down the cell junctions, HIV is able to penetrate the epithelium more deeply. Dr Hope’s group is now studying interactions between HIV and tissue obtained from circumcised men in an attempt to understand why circumcision is protective against HIV infection in men.

Founder viruses viruses were identified 15 days post-transmission; Dr Keane (Murdoch University, Australia) presented a it is possible that more than one founder virus was study of an acute heterosexual transmission of HIV-12. transmitted because of the traumatic nature of the A 51 year old, East African woman presented to the sexual contact. There appeared to be transmission clinic five days after non-consensual sexual contact of an adapted epitope in the shared recipient and with a man who was known to be HIV infected. p24 donor HLA C*04:01 restricted epitopes. Phylogenetic antigen was detected in the woman’s blood but analysis demonstrated that the viral strains from the the EIA and Western Blot results were negative, donor and recipient were more closely related to indicating early HIV infection prior to seroconversion. each other than to any strains in the dataset. Limited The woman had tested HIV negative in 2003 and HIV viral sequence change was observed in patient/ reported no subsequent risky exposures, apart donor HLA-restricted epitopes. Non-selective CTL from the non-consensual sex. The woman started responses were observed and may have contributed antiretroviral therapy (ART) one year after infection to the rapid rate of disease progression in this case. and her viral load dropped to ~50 copies/mL within a few weeks, after having being 70,000 copies/mL in the absence of therapy. Three founder/transmitted Compartmentalisation of HIV Paired blood and cervicovaginal lavage (CVL) Disclosure: samples were obtained at Day 0 and Week 16 from Wendy Smith, PhD has disclosed that she does not 28 women from Malawi and S Africa with chronic 3 serve as a consultant for any commercial companies. HIV infection . Viral loads were measured and single Dr Smith is a professional medical writer who works genome amplification and phylogenetic analysis of for Wordsmiths International Ltd (www.wordsmiths. env genes were carried out. The Slatkin-Maddison eu.com) test for compartmentalisation was applied. The CVL viral loads were significantly higher in women

6 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 6th Workshop on HIV Transmission

who had sexually transmitted infections (STI) than network in semen. These factors may affect the in those without STIs, even though the plasma sexual transmissibility of HIV-1. viral loads were similar in both groups. Genetic characterisation of HIV populations in the 10 paired Viral escape – possible mechanism for blood and genital tract samples demonstrated that immune escape clonal amplification of the virus had occurred in Several studies have demonstrated the importance each compartment. A significant amount of genetic of HIV-1 gp120 variable regions in virus infectivity and difference was observed between paired plasma immune escape; the majority of these experiments and CVL viral samples. Compartmentalisation was have been carried out on subtype B virus but the observed in 60% of subjects and it was significantly most prevalent subtype globally is subtype C5. Virus associated with higher CD4 cell counts, suggesting isolated from recently infected subjects tends to have that it was associated with the availability of target shorter V1-V2 loops and a lower number of putative cells and not due to reduced immunosurveillance in N-glycosylation sites (PNGS) than variants isolated a specific compartment. Longitudinal data suggest during chronic infection. Dr Cenci (Istituto Superiore that the HIV viral load in the female genital tract is di Sanita, Italy) reported the results of an analysis variable over time. Dr Dukhovlinova (University of of gp120 variable V1-V5 and C3 and C4 constant North Carolina at Chapel Hill, USA) suggested that regions from clade C viruses isolated from patients at the presence of a STI could affect the cytokine profile different disease stages. During chronic infection, the of the female genital tract and facilitate the influx of sequence of amino acids of the V1 and V4 regions and cells from nearby lymphoid tissue. Further studies the number of PNGS increased.New PNGS shifted are in progress to identify the cytokine profile and appeared in the C-terminus of all the variable regions tropism of compartmentalized viral strains. with the exception of V3, and in the constant regions near to the CD4 binding site, possibly protecting the virus from the immune response. During both recent Cytokine network in semen of HIV positive and late stage infection, a positive charge correlation men was observed between C3 and V5: this could Semen is a complex fluid that contains spermatozoa support the hypothesis that an open conformation and a number of soluble factors, including cytokines. would be the best fit for binding to cellular receptors. The replication of pathogens, such as HIV and At the contrary, the presence of a negative correlation herpesviruses, affects cytokine expression as well of positive electric charges between the C3 and V4 as is affected by cytokines. Blood and seminal regions in the Chronic stage could protect the C3-V4 fluid were obtained from 74 HIV-1-infected, ART epitope by immune system. naïve men and 33 uninfected men: viral loads and cytokine profiles were evaluated4. A relationship was observed between the HIV-1 viral load in the plasma HIV Transmission – Model Systems and the semen. No reactivated herpesviruses were A number of model systems, such as ex vivo cervical detected in samples from HIV negative men, with the tissue cultures, macaques and humanised mice, exception of low herpesvirus viraemia (CMV, HHV- have been used to investigate the transmission of 6 and HHV-7) in some semen samples. In HIV-1 retroviruses and potential methods of protecting infected men, EBV and CMV were detected in the against infection. majority of semen samples and their viral loads were significantly higher in the semen than the blood. HSV- 2, HHV-6, HHV-7 and HHV-8 were detected in HIV-1 Modelling HIV transmission and infected men’s semen but not in their blood. CMV dissemination reactivation was largely compartmentalized in the SIV infection of rhesus macaques can be used to HIV-1/CMV co-infected men: in 77% of these men, model HIV transmission and systemic dissemination CMV was only found in semen compared to 19% who of the virus, as well as investigating the effectiveness had detectable CMV levels both in blood and semen. of candidate vaccines and other HIV prevention Concurrent EBV and CMV infection was associated strategies6. Both single and limited number variant with significantly higher levels of HIV-1 shedding in infections can be simulated, using the rectal, vaginal the semen than in HIV-infected men co-infected with or penile route. SIV env and full length clones of only one of these herpesviruses. In HIV-infected men, founder viruses have been generated and shown HIV preferentially upregulated cytokines in semen to be functional in in vitro and in vivo assays, thus compared to blood. Based on the results of this study, enabling investigators to analyse the particular the investigators (NIH/NICHD, USA) concluded that characteristics of founder viruses. Transmitted HIV-1 infection is associated with seminal shedding founder clones recapitulate viral load profiles and of CMV and EBV and rearrangement of the cytokine the pathogenetic features of the parental virus in

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naïve rhesus macaques. Longitudinal analyses of acquire HIV from their sexual partners (Figure 1). Dr putatively single variant infections confirmed that Saba (San Raffaele Institute, Italy) has used human the transmission event involved one viral variant, cervical tissue explants to study the process of HIV regardless of the route of infection. infection ex vivo7. The average age of the donor was 50±1 years old. In this cervical tissue model, A model was established to enable Keele and X4 HIV-1 was only able to establish a productive colleagues (SAIC-Frederick/NIH, USA) to track infection in a few tissues that were enriched with SIVmac239 infection following intravaginal challenge early differentiated effector memory CD4 T cells so that the key events in early replication and systemic whereas R5 HIV-1 infection was supported efficiently. dissemination could be dissected6. Synonymous During R5 infection, the CD4 T cells appeared to be mutations were introduced into a viral isolate to create HIV-1 gag positive at an earlier stage of infection ten clones that were molecular but isogenic tagged than the macrophages. R5 HIV-1 replication in the and introduced into female macaques as a non- cervical explants was modulated by the phase of the traumatic vaginal challenge. Real time SGA sequence menstrual cycle. There appeared to be a ‘window analysis was used to identify the tagged clones in of vulnerability’ during the secretory stage of the the blood and tissue of euthanized macaques. There cycle (i.e. when progesterone levels were reaching a was considerable inter-animal variability in terms of peak) when the virus was able to infect the female the number of clones that were transmitted; in the genital tract tissues more easily, possibly because majority of infections, one major variant and several the release of progesterone caused changes in the minor variants were identified. Infections were multi- mucosa that facilitated infection. Infection was less focal and the virus does not appear to be uniformly likely during the proliferative phase of the menstrual distributed. Virus could be found in draining and then cycle and during the menopause. distal lymphoid tissues before it was distributed to the plasma, peripheral blood monocyte cells, gastro intestinal tract or spleen. Not all of the variants Characterisation of semen leukocytes that were identified at mucosal sites were found in Dr Bernard-Stoecklin (Comissariat a l’Energie peripheral sites. The initial results were obtained from Atomique, France) has investigated whether semen unsynchronised animals but current experiments are leukocytes act as ‘Trojan horses’ in SIV/HIV mucosal using macaques with synchronised menstrual cycles transmission by analysing the infection process so that the impact of hormones on SIV transmission in macaques8. In humans or animals with primary can be identified. infection, the CD4 T cell count in the semen falls rapidly whereas it tends to increase when ART is administered during chronic infection. Lymphocytes Productive HIV-1 infection of cervical tissue in the semen are activated and express higher levels ex vivo of CD69 (a proliferation marker) and HLADR (a late The human cervix is a major route by which women activation marker) than lymphocytes in the blood. HIV-1 heterosexual transmission in human cervix

DCs

CD4+ T cells Macrophages Figure 1. HIV-1 heterosexual transmission in human cervix Source: Dr Saba, San Raffaele Institute, Italy

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They express a number of chemokine receptors of maraviroc in macaques were similar to those in and integrins. T cells in the semen are almost all human beings who had taken 300 mg maraviroc. A central memory cells, which are the main targets co-receptor occupancy assay was used to analyse for SIV. They are present in the semen at every maraviroc binding to CCR5. Levels of maraviroc stage of the infection process. In summary, seminal that were found in the rectal tissues 2-3 days after leukocytes express markers that may favour HIV/SIV administration were associated with the maximum transmission. levels of CCR5 occupancy and protection against The impact of semen on HIV infectivity of target infection in vitro. cells has been controversial. The effects of semen on CD4 T cell phenotype and susceptibility to HIV infection were investigated by Balandya (Dartmouth Vaginal absorption of ARVs – the pig tailed Medical School, USA) et al9. They collected semen macaque model from HIV negative men and incubated centrifuged The efficacy of ARVs as microbicides probably seminal plasma from these samples with peripheral depends on how effectively they are absorbed into blood monocyte cells and X4 or X5 HIV. Levels of the vaginal mucosa. During the menstrual cycle, a HIV infection were assessed using TZM-bl cells number of physiological changes occur in the vaginal and intracellular staining for HIV p24. The results epithelium that may affect drug absorption (Figure of these experiments indicate that seminal plasma 2)12. Female pig tailed macaques have a bi-phasic protects CD4 T cells from HIV infection and reduces menstrual cycle, similar to humans, and so they T cell surface CD4 expression. Seminal plasma also can be used as a model to examine the effects of induces CD4 T cell expression of the CCR5 receptor menstrual cycle on vaginal drug absorption. During and mediates the preferential transmission of R5 the follicular phase, the vaginal epithelium is thick HIV. These data show that semen protects cardinal and keratinised; during the luteal phase, it is thin and target cells from HIV infection and contribute to the more susceptible to HIV infection. A gel containing previously unexplained preferential transmission of 5% FTC and 1% tenofovir was applied vaginally R5 HIV. once a week for four weeks and then drug levels were measured in the plasma at regular intervals. After a two week washout period, the experiment Pre-Exposure Prophylaxis (PrEP) models was repeated but the gel was applied rectally. In the Humanized mice (RAG-hu), which lack native B, T vaginal dosing experiments, there were higher levels and NK cells, have been utilised as a model system to of ARV drug absorption during the luteal phase than investigate the potential of maraviroc and raltegravir to the follicular phase. When the gel was applied to protect against HIV-1 vaginal transmission10. The mice the rectum, drug absorption was unaffected by the were engrafted with human CD34 cells and multi- menstrual phase. Maximum levels of drug absorption lineage human haematopoiesis was subsequently were observed within 7-10 days of peak progesterone detected in several organs. HIV-1 was able to infect levels and were not drug-dependent. It appears that RAG-hu mice via the vaginal or rectal mucosal physiological changes during the menstrual cycle, tissues. Oral administration of maraviroc or raltegravir such as vaginal epithelial thinning, may explain the for three days prior and post challenge provided absorption of ARVs formulated as a microbicide. 100% protection against HIV-1 infection. CD4 T cell counts declined rapidly in infected, non-treated control animals but the cell counts in the treated mice remained similar to the levels in uninfected control Prevention of HIV Transmission – animals. Additionally, maraviroc was formulated as a Antiviral and Medical Approaches topical microbicidal gel; it was completely protective Preventing new HIV infections is an essential against HIV-1 vaginal transmission in RAG-hu mice. component of controlling the global HIV epidemic. Prevention strategies include antiviral approaches, The pharmacokinetic and pharmacodynamic profile e.g. microbicides, and medical interventions, e.g. of a single oral dose of maraviroc (44 mg/kg) in use of ARVs to prevent transmission of HIV from rhesus macaques was studied by Garcia-Lerma and mother to child. PrEP, using single or combined colleagues (CDC, USA)11. Plasma levels of maraviroc ARVs, has been studied as a method of preventing peaked two hours after administration but levels in the transmission of HIV from an HIV positive person vaginal and rectal secretions peaked at 5 and 24 to his/her sexual partner(s). hours, respectively. Maraviroc was measurable in vaginal and rectal secretions for up to two and seven Preventing sexual transmission of HIV-1 days, respectively, suggesting that this antiretroviral CAPRISA 004 assessed the safety and effectiveness (ARV) may be useful for PrEP. The pharmacokinetics of a 1% tenofovir gel used as a microbicide up to

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Follicular Phase Luteal Phase

Estradiol

Progesterone Ovulation Day 1 7 14 21 28

Thick, keratinized Thin, non-keratinized, vaginal lining porous vaginal lining

Figure 2. Menstrual cycle phases Source: Dr Heneine, Centers for Disease Control, USA

12 hours before sex and within 12 hours after sex13. Dr Abdool Karim (University of KwaZulu-Natal, The effectiveness of the microbicide at 12 months South Africa) provided several additional insights was 50% and at 30 months it was 39%. The gel from the CAPRISA 004 trial13. In macaques, also provided 51% protection against herpes virus 2 genital inflammation has been associated with an (HSV-2) infection which infects 50-60% of S African increased risk of SIV acquisition. Tenofovir gel use sexually active adults. The results of CAPRISA 004 was not associated with elevated levels of genital were hailed as the new hope in HIV prevention, even inflammation compared to placebo. However, genital though the gel did not provide complete protection. tract inflammation prior to infection was associated with an increased susceptibility to HIV infection. Subsequent studies (Figure 3) have shown the Achieving detectable tenofovir levels in the female following successes: genital tract was associated with a significantly • oral PrEP with tenofovir/FTC prevented HIV infec- increased level of protection in women without tions in men who have sex with men (MSM), with elevated cytokine levels (p=0.05). The effectiveness an effectiveness of 44% at the end of the study of the tenofovir gel was not affected by the person’s (iPrEx trial); HSV-2 status. However, one possible hypothesis • ART prevents HIV transmission between sexual is that men with high semen viral loads were more partners, with an effectiveness of 96% (HPTN likely to transmit HIV than those with low semen viral 052); loads, possibly suggesting that tenofovir gel is less • oral PrEP with daily oral tenofovir or tenofovir/FTC effective if the viral load in the semen is high e.g. in provided 62% and 73% protection in serodiscor- men with acute or early infection. HIV transmission dant couples, respectively (Partners PrEP); in the vagina appears to be influenced by the host • daily oral tenofovir/FTC provided 63% protection (increased genital inflammation may be associated in heterosexual men and women (Botswana TDF2 with increased HIV acquisition); the agent (higher study). semen viral load may be associated with increased risk of infection); and the environment (higher drug In contrast, the FEM-PrEP study of oral tenofovir/FTC levels in the vagina may reduce the risk of infection). as PrEP in women was halted for futility. The reasons for the study’s outcome of no protection against HIV The results of the CAPRISA 004 study have been are being investigated but it is possible that there used to model the effects of widespread use of was poor adherence or inadequate drug levels were a 1% tenofovir gel microbicide in S Africa overall present at the possible site of infection. and specifically in KwaZulu Natal province14. The

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Study Effect size (CI) Treatment for prevention 96% (73; 99) (Africa, Asia, America’s ) PrEP for discordant couples 73% (49; 85) (Partners PrEP) PrEP for heterosexuals 63% (21; 48) (Botswana TDF2) Medical male circumcision 54% (38; 66) (Orange Farm, Rakai, Kisumu) PrEP for MSMs 44% (15; 63) (America’s, Thailand, South Africa) STD treatment 42% (21; 58) (Mwanza) Microbicide 39% (6; 60) (CAPRISA 004 tenofovir gel) HIV Vaccine 31% (1; 51) (Thai RV144)

0% 10 20 30 40 50 60 70 80 90 100% Efﬁcacy

Figure 3. Summary of clinical trial evidence for preventing sexual transmission of HIV in July 2011 Source: Dr. S. Abdool Karim, University of KwaZulu-Natal, Durban, South Africa13. investigators assumed that the presence of HSV- Hill, USA) provided an overview of the data to the 2 infection increases the risk of acquiring HIV by Workshop15, 16. The aim of the study was to determine 2-3 fold and, in co-infected people, increases HIV if providing ART to HIV infected individuals protected infectivity by 30-70% per act. HIV infection increases their serodiscordant sexual partners from acquiring HSV-2 shedding episodes. In KwaZulu Natal, the the virus; and to evaluate the optimal time to initiate number of prevented infections of HIV or HSV-2 would ART in order to reduce morbidity and mortality. A total be substantially greater in women than men. The of 1,763 serodiscordant couples were enrolled. The proportion of HSV-2 infections prevented would be HIV+ partner had to have a CD4 cell count of 350-550 approximately independent of the gel’s effectiveness cells/mm3 and he/she was randomised to receive against HIV but it would be affected by coverage (i.e. immediate ART or delayed ART (when the CD4 cell access to the microbicide). The relationship between count was <250 cells/mm3). On 28 April 2011, the HIV effectiveness and coverage on the proportion of Data Safety Monitoring Board recommended that the HIV infections prevented would be non-linear. On a results of the trial be announced as soon as possible. country-wide scale, the gel would prevent more HIV The study was not stopped but modifications to infections in provinces where the infection rate is the study design are in progress: all HIV positive high i.e. many more infections would be prevented in participants are now being offered ART. During the KwaZulu Natal than in Northern and Western Cape if trial, 39 infections occurred: 28 were linked and 27 of the microbicide coverage was assumed to be 90% these occurred in the delayed therapy arm and one and the effectiveness was assumed to be 54%. Only in the immediate therapy arm (p<0.001). Seventeen 113 women-years of microbicide usage would be infections occurred in the delayed ART arm when the required to prevent one HIV infection in women in index partner’s CD4 cell count was >350 cells/mm3. KwaZulu Natal, while it would require 445 women- A total of seven unlinked infections occurred: four years of usage in Western Cape. Dr Blower (UCLA, in the delayed ART arm and three in the immediate USA) concluded by stating that, in the light of financial ART arm. Four infections are still being analysed for constraints, a very effective control strategy would be evidence of linkage. to target the microbicide roll out to provinces with The difference between the two arms in terms of high HIV infection rates. morbidity and mortality did not meet the pre-set criterion of >20% but it was significant when no pre- HPTN 052 set value was used (p=0.01): 65 events occurred in The results of the HPTN 052 studied were published the delayed arm and 40 in the immediate arm15. The in the online version of the New England Journal of difference was driven by cases of extrapulmonary Medicine on 18 July 2011; Dr Cohen (UNC Chapel TB: 17 in delayed ART arm and three in the immediate

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arm (p=0.0013). There were a similar number of Circumcision deaths in each arm: 13 and 10, respectively. The The 2009-10 Demographic and Health Survey (DHS) study will continue for at least one more year to data from Lesotho have been analysed to determine determine the durability of the prevention benefit; the current prevalence of male circumcision and any differences between the two arms in terms of associated demographic factors for circumcised prevention benefit; clinical and toxicity events in both males; as well as to determine if male circumcision arms; and the level of adherence to ART. Dr Cohen has limited the spread of HIV19. Data on the HIV and explained that this was a proof of concept study, not circumcision status of 3,074 men was collected: the a public health study: ART was effective in preventing HIV prevalence was 18% in men aged 15-59 years; HIV transmission between monogamous couples in and ~56% of men were circumcised. Surprisingly, the this study. HIV prevalence was higher in circumcised men (20%) than uncircumcised men (15%). Male circumcision was more common in rural areas (61%) than urban Evaluating the effect of ‘Test and Treat’ on areas (36%) but HIV prevalence was lower in rural HIV transmission areas compared to urban areas: 17% vs. 20%. ‘Treatment as Prevention’ is the cornerstone of the The majority of men (79%) lived in rural areas. Only WHO’s Treatment 2.0 initiative and a number of ~8% of circumcisions were carried out using clinical pilot studies are in progress to evaluate the impact methods, while 92% were carried out with traditional of expanded access to treatment on HIV incidence methods, usually at an initiation school. This method at the population level. Dr Vasarhelyi (BC Centre does not completely remove the foreskin, and so for Excellence in HIV/AIDS, Canada) described her may be less protective against HIV acquisition than group’s efforts to develop a general performance medical circumcision. Approximately half of the men indicator for Seek and Treat strategies using were circumcised after becoming sexually active. surveillance data17. The indicator was then applied to The investigators concluded that the use of traditional surveillance data collected 2003-9 (before the STOP methods of circumcision, especially after men have HIV/AIDS launch) in British Columbia, a Canadian become sexually active, might limit the protective province, and to simulated data for 2011-17. The effect of male circumcision in Lesotho. outcome of the model was that the proportion of diagnosed HIV infections was approximately constant between 2003 and 2009 in British Columbia. To Prevention of Mother to Child demonstrate the performance of the indicator in Transmission of HIV (PMTCT) detecting changes in the proportion of diagnosed An HIV infected pregnant woman can transmit HIV cases, the model was applied to simulated data for to her baby at any point during pregnancy, labour 2011-17. The data were consistent with an annual and delivery or breastfeeding. Prevention strategies increase of 1% in the proportion of diagnosed HIV are therefore needed throughout this long period of infections since the launch of STOP HIV/AIDS. The time, Dr Scarlatti (San Raffaele Institute, DIBIT, Italy) development of an indicator for Seek and Test pointed out20. Administering combinations of ARVs programmes will enable the performance of such during pregnancy, labour and delivery and avoiding programmes to be evaluated at the population level. breastfeeding have reduced MTCT rates to almost zero in the developed world. The use of single dose nevirapine changed the perception that it was Activity of griffithsin plus ARVs against impossible to prevent MTCT in developing countries. subtype C HIV Although its use was associated with the emergence Griffithsin is a mannose-specific lectin that is being of NNRTI resistance, it not only reduced the number investigated as a potential microbicide18. The antiviral of paediatric HIV infections but also led to PMTCT potency of griffithsin in combination with tenofovir, initiatives in resource limited settings (RLS) using maraviroc or enfuvirtide against HIV-1 subtypes B ARV combinations. Since breastfeeding contributes and C, as well as a subtype B X4 virus, was assessed to paediatric health in RLS, a number of ARV-based in a range of assays. All of the combinations were interventions have been developed to protect a baby synergistic and provided superior antiviral potency from HIV infection during breastfeeding. against all of the strains studied, compared to Only a few viral variants are detected in newborns, griffithsin alone. Antagonism between the therapeutic regardless of the route of transmission (Figure 4). The agents was not observed. Griffithsin plus one or transmitted variant is either a major or minor maternal more ARVs has potential as a microbicide; studies viral variant. Viruses that are transmitted intra partum are ongoing in the USA to determine the safety and (during labour and delivery) tend to have shorter efficacy of this approach. variable loops and fewer PNG sites than those that are transmitted during pregnancy. R5 virus is the

12 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 6th Workshop on HIV Transmission

mother

Pregnancy Labour Breast Delivery feeding

Blood !! a SELECTIVE barrier? Placenta Secretions Milk Amniotic Blood ﬂuid Only FEW virus variants child detected in the newborn!

Figure 4. Is MTCT a selective or stochastic process? Source: Dr. G. Scarlatti, San Raffaele Institute, Milan, Italy20 predominant transmitted virus in MTCT: children together with their partner. Extrapolating these data who are infected with R5broad phenotype are more to the total Batswana population, Dr Lu stated that likely to experience early immunological failure than while the National program found 647 infant infections those who are infected with R5narrow phenotype through the Early Infant Diagnosis program, as many virus. R5 viruses preferentially cause dendritic cells as 1329 infant HIV infections may have occurred to extend cellular processes through the intestinal in 2010, with 672 (50.6%) due to incident cases of mucosa, thus enabling the R5, but not the X4, viruses maternal HIV infection that would not have been to cross the epithelial layer. Dendritic cells that are detected in routine antenatal care. Of the 17 infants infected with HIV also act as a local viral reservoir born to seroconverting women during the study, at the mucosal level. Understanding the precise three were found to be HIV positive: one baby died mechanisms by which MTCT occurs will assist in the before ART was initiated; one died after ART was efforts to prevent children being infected with HIV. initiated; and one was alive and taking ART when the study was completed. Dr Lu commented that these The topic of HIV incidence in pregnancy and the data have implications for PMTCT programmes since first post partum year was addressed by Dr Lu women continue to be at risk for HIV infection during (CDC, USA)21. Routine HIV antibody testing during pregnancy and while breastfeeding, despite a high antenatal care may miss acute infections that are still uptake of antenatal HIV testing and counselling. in the window period (prior to the development of Women who test HIV negative during pregnancy will antibodies) or infections that occur during pregnancy. breastfeed their babies, breastfeeding babies are New HIV infections during late pregnancy and at high risk for mother-to-child transmission in the breastfeeding are associated with a very high risk of setting of an acute maternal HIV infection. Women MTCT. In 2010, Dr Lu and colleagues undertook a are likely to use condoms for protection. However, study of 417 women who had had negative HIV tests couples testing and counselling tends to be under- during pregnancy and who were approximately one used. Many women were not aware of their partners’ year post partum. The one year HIV incidence in HIV status, which was the only significant risk factor these women was 3.8%. Risk factors for HIV infection found for incident HIV, even in this small cohort. were evaluated with a behavioural survey. Although Based on these data, it has been suggested that 20% of the women had had more than one sexual HIV negative women should be retested when they partner in the previous two years, this finding was not bring their babies to the clinic for immunization (4 associated with HIV infection. Women who knew the months post partum) or earlier if other risk factors are HIV status of their partner were significantly less likely present. Educational material needs to be modified to acquire HIV than those who did not know. Nearly to explain the risks of HIV infection during pregnancy half (183/417, 43.9%) of the women had been tested and breastfeeding. Access to family planning, STI

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clinics and couples testing and counselling needs to Iran) pointed out that non-IV drug users also be improved. participate in high risk behaviour, such as having unprotected or transactional sex23. Dr Khayatkhoei therefore compared the prevalence of HIV in IDU Modes of Transmission and HIV and non-IV drug users in the Imamhossein Hospital Prevention Efforts in Vulnerable Detoxification Center in Tehran, Iran, in a cross Populations sectional study between March 2010 and April 2011. The Center is a referral centre that treats Drug users approximately 600 patients per day in the Emergency Obtaining precise information on the number of Department. In Iran, approximately two million people intravenous drug users (IVDU) globally is challenging are addicted to drugs; 300,000 of them are IVDUs. In but there are believed to be approximately three million 2006, IVDU was the major route of HIV transmission IVDUs living with HIV worldwide22. HIV transmission in Iran. The study population was composed of 200 occurs by sharing contaminated syringes with other IVDUs and 200 non-IV DUs. Patients had to have IVDUs as well as unprotected sex with HIV positive been opioid drug abusers for at least three years. Of partners. Other factors associated with HIV acquisition the IVDUs, 12.5% (25/200) were HIV positive while include unstable housing; and the intensity of use of this figure was 3.5% (7/200) for non-IV DUs. The risk intravenous cocaine. In certain settings, age, gender of acquiring HIV was 3.9 times higher in IVDUs than and use of crack cocaine have been shown to be risk in non-IV DUs. Dr Khayatkhoei stressed that the HIV factors for HIV infection. Preventing HIV transmission prevalence in non-IV DUs is a concern since 82% of amongst IVDUs is complex, mainly because of its illicit all drug abusers are in the reproductive age range nature, and has to take into account a wide range of and therefore would be expected to be sexually structural, social and individual factors. Needle and active. She recommended that healthcare workers syringe programmes, as well as opioid substitution are sensitised to this issue and that HIV education therapy (OST), have been shown to be effective in programmes be developed to decrease behavioural reducing HIV transmission amongst IVDUs but risk factors in both IVDUs and non-IV DUs. political pressures often make it difficult to ensure that prevention programmes provide a complete package of interventions. Data from Australia have Young girls shown that full harm reduction programmes are very HIV disproportionately affects young girls in sub- effective, while programmes that only offer a few Saharan Africa. Dr Kaggwa (PACE, Uganda) explained harm reduction components are less successful. that, in Uganda, this part of the epidemic is driven OST is only useful for people who are dependent on by cross generational sex (CGS): 10% of Ugandan opioids; it is ineffective for cocaine users. Effective girls aged 15-19 years had had sex with a man who OST coverage is poor on a global level, even though was at least 10 years older in the previous 12 months good OST programme retain IVDUs in care for (Ministry of Health survey 2006). In partnership longer and OST clients are six times less likely to with Johnson and Johnson, the PACE programme become HIV positive than IVDUs who do not enter has implemented an anti- CGS project called ‘Go treatment. Increased access to ART by IVDUs in Getters’ in 50 secondary schools in four regions Vancouver has been associated with decreases in Uganda. A cross sectional survey was carried both in the community plasma viral load and the out in a representative sample of 2,410 girls aged HIV incidence density. Despite these successes, 15-19 years from 30 secondary schools to assess there is a considerable resource gap – several billion sexual behaviour and its determinants. Schools were dollars – between the annual amount spent on harm classified as low category (LCS) or high category reduction programmes and the estimated total need. (HCS), depending on the amount of fees and rates of Dr Bruneau (University of Montreal, Canada) called university entry as a reflection of the girls’ economic for comprehensive healthcare packages for IVDUs. circumstances. CGS was more common in LCS than Decreases in the future HIV prevalence and disease HCS: 9.4% vs. 2.6%. Young girls who had had CGS burden among IVDUs can only be accomplished by were more likely to report early sexual debut; have intensifying harm reduction measures among high- multiple older sexual partners; have low confidence risk persons and expanding health care access for in their ability to reject older men’s advances; and to those at the greatest risk of disease and progression, perceive CGS as socially acceptable. Half of the girls including access to HIV prevention technologies had a boyfriend at the time of the survey and 22% such as PrEP. had had sexual intercourse at some point in their life. In previous year, 22% had had sex and 20% had had Although IVDU is a major risk factor for HIV sex with multiple sexual partners. Girls from HCS transmission, Dr Khayatkhoei (Teheran University, were more confident in their ability to reject older

14 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 6th Workshop on HIV Transmission

men’s advances; had social support not to engage virus evolved to become an atypical variant(s). in CGS; agreed that women are more at risk of HIV if 3. Persistence – when the transmitted resistant virus they have CGS; and had higher self esteem than girls persisted in the new host due to a small difference from LCS. Based on these results, HIV prevention in the virus’ replicative capacity and/or the emer- programmes should enhance girls’ life skills so that gence of compensatory mutations that became they are more confident in rejecting older men’s fixed in the population. sexual advances; campaign against CGS; address The clinical implications of TDR were studied the social norms that support CGS; and emphasize retrospectively in the EuroCoord-CHAIN study of the risks associated with CGS. >10,000 patients who started ART after 1997 and for whom genotypic and clinical follow up data were available. Although the majority of the patients Transmitted Drug Resistance (TDR) (90.5%) were infected with fully susceptible virus, approximately 10% were infected with TDR virus. Half Global trends of these patients were treated with a regimen that Dr Wensing (University Medical Centre Utrecht, The was fully active and half received a regime that the Netherlands) addressed the issue of transmitted virus was resistant to. Although the level of CD4 cell drug resistance (TDR) worldwide24. The SPREAD recovery was similar in all of the patients, individuals network is present in 34 European countries. In order who were treated with sub-optimal regimen had to collect information on a representative set of newly a higher risk of virological failure. Patients who diagnosed patients, prospective data are collected received fully active regimens had a similar outcome annually in 28 SPREAD countries from patients to patients infected with susceptible virus if they were with evidence of recent infection (<1 year) and from treated with ritonavir boosted PIs (PI/r) but patients patients with an unknown duration of infection. Based who took NNRTIs were more likely to experience on these data, the prevalence of TDR remained stable therapy failure. The reasons for this difference are in Europe between 2002 and 2007: ~8-9% for any not yet clear but it is possible that the higher genetic class of ARV; ~5-6% for NRTIs; ~3-4% for NNRTIs; barrier to PI/r was a factor. It is also possible that and ~2-3% for PIs. Nationwide data are not available the presence of NNRTI-resistant minority variants for the USA but a number of city or state surveys affected the clinical outcome. Monitoring TDR is have demonstrated a similar rate of transmitted drug a critical part of ensuring that HIV prevention and resistance in various risk groups (~10%). The WHO treatment programmes are successful. has developed standardised methods to assess transmitted drug resistance in RLS, especially in recently infected, ART naïve populations. Between European trends in TDR 2002 and 2009, 53 surveys had been completed Prof. Boucher (Erasmus Medical Centre, The in 22 countries: 83% showed low rates of TDR and Netherlands) described the results of a study by 17% had moderate rates of TDR. The overall TDR the European Society for Antiviral Resistance to prevalence was 3.7%. Of the 11 surveys conducted understand the spread of TDR in newly diagnosed in 2009, five showed moderate levels of TDR, which European patients, using a pre-defined strategy that may have implications for treatment and prevention ensured representative sampling25. Epidemiological, programmes in these RLS. clinical and virological data were collected The majority of TDR is due to single mutations, prospectively from 2,800 patients between 2002 but resistance profiles differ between treated and and 2005 and 1,630 patients between 2006 and untreated individuals24. For example, the M184V and 2007. Approximately half of the patients were MSM T215Y mutations are far more common in treated (48%), 35% were heterosexual and 8% were IVDUs. individuals than untreated individuals. It has been The majority (79%) were male. Fifty five percent hypothesised that treated individuals are not the most originated in W Europe; 21% from Eastern Europe important source of drug resistant virus, especially and Central Asia; 11% from Sub Saharan Africa; as ARV resistant viruses tend to be transmitted less and 12% from other continents. The most important efficiently than susceptible viruses. It is possible that mutations that were detected included T215Y, M41L, drug resistant viruses evolve in the new host in the K103N and L90M. The prevalence of drug resistance absence of drug selective pressure. After conducting was significantly higher in MSM than other groups a literature survey of cases of TDR, Dr Wensing and in relation to any ARV class, NRTIs and NNRTIs but her colleagues identified three different evolutionary not PIs. Trends towards an increase in resistance pathways: to any ARV class and to NRTIs over time were 1. Reversion – when the transmitted resistant virus observed in MSM; this change was significant for reverted to wild type in the new host. NNRTIs (+4%, p=0.008). By contrast, there was a 2. Atypical variants – when the transmitted resistant trend towards decreased (any ARV class and NRTIs)

Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 15 Report

or stabilised (PIs and NNRTIs) levels of resistance in circulating strains. heterosexuals. Prof. Boucher concluded that there are still single TAMs and revertants circulating in HIV positive Europeans, especially MSM. Resistance to TDR and clusters NNRTIs has increased, mainly in MSM, while the The early stage of HIV infection is a window of transmission of mutations associated with resistance opportunity for prevention efforts since newly infected to PIs has decreased in recent years. individuals are at high risk of transmitting HIV during this period (Figure 5)27. Lack of knowledge about their status means that they are less likely to take protective TDR in newly diagnosed Japanese patients measures against transmitting HIV. Clusters of Viral samples from 408 newly diagnosed (2007-10) infections of both wild type and drug resistant virus patients at Nagoya Medical Center, Japan, were have been identified within sexual networks. Over tested for drug resistance using genotypic assays26. time, the size and number of clusters in a community Approximately one third (31%) of the patients had tend to increase. Clustering can lead to the onward seroconverted within the 155 days prior to testing while transmission of drug resistant sub-epidemics if these the remaining patients were classed as ‘long term’ mutations do not reduce the replication capacity of seroconverters. Japanese MSM were diagnosed the virus. In some cases, a compensatory mutation at a significantly earlier stage in their infection than arises that reverses the fitness deficits imposed by non-Japanese patients (p<0.01) or those who a specific mutation e.g. a virus carrying E138K plus had acquired HIV via risk factors other than MSM M184I/V has the same replication capacity as wild (p<0.05). TDR was observed in similar proportions in type virus. This may have clinical implications for both recent and long term seroconverters: resistance patients who fail therapy with etravirine or other novel to any ARV class was observed in 16% of samples. NNRTIs. It is essential that compensatory mutations, Resistance to PIs was observed in 7.1% of samples such as E138K, are monitored in future TDR studies. from recent seroconverters compared to 9.6% of long term seroconverters. The figures for NRTIs Mathematical modelling has been used to identify and NNRTIs, respectively, were 7.9% and 1.6% in HIV variants that are most likely to generate large the recent seroconverters and 5.3% and 2.1% in the transmission clusters and to investigate the effect long term seroconverters. There were no statistically of more sensitive resistance detection assays significant differences between the two groups in on increasing observed persistence times28. The terms of TDR. The mutations, T215X and M46I/L stochastic model of HIV transmission used 10 were detected in samples from both recent and variants, each with a single point mutation that long term seroconverters, suggesting that they have conferred resistance to NRTIs or NNRTIs. The stabilised within the viral population and become results of the model suggest that there could be a

Early stage infection: The window of opportunity for prevention

1/5 HIV+ Untested Viral load & Viral Infectivity Ag + Ab-

HAART

0 6 mo 2 yrs 5 yrs 10 yrs > 20 yrs

Acute/recent Chronic Infection Chronic treated

CLUSTERING >50% 10-20% <<10% Figure 5. Time course of HIV infection Source: Dr. M. Wainberg, McGill University, Montreal Canada27.

16 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 6th Workshop on HIV Transmission

hidden epidemic of HIV strains with intermediate may reduce the risk of onward transmission of these to low fitness. The use of assays with increasing mutated viruses. sensitivity could substantially increase the detection The M41L mutation is associated with resistance to of intermediate fitness strains. Small differences in NRTIs; it is a thymidine analogue mutation (TAM). fitness result in significant differences in persistence The presence of M41L and at least two other TAMs is times, cluster sizes and transmission chain lengths. associated with resistance to tenofovir but not to FTC. Strains with high fitness costs (>6%), such as K65R, Dr Pingen (University Medical Centre Utrecht, The are rarely transmitted and are rarely detected in Netherlands) and colleagues have used genetically clusters. engineered and patient-derived viruses to determine the impact of M41L on resistance to tenofovir and FTC30. All viruses that carried M41L as the only Transmissibility of drug resistant variants resistance-related mutation were fully susceptible M184V is one of the most common mutations to both NRTIs. In vitro selection experiments were in patients who fail therapy; it is associated with carried out in which the viruses were exposed to resistance to NRTIs. A macaque model of infection increasing concentrations of tenofovir, FTC or both has been used to determine the impact of M184V drugs. After 5-6 passages, the complete RT gene was on viral transmissibility29. The M184V mutation was sequenced. The results showed that the presence of introduced into a R5 tropic SHIV genetic background M41L did not prevent the selection of K65R or select and the transmissibility of the virus was evaluated for additional TAMs. M41L did not have a major effect using a repeat exposure rectal challenge model. on the development of resistance to tenofovir and/or The susceptibility of the variant to FTC was similar FTC, suggesting that therapy with these NRTIs could to that of HIV. At standard doses of virus, the be initiated even in the presence of a M41L mutation. variant was not very transmissible. When the dose was increased four-fold, the variant had similar transmission efficiency to that of wild type virus. The high fitness cost of the M184V mutation resulted in a reduced peak viraemia compared to wild type virus, even when higher doses of the mutated virus were used. Based on the results from this animal model, the presence of mutations that reduce viral fitness

19 - 20 JULY 2012 WASHINGTON DC, USA

MARK - THE - DATE 7th Workshop on HIV Transmission 19 - 20 July 2012, Washington DC, USA

Abstracts & Presentations of the 6th Workshop on HIV Transmission are available online at www.virology-education.com

Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 17 Report

Reference 1. Hope, T. Cell Biology of HIV Sexual Transmission. 19. Coburn, B., Why doesn’t male circumcision work? in 6th International Workshop on HIV Transmission. Reviews in Antiviral Therapy & Infectious Diseases, 2011. Rome, Italy. 2011. 7: p. 27. 2. Keane, N., Limited acute CTL escape among three 20. Scarlatti, G. Mother-to-Child transmission of HIV- founder viruses in a case of acute heterosexual 1: Advances and controversies. in 6th International transmission of HIV-1 infection. Reviews in Antiviral Workshop on HIV Transmission. 2011. Rome, Italy. Therapy & Infectious Diseases, 2011. 7: p. 3. 21. Lu, L., HIV incidence in women during the first 3. Dukhovlinova, E., HIV-1 viral populations in the female postpartum year and implications for PMTCT genital tract can be genetically distinct from virus in programs û Francistown, Botswana, 2010. Reviews in the blood. Reviews in Antiviral Therapy & Infectious Antiviral Therapy & Infectious Diseases, 2011. 7: p. 14. Diseases, 2011. 7: p. 4. 22. Bruneau, J. Preventing HIV transmission among 4. Introini, A., HIV-1 and reactivated coinfecting Herpes Injection Drug Users: a global perspective. in 6th viruses rearrange the cytokine network in semen of International Workshop on HIV Transmission. 2011. infected individuals. Reviews in Antiviral Therapy & Rome, Italy. Infectious Diseases, 2011. 7: p. 5. 23. Khayatkhoei, M., Comparison of the prevalence of 5. Cenci, A., Characterization of variable regions of HIV infection among different types of drug abusers the Env protein of HIV-1 subtype C obtained from in Imamhossein Detoxification Center, Tehran, Iran. individuals at different disease stages in Sub-Saharan Reviews in Antiviral Therapy & Infectious Diseases, Africa. Reviews in Antiviral Therapy & Infectious 2011. 7: p. 22. Diseases, 2011. 7: p. 6-7. 24. Wensing, A. Transmission of drug resistant HIV; global 6. Keele, B. Modeling HIV Transmission and Systemic trends and implications for first line therapy. in 6th Dissemination in Rhesus Macaques. in 6th International International Workshop on HIV Transmission. 2011. Workshop on HIV Transmission. 2011. Rome, Italy. Rome, Italy. 7. Saba, E., Productive HIV-1 infection of cervico-vaginal 25. Boucher, C., Transmission of HIV resistant to non- tissue ex vivo. Reviews in Antiviral Therapy & Infectious nucleoside RT inhibitors is rising in Europe. Reviews in Diseases, 2011. 7: p. 9. Antiviral Therapy & Infectious Diseases, 2011. 7: p. 15. 8. Bernard-Stoecklin, S., Characterization of semen 26. Hattori, J., Molecular epidemiology of transmitted leukocytes in Macaques infected by SIV. Reviews in drug-resistant HIV among newly diagnosed individuals Antiviral Therapy & Infectious Diseases, 2011. 7: p. 10. in Japan. Reviews in Antiviral Therapy & Infectious 9. Balandya, E., Semen protection of CD4+ T cells is Diseases, 2011. 7: p. 16. less potent against R5 tropic HIV. Reviews in Antiviral 27. Wainberg, M., Transmission within clusters of drug- Therapy & Infectious Diseases, 2011. 7: p. 11. resistant variants of HIV-1. Reviews in Antiviral Therapy 10. Neff, C., Pre-exposure prophylaxis by anti-retrovirals & Infectious Diseases, 2011. 7: p. 17. maraviroc and raltegravir protects against HIV-1 28. Wagner, B. HIV drug resistance mutations: identifying vaginal transmission in humanized mice. Reviews in variants most likely to generate large transmission Antiviral Therapy & Infectious Diseases, 2011. 7: p. 12. clusters. in 6th International Workshop on HIV 11. Garcia-Lerma, G., Pharmacokinetic and Transmission. 2011. Rome, Italy. pharmacodynamic profile of maraviroc in rhesus 29. Garcia-Lerma, G. Reduced transmissibility of a drug- macaques after a single oral dose. Reviews in Antiviral resistant SHIV162P3 isolate containing the M184V Therapy & Infectious Diseases, 2011. 7: p. 13. mutation in macaques. in Reviews in Antiviral Therapy 12. Heneine, W., Substantial changes in vaginal absorption & Infectious Diseases. 2011. 19. of antiretroviral drugs from gels during the menstrual 30. Pingen, M., The frequently transmitted M41L mutation cycle in Macaques. Reviews in Antiviral Therapy & in RT does not affect the in vitro selection of resistance Infectious Diseases, 2011. 7: p. 24. against tenofovir and emtricitabine. Reviews in Antiviral 13. Abdool Karim, S. Tenofovir gel and HIV transmission: Therapy & Infectious Diseases, 2011. 7: p. 20. some insights from the CAPRISA 004 trial. in 6th International Workshop on HIV Transmission. 2011. Rome, Italy. 14. Blower, S., Preventing HIV and herpes infections: Predicting the impact of the CAPRISA tenofovir gel in South Africa. Reviews in Antiviral Therapy & Infectious Diseases, 2011. 7: p. 25. 15. Cohen, M. Update on HPTN 052. in 6th International Workshop on HIV Transmission. 2011. Rome, Italy. 16. Cohen, M., et al. (2011) Prevention of HIV-1 Infection with Early Antiretroviral Therapy. NEJM. Available from: . 17. Vasarhelyi, K., Evaluating the impact of “Treatment as Prevention” on reducing HIV transmission, using surveillance data. Reviews in Antiviral Therapy & Infectious Diseases, 2011. 7: p. 26. 18. Schols, D., Synergistic activity of griffithsin in combination with tenofovir, maraviroc and enfuvirtide against HIV-1 subtype C. Reviews in Antiviral Therapy & Infectious Diseases, 2011. 7: p. 8.

18 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement In today’s HIV landscape, we expect to keep them there, with durable suppression, well-established tolerability and convenient dosing.1–3 So they can concentrate on dealing with the challenges of life.

Voor productinformatie zie elders in deze uitgave. NLRZ-K0003 08/11 687HQ11PM201(3)

NLRZK0003_Ad_v5_210x297.indd 1 8/31/11 11:12 AM Verkorte productinformatie REYATAZ® Samenstelling: REYATAZ®, harde capsules, bevatten 150, 200 of 300 mg atazanavir per capsule. Indicaties: REYATAZ capsules, gelijktijdig toegediend met lage doseringen ritonavir, zijn bestemd voor de behandeling van hiv-1 geïnfecteerde volwassenen en pediatrische patiënten in de leeftijd van 6 jaar en ouder in combinatie met andere antiretrovirale middelen. Gebaseerd op de beschikbare virologische en klinische gegevens van volwassen patiënten, is er geen voordeel te verwachten bij volwassen patiënten met stammen die resistent zijn tegen meerdere proteaseremmers (≥ 4 PI mutaties). Er zijn zeer beperkte gegevens beschikbaar van kinderen in de leeftijd van 6 jaar tot jonger dan 18 jaar. De keuze voor REYATAZ bij voorbehandelde volwassen en pediatrische patiënten dient gebaseerd te zijn op individuele virale resistentie tests en de behandelingshistorie van de patiënt. Dosering: volwassen patiënten – De aanbevolen dosering van REYATAZ capsules voor volwassenen is 300 mg eenmaal daags samen met eenmaal daags 100 mg ritonavir en voedsel. pediatrische patienten vanaf 6 jaar – De dosering van REYATAZ capsules bij pediatrische patiënten is gebaseerd op lichaamsgewicht (15-<20 kg: 150 mg, 20-<40 kg: 200 mg, ≥40 kg: 300 mg; samen met 100 mg ritonavir en voedsel). De beschikbare gegevens ondersteunen niet het gebruik bij pediatrische patiënten die minder dan 15 kg wegen. pediatrische patiënten jonger dan 6 jaar: REYATAZ wordt niet aanbevolen. Contra-indicaties: Overgevoeligheid voor atazanavir of voor één van de hulpstoffen; leverinsufficiëntie; gelijktijdig gebruik met PDE-remmer sildenafil voor de behandeling van uitsluitend PAH, rifampicine, St. Jans kruid (Hypericum perforatum) en met substraten van de isovorm CYP3A4 van cytochroom P450 die een smalle therapeutisch breedte hebben (zoals astemizol, terfenadine, cisapride, pimozide, kinidine, bepridil en ergot alkaloïden; met name ergotamine, dihydroergotamine, ergonovine, methylergonovine). Bijzondere waarschuwingen: Patiënten met chronische hepatitis B of C die behandeld worden met een antiretrovirale combinatietherapie hebben een verhoogd risico op ernstige en potentieel fatale leverbijwerkingen. Extra voorzorgsmaatregelen kunnen nodig zijn bij gebruik van REYATAZ bij hemofilie patiënten en bij patiënten met onderliggende leverstoornissen. REYATAZ met ritonavir wordt niet aanbevolen bij patiënten die hemodialyse ondergaan. Speciale voorzichtigheid is nodig bij patiënten met bestaande cardiale geleidingsproblemen (tweedegraads of hoger atrioventriculair of complexe bundeltakblokkade) of risicofactoren (bradycardie, lang congenitaal QT, electrolyt verstoringen), of bij gebruik in combinatie met andere geneesmiddelen die mogelijk het PR- en/of QT-interval verlengen en cardiale controle bij kinderen wordt aanbevolen op geleide van de aanwezigheid van klinische bevindingen. Er zijn meldingen geweest van toegenomen bloeding bij patiënten met type A en B hemofilie. Evaluatie van de fysische kenmerken van de redistributie van vet moet onderdeel uitmaken van klinische beoordeling. Lipiden-stoornissen dienen klinisch passend te worden behandeld. Het ontstaan van diabetes mellitus, hyperglykemie en exacerbatie van bestaande diabetes mellitus zijn gemeld voor patiënten, die proteaseremmers kregen in sommige gevallen ook geassocieerd met keto-acidose. Reversibele verhogingen van indirect (niet-geconjugeerd) bilirubine gerelateerd aan remming van UDP-glucuronosyltransferase (UGT) werden gezien in patiënten die werden behandeld met REYATAZ. Hoewel men aanneemt dat bij de etiologie vele factoren een rol spelen zijn gevallen van osteonecrose vooral gemeld bij patiënten met voortgeschreden hiv-infectie en/of langdurige blootstelling aan CART. Immuunreactiveringssyndroom kan optreden. Alle symptomen van de ontstekingsreactie moeten worden beoordeeld en zo nodig worden behandeld. Nefrolithiasie is gemeld en diverse interacties met geneesmiddelen waaronder: statines, NNRTI’s, sterke CYP3A4 inductoren en/of remmers, PDE-5 remmers voor de behandeling van erectieledisfunctie, antimycotica, gluco- en/of corticosteroïden, salmeterol, maagzuurremmers. Bij gelijktijdig gebruik van een oraal anticonceptivum dient deze tenminste 30 ug ethinylestradiol te bevatten. REYATAZ capsules bevatten lactose. Bijwerkingen: volwassen patiënten – oedeem, palpitaties, hoofdpijn, perifere neuropathie, syncope, amnesie, duizeligheid, slaperigheid, dysgeusie, oculair icterus, dyspneu, braken, diarree, buikpijn, misselijkheid, dyspepsie, pancreatitis, gastritis, opgezette buik, orale aften, flatulentie, droge mond, nierstenen, hematurie, proteïnurie, pollakisurie, pijnlijke nier, huiduitslag, urticaria, alopecia, pruritis, vesiculobulleuze huiduitslag, eczeem, vasodilatatie, spieratrofie, arthralgie, myalgie, myopathie, gewichtsafname, gewichtstoename, anorexie, toegenomen eetlust, hypertensie, lipodystrofie syndroom, moeheid, pijn op de borst, malaise, koorts, asthenie, verstoorde manier van lopen, allergische reacties, geelzucht, hepatitis, hepatosplenomegalie, gynaecomastie, depressie, verwardheid, angst, slapeloosheid, slaapstoornissen, abnormale dromen; pediatrische patiënten – veiligheidsprofiel over het geheel genomen vergelijkbaar met dat gezien bij volwassenen, asymptomatische eerste en tweedegraads atrioventriculaire blokkade. Afleverstatus: UR. Vergoeding en prijzen: volledige vergoeding; voor prijzen zie Z-index. Zie de volledige Samenvatting van Productkenmerken voor aanvullende informatie. Bristol-Myers Squibb BV, Woerden, tel: 0348-574222. Datering: mei 2011

1. Daar ES et al. Ann Intern Med. 2011;154(7):445-456 2. Molina JM and the CASTLE Study Team. J Acquir Immnune Defic Syndr. 2010;53(3):323-332. 3. REYATAZ®/r, SmPC. Available at www.ema.europa.eu. Accessed May 2011.

Date of preparation: August 2011 687HQ11PM201(3) NLRZ-A0018

NLRZ_A0018_VPIVERKORTE PRODUCTINFORMATIE (210x148mm)_v1b.indd ATRIPLA 600 mg1 / 200 mg / 245 mg Als de patiënten een ernstige uitslag ontwikkelen die gepaard gaat met blaren, desquamatie, mucosaletsels8/30/11 4:39 of PM filmomhulde tabletten koorts, moet de behandeling met Atripla worden stopgezet. Hulpstoffen: Dit geneesmiddel bevat 1 mmol (23,6 mg) natrium per dosis, waarmee rekening moet worden gehouden bij patiënten met een gecontroleerd natriumdieet. Samenstelling: Elke filmomhulde tablet bevat 600 mg efavirenz, 200 mgemtri - efavirenz 600mg/emtricitabine 200mg/ Zwangerschap: Atripla dient niet tijdens de zwangerschap te worden gebruikt, tenzij strikt noodzakelijk (d.w.z. er citabine en 245 mg tenofovirdisoproxil (als fumaraat). Farmaceutische vorm: Fil- tenofovir disoproxil (as fumarate) 245mg Tablets zijn geen andere passende behandelingsopties) Vruchtbare vrouwen: Bij vrouwen die Atripla ontvangen, moet momhulde tablet. Roze, capsulevormige, filmomhulde tablet, met aan de ene kant zwangerschap worden voorkomen. Borstvoeding: Vanwege het gevaar van HIVoverdracht en de mogelijkheid “123” gegraveerd en aan de andere kant niets. Farmacotherapeutische groep: HAART in 1 van ernstige bijwerkingen bij baby’s die borstvoeding krijgen, dienen moeders te worden geïn strueerd geen Antivirale geneesmiddelen voor de behandeling van HIVinfecties, combinaties, borstvoeding te geven als ze Atripla ontvangen. Bijwerkingen: De meest gerapporteerde, zeer vaak (≥ 1/10) ATCcode: J05AR06. Indicaties: Atripla is een vaste dosiscombinatie efavirenz, emtricitabine en tenofovirdisoproxilfumaraat. bijwerkingen zijn: duizeligheid, misselijkheid, huiduitslag,abnormale dromen. Vaak (≥ 1/100, <1/10) werden de volgende Het is geïndiceerd voor de behandeling van infectie met humaan immunodeficiëntievirus1 (HIV1) bij volwassenen met bijwerkingen waargenomen: anorexie, nachtmerrie, depressie, depressieve stemming, angst, slapeloosheid, stemmings- een virussuppressie tot HIV1RNA-concentratie < 50 kopieën/ml onder hun huidige antiretrovirale combinatietherapie verandering, slaapstoornis, slaperigheid, hoofdpijn, stupor, lethargie, aandachtsstoornis, vertigo, euforie, opvliegers, gedurende meer dan drie maanden. Er mag bij patiënten geen virologisch falen zijn opgetreden bij eerdere antiretrovirale diarree, braken, abdominale pijn, flatulentie, opgezette buik, droge mond, nachtelijk zweten, jeuk, hyperpigmentatie therapie en het moet bekend zijn dat patiënten voor het begin van hun eerste antiretrovirale behandeling niet geïnfecteerd van de huid, dermatitis, verhoogde creatininespiegel in het bloed, verminderde eetlust, vermoeidheid, toe genomen ener- waren door virusstammen met mutaties die een significante resistentie veroorzaken tegen een van de drie componenten gie, koorts. Soms (> 1/1.000, <1/100): herverdeling van de vet, hypertriglyceridemie, gewichtsverlies, verwarring, desori- van Atripla. Contra-indicaties: Overgevoeligheid voor de werkzame bestanddelen of voor één van de hulpstoffen. entatie, verandering in de persoonlijkheid, stemmingswisselingen, verminderde libido, amnesie, ataxie, evenwichts- Atripla mag niet worden gebruikt bij patiënten met een ernstige leverfunctiestoornis (CPT graad C). Atripla mag niet stoornis, onsamenhangende spraak, wazig zien, veranderde visuele diepte-perceptie, dygeusie, acute pancreatitis, gelijktijdig met terfenadine, astemizol, cisapride, midazolam, triazolam, pimozide, bepridil of ergotalkaloïden (bijvoorbeeld orale paresthesie, orale hypo-esthesie, urticaria, droge huid, eczeem, acute hepatitis, myalgie, borstvergroting, zich ab- ergotamine, dihydro-ergotamine, ergonovine en methylergonovine) worden gebruikt, omdat competitie door efavirenz normaal voelen, zich zenuwachtig voelen, rillingen, neutropenie, asthenie, zich dronken voelen, paranoia, psychomotri- om cytochroom P450 (CYP) 3A4 kan resulteren in een inhibitie van het metabolisme en potentieel ernstige en/of levens- sche agitatie,waanvoorstellingen, agressie, nervositeit. Verpakking: HDPE flacon met een kinderveilige sluiting, met bedreigende bijwerkingen kan uitlokken (bijvoorbeeld hartritmestoornis, langdurige sedatie of respiratoire depressie). 30 filmomhulde tabletten en eensilicagel droogmiddel. Doos met 1 of 3 flacons.Afleverstatus: UR. Vergoeding: volle- Kruidengeneesmiddelen met St.Janskruid (Hypericum perforatum) mogen niet worden gebruikt als tegelijkertijd ook dige vergoeding. Prijs: zie Z-index. Registratiehouder: Gilead Sciences International Limited, Cambridge CB21 6GT, Atripla wordt gebruikt, vanwege het risico van een lagere plasmaconcentratie en een geringer klinisch effect van Verenigd Koninkrijk. Datum: 05/2010. Bestudeer de samenvatting van productkenmerken alvorens Atripla voor te schrijven efavirenz. Efavirenz verlaagt de plasmaconcentratie van voriconazol sterk, terwijl voriconazol de plasmaconcentratie in het bijzonder vanwege dosering, bijwerkingen, waarschuwingen en voorzorgen bij gebruik, en interacties. Neem voor van efavirenz juist sterk verhoogt. Aangezien Atripla een combinatieproduct met vaste doses is, kan de dosering van meer inlichtingen contact op met de lokale vertegenwoordiger: Gilead Sciences Netherlands B.V., WTC Tower D, efavirenz niet worden gewijzigd; daarom mogen voriconazol en Atripla niet gelijktijdig worden toegediend. Waarschuwing Floor 7, Strawinskylaan 779, 1077 XX Amsterdam. en voorzorgen: Als vaste combinatie dient Atripla niet gelijktijdig toegediend te worden met andere geneesmiddelen die een van dezelfde werkzame componenten bevatten: efavirenz, emtricitabine of tenofovirdisoproxilfumaraat. Referenties: 1. Staszewski S, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine Vanwege overeenkomsten met emtricitabine dient Atripla niet gelijktijdig toegediend te worden met andere cytidine- and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999;341:1865–1873. 2. Robbins GK, et al. Comparison analogen, zoals lamivudine. Atripla dient niet gelijktijdig toegediend te worden met adefovirdipivoxil. Lactaatacidose: Bij of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293–2303. 3. Van Leth F, et al. het gebruik van nucleoside-analogen is melding gemaakt van lactaatacidose, gewoonlijk samengaand met hepatische Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and steatose. De behandeling met nucleoside-analogen moet gestopt worden bij het optreden van symptomatische hyper- lamivudine: a randomised open-label trial, the 2NN study. Lancet 2004;363:1253–1263. 4. Riddler SA, et al. Class-sparing regimens lactatemie en metabole acidose/lactaatacidose, progressieve hepatomegalie of snel stijgende aminotransfe rasespiegels. for initial treatment of HIV-1 infection. N Engl J Med 2008;358:2095–2106. 5. Lennox J, et al. Raltegravir versus efavirenz regimens Om het risico van lactaatacidosise te minimaliseren bij toediening van nucleoside-analogen moeten de patiënten in treatment-naive HIV-1–infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune nauwgezet worden gevolgd. Leverziekte: Atripla is gecontra-indiceerd bij patiënten met een ernstige leverfunctie- Defic Syndr 2010. [Epub ahead of print]. 6. Gotuzzo E, et al. 17th Conference on Retroviruses and Opportunistic Infections. 16–19 February stoornis. Omdat efavirenz hoofdzakelijk wordt gemetaboliseerd door het cytochroom-P450-systeem (CYP450-systeem), 2010. San Francisco, CA. Abstract K-127. Poster 514. 7. Gallant JE, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, is bij toediening van Atripla aan patiënten met een lichte tot matig-ernstige leverziekte voorzichtigheid geboden. lamivudine, and efavirenz for HIV. N Engl J Med 2006;354:251–260. 8. Martinez E, et al. J Acquir Immune Defic Syndr. 2009 Jul De leverziekte moet periodiek door middel van laboratoriumonderzoek worden gecontroleerd. Patiënten met HIV en 1;51(3):290-7. 9. Sax P, et al. Abacavir–lamivudine versus tenofovir–emtricitabine for initial HIV-1 therapy. N Engl J Med gelijktijdige infectie met hepatitisB- of Cvirus (HBV of HCV): Patiënten met chronische hepatitis B of C die een antire- 2009;361:2230–2240. 10. Smith KY, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or trovirale combinatietherapie ondergaan, lopen een verhoogd risico op ernstige en potentieel fatale leverbijwerkingen- tenofovir/ emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009;23:1547–1556. 11. Martin A, et al. Simplification Stoppen van de behandeling met Atripla bij patiënten met gelijktijdige infectie met HIV en HBV kan gepaard gaan met of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clin Infect Dis ernstige acute exacerbaties van hepatitis. Psychische symptomen: Bij patiënten die met efavirenz zijn behandeld, zijn 2009;49:1591–1601. 12. Post FA, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine psychische bijwerkingen gemeld. Patiënten met een voorgeschiedenis van psychische stoornissen lijken een groter versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviralnaive, HIV-1–infected adults: 48-week results from the risico te hebben op deze ernstige psychische bijwerkingen. Convulsies: Bij patiënten die efavirenz gebruikten, zijn ASSERT study. J Acquir Immune Defic Syndr 2010 sept;55(1):49-57. 13. Arribas JR, et al. Tenofovir disoproxil fumarate, emtriciabine, convulsies waargenomen, meestal bij een bekende voorgeschiedenis van toevallen. Bij alle patiënten met toevallen in and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients. J Acquir Immune Defic Syndr de voorgeschiedenis moet voorzichtigheid worden betracht. Nierfunctiestoornis: Het gebruik van Atripla wordt niet 2008;47:74–78. 14. DeJesus E, et al. Simplification of antiretroviral therapy to a singletablet regimen consisting of efavirenz, aanbevolen bij patiënten met een matig-ernstige of ernstige nierfunctiestoornis.Het gebruik van Atripla dient te worden emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected vermeden bij gelijktijdig of recent gebruik van een nefrotoxisch geneesmiddel. Indien gelijktijdig gebruik van Atripla en patients. J Acquir Immune Defic Syndr 2009;51(2):163–174. 15. Hodder SL, et al. Patient-reported outcomes in virologically nefrotoxische middelen (bv. aminoglycosiden, amfotericine B, foscarnet, ganciclovir, pentamidine, vancomycine, suppressed, HIV-1-infected subjects after switching to a simpliofied, single-tablet regimen of efavirenz, emtricitabine, and tenofovir cidofovir, interleukine2) onvermijdelijk is, moet de nierfunctie wekelijks worden gecontroleerd. Het wordt aangeraden DF. AIDS Patient Care STDs 2010;24(2);87–96. 16. Airoldi M, et al. One-pill once-a-day HAART: a simplification strategy that improves om bij alle patiënten de creatinineklaring te berekenen voordat wordt begonnen met de behandeling met Atripla. adherence and quality of life of HIV-infected subjects. Patient Prefer Adherence 2010;4:1–11. De nierfunctie (creatinineklaring en serumfosfaat) wordt gedurende het eerste jaar ook elke vier weken gecontroleerd en daarna elke drie maanden. Aangezien Atripla een combinatieproduct is en het doseringsinterval van de individuele componenten niet kan worden gewijzigd, moet de behandeling met Atripla worden onderbroken bij patiënten bij wie een creatinineklaring van < 50 ml/min of een afname van het serumfosfaatgehalte naar < 1,0 mg/dl (0,32 mmol/l) is bevestigd. Huidreacties: Lichte tot matig-ernstige huid uitslag is gemeld bij gebruik van de individuele componenten van Atripla. Report

3rd International Workshop on HIV Pediatrics 15 - 16 July 2011 in Rome, Italy Report

Progress and Controversies in Pediatric HIV Care

Report on the 3rd International Workshop on HIV Pediatrics

J. Ananworanich1, C. Boucher2, D. Burger3, E. Capparelli4, M. Cotton5, C. Giaquinto6, D. Mbori-Ngacha7, L. Mofenson8

1The Thai Red Cross AIDS Research Center, Thailand, 2Erasmus Medical Center Rotterdam, The Netherlands, 3University of Nijmegen, The Netherlands, 4University of California San Diego, California, USA, 5Stellenbosch University J8/Tygerberg Children’s Hospital,South Africa, 6University of Padova, Italy, 7UNICEF East and Southern Africa Region, South Africa, 8National Institutes of Health, Bethesda, USA

Written by Mark Mascolini on behalf of the Organizing Committee

Growing up with HIV poses different challenges in resource-rich and poor countries, attendees learned in the opening session of 3rd International Workshop on HIV Pediatrics. But similar challenges in both regions are not hard to find, according to keynote speakers Rohan Hazra1 (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland) and Philippa Musoke2 (Makerere University, Kampala).

Two prospective pediatric cohorts in the United limited settings, noting that 400,000 infants become States recorded dramatic drops in mortality from the infected with HIV every year, 90% of them in sub- days before combination antiretroviral therapy (cART) Saharan Africa.2 While mortality was falling steeply in to more recent years,3,4 Hazra noted. The 3553-child HIV-positive US children by 2004,4 an African meta- PACTG 219/219C cohort recorded a mortality analysis of perinatal prevention trials in breastfeeding plummet from 7.2 per 100 person-years in 1994 to infants reported from 1999 through 2002 found that 0.6 per 100 person-years in 2006.3 In the 364-child 52.5% of children who became infected had died at PACTS/PACTS-HOPE birth cohort, mortality waned 2 years of age and 60% by 2.5 years.5 from 18 per 100 person-years in 1986 to 0.8 per 100 Delayed diagnosis and treatment of HIV in resource- person-years in 2004.4 But for youngsters with HIV, poor countries explains much of the high mortality, decades-long survival with HIV means decades of Musoke said. When women with HIV are not coping with potential central nervous system disease, diagnosed during pregnancy, their HIV-positive metabolic and insulin dysregulation, and bone, liver, infants also go undiagnosed. Access to HIV DNA renal, and cardiovascular disease. Atherosclerosis testing of dried blood spots is limited in many low- does begin in childhood, Hazra stressed. income countries, so undiagnosed HIV often persists in newborns. When children are diagnosed, lack of “The use of [cART] has transformed HIV infection appropriate pediatric formulations—and sometimes in children from a fatal illness to a chronic health perinatal exposure to nevirapine—complicate their condition,” Hazra observed, and, “as with other treatment. Malnutrition, tuberculosis, and other chronic conditions, long-term treatment, monitoring, afflictions complicate the course of children who are and management will be critical, and many challenges diagnosed and begin treatment. will be faced as these children age into adulthood.” At the same time, he argued, survival of perinatally Around the world, UNAIDS estimates that 38% of infected children into adulthood in rich countries children eligible for cART begin treatment, compared should encourage “expansion of pediatric treatment with 43% of adults.6 Across sub-Saharan Africa, only programs in low-resource countries, where most 35% of cART-eligible children get treated, but rates HIV-infected children live.” are higher in South Africa (65%) and Botswana (80%).

Philippa Musoke spoke for that majority in resource- As in high-income countries, children typically respond well to cART in low- and middle-income countries. Musoke cited a 3936-child study of Disclosure: children starting cART before the age of 5 years, Mark Mascolini has disclosed that he has not 90% of them in Africa and the rest in Asia.7 After a received grants or (research) support from any median cART duration of 10.5 months (interquartile commercial entity or served as consultant for such a range [IQR] 3.7 to 20.6), 6.3% of children in this company. cohort had died and 10.3% were lost to follow-up. Most deaths, 55%, occurred in the first 6 months of

22 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

treatment, and only 3.8% of children experienced rather than waiting until a drop to 250 cells/mm3 severe antiretroviral toxicity. lowered the risk of a clinical event 40% (P = 0.01).11

Musoke listed a set of challenges in adolescent HIV PREDICT is an open-label trial in Thailand and care in resource-poor settings, all of which could be Cambodia that randomized antiretroviral-naive cited as challenges in high-income countries: children from 1 to 12 years old to start cART • Knowledge of HIV infection immediately or to close monitoring every 3 months • Linking to (and retaining in) health care and to begin cART when the CD4 percent fell below • Accepting (and adhering to) therapy 15%.8 All children were naive to antiretrovirals, • Mental health issues had a CD4 percent between 15% and 24% upon • Complexities of transition to adult care enrollment, and had CDC stage A or B disease. • High risk of HIV transmission to sex partners Primary endpoints were AIDS-free survival and neurodevelopment as measured by the Berry visual- Hazra interleaved his data slides with quotes from US motor integration score at week 144. PREDICT children asked for their thoughts about growing up investigators recruited 300 children (180 Thais and with HIV. “At first, I didn’t think that I was going to grow 120 Cambodians) at seven clinical research sites in up with HIV,” one youngster remarked. “I thought I was Thailand and two in Cambodia. Study retention was going to die from HIV.” Now that HIV-positive children 97%. Health workers measured CD4 percent every around the world are learning that death is not a 3 months. All children started the same regimen— short-term inevitability, HIV pediatricians everywhere nevirapine, zidovudine, and lamivudine are learning that cross-cultural exchanges like those possible at the International HIV Pediatrics Workshop Median age was 6.4 years in both treatment arms. can afford the deepest insights into a virus that does Forty-six children (15%) were 1 to 3 years old, 67 not pause at Passport Control. (22%) were 4 to 5, and the rest were older than 5 years of age. In the immediate and deferred arms, 52% and 64% were girls, median CD4 percent stood Pediatric cART: Controversies and at 19% and 20%, and median viral load measured Insights 4.9 and 4.7 log10 copies/mL. Median weight-for-age Z score and height-for-age Z score were similar in the Immediate cART does not prolong survival two groups (-1.3 in both arms for weight and -1.6 to in 1- to 12-year-olds -1.7 for height). Contrary to findings in infants under 1 year old and in adults, a 144-week randomized trial in Thailand After 144 weeks of follow-up, AIDS-free survival was and Cambodia found that immediate cART for 97.9% in the immediate-cART group and 98.7% in 1- to 12-year-olds with moderately advanced HIV the deferred group, a nonsignificant difference (P infection did not prolong survival, delay progression = 0.49). Incidence of CDC class C events was 7.6 to AIDS, or improve neurodevelopment.8 Children in per 1000 person-years in the immediate group and the immediate treatment group did grow faster than 4.9 per 1000 person-years in the deferred group (3 those in the delayed treatment group, and they had events versus 2). The Berry visual-motor integration lower rates of thrombocytopenia and herpes zoster. test score did not differ significantly between the immediate and deferred arms (84.7 and 86.8, P The findings run counter to results of the South = 0.50) at 144 weeks. The PREDICT investigators African CHER trial, which found that immediate called the Berry score a crude measurement of cART for children under 1 decreased mortality neurodevelopment, and they are further analyzing by 76% and HIV progression by 75%.9 As a result cognitive function and fine motor test results. of that trial, the World Health Organization (WHO) recommends immediate cART for children up to 2 Incidence of thrombocytopenia (abnormally low years old regardless of CD4 count, CD4 percent, platelets) was lower in the immediate arm (2.5 versus or WHO clinical stage.10 For 2- to 5-year-olds, WHO 24.4 per 1000 person-years, hazard ratio [HR] 9.7, P recommends cART for those with a CD4 count at or = 0.03), as was incidence of herpes zoster (7.5 versus below 750 cells/mm3 or a CD4 percent at or below 31.8 per 1000 person-years, HR 4.2, P = 0.03). All 25%, whichever is lower, regardless of WHO clinical 10 cases of thrombocytopenia in the deferred arm stage. For children 5 or older, WHO advises starting occurred before cART began, and 9 of 13 cases of cART for all with a CD4 count below 350 cells/mm3, herpes zoster occurred before cART began. Weight- regardless of WHO clinical stage. In adults, the for-age Z score improved more in the immediate arm international HPTN 052 trial found that starting cART (0.20 versus 0.08, P = 0.074), as did height-for-age Z at a CD4 count between 350 and 550 cells/mm3 score (0.23 versus 0.00, P = 0.003).

Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 23 Report

%CD4 after start ART 40

Immediate

30 Deferred %4DC 20

P=0.74 10 0 12 24 36 48 60 72 84 96 108 120 132 144

Weeks after commencing ART

IMMEDIATE 149 148 147 147 145 143 144 142 142 142 142 142 142

DEFERRED 68 67 60 57 54 51 46 38 27 19 14 8 6

Figure 1. Gains in CD4 percent did not differ between the immediate-cART arm and the delayed arm after treatment began in the randomized PREDICT trial, which found no mortality difference between the immediate and deferred arms after 144 weeks. Source: Thanyawee Puthanakit, HIV-NAT, Bangkok.8

Gains in CD4 percent did not differ significantly lower in Thailand and Cambodia than in some other between the two study arms after cART began (P = developing countries. Finally, the results should be 0.74) (Figure 1). And proportion of children reaching a considered with special caution in 1- to 3-year-old viral load below 50 copies/mL after treatment began children, who represented only 15% of the study did not differ between the immediate and deferred population. arms.

Because PREDICT found that HIV-positive children NNRTI or PI first? who survive beyond infancy with moderate immune Clues from four big studies suppression had slow disease progression, the Whether to start cART in infants and children with investigators suggested clinicians have the option a regimen based on a nonnucleoside reverse to monitor such children closely and to start cART transcriptase inhibitor (NNRTI) or a protease inhibitor when the CD4 percent drops below 15% (although (PI) is a pressing question whose answer depends that approach would fall outside WHO guidelines). on an array of variables including exposure to single- The PREDICT team proposed that this approach dose nevirapine (sdNVP) or other antiretrovirals for may be useful when children and families are not prevention of mother-to-child transmission (PMTCT) ready to embark on lifelong therapy and when cART and the availability of appropriate, convenient programs are scaling up to cover all children in need. formulations, which typically means generic products in low- and middle-income countries. But the investigators cautioned that clinical application of study results should be considered with For children under 3 years old, US Department of the following caveats: First, entry criteria stipulated Health and Human Services (DHHS) guidelines that all participants had survived at least the first recommend two nucleos(t)ide reverse transcriptase year of life without antiretroviral therapy, without an inhibitors (NRTIs) plus lopinavir/ritonavir, with AIDS disease, and without a CD4 percent decline nevirapine now listed as an alternative (in children not below 15%; and two thirds of study participants exposed to nevirapine perinatally).12 Because children had survived the first 5 years of life without AIDS or in both the nevirapine-exposed and unexposed cART. Thus by definition these children had slowly cohorts of IMPAACT P1060 (summarized below) had a progressive disease. Second, study participants had better CD4 response and better growth than children their CD4 percent measured every 3 months, an in the lopinavir/ritonavir arm, this panel decided that interval that is more frequent than the usual 6 to 12 “liquid nevirapine remains an acceptable alternative months in clinical practice in developing countries. for infants not exposed to single-dose nevirapine Third, morbidity and mortality background rates (for for PMTCT who cannot tolerate lopinavir/ritonavir.” example, form diarrhea and pneumonia) are probably For children 3 to 6 years old, DHHS recommends

24 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

Time to off study treatment or virologic failure 1.0

0.8

VF no 0.6 LPV/r

0.4 NVP

Week 24 failure rate TRT with with TRT on 0.2

. op . Week 24: NVP - LPV/r: 21.5% (p<0.001) Pr 0.0 Weeks 0 24 48 72 96 120 144 168 N at risk: NVP 147 109 68 47 25 20 12 7 LPV/r 140 125 93 54 33 26 17 9

Figure 2. Among children not perinatally exposed to nevirapine in IMPAACT P1060 cohort 2, those randomized to treatment with a nevirapine regimen had a 21.5% higher failure/discontinuation rate at 24 weeks than did children randomized to lopinavir/ritonavir. Source: Paul Palumbo, Dartmouth-Hitchcock Medical Center.13 two NRTIs plus efavirenz or lopinavir/ritonavir. And Study participants were 6 months to 3 years old for children 6 years old or older, the panel prefers and eligible for cART by WHO criteria.10 The primary two NRTIs plus atazanavir/ritonavir, lopinavir/ endpoint in both cohorts was (1) virologic failure ritonavir, or efavirenz. WHO guidelines divide first-line by week 24, or (2) permanent discontinuation of treatment choices by age (under 12 months, 12 to nevirapine or lopinavir/ritonavir by week 24, or (3) 24 months, 24 months to 3 years, and 3 or older) death. The investigators defined virologic failure as a and according to perinatal exposure to nevirapine or confirmed viral load decline less than 1 log10 copies/ other antiretrovirals, recommending regimens based mL (10-fold) between weeks 12 and 24 or a viral load on lopinavir/ritonavir, nevirapine, or efavirenz.10 above 400 copies/mL at week 24.

The 3rd International Workshop on HIV Pediatrics Children in cohort 1 (the nevirapine-exposed group) offered insight into this question in reviews of three had (1) an HIV diagnosis by 60 days of age, or (2) randomized trials (IMPAACT P1060, PENPACT 1, and strict formula feeding, or (3) an AIDS-defining event NEVEREST 2) and one large cohort study (EPPICC). by 60 days of age. These children came from four Presenting IMPAACT P1060 data, Paul Palumbo study sites in South Africa and one each in India, (Dartmouth-Hitchcock Medical Center, Lebanon, Malawi, Tanzania, Uganda, Zambia, and Zimbabwe. New Hampshire) rated nevirapine a very good Almost all children, 95%, were infected with HIV-1 pediatric antiretroviral because of its potency, user- subtype C, and 20% breastfed.13,14 friendly formulations, good tolerability, temperature Cohort 1 included 82 children taking nevirapine and tolerance, and cost-effectiveness.13 A “parade of 82 taking lopinavir; both groups had a median age reports” documenting slowly fading resistance to of 0.7 year and a median viral load above 750,000 nevirapine after perinatal exposure began in 2000, copies/mL at study entry. Median baseline CD4 Palumbo noted. As these four studies show, the percents were 18.9% in the nevirapine group and choice between nevirapine (or efavirenz) and a 19.7% in the lopinavir group. More children taking ritonavir-boosted PI is not clear-cut. nevirapine than lopinavir (62% versus 50%) had at least WHO stage 3 disease. Median follow-up stood • IMPAACT P1060. at 48 weeks (range 0 to 125 weeks). IMPAACT P1060 focused on two cohorts, one exposed to sdNVP and one not exposed.13 The Among nevirapine-exposed children under 12 investigators randomized children to nevirapine or months old, virologic failure or discontinuation rates lopinavir/ritonavir, both with zidovudine/lamivudine. at 24 weeks were 45.3% in the nevirapine group

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and 23.3% in the lopinavir groups. Virologic failure/ higher versus a lower viral load (above 1000 versus discontinuation rates at 24 weeks in children 12 above 30,000 copies/mL).15,16 Of the 263 analyzed months or older were 28.9% in the nevirapine group study participants, half were from Europe, 27% from and 17.5% in the lopinavir group. Among all children the United States, 20% from Brazil or Argentina, and without pretreatment nevirapine resistance on a 3% from the Bahamas or Puerto Rico. There were standard assay, 24-week failure rates were 35.8% 218 children (83%) in follow-up at the end of the trial among those taking nevirapine and 20.3% among in August 2009, and median follow-up stood at 5 those taking lopinavir (P = 0.06). Among the 18 years. children with a pretreatment nevirapine resistance mutation (Y181C in 15 and K103N in 3), failure rates Study participants had a median age of 6.5 years were 83.3% with nevirapine and 18.2% with lopinavir, (range 1 month to 17.8 years), 53% were boys, and a highly significant difference (P = 0.001). 79% were vertically infected. Half were black, one quarter white, and one quarter Hispanic or another The 288 children in cohort 2 (not exposed to race or ethnicity. Median pretreatment CD4 percent nevirapine) came from four sites in South Africa and stood at 17% (IQR 10% to 25%) and median viral one each in India, Malawi, Tanzania, Uganda, Zambia, load at 5.1 log10 copies/mL (about 126,000 copies/ and Zimbabwe. These children had a median age mL). Only 15% of children received antiretrovirals for of 1.7 years, and 73% were older than 12 months. PMTCT, and 4% had one or more major resistance Median pretreatment viral load stood at 535,000 mutations when PENPACT 1 began. copies/mL and median CD4 percent at 15%. Most of the children, 81%, were breastfeeding. Median At the end of the trial, 70% of children remained on follow-up was 60 weeks. As in cohort 1, children their initial regimen, and the proportion switching were randomized to lopinavir/ritonavir or nevirapine antiretroviral classes did not differ between study plus zidovudine/lamivudine. arms (P = 0.64). Only 7% of children switched to a third-line regimen by the end of follow-up, and In cohort 2, virologic failure or off-study rates at week proportions did not differ between randomized arms. 24 were 40.8% with nevirapine versus 19.3% with Among children who changed regimens, the switch lopinavir (P < 0.001) (Figure 2). Failure or off-study point was significantly lower in those randomized rates were significantly higher with nevirapine among to switch at 1000 copies/mL than among those children under 12 months old (41.5% versus 19.4%, P randomized to switch at 30,000 copies/mL (6720 = 0.030) and children 12 months old or older (40.6% versus 35,712 copies/mL, P < 0.01). Estimated time versus 19.2%, P = 0.001). Rates of discontinuation until 10% of children in the 1000-copy-switch group because of toxicity were higher with nevirapine than changed regimens was 54 weeks, compared with with lopinavir for children under 12 months old (7/41 95 weeks until 10% of children in the 30,000-copy- or 17% versus 1/36 or 3%) and for older children switch arm changed. (22/106 or 21% versus 5/104 or 5%). Change in viral load from baseline to year 4, the Palumbo showed modeling data suggesting that the primary endpoint, did not differ significantly between once-daily lead-in dose of nevirapine may be too low the PI group (-3.16 log) and the NNRTI group (-3.31 given the high starting viral loads in these children log) (difference -0.15 log, P = 0.26). Proportions with and possible adherence difficulties. Pharmacologist a viral load below 400 copies/mL at week 204 did David Burger (University Medical Center, Nijmegen, not differ between the PI group and the NNRTI group Netherlands) suggested that the ultimate twice-daily (82% in both) or between the 1000-switch group nevirapine dose may also be too low in this population and 30,000-switch group (83% versus 80%, P = and deserves further evaluation. Palumbo added that 0.43). Suppression rates with a 50-copy assay were some children in cohort 2 had nevirapine resistance similar in the two randomized comparisons. CD4 mutations at baseline, and IMPAACT investigators are percent changes also proved similar in these two assessing pretreatment samples with more sensitive comparisons. Adverse event rates did not differ by assays. Standard genotyping detected Y181C in 4 trial assignment. children and K103N in 1 before treatment in cohort 2. Among children in whom treatment failed, mutations conferring resistance to PIs were uncommon, and • PENPACT 1. low-level resistance to lopinavir/ritonavir emerged in Also designated PENTA 9 and PACTG 390, PENPACT only 1 child. Among children whose NNRTI regimen 1 was an open-label trial that randomized children failed, NNRTI mutation rates did not differ by viral load to begin antiretroviral therapy with a PI or an NNRTI switch point, because NNRTI-resistant HIV is selected combination and to switch after virologic failure at a very early during virologic failure. In the NNRTI arm,

26 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

NRTI mutations accumulated in approximately 10% below 400 copies/mL for more than 3 months were more children in the 30,000-switch group than in randomized to keep taking lopinavir/ritonavir or to the 1000-switch group. This accumulation rate was switch to nevirapine. A significantly higher proportion lower than predicted, and NRTI mutations were even in the switch arm maintained a viral load below 50 less likely to develop in PI recipients. copies/mL to week 52 (56.2% versus 42.4%, P = 0.01). But a significantly higher proportion in the Gareth Tudor-Williams (Imperial College, London) lopinavir/ritonavir maintenance group kept their viral noted that PENPACT 1 is the first randomized trial in load below 1000 copies/mL (98% versus 80%, P = the cART era with follow-up long enough to address 0.001). the consequences of early versus later switching after virologic failure. He suggested the trial raises Ashraf Coovadia (Rahima Moosa Mother and Child the question whether nevirapine-exposed infants Hospital, Johannesburg), first author of the published starting lopinavir/ritonavir should delay switching report, updated results through 48 months at the at virologic failure, because PI resistance rates 3rd HIV Pediatrics Workshop.18 Probability of ever were low in children in whom a PI failed and—after reaching a viral load above 50 copies/mL remained emergence of M184V— further NRTI mutations were lower in the nevirapine switch group at 24 months slow to evolve. Tudor-Williams also cautioned that (51% versus 68%), 36 months (60% versus 69%%), PENPACT 1 results cannot be compared with those and 48 months (63% versus 75%). The proportion of IMPAACT P106013 because of the different study of children with a confirmed viral load above 1000 populations and follow-up times. copies/mL remained stable at 24% in the nevirapine- switch arm through 48 months, while the proportion with a confirmed 1000-copy rebound in the lopinavir/ • NEVEREST 2. ritonavir group rose from 5% at 12 months to 11% at How to apply results of NEVEREST 2 has perplexed 48 months. clinicians since these findings were presented at the 1st HIV Pediatrics Workshop and published soon In the nevirapine-switch group, 59% of all confirmed thereafter.17 The study involved nevirapine-exposed rebounds above 1000 copies/mL occurred by month South African children who began cART with a PI- 6 and the rest occurred by month 12 (Figure 3). In the based regimen (lopinavir/ritonavir or ritonavir). The lopinavir-maintenance group, only 10% of confirmed 195 children who reached and maintained a viral load rebounds above 1000 copies/mL occurred by month

Percent of All “Failures” (con rmed >1 000cp/mL) occurring by different time points post randomization

100%

41% 75% 50%

By 48m 50% By 12m By 6m 40% 59% 25%

10% 0% LPV/r Stay NVP Switch

Half of all failures All failures detected detected after within 12 mos of 12 mos of ART starting ART

Figure 3. Among nevirapine-exposed South African children who started a lopinavir/ritonavir regimen, reached and maintained a viral load below 400 copies/mL for more than 3 months, and were randomized to maintain lopinavir/ritonavir or switch to nevirapine in NEVEREST 2, all virologic failures in the nevirapine group occurred within 12 months of the switch, while half of failures in the lopinavir/ritonavir group occurred between months 12 and 48. Source: Ashraf Coovadia, Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa.18

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6, another 40% occurred by month 12, and the study populations). To assess first-line responses in remaining 50% occurred by month 48. infants, and to determine antiretroviral switch rates and switch predictors, European researchers pooled Among children with a confirmed viral load above data from nine cohorts in which children younger 1000 copies/mL after randomization, the failure rate than 12 months old started cART between 1996 and did not differ between the nevirapine and lopinavir 2008.19 arms in children with no detectable pretreatment mutations. But among those with detectable European Pregnancy and Paediatric HIV Cohort pretreatment NNRTI mutations, the failure rate was Collaboration (EPPICC) investigators defined significantly higher in the nevirapine-switch group virologic response as a viral load below 400 copies/ (above 50%) than in the lopinavir-maintenance group mL, CD4 response as absolute change in CD4 Z (below 15%) (P = 0.02). score from baseline, and switch to second-line therapy as simultaneously changing either (1) three Median CD4 percent at 24 weeks was higher in the or more drugs for any reason or (2) two drugs nevirapine group than the lopinavir group (33.2% because of treatment failure. For purposes of this versus 30.0%, P < 0.0001), but it is unclear whether analysis, treatment interruption meant stopping all this difference is clinically meaningful. CD4 percent antiretrovirals for 14 or more days. declined by at least 10% in significantly more children staying with lopinavir than switching to nevirapine The analysis involved 437 infants, 39% in the United (16.3% versus 3.2%, P = 0.004). Weight for age Kingdom and Ireland, 23% in Italy, 19% in France, fell by more than 1 Z score in significantly more and the rest in other European countries. Median age children maintaining lopinavir (13.1% versus 4.2% when cART started was 3.6 months (IQR 2.1 to 5.8), in the nevirapine-switch group, P = 0.03). Grade and 31% of infants had an AIDS diagnosis before 2 alanine aminotransferase (ALT) elevations were treatment began. Mothers of 34% of these infants significantly more frequent in the nevirapine group had taken antiretrovirals during pregnancy, and 28% than the lopinavir group (11.5% versus 2%, P = 0.05), of infants received neonatal antiretroviral prophylaxis. and there was a trend toward a higher proportion of One third of infants were breastfed. Most regimens grade 3/4 ALT elevations in the nevirapine arm (5.2% included either a PI or an NNRTI: versus 4%, P = 0.08). • Unboosted PI plus two NRTIs: 38% • Ritonavir-boosted PI plus two NRTIs: 15% NEVEREST 2 investigators concluded that switching • NNRTI plus two NRTIs: 24% to an NNRTI regimen after perinatal NNRTI exposure • NNRTI plus three NRTIs: 14% and virologic suppression with lopinavir/ritonavir • PI plus NNRTI plus NRTI or three NRTIs: 8% “can be accomplished safely if adequate virological monitoring is in place.” They observed that failure The virologic suppression rate rose from 53% in after a switch to nevirapine occurs within 1 year 1996-1999 to 57% in 2000-2003 and to 77% in 2004- of the switch, and that viral load monitoring can 2008. Martina Penazzato (University of Padova, Italy, detect these failures and signal the need to return and CTU-MRC, London), who presented results for to lopinavir/ritonavir. The researchers believe more EPPICC, suggested that improving virologic response study is needed to discern the clinical significance of rates reflect better regimen efficacy, more adequate low-level viremia and the worse CD4 response in the dosing, and “personalized HIV management leading lopinavir-maintenance group. to better caregiver adherence.”

Every 10-fold higher pre-cART viral load lowered • EPPICC. chances of virologic suppression at 12 months by Four in 5 European infants starting their first cART 33% (adjusted odds ratio [AOR] 0.67, 95% CI 0.50 to regimen after 1996 were still taking their first- 0.89, P = 0.006). Compared with starting an NNRTI line regimen 2 years later, and two thirds had not plus two NRTIs, starting an NNRTI plus three NRTIs switched or interrupted antiretrovirals 5 years later, tripled chances of suppression at 12 months (AOR according to results of a 9-cohort analysis.19 By 3.00, 95% CI 1.24 to 7.23, P < 0.001). The study found several measures, the best first-line regimen was one no evidence that other first-line regimens improved NNRTI plus three NRTIs. or worsened chances of suppression compared with WHO recommends immediate cART for children up an NNRTI plus two NRTIs. to 2 years old,10 but data on response to early cART are sparse and, as discussed above, IMPAACT 106013 Among 203 infants with pretreatment and 12-month and PENPACT 115 reached different conclusions CD4 counts available, median CD4 change was 520 on the optimal first-line regimen (in highly different cells/mm3 (IQR 271 to 1340), median CD4 percent

28 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

Cumulative probability of switch/planned TI 60

switch/TI 50

40 36% (31%-41%)

30 switch

20 planned TI

Cumulatieve incidence (%) 10

0 0 2 4 6 8 10 Number of years from cART initiation

Figure 4. Analysis of 437 European infants starting their first antiretroviral combination determined that almost two thirds (64%) were still taking their initial regimen after 5 years of follow-up. Source: Martina Penazzato, University of Padova, Italy, and Clinical Trials Unit, Medical Research Council, London, for the European Pregnancy and Paediatric HIV Cohort Collaboration.19 change 6% (IQR -6% to 16%), and median CD4 Z 36% at 5 years (Figure 4). Thus at the 5-year point score change 0.92 (IQR -0.14 to 2.34). Median CD4 Z 64% of children had taken their initially prescribed score rose by 2.29 in infants starting an NNRTI plus regimen consistently. three NRTIs, compared with 0.65 in those starting an This study is the first to find that an NNRTI plus three NNRTI plus two NRTIs and 0.91 in those starting a NRTIs promote better virologic and immunologic ritonavir-boosted PI. Infants whose mothers received responses than standard three-drug regimens that ART during pregnancy had smaller CD4 Z score include an NNRTI or a boosted PI. Penazzato noted gains at 12 months than infants whose mothers did that further evaluation of first-line cART options and not receive ART. interruption strategies awaits final analyses of the randomized CHER9 and ARROW20 trials. During a median follow-up of 5.9 years (IQR 2.3 to 7.6), 77 of 437 infants (18%) switched to a second- line regimen. Among those who switched, 61% had Viral load at 6 weeks of age predicts never reached a viral load below 400 copies/mL on mortality up to 1 year their first regimen. Switch rates were 3.9 per 100 Zimbabwean infants with a viral load above the person-years in children starting an NNRTI plus two group median at 6 weeks of age had a tripled risk of NRTIs, 2.1 per 100 person-years in children starting death during the first 6 months of life, according to an NNRTI plus three NRTIs, and 1.3 per 100 person- results of a retrospective analysis involving children years in those starting a boosted PI and two NRTIs; in the years before access to antiretroviral therapy or Penazzato cautioned that these results rest on sparse cotrimoxazole.21,22 Among infants alive at 6 months, data. Ever attaining a viral load below 400 copies/ a high 6-week viral load doubled the risk of death mL lowered chances of switching 77% (AOR 0.23, through 1 year of age. 95% CI 0.15 to 0.37, P < 0.001), whereas a confirmed viral rebound raised chances of switching almost 23 Although viral loads are usually very high in infancy, times (AOR 22.8, 95% CI 5.47 to 95.14, P < 0.001). US research has linked viral load in infants and children with disease progression and death.23-26 While 28% of children had one or more treatment Because the value of viral load in predicting HIV interruptions, 12% had a planned treatment disease progression or death in African infants interruption. Among all children with a treatment remains unclear, researchers in Zimbabwe undertook interruption, 38% had a viral load below 400 copies/ this study. Andrew Prendergast (ZVITAMBO Project, mL at the first interruption. Cumulative probability of a Harare) and colleagues analyzed data from the regimen switch or planned treatment interruption was ZVITAMBO vitamin A trial, which took place in

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Table 1. Predictors of mortality by 6 and 12 months of age in Zimbabwe

Adjusted hazard 95% CI P ratio Mortality through 6 months of age Infant viral load above vs below median* 3.07 2.16 to 4.38 <0.001 Maternal CD4 count 200-350 vs >350 2.01 1.34 to 3.01 0.001 Maternal CD4 count <200 vs >350 1.70 1.11 to 2.62 0.015 Mortality through 12 months of age Infant viral load above vs below median* 2.16 2.03 to 4.38 <0.001 Maternal CD4 count 200-350 vs >350 1.69 1.07 to 2.67 0.025 Maternal CD4 count <200 vs >350 1.94 1.19 to 3.16 0.008

*Median 1.59 million copies/mL. Source: Andrew Prendergast, ZVITAMBO Project, Harare, Zimbabwe.21

Zimbabwe from 1997 through 2001.22 Viral suppression rates similar with The analysis involved 453 HIV-positive infants with continuous therapy and treatment a 6-week plasma sample available, including 151 interruption infected in utero and 302 infected intrapartum. Those Two years after a planned treatment interruption (PTI) two groups did not differ significantly in gender, trial in children ended, viral suppression rates were weight at birth or 6 weeks, hemoglobin at birth or 6 high and similar in children randomized to the PTI weeks, or rates of vaginal delivery (87.8% and 90.3%) arm and to the continuous therapy arm.27 Nadir CD4 or mixed breastfeeding (58.9% and 56.3%). Mothers percent above 20% was associated with better CD4 of children infected in utero had a significantly higher recovery after cART resumed in the PTI arm. CD4 count (median 405 versus 355 cells/mm3, P = 0.004) but also a higher viral load (mean 4.52 versus The PENTA 11 trial randomized 109 children to 4.38 log10 copies/mL, P = 0.055). continuous cART or CD4-guided PTI if they had (1) a viral load below 50 copies/mL and (2) a CD4 Mortality through 6 months was marginally lower in percent at or above 30% for 2- to 6-year-olds or a the intrapartum group than the intrauterine group (P CD4 percent at or above 25% and a CD4 count at or = 0.07) and in intrapartum girls versus intrauterine above 500 cells/mm3 if they were 7 to 15 years old.28 girls (P = 0.07). Median viral load at 6 weeks stood at After a median follow-up of 130 weeks, no child in 1,589,041 copies/mL (IQR 514,809 to 4,965,854) and either group had a CDC stage C event, though the did not differ significantly between the intrapartum PTI group endured more minor clinical events. group and the intrauterine group or between boys and girls. Multivariate analysis determined that a Alexandra Compagnucci (INSERM SC10, Paris) 6-week viral load above the median value tripled the presented long-term follow-up on 101 of the 109 risk of death through 6 months of age and doubled PENTA 11 participants, 79 from Europe and 22 from the risk of death through 12 months of age among Thailand. Fifty children were in the PTI arm and 51 those alive at 6 months (Table 1). Lower maternal CD4 in the continuous-therapy arm. All 101 children count also independently predicted infant mortality at completed 1 year of follow-up, 95 completed 2 6 and 12 months. years, and median follow-up stood at 4.6 years. At the end of PENTA 11, median ages were 11.3 in the The researchers concluded that viral load measured PTI group and 12.1 in the continuous group, median at a single point—at 6 weeks of age—independently CD4 percents 32% and 36%, and proportions with a predicts mortality in infants who have not begun viral load below 50 copies/mL 60% and 76%. antiretroviral therapy. They proposed that “rapid suppression of viremia may be important to reduce Up to the end of the main trial, children in the PTI mortality” in infants, a concept supported by results arm spent 45.2% of the time off cART, compared of the CHER trial.9 with 4.1% in the continuous-therapy arm. During overall follow-up after the end of the main trial, PTI participants spent 10.4% of the time off cART,

30 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

Table 2. CD4 and viral load outcomes 1 and 2 years after the end of the PENTA 11 treatment interruption trial

Mean or proportion Follow-up Continuous cART PTI Difference or P year risk ratio: PTI vs continuous CD4 percent +1 35.8 32.7 -3.5 0.014

+2 36.0 34.6 -1.6 0.27 CD4 count +1 925 808 -126 0.048 +2 864 832 -42 0.44 HIV RNA <50 +1 90% 77% 0.85 0.074 copies/mL +2 86% 82% 0.95 0.57

PTI: Planned treatment interruption. Source: Alexandra Compagnucci, INSERM SC10, Paris.27 compared with 1.3% of time in the control arm. In an One year after the main trial ended, CD4 percent and analysis excluding follow-up of children on a PTI at CD4 count were significantly lower in the PTI group the end of the main trial before they restarted cART, than in the continuous-cART group (Table 2). But 2 proportion of time spent off cART was 4.7% in the years after the main trial ended, those differences PTI group and 1.3% in the continuous-cART group. diminished and were no longer statistically significant. One year after the main trial ended, the proportion of At the end of long-term follow-up, no child had died children with a viral load below 50 copies/mL was and no new CDC stage C event developed. One child marginally lower in the PTI group (P = 0.074), but that had a new CDC stage B event, osteomyelitis, which difference was negligible 2 years after the main trial developed during the main trial in the PTI group. ended (Table 2, Figure 5). Weight- and height-for-age Z scores did not differ In an adjusted analysis of CD4 recovery based on significantly between study arms after 1 and 2 years measurements since children resumed cART after of long-term follow-up. their latest treatment interruption, estimated mean difference in CD4 percent between those with a nadir Two children in each study arm switched antiretrovirals at or above 20% versus below 20% was 3.7% (95% for treatment failure or toxicity after the end of the CI 0.7 to 6.7, P = 0.02). Mean total cholesterol in the main trial. Five children in the PTI group and none in 24 months after the end of the main trial did not differ the control group switched antiretrovirals for regimen between the PTI group and the control group. simplification.

Proportion HIV-1 RNA <50 copies/ml from end of main trial

100

CT 40 PTI

20 Proportion <50 c/ml (%) <50 c/ml (%) Proportion

0 0 6 12 18 24 Months from end of main trial

Figure 5. Two years after the end of the PENTA 11 treatment interruption trial,28 proportions of children with a viral load below 50 copies/mL were virtually identical in the planned treatment interruption (PTI) group and the continuous-therapy (CT) group. Source: Alexandra Compagnucci, INSERM SC10, Paris.27

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Table 3. Kaplan-Meier 1-year mortality risk according to CD4 percent, CD4 count, and age

Age of child

Under 24 months 24 to 35 months 36 months or older

CD4% <10 21.2% 4.4% 4.6% CD4% 10 to 14.9 7.4% 2.2% 1.9% CD4% 15 to 19.9 3.0% 1.3% 0.9% CD4% >20 2.2% 1.3% 0.5% CD4 count <100 35.1% (No events) 8.6% CD4 count 100 to 199 8.8% (No events) 2.9% CD4 count 200 to 349 10.2% 2.7% 1.6% CD4 count 350 to 499 10.0% 2.3% 0.9% CD4 count 500 to 749 8.5% 3.6% 0.4%

Source: Mary-Ann Davies, University of Cape Town, South Africa, for IeDEA-SA.29

Although antiretroviral treatment interruptions are to increase rapidly in distinct age groups.29 They considered unsafe for adults, viability of this strategy planned this study to determine 1-year mortality risk remains an important research topic in children, according to age and current CD4 percent and count who face decades of continuous treatment unless of children taking cART in southern Africa. interruptions prove feasible. PENTA investigators are pursuing neurocognitive and immunologic The analysis focused on 17,173 children under 16 substudies in trial participants. years old beginning a first-line regimen and having at least 180 days of follow-up in IeDEA-SA collaborating cohorts. The investigators considered every time at CD4 predictors of mortality as guides to which CD4 count or percent was measured after the switching antiretrovirals first 4.5 months (135 days) on cART as the start of an When viral load monitoring is not possible, a CD4 observation with time set at 0 and continuing until the percent below 10% may serve as an antiretroviral- first of (1) 365 days, or (2) date of death, or (3) date of switch signal for children 24 to 35 months old, transfer out, or (4) date of last visit if the child was lost according to results of a 17,000-child analysis in the to follow-up or remained in care at the time of data International Epidemiologic Databases to Evaluate transfer. Independent variables in Weibull models AIDS in Southern Africa (IeDEA-SA).29 A lower to predict probability of death were age category threshold might be considered for older children, (under 24 months, 24 to 35 months, 36 months or IeDEA-SA researchers suggested. older), CD4 percent and its square at the start of the observation, and CD4 count and its square at the Clinicians without access to routine viral load start of the observation. monitoring must rely on clinical and CD4 changes to decide when to switch an adult or child from one As one would expect, 1-year risk of death was higher regimen to another. But because immunologic failure at lower CD4 percents or counts and younger ages has a low positive predictive value for virologic failure, (Table 3). Davies cautioned that these estimates are reliance on CD4 changes may lead to unnecessary based on small numbers of children with low CD4 switching in a person without virologic failure. percents or counts in the two younger age groups. Mary-Ann Davies (University of Cape Town, South She added that censoring due to loss of follow-up Africa) and IeDEA-SA colleagues proposed that an may have resulted in an underestimate of mortality alternative approach for clinics without viral load risk. monitoring could be based on CD4 percent and CD4 count thresholds below which mortality begins In children 24 to 35 months old, the Weibull model

32 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

determined that mortality risk reached 5% at a CD4 state that “viral load determination is desirable, percent of 10%, and started to rise steeply as CD4 but not essential, prior to initiating ART” and that percent dropped further. In older children, mortality “viral load should be assessed to confirm clinical risk reached 5% at a CD4 percent of 5% and rose or immunological failure where possible, prior to more steeply below this value. A CD4 percent of switching a treatment regimen.”10 10% is the 2010 WHO threshold for switching cART in 24- to 59-month-old children.10 WHO guidelines Pediatrics Workshop attendees mulled the question call for switching 24- to 59-month-old children at a of routine HIV RNA monitoring during a debate by two CD4 count of 200 cells/mm3, which in IeDEA-SA leading international pediatric investigators—Louise children this age was associated with a mortality risk Kuhn (Columbia University, New York) arguing that of nearly 10%, rising steeply as CD4 count dropped monitoring should be routine for children in resource- further. In children older than 35 months mortality limited settings,30 and Diana Gibb (Medical Research risk was 5% at a CD4 count of 100 cells/mm3 and Council, UK) maintaining that it should not.31 rose steeply as CD4 dropped below this. This is the WHO guideline threshold for switching to second-line Kuhn launched her case for routine viral load testing cART in children 60 months old and older. by citing recent research indicating that annual monitoring could cut the cART failure rate 75% The IeDEA-SA investigators reached the following in Thai children,32 that routine testing using the conclusions for age-related risk of death based on WHO failure threshold of 5000 copies/mL “adds CD4 percent and count: independent predictive value to immunological and • The WHO guideline for switching to second-line clinical assessments for identification of children cART at a CD4 percent of 10% is associated with receiving HAART who are at risk for significant HIV- a 5% risk of dying in the next year for all children related illness,”33 and that regular monitoring may 24 months old and older. prevent emergence of NNRTI mutations in children • For children 36 months old and older, the risk of whose NNRTI regimen is failing.34 dying reaches 5% only at a CD4% of 5%. • For children 24 to 35 months old, 1-year morta- The argument favoring routine viral load monitoring, lity risk rapidly approaches 10% at a CD4 count Kuhn maintained, rests mainly on three pillars: of 200 cells/mm3 and rises steeply as the CD4 • Plasma HIV RNA is an excellent marker that di- count falls further. rectly tracks the underlying mechanism driving • For children 36 months old and older, a CD4 HIV disease. count of 100 cells/mm3 is associated with less • Viremia is an early marker allowing for prompt ac- than a 5% risk of death in the next year. tion. • Cost arguments favor routine monitoring over the These findings are relevant to the continuing long term. controversy over whether viral load monitoring should be routine for children in resource-poor settings, a Viral load assays are accurate and reproducible, question formally debated at the Pediatrics Workshop Kuhn noted, and they strongly predict negative (see next section). clinical outcomes in children taking cART. In a study of treated Brazilian children, a viral load above versus below 5000 copies/mL independently raised Should viral load monitoring be routine in the risk of a WHO stage 3 or 4 event by more than resource-poor settings? 80% (adjusted hazard ratio [AHR] 1.81, 95% CI 1.05 No clinician would dream of caring for HIV-positive to 3.11, P = 0.033).33 Every 0.5-log higher viral load children in high-income countries without regular boosted that risk almost 15% (AHR 1.14, 95% CI 1.03 viral load monitoring. US guidelines, for example, to 1.27, P = 0.016). When an antiretroviral regimen say “HIV RNA copy number should be assessed as fails, Kuhn added, rebounding viremia is an “early soon as possible after a child has a positive virologic warning signal,” spiking well before CD4 counts test for HIV and every 3 to 4 months thereafter; more wane or HIV-related symptoms emerge. frequent evaluation may be necessary for children experiencing virologic, immunologic, or clinical Although Gareth Tudor-Williams emphasized the deterioration or to confirm an abnormal value.”12 overall slow emergence of NRTI mutations upon failure of an NNRTI regimen in PENPACT 1 (see But in countries where viral load monitoring remains above),15,16 Kuhn cited additional data from this trial too high in cost and too hard to access, the question indicating that three or more NRTI mutations arose of routine testing remains unresolved for children significantly more often in children randomized to and adults. WHO guidelines for infants and children switch from an NNRTI regimen at 30,000 copies/

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Table 4. Accumulation of NRTI mutations with low versus high viral load switch in PENPACT 116

Switch from NNRTI regimen at:

1000 copies/mL 30,000 copies/mL P Number of children 68 64 1 to 2 major NRTI mutations 22% 20% 3 or more major NRTI mutations — 11% 0.001 1 to 2 TAMs 5% 8% 3 or more TAMs — 7% 0.08

TAMs, thymidine analog mutations.

mL rather than 1000 copies/mL (P = 0.001) (Table The usual answer to the first question, Gibb 4).16 There was also a trend toward more frequent observed, is to guide decisions on when to start emergence of three or more thymidine analog cART and when to switch cART. But a 2003 meta- mutations in the 30,000-copy-switch group (P = analysis of 4000 children not receiving cART or 0.08). zidovudine monotherapy determined that, although CD4 measures and viral load both independently Although the high initial cost of viral load testing predicted mortality in the short term, CD4 weighs against its use in resource-limited settings, readings were much stronger predictors of disease Kuhn argued that long-term costs favor routine progression and death.35 monitoring if it delays use of more expensive second- line regimens. The Thai study cited above estimated Although viral load is also an independent predictor a cost of $359 for preventing 1 year of virologic failure of disease progression before and during cART in through optimal viral load monitoring versus $3393 adults, Gibb observed, CD4 measures are a much for preventing 1 year of virologic failure and including better predictor of immediate risk of death, and antiretroviral costs.32 These investigators proposed several studies found that viral load adds little further that optimal monitoring timing in similar settings may prognostic information to CD4 count: be once in the first 6 months of cART then annually. The DART trial in Uganda and Zimbabwe enrolled Kuhn maintained that routine viral load testing 3321 symptomatic, antiretroviral-naive adults with may also have spinoff benefits, such as providing CD4 counts below 200 cells/mm3 and randomized opportunities for caregiver and child education them to laboratory and clinical monitoring or to and for adherence counseling. The question is not clinically driven monitoring alone.36 Gibb, one of the whether viral load monitoring should be routine, she DART investigators, noted that CD4 monitoring every concluded, but (1) how frequently testing should be 12 weeks had no impact on disease progression done, (2) what viral load thresholds should be used, during the first 2 years of cART, and after that it had (3) what response algorithms will work best, (4) how only a small impact on progression that appeared monitoring systems can be improved, (5) how testing to be driven by a later switch to clinical monitoring. can be made simpler and less expensive, and (6) Although DART did not assess viral load monitoring, how more and better pediatric treatment options can she explained, after 6 years of cART about 80% of be developed. DART patients had a viral load below 50 copies/mL Framing her rebuttal against routine viral load and about 75% were still taking their first regimen. monitoring in children seen in resource-constrained settings, Diana Gibb posed three questions:31 The unpublished HBAC trial randomized 1200 1. What impact does viral load monitoring have on Ugandan adults to (1) clinical monitoring, (2) clinical important outcomes? plus CD4 monitoring, or (3) clinical plus CD4 plus 2. How affordable and feasible is viral load monito- virologic monitoring. When compared with clinical ring in low-income settings? monitoring alone, CD4 and viral load monitoring had 3. What are the competing priorities? a marginally significant benefit in preventing AIDS or death. But there was no significant difference

34 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

between the CD4-and-viral load monitoring group there is a choice. Two workshop studies addressed and the CD4-and-clinical monitoring group. second-line questions: A six-country African study assessed durability of first-line regimens and reasons The PHPT-3 trial randomized 716 Thai adults to a for switching,45 while an Asian study analyzed conventional viral load-driven cART switch strategy efficacy of ritonavir-boosted PI regimens after failure or to a CD4-driven switch.37 Through 60 months of of a nonnucleoside combination.46 cART, time to clinical failure (CD4 count below 50 cells/mm3, new AIDS event, or death) was almost IeDEA-West African investigators reported that only identical in the two study arms, and 38% of events small proportions of children who met clinical or occurred within the first 6 months of treatment. immunologic failure criteria in this region switched to In the recently completed PENPACT 1, Gibb reminded a second-line regimen. These researchers collected attendees, viral suppression rates in children taking data from nine clinical centers in six countries— cART for 4 or more years did not differ between Benin, Burkina Faso, Côte d’Ivoire, Ghana, Mali, those who switched when the viral load increased to and Senegal.45 They included children under 16 1000-copies/mL versus those who waited until the years old starting three or more antiretrovirals from viral load rose to 30,000-copies/mL (around a year 2000 through 2009 and with at least one available later on average), regardless of whether they were measurement of CD4 count, CD4 percent, or WHO taking a PI or an NNRTI.16 clinical stage during the first-line regimen. Routine viral load monitoring is not available throughout most Although several groups have described adult African of West Africa. data showing that those switching treatment based on clinical symptoms may have an undetectable The researchers defined clinical failure as appearance viral load (and are thus deemed to have switched or reappearance of a WHO clinical stage 3 or 4 “unnecessarily”), a recent analysis of data from the event after at least 24 weeks of cART in a treatment- DART study showed this was rare if the CD4 was adherent child. They defined immunologic failure as below 250 cells/mm3.38 Therefore, Gibb argued, reaching or returning to a CD4 percent below 10% use of a 250-CD4 threshold could prevent many for 2- to 5-year-old adherent children or reaching or “unnecessary” switches to second-line treatment. returning to a CD4 count below 100 cells/mm3 for (Gibb did not mention the 17,000-child IeDEA-SA adherent children 5 or over after the first 24 weeks cohort study summarized in the preceding section of therapy. A regimen switch meant (1) changing of this article, which found that a CD4 percent below from three NRTIs to two NRTIs plus a one PI or one 10% may be a useful antiretroviral-switch signal for NNRTI, or (2) changing from two NRTIs plus one PI to children 24 to 35 months old.29) three NRTIs or to two NRTIs plus one NNRTI, or (3) changing from the PI class or the NNRTI class. To address the question of cost, Gibb cited four model-based cost-effectiveness studies of viral In 2797 children the overall 24-month probability of load monitoring, which calculated costs per life- switching to a second-line regimen was 23.3% (95% year gained ranging from $2526 to $15,25039-42— all CI 21.5 to 25.4). In the 2450 children (88%) without estimates above the 3-fold gross domestic product study-defined clinical or immunologic failure, the cutoff used to determine cost-effectiveness of 24-month probability of switching was 25.3% (95% interventions in resource-limited countries.43,44 CI 23.2 to 27.7). The 227 children (8%) with clinical failure had a 24-month switching probability of only Gibb concluded that “routine viral load monitoring is 2.1% (95% CI 0.8 to 5.5). And the 120 children with not necessary and should not be routine for children immunologic failure (4%) had a 24-month switching in resource-limited settings” because: (1) its impact probability of 26.4% (95% CI 18.8 to 36.4). on disease-free survival is very modest, (2) it is not cost-effective, and (3) “its routine use will be a barrier Median time to switch in all 456 children (16%) who to the goal of maximising ART coverage and actually changed to a second-line regimen was 7 months lead to lives lost.” (IQR 3 to 16). A large majority of these children—425 or 93.2%—switched without meeting clinical or Evidence from two studies on second-line immunologic failure criteria. Withdrawal of nelfinavir in switching 2007 accounted for most of this nonfailure switching. Although HIV Pediatric Workshop attendees weighed Among switchers, 285 children (62.5%) switched data from four studies on first-line cART options from a first-line nelfinavir regimen. for children in countries rich and poor,13-19 for a growing number of children everywhere the question The low switch rates in children who did meet clinical has become which second-line regimen to chose—if or immunologic failure criteria, the investigators

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suggested, indicates “missed opportunities for Two variables independently predicted immune switching to second-line therapy,” perhaps because recovery, defined as a CD4 percent at or above 25% key second-line agents such as lopinavir/ritonavir in children younger than 5 years or a CD4 count at or were not available. The IeDEA-West Africa team above 500 cells/mm3 in older children: stressed the importance of advocating for access to • Younger age: OR 0.8 per additional year (95%CI monitoring tools and to second-line antiretrovirals for 0.7 to 0.9), P < 0.001 pediatric HIV programs. • CD4 count at or above 200 cells/mm3 at the switch: OR 7.7 (95% CI 2.8 to 21.5), P = 0.003 Researchers from the TREAT Asia Pediatric HIV Observational Database (TApHOD) retrospectively The TApHOD researchers concluded that one third studied 153 children who switched from a first-line of children in this Asian cohort do not reach an NNRTI-based regimen (taken for at least 24 weeks) undetectable viral load 2 years after switching from to a PI-based regimen (taken for at least 24 weeks) an NNRTI regimen to second-line lopinavir/ritonavir- up to 20 March 2010.46 All children were younger based cART that includes recycled NRTIs. They than 18 years old at the switch and had not taken a observed that hyperlipidemia was common after PI before the switch. such a switch. The study group included 80 girls (52%) and 73 boys with a median age of 10 years (IQR 7 to 12), a median CD4 percent of 12.5% (IQR 5.2 to 20.0), a median PMTCT: Emerging Issues, Persisting CD4 count of 237 cells/mm3 (IQR 90 to 466), and Controversies a median viral load of 4.6 log10 copies/mL (IQR 3.9 to 5.0). Proportions of children with WHO stage 1, South African PMTCT program cuts early 2, 3, and 4 disease were 7%, 25%, 42%, and 26%. transmission rate below 4% Median first-line duration was 2.6 years (IQR 1.5 to Nine years after South Africa launched a program for 3.8). Most children (83%) switched to a lopinavir/ prevention of mother-to-child transmission (PMTCT) ritonavir regimen, while 16% switched to an indinavir/ of HIV, the transmission rate fell below 4% in the first ritonavir regimen and 1% to atazanavir/ritonavir. 4 to 8 weeks of life, according to preliminary results of a nationwide population-based analysis.47 Median weight-for-age Z score did not change significantly from the switch point (week 0) (-1.9) to South Africa began its PMTCT program in 2002 with week 48 (-1.9) or week 96 (-1.7). In contrast, median single-dose nevirapine and later added zidovudine or CD4 percent rose from 13.8% at week 0 to 20.3% combination antiretrovirals for mothers (depending at week 48 and 22.8% at week 96 (P < 0.001). on maternal CD4 count) and extended zidovudine or Proportions of children with viral loads below 400 nevirapine for infants. Estimated national mother-to- and 50 copies/mL were 0% and 0% at week 0, 60% child transmission rates in infants up to 2 months old and 49% at week 48, and 65% and 62% at week stood at 8.2% in 2008 and 5.8% in 2009. 96 (P < 0.001 for both comparisons). Median total cholesterol rose significantly from 167 mg/dL at Ameena Goga (Medical Research Council, South week 0 to 187 mg/dL at week 96 (P = 0.002), while Africa) presented results of the new study, which median triglycerides climbed from 120 mg/dL at involved caregiver-infant pairs making the 6-week week 0 to 160 mg/dL at week 96 (P = 0.006). Median infant immunization visit from June through high-density lipoprotein cholesterol did not change December 2010. The investigators (Goga, Thu-Ha significantly over the study period. Dinh and Debra Jackson) identified HIV-exposed infants through caregiver report of maternal HIV Multivariate analysis identified four independent positivity or through ELISA analysis of dried blood predictors of virologic suppression below 400 spots. They tested samples of HIV-exposed infants copies/mL at 48 weeks: with qualitative HIV DNA PCR to identify infected • Longer duration of first-line NNRTI regimen: OR infants. 1.8 per additional year (95% CI 1.2 to 2.9), P = 0.006 The researchers determined that 3003 infants in 9915 • Younger age: OR 0.8 per additional year (95% CI caregiver-infant pairs (30.3%) had been exposed to 0.7 to 0.9), P = 0.007 HIV, and 2958 of these 3003 infants (98.5%) had PCR • Higher weight-for-age Z score: OR 1.7 per test results. Most mothers of HIV-exposed children standard deviation (95% CI 1.1 to 2.7)), P = 0.020 (79.8%) were not married or cohabitating. In the 8 • HIV RNA below 10,000 copies/mL at switch: OR days before the study visit, 20% of women practiced 12.6 (95% CI 1.9 to 81.8), P = 0.049 exclusive breastfeeding, 18% mixed breastfeeding, and 62% no breastfeeding. Almost two thirds of

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Table 5. Factors associated with mother-to-child transmission at 6 weeks in South Africa

Adjusted odds ratio 95% CI

Compared with maternal cART

Either maternal ARV or infant ARV prophylaxis 5.2 2.7 to 10.0

<10 weeks of maternal zidovudine plus infant ARV 2.4 1.2 to 5.1 prophylaxis 11 to 30 weeks of maternal zidovudine plus infant ARV 1.7 0.9 to 3.5 prophylaxis Compared with exclusive breastfeeding or no breast milk

Mixed breastfeeding 1.6 1.0 to 2.5

ARV, antiretroviral; cART, combination antiretroviral therapy. Source: Ameena Goga, Medical Research Council, South Africa.47 mothers of HIV-exposed children (62%) said the that the national South African MTCT rate 4 to pregnancy was unplanned. 8 weeks after delivery stands at approximately 3.5%. They suggested that rate may be lowered by Infant HIV prevalence at 4 to 8 weeks (weighted for optimizing antiretroviral use during pregnancy and sample realization and population live births in 2009) perinatally and by reducing mixed feeding. ranged from 0.6% (95% CI 0.3 to 0.9) in Gauteng province to 2.1% (95% CI 1.5 to 2.7) in Mpumalanga province. National infant HIV prevalence stood at High HIV incidence during pregnancy and 1.1% (95% CI 0.1 to 1.3). Weighted MTCT rate at 4 breastfeeding in Botswana to 8 weeks ranged from 1.7% (95% CI 0.1 to 4.2) in Batswana women who have a negative HIV test during Northern Cape province to 6% (95% CI 3.8-8.2) in pregnancy remain at high risk for HIV infection later Free State province. The national weighted MTCT in pregnancy and during breastfeeding, according to rate was 3.5% (95% CI 2.9 to 4.1). results of a 417-woman study.48 Centers for Disease Control and Prevention (CDC) investigators warned Compared with maternal cART, use of either maternal that undiagnosed incident HIV infection in pregnant or infant antiretroviral prophylaxis raised the risk of or nursing mothers could result in unanticipated MTCT more than 5 times, and 10 or fewer weeks transmission of the virus to infants. of maternal zidovudine plus infant antiretroviral prophylaxis more than doubled the risk (Table 5). HIV testing early in pregnancy is “a critical first Compared with maternal cART, there was a borderline step” to reducing HIV transmission, Lydia Lu and association between 11 to 30 weeks of maternal CDC colleagues noted. But an early negative test zidovudine plus infant antiretrovirals and higher is no guarantee that women will remain free of HIV MTCT risk. Compared with exclusive breastfeeding throughout pregnancy and nursing. In Botswana or no breastfeeding, mixed breastfeeding increased more than 95% of pregnant women get tested for HIV the MTCT risk 60%. Variables that did not affect at a median 22 weeks gestation, and HIV prevalence transmission risk in this analysis were caesarean stood at 32.5% among 43,000 women tested at section, planned versus unplanned pregnancy, or antenatal clinics in 2009. Early infant testing indicates physician versus nonphysician birth attendant. that 4.2% of HIV-exposed infants in Botswana test positive on their first test. Goga and colleagues cautioned that their analysis is limited by its reliance on primary or community In 2008 CDC-Botswana investigators retested health centers, by exclusion of sick infants needing 400 women in a postlabor ward after they had emergency care and infants older than 8 weeks, by a tested negative during pregnancy. HIV incidence sample realization below 75% in three provinces, and in these women was 1.3%. As a result the CDC by potential recall bias. recommended routine HIV retesting during the third trimester or in the maternity ward for women missed Given those limitations, the investigators concluded in the third trimester. These researchers planned a

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follow-up study for 2010 to determine HIV prevalence an incident HIV infection in late pregnancy became in women during the first postpartum year after they infected, and 36% of infants exposed to an incident tested negative during pregnancy. HIV infection during breastfeeding became infected. If 73% of the 377 women infected during pregnancy The 2010 study involved 417 women with a in the Botswana study transmitted HIV, 275 infants documented negative HIV test during pregnancy who would be infected. If 36% of the 1103 women brought a 9- to 15-month-old child to an immunization infected during breastfeeding in the Botswana study clinic. Women were tested and counseled according transmitted HIV, 397 infants would be infected. to the standard Botswana algorithm, and they Early infant testing indicates that the transmission were interviewed about risk behaviors and feeding rate to HIV-exposed infants in Botswana (where practices. PMTCT is mature and has high uptake) is only 4.2%, or about 587 infants annually. Thus the estimated Eighteen of these 417 women (4.3%) had a positive total number of infected infants is 1259, with 672 of HIV test, and the investigators estimated 52-week those 1259 (275 + 397, or 53.4%) infected through incidence at 3.8%. Because 43,000 women become an undiagnosed maternal HIV infection acquired later pregnant in Botswana every year and 32.5% tested in pregnancy or while nursing, and in the absence of positive in antenatal clinics in 2009, the CDC team PMTCT interventions. figured that the remaining 67.5%, or 29,025 women, are assumed to be HIV negative (Figure 6). Based on The 18 HIV-exposed infants of mothers with a new the 2008 incidence study findings, the researchers HIV diagnosis in this study had a median age of 10 estimated that 377 of these 29,025 women (1.3%) months when the infants were tested for HIV. All 18 become infected during late pregnancy. The 2010 infants had some exposure to breast milk, and 5 were study estimated 1103 (3.8%) become infected during still breastfeeding at recruitment for the study. Three breastfeeding. of 18 infants (17%) had a positive HIV test; because the 5 HIV-exposed infants who were breastfeeding Next the CDC team estimated the impact of maternal at the time of recruitment did not return for testing, HIV incidence on new infections in infants during their final HIV status was not determined. In the entire 2010. To do so the investigators relied on a 2005 study cohort, 259 infants (62%) were breastfeeding study of Zimbabwean women who became infected at the time of recruitment. Overall median age at with HIV during pregnancy or while breastfeeding.49 weaning was 7 months. That study found that 73% of infants exposed to

Estimated infections in pregnant and post-partum women, Botswana 2010

43000 pregnant women

Women diagnosed Women assumed before during ANC to be HIV-negative 13975 (32.5%)* 29025 (67.5%)

Women infected Women infected * 2009 ANC during late pregnancy while breastfeeding Sentinel Surveillance 377 (1.3%) 1103 (3.8%)

Figure 6. Based on 2008 and 2010 studies of 417 Batswana women who tested negative for HIV during pregnancy and were retested at the time of delivery (2008) or in the year after delivery (2010), CDC researchers estimated that 1.3% of pregnant women became infected with HIV during late pregnancy and 3.8% became infected while breastfeeding in 2010. Source: Lydia Lu, Centers for Disease Control and Prevention.48

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Predicted IP transmission rate: With vs. Without sdNVP

0.05 standard treatment standard treatment + sdNVP 0.04

0.03

0.02

0.01 3 to 4 –fold reduction Intrapartum perinatal transmission rate 0 0 10 20 30 40 50 60 Duration of maternal ZDV treatment (days)

Figure 7. Bayesian modeling determined that adding single-dose nevirapine (sdNVP) to maternal lopinavir/ ritonavir-based cART would lower intrapartum HIV transmission risk 3- to 4-fold. Source: Marc Lallemant, Chiang Mai University, Chang Mai, Thailand.50

Lu and coworkers concluded that Batswana women CI 1.3 to 2.4), while each log10 higher viral load more assumed to be HIV-negative during pregnancy and than doubled the transmission risk (AOR 2.3, 95% CI the first year after delivery will breastfeed, although 1.1 to 4.8). some of them may have acquired HIV infection after their initial negative test. The investigators proposed In planning the Bayesian analysis, Lallemant and that infants may remain at significant risk for HIV coworkers hypothesized that pregnant women infection in Botswana even when mothers have a with fewer than 8 weeks of prophylaxis did not negative HIV test during pregnancy. have enough time to suppress viral replication and that adding maternal and infant sdNVP to maternal lopinavir-based cART would significantly reduce the Modeling suggests advantage in adding risk of intrapartum transmission. Using transmission sdNVP to maternal cART data from 3876 women enrolled in PHPT-1, 2, and A Bayesian inference model determined that adding 5, the model assumed (1) that maternal prophylaxis single-dose nevirapine (sdNVP) to lopinavir/ritonavir- duration directly affects viral load at delivery, and based cART for pregnant women with fewer than (2) that viral load at delivery directly affects risk of 8 weeks of antiretroviral prophylaxis would lower intrapartum transmission. Monte Carlo simulations the risk of perinatal HIV transmission 3- to 4-fold.50 predicted transmission rates with and without Marc Lallemant (Chiang Mai University, Chang Mai, sdNVP in relation to duration of maternal and infant Thailand) and colleagues based the model on data prophylaxis. from three PMTCT trials in Thailand. The model estimated an HIV transmission rate of PHPT-5, a 2008-2010 randomized trial of three 2.6% (95% probability interval [PI] 0.5% to 9.2%) for PMTCT strategies (clinicaltrials.gov NCT00409591),51 the standard of care (lopinavir/ritonavir-based cART stopped prematurely when Thailand revised its during pregnancy and zidovudine for the newborn). PMTCT guidelines to recommend lopinavir-based Adding sdNVP to the standard of care lowered the cART for all HIV-positive pregnant women as soon as estimate to 0.8% (95% PI 0.1% to 2.9%). Maternal possible after the first trimester. When trial data were sdNVP would decrease the risk of intrapartum analyzed, the overall transmission rate was 2.2%, with transmission approximately 60% (AOR 0.39, 95% CI no difference between treatment arms. Multivariate 0.21 to 0.67). Lallemant and colleagues calculated a analysis determined that shorter zidovudine 3- to 4-fold lower intrapartum transmission risk with prophylaxis duration almost doubled the risk of HIV addition of sdNVP (Figure 7). transmission (AOR 1.8 per weekly decrement, 95%

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Higher CD4 count during pregnancy (average + and infants with any evidence of breastfeeding. 1 standard deviation [SD] versus average) would lower intrapartum transmission risk more than 35% Most mothers of the 1000 selected infants were of (AOR 0.63, 95% CI 0.49 to 0.80). Gestational age black (48.6%) or mixed black/white race (28.6%), at delivery (average +/- 1 SD versus average) would were relatively young (median age 26), had relatively increase transmission risk (AOR 1.34, 95% CI 1.07 high CD4 counts (median 466 cells/mm3), and had to 1.64). detectable virus at delivery (median viral load 13,580 copies/mL). The study group included 766 infants Trial simulation determined that an ethical and from Brazil and 234 from South Africa. Their median scientifically sound single-arm trial with comparison birth weight was 3012.5 g (6.6 pounds). to historical data and with optimal stopping rules could be designed with fewer than 400 women to The overall rate of infectious serious (grade 3 to test the hypothesis that adding maternal and infant 5) adverse events was 60 per 100 infant-years, sdNVP to the standard of care lowers the risk of HIV and rates were similar in Brazil (61 per 100 infant- transmission. years) and South Africa (59 per 100 infant-years). Gastrointestinal serious adverse events were more frequent in South Africa (24.2 versus 4.7 per 100 Impact of formula feeding on HIV-exposed infant-years), while congenital serious adverse events infants in Brazil and South Africa (usually congenital syphilis) were more frequent in HIV-exposed but uninfected formula-fed South Brazil (21.8 versus 3.6 per 100 infant years). Almost African infants had a higher risk of death if born to one quarter of infants (23%) had at least one infectious mothers with a high viral load or if they had a low birth serious adverse event. weight, according to results of a 1000-infant study in South Africa and Brazil.52 Karin Nielsen-Saines Mean weight-for-age Z score (WAZ) at birth was (University of California, Los Angeles ) and HPTN lower in South Africa than Brazil (-0.95 versus -0.49), 040 colleagues reported that high maternal viral load while mean height-for-age Z score (HAZ) at birth was and lower maternal education were associated with similar in South Africa (-0.40) and Brazil (-0.54) (Figure infectious significant adverse events in the overall 8). Defining malnutrition as a WAZ at or below -2, the study group. investigators determined that 11% of South African infants and 6% of Brazilian infants had malnutrition The analysis involved formula-fed infants enrolled at 6 months. WAZ and HAZ declined in both the in NICHD HPTN 040, a phase 3 trial conducted South African and Brazilian cohorts from birth to the between April 2004 and January 2011 at 17 sites month-1 visit, then rebounded to near-normal values in Brazil, South Africa, Argentina, and the United through month 6 (Figure 8). States.53 This randomized open-label trial compared At 6 months 15 of 234 South African infants (6.4%) the safety and efficacy of three infant antiretroviral had died, compared with 7 of 766 Brazilian infants regimens to prevent vertical HIV transmission. Overall (0.9%). Six-month mortality incidence was 64.1 per HIV transmission and intrapartum transmission 1000 infant-years in South Africa and 9.1 per 1000 were lower in the two- and three-drug arms (single- infant-years in Brazil. In comparison, 12-month dose zidovudine for 6 weeks plus three doses of overall infant mortality incidence stood at 56 per nevirapine, and single-dose zidovudine for 6 weeks 1000 infant-years in South Africa and 19 per 1000 plus nelfinavir and lamivudine for the first 2 weeks) infant-years in Brazil according to 2006 WHO data. than in the one-drug arm (single-dose zidovudine for 6 weeks). Multivariate analysis identified four factors that independently affected the risk of infant mortality Primary aims of the new analysis were to assess the and three that independently affected the risk of frequency of and risk factors for severe morbidity infectious serious adverse events in infants: and mortality in a representative subcohort of 1000 HIV-exposed but uninfected formula-fed infants from Risk of infant mortality: Brazilian and South African HPTN 040 sites.52 The • South African versus Brazilian birth: AOR 6.22, study included live HIV-exposed infants who were 95% CI 2.46 to 15.75, P < 0.0001 HIV-negative at their 3-month visit and completed 6 • Higher maternal viral load at delivery: AOR 1.71, months of follow-up. The study pool included HIV- 95% CI 1.01 to 2.91, P = 0.0476 exposed infants who died before the 6-month visit • WAZ at birth < -2 to > -3: AOR 5.16, 95% CI 1.80 and were not determined to be HIV-positive until the to 14.77, P = 0.0022 time of death. The analysis excluded HIV-positive • WAZ at birth < -3: AOR 6.18, 95% CI 1.80 to infants, infants with fewer than 6 months of follow-up, 21.31, P = 0.0039

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Weight-for-Age and Heigt-for-Age Z-scores by study visit n=1000 Infants - 0.05 -0.09 Brazil WAZ - 0.15

- 0.25

- 0.35 -0.34 Brazil HAZ -0.40 - 0.45 -0.49 -0.53 South Africa WAZ - 0.55 -0.54 -0.56

- 0.65 -0.67 -0.67 South Africa HAZ - 0.75 -0.86 -0.79

Mean Z- score - 0.85 -0.85 - 0.95 -0.95 -0.95

- 1.05 -1.06 - 1.15 -1.13

- 1.25 Birth Month 1 Month 3 Month 6 Study Visit

Figure 8. Figure 8. Mean weight-for-age Z score (WAZ) was lower at birth in HIV-exposed but uninfected South African neonates than in Brazilian neonates in a 1000-infant analysis of HPTN 040. Mean height-for-age Z score (HAZ) was similar in the two groups at birth. Both scores declined in both cohorts through 1 month of age, then rebounded. South African WAZ remained substantially lower than Brazilian WAZ at 6 months (-0.53 versus -0.09). Source: Karin Nielsen-Saines, University of California, Los Angeles.52

Risk of infant infectious serious adverse event: Hospital has offered routine postpartum testing • Maternal education of 8 years (versus more): AOR since 2008. But follow-up rates are poor, especially 3.47, 95% CI 1.49 to 8.09, P = 0.0040 in newly diagnosed women, and loss to follow-up at • Maternal education < 8 years (versus more): AOR this time breaks the cascade of care, prevention, and 3.65, 95% CI 1.71 to 7.80, P = 0.0009 monitoring. • Maternal viral load at delivery > 1,000,000 copies/ mL: AOR 9.92, 95% CI 1.56 to 63.08, P = 0.0151 In an attempt to improve retention in care, Karl- Nielsen-Saines and coworkers concluded that Günter Technau (University of the Witwatersrand, mortality of HIV-exposed but uninfected formula-fed Johannesburg) and colleagues planned this study infants was lower than the general-population rate in of mobile text messaging to postpartum HIV-positive Brazil but slightly higher than the general-population women. The study called for 10 weeks of texted rate in South Africa. South African mortality rates for encouragement and reminders for infant PMTCT this group were similar to those of HIV-exposed but medication and appointments. There were three uninfected infants in Zimbabwe.54 study groups: women who agreed to text messaging randomized 1:1 to receive messages (group A1, n = 160) or not to receive messages (group A2, n = 177), Text messaging improves infant follow-up and a third group of women who declined texting in Johannesburg (group B, n = 81) Mobile (cell) phone text messaging to HIV-positive mothers attending a Johannesburg clinic significantly Proportions of women whose infants kept an HIV improved infant HIV testing follow-up, according to DNA PCR test visit were 90.5% in group A1, 78.2% preliminary results of a randomized study.55 The in group A2, and 63.0% in group B (group A1 versus finding held true for women diagnosed with HIV only group B, P = 0.003; group A2 versus group B, P = at delivery and whose infants thus had a higher risk 0.04). When the investigators considered only the of HIV infection and mortality. 51 women diagnosed with HIV at delivery, PCR test Rahima Moosa Mother and Child Hospital in follow-up rates were 86.7% for group A1, 41.7% for Johannesburg, South Africa performs approximately group A2, and 40.9% for group B. 10,000 deliveries annually, about 25% to 30% of them in HIV-positive women. Because testing For the whole study group, return rates to collect women for HIV at delivery can be difficult, the PCR results were 67.3% in group A1, 61.9% in group

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Table 6. Impact of cART on vertical HIV transmission at 6 months in Africa

Trial: countries Antiretroviral regimen CD4 count Transmission rate

Mma Bana: Botswana57 Abacavir, zidovudine/lamivudine or >200 cells/mm3 2.1%

Lopinavir/ritonavir, zidovudine/ >200 cells/mm3 0.4% lamivudine Kesho Bora: Burkina Lopinavir/ritonavir, zidovudine/ 200 to 500 cells/ 4.9% Faso, Kenya, South lamivudine mm3 Africa58 KiBS: Kenya63 Zidovudine/lamivudine plus 350 to 500 cells/ 3.8% nevirapine or nelfinavir mm3 >500 cells/mm3 3.3%

Source: François Dabis, Université Bordeaux Segalen, France.61

A2, and 23.5% in group B. For newly diagnosed recommended cART (from 14 weeks’ gestation to 1 women, return rates with 67.7% for group A1, 33.3% week after breastfeeding stops) as PMTCT option B for group A2, and 4.5% for group B (P = 0.04 for for women judged not to need cART for their own group A1 versus group A2). health.59 The alternative PMTCT regimen proposed by WHO, the so-called option A, is antepartum At the time of the Pediatrics Workshop presentation, maternal zidovudine, single-dose nevirapine at labor, PCR results were available for 309 infants, 18 of and in certain cases zidovudine plus lamivudine whom (6%) were HIV-positive. Among 26 women during labor and delivery and postpartum, plus with HIV diagnosed at delivery, 4 (15%) had infants infant antiretroviral prophylaxis, which varies with a positive PCR test. Among 349 infants with vital depending on feeding status. In the United States, status data, 8 (2.3%) died before 6 weeks of age. where breastfeeding by HIV-positive mothers is not Among 32 women diagnosed with HIV at delivery, 2 recommended, Department of Health and Human (6.3%) had infants who died before 6 weeks. Services guidelines call for at least three antiretrovirals for pregnant women who do not require treatment for Technau and colleagues concluded that cell text their own health, regardless of HIV RNA in plasma.60 messaging improves follow-up for infant HIV DNA PCR testing and offers additional support for women Pediatrics Workshop organizers invited two PMTCT newly diagnosed with HIV at delivery. (“Sitting alone experts to debate the proposition that all HIV-positive in the room,” one woman told a staff member, “I felt pregnant women would take cART, with François like I had a friend” when the text message came.) Dabis (Université Bordeaux Segalen, France) making The investigators noted that texting is an inexpensive the case in favor of triple therapy61 and Jeffrey Stringer intervention, costing about $1.20 per woman for 10 (University of Alabama at Birmingham, United States, weeks of messaging. They cautioned that this is not and CIDRZ, Zambia) taking the opposite stance.62 a “blanket intervention” but requires careful individual counseling to achieve good results. The researchers Dabis advanced three arguments for cART as also noted that women may change cell phones or PMTCT: lose access to them, so a central log-in facility may be needed for optimal results. 1. Maternal universal cART prevents almost all pediatric HIV infections. Should all HIV-positive pregnant women 2. Maternal universal cART saves children’s lives. receive cART? 3. Maternal universal cART saves mothers’ lives. Cohort studies47,56 and two randomized trials57,58 found advantages for mothers and neonates To support his first point, Dabis cited three studies, when the mother began combination antiretroviral starting with the Mma Bana trial in Botswana, which therapy (cART) to prevent vertical HIV transmission found 6-month transmission rates of 0.4% with (reference47 is reviewed above). Since 2010 WHO has lopinavir/ritonavir plus zidovudine/lamivudine and

42 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

2.1% with abacavir plus zidovudine/lamivudine taken Dabis reported that 15 African countries have picked by breastfeeding mothers (Table 6).57 The Kesho WHO option A for PMTCT (maternal zidovudine plus Bora trial in Burkina Faso, Kenya, and South Africa infant antiretroviral prophylaxis), while 20 prefer option recorded a 4.9% transmission rate at 6 months B (triple therapy from 14 weeks’ gestation to 1 week in infants of women taking lopinavir/ritonavir plus after breastfeeding stops). Four countries consider zidovudine/lamivudine.58 The single-arm KiBS study either option, while Malawi now recommends cART in Kenya recorded 6-month transmission rates of (efavirenz plus tenofovir/emtricitabine) for life in 3.3% among women with a CD4 count above 500 pregnant women regardless of CD4 count—option cells/mm3 and 3.8% for those with counts between B+. Dabis maintained that Malawi’s stance is no 350 and 500 cells/mm3 while taking zidovudine/ longer a theoretical option, because it is simple to lamivudine plus nevirapine or nelfinavir.63 implement, minimizes vertical HIV transmission, protects the next pregnancy, improves maternal The infant life-saving potential of cART became clear health and survival, reduces sexual transmission of even earlier, Dabis maintained, in a 2004 pooled HIV, reduces the risk of tuberculosis,11 and treats analysis of infants born to HIV-positive African hepatitis B coinfection. He noted, though, that this mothers in the absence of any maternal antiretroviral approach requires careful monitoring of acceptability, therapy.5 This 3468 mother-child pair study found feasibility, outcomes, and safety. that 35.2% of the 693 HIV-infected children born to these mothers died before 1 year of age and 52.7% Stringer began his argument by asking if there is died by age 2. Maternal death was the strongest any reason to prefer cART for women who do not predictor of overall infant death (combining HIV- meet WHO criteria for triple therapy and have a CD4 infected and uninfected children), more than doubling count above 350 cells/mm3. To begin addressing the risk for a child whose mother died compared with this question, he cited the BAN trial in Malawi, those whose mothers survived (AOR 2.27, 95% CI which randomized 2369 HIV-positive, breastfeeding 1.62 to 3.19). Maternal CD4 cell count below 200 mothers with a CD4 count of 250 cells/mm3 or cells/mm3 almost doubled the risk of overall infant higher and their infants to (1) a maternal antiretroviral death compared with infants of mothers with no regimen, (2) infant nevirapine, or (3) no extended immunodeficiency (AOR 1.91, 95% CI 1.39 to 2.62). postnatal antiretroviral regimen (the control group).66 Among the 693 HIV-infected children born to these Median maternal CD4 counts stood at 429 cells/ HIV-positive mothers, maternal death also almost mm3 in the cART arm and 440 cells/mm3 in the doubled the risk of infant death (AOR 1.84, 95% infant-nevirapine arm. At week 28 HIV transmission CI 1.21 to 2.82), as did maternal CD4 count below rates were significantly lower in the cART arm (2.9%, 200 cells/mm3 (AOR 1.86, 95% CI 1.27 to 2.75). In P = 0.009 versus control) and the infant-nevirapine other words, maternal cART, if available, would have arm (1.7%, P < 0.001 versus control) than in the dramatically changed the mortality pattern of all control group (7.0%). But the transmission rate did children born to HIV-positive mothers. not differ significantly between the two intervention arms (P = 0.10). To make the point that cART promotes survival of Does cART for pregnant women offer maternal HIV-positive mothers, Dabis cited results of a study advantages over WHO option A? Starting cART at showing that HIV-positive mothers in Zimbabwe had a CD4 count above 200 cells/mm3 clearly offers a a 54 times higher risk of death than HIV-negative survival advantage in low-income countries, Stringer women in the 24 months after delivery if their CD4 noted, citing a Haitian trial that randomized 816 count lay below 200 cells/mm3.64 In contrast, adults with a CD4 count between 200 and 350 cells/ compared with the HIV-negative group, HIV-positive mm3 to begin cART within 2 weeks of enrollment women with 400 to 600 cells/mm3 had a 5.4 times or to wait until their count fell below 200 cells/ higher risk of death in the 24 months after delivery, mm3.67 Through 36 months of follow-up, early cART much lower than the risk in women with a CD4 significantly improved survival probability by Kaplan- count below 200 cells/mm3 but still very high. Dabis Meier analysis (P = 0.001). also invoked results of the recent HPTN 052 trial to But starting cART sooner also poses some risks, make the points that cART started at a CD4 count Stringer cautioned, as found in a (yet-unpublished) between 350 and 550 cells/mm3, rather than below study of 39,764 women starting cART in Lusaka, 250 cells/mm3, independently lowers the risk of HIV Zambia. Through 6 years of follow-up, rates of four transmission to cohabitating partners65 and also “bad events” rose gradually but steadily: missing reduces the risk of tuberculosis and overall severe five pharmacy visits, needing single-antiretroviral morbidity and mortality (combined) in the treated substitution, changing to second-line cART, and person.11 becoming lost to follow-up. The Kaplan-Meier estimate of at least one “bad event” rose to about

Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 43 Report

Results: HIV prevalence among those tested

0,4

0,35

0,3

0,25

0,2 Female 0,15 Male HIV prevalence HIV prevalence

0,1

0,05

0 12 13 14 15 16 17 18 19 20 21 22 23 24 Age (years)

Figure 9. HIV prevalence in adolescents and young adults tested in a Durban outpatient clinic was higher in females starting around age 17. Although prevalence rose in both young women and young men in their early 20s, the rate was significantly higher among young women than men from 18 to 24 years of age (P < 0.01). The arrow indicates the average age of sexual debut in South Africa. Source: Lynn Ramirez-Avila, Children’s Hospital Boston.68

50% after 2 years of follow-up and to about 80% high in the tested group—14% in young men and after 6 years. 22% in young women.

The antepartum testing and postpartum prescribing South Africa has about 15 million people between 15 of WHO options A and B are similar in complexity, and 24 years old, and their HIV prevalence stands at Stringer argued. Finally, he reminded attendees that 8.7%. The HIV rate rises steeply during the transition antiretroviral access remains limited in many low- from adolescence to adulthood: Prevalence is 6.7% income countries. He maintained that starting cART among 15-to-19-year-old girls and 32.7% among early in pregnant women could deprive others in 25-to-29-year-old women. Only about one quarter of greater need of therapy. girls and young women and 15% of boys and young men report being tested for HIV. Stringer offered four conclusions: (1) Women who need cART for their own health should get it. (2) Lynn Ramirez-Avila (Children’s Hospital Boston) There is no randomized evidence of improved infant and colleagues at Durban’s McCord Hospital or maternal outcomes with universal maternal cART. and Massachusetts General Hospital assessed (3) cART is not simpler or cheaper than well-planned completion of HIV testing by adolescents and young short-term antiretroviral prophylaxis. (4) Starting adults who came to this outpatient clinic, which has cART too early in healthcare systems already flush a routine HIV testing program, and to determine HIV with patients could prevent those in immediate need prevalence in those who got tested. Everyone 12 from gaining access. years old or older who comes to the clinic is offered routine opt-out HIV testing, which means a health worker tells them they will be tested unless they HIV Testing, Condom Use, Toxicity, and decline testing, as sanctioned by South African law. Resistance Those who agreed had concurrent fingerprick rapid tests. Testing is included in the clinic fee. Low HIV testing rate in adolescents at Durban clinic The February 2008 to December 2009 study involved In a Durban clinic with a well-established HIV testing 956 adolescents 12 to 17 years old and 2351 young program, only one third of adolescent boys and half adults 18 to 24 years old. Girls and young women of girls had HIV testing.68 About two thirds of young comprised 55% of the adolescent group and 63% adults agreed to testing, and HIV prevalence was of the young adult group. HIV testing rates were

44 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

significantly higher among girls than boys in the Most young people accept opt-out HIV adolescent group (49% versus 33%, P < 0.01), but testing in DC emergency room rates were similar in young women and men (66% Three quarters of 13- to 24-year-olds accepted and 63%). Ramirez-Avila suggested the possibility rapid opt-out HIV testing in a hospital emergency that prior HIV testing or known HIV status could department in Washington, DC, the city with the explain why some youngsters declined testing. highest HIV prevalence in the United States and one with a largely African-American population.69 Sixty-two of 389 tested adolescents (16%) had a positive HIV testing, including 42 girls (16%) and In 2006 the CDC recommended opt-out HIV 20 boys (16%). Among 1523 tested young adults, screening for all 13- to 64-year-olds seeking medical 288 (19%) had a positive test, including 213 young care, regardless of perceived HIV risk, though the women (22%) and 75 young men (14%), a significant CDC does not suggest the best way to implement difference (P < 0.01). HIV prevalence in both boys this policy.70 Although numerous studies show that and girls was high around 14 years of age, declined opt-out HIV testing is generally well accepted in in the later teens, and rose again in the early 20s hospital emergency departments in the United (Figure 9). The researchers had no data to explain the States, adolescents and young adults made up only prevalence blip around age 14. small parts of these study populations. Ramirez-Avila and colleagues cautioned that this outpatient clinic may not be representative of public Washington, DC, the capital of the United States, sector clinics because there is a fee for clinic services. has an HIV prevalence around 3%,71 about 6 times Also, reported prevalence involves only youngsters the national rate. Children’s National Medical Center who agreed to testing, so overall prevalence in this in Washington launched an opt-out oral-fluid HIV age group may be lower. screening program in March 2009 for adolescents The investigators concluded that HIV testing rates are and young adults 13 years old or older. Natella low but positive test rates are high in this population. Rakhmanina and colleagues planned this study to They believe these findings point to (1) the need for evaluate implementation of the screening program further studies evaluating individual and clinic-level during its first 20 months and to identify barriers factors that result in HIV testing uptake by youth to opt-out screening in a large urban pediatric and (2) an “urgent need to offer comprehensive and emergency department. youth-friendly HIV testing to adolescents and young adults in epidemic settings.” Rakhmanina reported that development of the HIV screening plan involved all relevant staff, including Screening Algorithm

Patient Triaged

No Patient is given Age ≥ 13? appropratie care Yes

Patient and guardian (if present) are informed of No the Opt-Out HIV testing

Testing Accepted?

Yes

Patient and Guardian are informed that the test result will be disclosed to the patient rst and then shared with the guardian, unless the patient refuses.

Patient given information Terms of disclosure accepted? No about alternate locations of testing and Yes information about testing

Patient Tested

Figure 10. An HIV screening algorithm for youngsters visiting a Washington, DC, pediatric emergency department considered input from all relevant staff sectors, patients, and parents or guardians. This approach yielded high acceptance rates in the first 20 months of implementation. Source: Natella Rakhmanina, Children’s National Medical Center, Washington, DC.69

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hospital administration, emergency personnel, Adolescents and young adults account for infectious disease and adolescent health staff, and approximately half of all new HIV infections in the laboratory specialists. Evaluating attitudes of patients United States every year. Among the 20,000 teens and parents or guardians was helpful in developing who become infected annually, 75% are members the screening algorithm (Figure 10). In the program’s of racial or ethnic minorities. Teens are particularly initial stages, nursing staff offered HIV testing with a vulnerable to HIV because (1) half of them begin physician order. Later the hospital shifted to a triage sexual intercourse before age 16, when they are nursing-generated order for HIV testing and added emotionally and biologically immature, (2) many use dedicated testing personnel. alcohol and drugs before having sex, and (3) about two thirds do not use condoms consistently. Through the entire study period, 25,737 adolescents and young adults visited the emergency department, To promote safer sex behaviors among adolescents of whom 4566 (17.7%) got tested for HIV. The attending an urban emergency department, Yvette screening rate rose more than 12-fold from May Calderon (Jacobi Medical Center, Bronx, NY) and 2009, when 35 patients agreed to testing, to April colleagues planned this randomized trial comparing 2010, when 428 accepted testing. Proportions of the effectiveness of a theory-based HIV educational patients approached for HIV screening climbed from video with conventional in-person HIV counseling. 10% in March-August 2009, to 26% in September The study began with qualitative research involving 2009-February 2010, to 39% in March-August 2010, 100 Bronx teens to develop the video series, which and to 45% in September-October 2010. provided tailored messaging according to individuals’ In those four study periods, acceptance rates were initial intentions to use condoms. Those least likely 78%, 64%, 75%, and 70% and proportions actually to use condoms viewed a video that demonstrated tested were 73%, 56%, 70%, and 68%. Age averaged the negative consequences of not using condoms. about 16.5 across the four study periods. African Those more likely to use condoms viewed a video Americans comprised large majorities of tested that reinforced condom use as a positive behavior youngsters in every study period, a reflection of the and showed other teens’ views on using condoms as population the hospital serves. a positive behavior. All participants watched a video that demonstrated proper use of male and female Rates of reactive tests in the four study periods were condoms and dental dams. 0.35%, 0%, 0.19%, and 0.26%. Numbers of people who had a confirmed HIV diagnosis and were linked Study participants had to be between 15 and 21 to care were 1, 0, 3, and 0. Primary reasons for not years old, sexually active, and clinically stable. All offering HIV testing were lack of time (23.9%), deferral came to the emergency department on Monday by staff (25.8%), and medical reasons including through Friday between the hours of 8 AM and 4 PM. unstable condition (16.9%). (Many sought care for reproductive health problems.) All participants completed pre- and post-intervention The investigators concluded that routine opt-out tests on three variables hypothesized to reduce rapid oral fluid HIV screening is accepted by most unsafe sexual behavior: intention to use condoms, youth attending a pediatric emergency department. condom outcome expectancy, and condom self- Transition from physician- to triage nurse-generated efficacy (belief in one’s ability to use condoms HIV testing orders and addition of dedicated effectively). HIV testing was optional in both study testing staff significantly increased testing rates. arms. Rakhmanina and colleagues believe that having the emergency department staff perform the tests and The investigators randomized 102 participants developing a billing procedure will be necessary to (60.8% female) to the video group and 101 (55.4% integrate this screening program into the hospital’s female) to the standard-counseling group. Similar standard of care. proportions in the video and counseling groups were Hispanic (59.8% and 57.4%), and similar proportions were black (34.3% and 42.6%). While 20.6% in the Video better than counseling in improving video group were under 18 years old, 25.7% in the Bronx teens’ views on condom use counseling group were younger than 18. Two thirds Among sexually active teens and young adults who in each group had a prior HIV test. came to the emergency department at a Bronx medical center, a video series did better than Nearly all study participants reported vaginal sex in standard counseling in improving scores on intention the past year (97.1% in the video group and 96.0% to use condoms.72 in the counseling group). Similar proportions had oral sex in the past year (72.5% video and 62.4%

46 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

Table 7. Pre- to post-test change in sexual risk variables in Bronx teens

Video series Counseling Mean difference P mean change mean change (video vs counseling) Condom use intention score +0.98 –0.04 1.02 0.01

Condom self-efficacy +0.31 +0.05 0.26 0.03

Male condom outcome +0.19 +0.04 0.15 0.30 expectancy Female condom outcome +0.16 –0.04 0.20 0.06 expectancy

Source: François Dabis, Université Bordeaux Segalen, France.61

counseling) and anal sex in the past year (26.5% in the NEVEREST trial, which randomized nevirapine- and 21.8%). Mean numbers of sex partners were exposed children who reached an undetectable viral also similar in the video and counseling groups: 1.41 load while taking lopinavir/ritonavir plus stavudine/ and 1.42 male partners, and 2.16 and 2.13 female lamivudine to continue that regimen or switch to partners. nevirapine with stavudine/lamivudine.17,18 The analysis Mean change in the three outcome measures involved 85 children in the lopinavir group and 71 in consistently (and often significantly) favored the video the nevirapine group. group (Table 7). The video’s impact on condom use intention score did not differ by gender or ethnicity. At the NEVEREST 2 exit visit, age averaged 5.2 years in the lopinavir group and 5.0 in the nevirapine group, Calderon and colleagues concluded that a youth- and the groups were evenly divided by gender. At friendly video can be a valid way to provide post-test that point cART duration averaged 4.2 years in the PI HIV education and prevention messages in an urban group and 4.1 years in the nevirapine group. Weight- emergency department serving a high proportion and height-for-age Z scores and body mass index of minority youth. They noted that longitudinal Z scores did not differ significantly between the two studies are needed to determine how long such an groups. High proportions in each group had a viral intervention can affect risk-reduction behavior in this load below 50 copies/mL (84.7% in the PI group and age group. 91.6% in the NNRTI group). The nevirapine group had a higher median CD4 count (1480 versus 1356 cells/ mm3, P = 0.049). Lipid and body fat disadvantages with PIs vs NNRTIs in African children Mean total cholesterol was significantly higher in Compared with South African children who switched the PI group, and a higher proportion of children to an NNRTI-based regimen, those who stayed with taking lopinavir had a total cholesterol level above a PI combination had unfavorable lipid profiles and 200 mg/dL (Table 8). The PI group had lower mean body fat changes, according to results of a 156-child high-density lipoprotein (HDL) cholesterol, higher analysis.73 low-density lipoprotein (LDL) cholesterol, and a higher (worse) total-to-HDL cholesterol ratio. Mean Numerous studies report body fat abnormalities— triglycerides were significantly higher in the PI group, collectively called lipodystrophy—and dyslipidemia and a higher proportion of PI-treated children had a in children taking antiretrovirals in high-income triglyceride level above 150 mg/dL. countries. But little work has addressed these abnormalities in sub-Saharan Africa. Antiretroviral- A sum of skinfold measures was significantly higher associated lipid changes early in life could have in the PI group (43 versus 39 mm, P = 0.029), and profound long-term consequences for children who percentage of body fat by bioimpedance analysis was will be taking antiretrovirals for decades. significantly higher in children taking lopinavir (17% versus 14%, P = 0.042). The groups did not differ in This analysis by Stephanie Shiau (Columbia University, percentage of upper arm fat, but mean percentage New York, NY) and colleagues compared lipid and of upper thigh fat was higher in the PI group (22% body fat changes in South African children enrolled versus 19%, P = 0.021). A ratio of midthigh skinfold

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Table 8. Lipid changes after 4 years of continued lopinavir versus a switch to nevirapine in South African children

Lopinavir/ritonavir Nevirapine P (n = 85) (n = 71) Total cholesterol (mg/dL) 171 + 39 161 + 31 0.05

Total cholesterol > 200 mg/dL (%) 16 6 0.03

HDL cholesterol (mg/dL) 51 + 14 59 + 16 0.006

LDL cholesterol (mg/dL) 100 + 34 88 + 27 0.018

Total-to-HDL ratio 3.6 + 1.1 2.9 + 0.9 < 0.001 Triglycerides (mg/dL) 94 + 39 72 + 29 < 0.001

Triglycerides > 150 mg/dL (%) 11 2 0.038

Source: Stephanie Shiau, Columbia University, New York, for the NEVEREST trial.73

sum/skinfold sum was significantly higher in children from Europe, 87.5% were white, and age averaged taking lopinavir (0.24 versus 0.23, P = 0.046). A ratio 22.8 years. of trunk-to-thigh fat was significantly lower in the PI group (0.55 versus 0.57, P = 0.03). Miguel de Mulder (Hospital Ramón y Cajal, Madrid) and coworkers genotyped plasma samples from 44 Shiau and colleagues concluded that, compared with youngsters collected closest to the transfer time. At children who switched to the nevirapine regimen, that point, 64% of the study group had a CD4 percent those who continued taking lopinavir/ritonavir had between 15% and 24%, and 29% had a higher CD4 unfavorable cholesterol and triglyceride alterations, percent. Viral loads were below 50 copies/mL in greater overall trunk fat, but less trunk fat in relation to 37%, 51 to 499 copies/mL in 22%, and higher in thigh fat. They proposed that simple anthropometric 42%. Most people in this study group, 82.9%, were measurements, like those used in this study, taking antiretrovirals at the time of transfer. “appear to be a valuable method to measure body fat in young children on ART.” And they cautioned Two thirds of study participants (65%) had at least that unfavorable lipid alterations in children may one resistance mutation, 65% had an NRTI mutation, increase long-term cardiovascular risk and “should 49% had a PI mutation, and 33% had an NNRTI be considered in antiretroviral treatment strategies.” mutation. While 41% had mutations conferring resistance to two or more antiretroviral classes, 18% had resistance to three classes. The most frequent High resistance rates in Spanish NRTI mutations were D67N (50%), M41L (45%), and youngsters transferred to adult care L210W (32.5%). Only 17.5% had the M184V mutation. Although Spanish youngsters infected with HIV The most common PI mutations were L90M (37.5%), during childhood had good immunologic and M46I (37.5%), and V82A (17.5%). The most common virologic control when transferred to adult care, two NNRTI mutations were K103N (17.5%) and Y181C thirds had NRTI-related mutations and almost half ( 7.5%). had PI-related mutations.74 The investigators cautioned that this relatively high This study involved young people in the Madrid mutation prevalence “could compromise future long- Cohort of HIV-1-Infected Children, an eight-hospital term ART and clinical management in vertically HIV-1- collaboration established in 2000. Of the 534 infected patients.” They encouraged multidisciplinary children enrolled, 198 (37%) are in follow-up, 88 follow-up and psychosocial support for pediatric (16%) transferred to adult units, 64 (12%) were lost to patients transferring to adult units and new strategies follow-up, and 184 (35%) died. Among the 88 cohort to increase adherence. members transferred to adult units, 52% were young women, half were infected in 1986-1990, 95.5% were

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New data on TB, other Co-infections, two NRTIs plus ritonavir for infants under 6 months HIV in CSF old, two NRTIs plus lopinavir/ritonavir for children from 6 months to 3 years old or weighing less than TB therapy raises virologic failure risk in 10 kg, and two NRTIs plus efavirenz for children South African children older than 3 years. Children taking lopinavir/ritonavir Younger age and tuberculosis cotreatment when cotreatment began switched to ritonavir for the independently raised the risk of virologic failure of duration of cotreatment. antiretroviral therapy in a retrospective study of 218 South African children.75 Of the 218 children studied, 79 (36%) had TB and 139 did not. Median age was 21 months in the TB group TB coinfection is a major complication of HIV infection and 36 months in the no-TB group (P = 0.0006), throughout sub-Saharan Africa. Whereas global TB and weight-for-age Z score was significantly lower in incidence in 2009 stood at 164 per 100,000 people, children with TB -3.27 versus -1.87, P < 0.0001). A incidence measured 340 in Africa, 500 in South significantly higher proportion in the TB group was Africa, 877 in Cape Town, and 1600 in Khayelitsha, taking a PI regimen (72% versus 42%, P = 0.0001). a district outside Cape Town. Elisabetta Walters Median baseline CD4 percent was marginally lower (Stellenbosch University, Cape Town) and colleagues in the TB group than in the no-TB group (12% versus planned this retrospective study to explore virologic 13.5%, P = 0.057), but median baseline viral load outcomes of cART-treated children also receiving was similar in the two groups (5.77 versus 5.67 log10 treatment for TB and children on cART only. copies/mL, P = 0.159).

The analysis included children starting cART between Independently of TB cotreatment, virologic January 2003 and December 2005 and being suppression 6 and 12 months after cART began was treated for TB between April 2002 and December best in the NNRTI group, followed by the lopinavir/ 2008 at Cape Town’s Tygerberg Children’s Hospital. ritonavir group and the ritonavir group. Kaplan-Meier The cotreatment group included children treated for analysis determined that time to virologic failure TB between April 2002 and December 2008 and was significantly faster in children receiving anti-TB receiving cART and anti-TB therapy together for therapy and in children under 1 year old (Figure 11). at least 2 weeks. Walters and colleagues defined virologic failure as two consecutive 6-monthly viral Statistical analysis that adjusted for gender, age, anti- loads above 5000 copies/mL. cART was given TB cotreatment, weight-for-age Z score, and baseline according to 2003-2005 South African guidelines: CD4 count and viral load identified younger age and

KM time to failure curve stratiﬁed KM time to failure curve stratiﬁed by TB co -treatment by age group

Kaplan-Meier survival estimates 1.00 Kaplan-Meier survival estimates strati ed by agegroup 0.95 0.90 1.00 3-5yr 0.85 No TB 0.90 0.80 0.80 0.75 1-3yr 0.70 0.70 0.65 0.60 TB <1yr 0.60 0.50

P=0.0002 p=0.0002

Figure 11. Virologic failure of cART by Kaplan-Meier analysis was significantly faster in South African children also being treated for TB than in those without TB and in children younger than 1 year old than in older children Source: Elisabetta Walters, Stellenbosch University, Cape Town.75

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anti-TB cotreatment as independent predictors of status, isoniazid versus placebo use, infant age virologic failure. Type of antiretroviral therapy could at TB diagnosis, maternal age at infant diagnosis, not be assessed as a predictor of failure because of household type (formal versus informal), access to strong colinearity between type of therapy and age water, more or fewer than 3 people in the household, (the youngest children were all taking PIs). or presence of an adult over 55 years old in the household. The researchers cautioned, though, that Walters and coworkers questioned whether age this analysis rests on a small sample size. may be a surrogate for other factors contributing to virologic failure in this analysis. They called for Violari and colleagues proposed that in countries with further work to identify and implement TB preventive a high TB burden, TB exposure of children can occur strategies, new antiretroviral strategies for coinfected outside the home more frequently than in the home. children, and alternatives to rifampin for children with They recommended that future studies of childhood TB. TB should undertake aggressive community contact tracing to learn the origin of incident TB.

Most South African infants with TB do not have household TB contact Almost 25% of febrile African children Two thirds of HIV-positive or HIV-exposed infants starting cART have bacteremia coinfected with TB did not have an identifiable Almost one quarter of HIV-positive African children household contact for their TB, despite intensive enrolled in the ARROW trial in whom fever developed tracing, according to results of a 45-infant study had bacteremia, usually in the first 3 months of in Cape Town, Durban, and Johannesburg, South antiretroviral therapy.78 Streptococcus pneumoniae Africa.76 Avy Violari (Chris Hani Baragwanath Hospital, was the most frequently isolated pathogen. Soweto, South Africa) and coworkers identified only 3 adult nonhousehold contacts for these children. ARROW is an open-label randomized trial of first- line cART and monitoring strategies at three sites in To determine TB contact status in children, the Uganda and one in Zimbabwe. The 1206 children researchers assessed participants in the P1041 enrolled have a median age of 6 years (IQR 2 to 9), study, a phase 2/3 double-blind trial that randomized 51% are girls, and 99.4% were vertically infected with HIV-positive and exposed children in South Africa HIV. Median follow-up at the time of this analysis was and Botswana to daily isoniazid or matching placebo 156 weeks and maximum follow-up 210 weeks. for 96 weeks.77 All P1041 participants were 3 to 4 months old at recruitment and had Bacille Calmette- Victor Musiime (Joint Clinical Research Centre, Guérin (BCG) vaccination at birth. The study excluded Kampala) and colleagues assessed ARROW infants with a TB exposure history before enrollment enrollees in whom febrile illness developed, or previous or current treatment for TB. Isoniazid performing blood cultures and sensitivity analyses prophylaxis did not improve TB-disease-free survival of isolated pathogens. Most children were receiving in HIV-positive children or TB-infection-free survival cotrimoxazole prophylaxis, most had received in HIV-exposed but negative children immunized with Haemophilus influenzae type B vaccination, but none BCG vaccine. had received pneumococcal vaccination.

Violari and colleagues studied all children with definite Culturing 848 samples from 461 children, the or probable TB for microbiologically confirmed TB investigators found that 123 samples (14.5%) from contacts. The analysis involved 22 HIV-positive 105 children (22.8%) were positive. Among the 105 children and 23 HIV-exposed but uninfected children, children with positive isolates, median age was with the following numbers and identified contacts 4 years (range 0.5 to 15), and 54 (51%) were girls. from three study sites: Culture positivity rates were 18.8% within 3 months • Johannesburg: 32 children, 10 household con- of starting cART, 4.2% between 3 and 11 months, tacts, 2 nonhousehold contacts and 1.6% from month 12 onward. • Cape Town: 10 children, 3 household contacts, 1 nonhousehold contact The most prevalent pathogens were S pneumoniae • Durban: 3 children, no contacts identified (28%), Staphylococcus aureus (9%), other staph species (9%), other strep species (8%), Klebsiella Overall, the investigators identified contacts for pneumoniae (5%), Salmonella species (5%), and 16 of 45 children (35.5%). Among children with Pseudomonas aeruginosa (5%). protocol-defined TB, no differences could be found between those with and without contacts in HIV Among S pneumoniae isolates, 8 of 22 (36%) were

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Antibiotic susceptibility patterns of other bacteraemia isolates Number of susceptible isolates (percentage) Name of antibiotic S. aureus Salmonella E.coli P.aeruginosa K.pneumoniae spp

Ceftriaxone 4/5(80%) 5/5(100) 2/2(100) 1/2(50) 0/2(0)

Cefotaxime 3/4(75%) 2/2(100) 2/2(100) - 0/1 (0) Meropenem/ - 2/2(100) 3/3(100) 2/2(100) 2/2(100) Imipenem Cipro oxacin 3/3(100%) 3/3(100) - 2/2(100) 1/1(100 )

Amikacin - - 2/2(100) 1/1(100) 1/1(100)

Gentamicin 3/5(60) 3/4(75) 1/2(50) 2/3(67) 0 /2(0) Erythromycin 5/8(63) - - - -

Chloramphenicol 1/1(100) 0/1(0) - 0/1(0) -

Penicillin 1/4(25) 1/4(25) 0/2(0) 0/1 (0) 0 /3(0) Cotrimoxazole 0/8(0) 1/3(33) 0/2(0) 0/1 (0) 0/1(0)

Figure 12. Antibiotic susceptibility testing of isolates other than S pneumoniae in 105 of 461 children (22.8%) with positive blood cultures in the ARROW trial showed high rates of resistance to the most frequently prescribed antibiotics. S pneumoniae isolates were also often resistant to common antibiotics (see text). Source: Victor Musiime, Joint Clinical Research Centre, Kampala.78 resistant to oxacillin, 8 of 19 (42%) were resistant response to HBV vaccination was poor in children to penicillin G, 21 of 22 (95%) were resistant not receiving cART, with a low CD4 count, or with a to cotrimoxazole, and 5 of 5 were resistant to detectable viral load. gentamicin. All S pneumoniae isolates were susceptible to ceftriaxone, vancomycin, clindamycin, HBV prevalence is assumed to be high in Cambodia, cefotaxime, amoxicillin/clavulanic acid, cefuroxime, but rates of HBV and HCV infection in the general and chloramphenicol; 89% were susceptible to population are not well documented. Little is known erythromycin, 85% to amoxicillin, and 71% to about HBV or HCV coinfection in HIV-positive ampicillin. Other bacteremia isolates were usually children. HBV vaccination, which is essential for susceptible to meropenem/imipenem, ciprofloxacin, HBV-negative people with HIV, became part of amikacin, ceftriaxone, and cefotaxime, while most Cambodia’s National Immunization Program in 2005. were resistant to chloramphenicol, penicillin, and A cross-sectional study involved 974 HIV-positive cotrimoxazole (Figure 12). children seen between April 2009 and March 2010 at the National Pediatric Hospital, which had 1180 Musiime and colleagues believe high rates of HIV-infected children in care in December 2010. Sam resistance to commonly used antibiotics suggest that Sophan (National Pediatric Hospital, Phnom Penh) newer agents like ceftriaxone may be more effective and colleagues estimated that 20% of all HIV-positive for HIV-positive children with possible bacteremia. children in Cambodia are in follow-up at the National The high prevalence of S pneumoniae in this Pediatric Hospital. The investigators defined HBV pediatric population suggested to the investigators infection as a positive hepatitis B surface antigen “a need for effective prophylactic antibiotics and/or (HBsAg) test and HCV infection as a positive anti- pneumococcal vaccination.” HCV antibody test.

A prospective study involved children eligible for HBV and HCV rates 5% and 1% in HIV- HBV vaccination (negative for HBsAg and hepatitis positive Cambodian children B surface antibody), who received Engerix-B A study of nearly 1000 HIV-positive children in immunization at months 0, 1, and 6. Children with a Cambodia determined that approximately 5% have severe opportunistic infection or a CD4 percent below hepatitis B virus (HBV) coinfection and almost 1% 10% were not vaccinated. An anti-HBs antibody have hepatitis C virus (HCV) coinfection.79 Antibody level above 100 mIU/mL 1 month after vaccination

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The response rate associated with CD4+ status:

% 80 CD4 ≥350 cells/mL or ≥15% 70 67,5 70 (N=759)

60 CD4 <350 cells/mL or <15%

50 (N=30) 40 32,5 30 30 RR: 2.3 20 95% CI: 1.3-3.9 10 P -value: 0.0001 0 <10 mIU/mL ≥10 mIU/mL

Figure 13. Cambodian children with a CD4 percent at or above 15% or a CD4 count at or above 350 cells/ mm3 had more than a doubled chance of responding to HBV vaccination compared with children with lower CD4 measures. Source: Sam Sophan, National Pediatric Hospital, Phnom Penh.79

was considered full protection, a level between 10 a doubled chance of responding to vaccination with and 100 mIU/mL was considered a poor response a titer at or above 10 mIU/mL (RR 2.3, 95% CI 1.3 to requiring a single booster, and a level below 10 mIU/ 3.9, P = 0.0001) (Figure 13). An HIV RNA load below mL was considered failure to respond. 400 copies/mL raised the chance of an anti-HBs antibody response 60% (RR 1.6, 95% CI 1.3 to 1.8, The study group had a median age of 8.7 years (IQR P = 0.0001). 5.7 to 11), and 478 (49%) were girls. Most children (799, 82%) were receiving cART for a median duration Sophan and colleagues concluded that a high of 31 months (IQR 14 to 47), while 175 (18%) had CD4 count and undetectable viral load are good never received antiretrovirals. More than half of these predictors of the need for HBV vaccination boosting. children (61.9%) were born in Phnom Penh. Forty- They proposed that routine HBV vaccination for HIV- six children (4.7%) were HBsAg-positive, 122 (12.5%) positive children without knowledge of CD4 levels or were anti-HBs-positive, and 9 (0.9%) were anti-HCV- viral load may not yield a good serologic response. positive. Median age of HBV-coinfected children The investigators advised deferring HBV vaccination stood at 9.8 years (range 1.3 to 16.3), compared with for children until after cART controls HIV. a median age of 2.6 years (range 0.4 to 14.5) for HCV- coinfected children. Among 145 children who received HBV vaccination Low CSF HIV load in youth with PML or as part of the National Immunization Program after measles encephalitis 2004, anti-HBs antibodies developed in only 28 Romanian adolescents and young adults had lower (19.3%). Among 236 children whose caregivers HIV RNA in cerebrospinal fluid (CSF) than in plasma if reported that they received three vaccine doses at they had progressive multifocal leukoencephalopathy private clinics, anti-HBs antibodies developed in only (PML) or subacute measles encephalitis.80 But they 60 (25.4%). Among 789 HIV-positive children eligible had equivalent or higher viral loads in CSF and for HBV vaccination at the National Pediatric Hospital, plasma if they had HIV encephalopathy. median age was 8.6 years (IQR 5.8 to 10.9) and 387 (49%) were girls. In that group, 492 (62.3%) attained Higher HIV RNA in CSF correlates with neurocognitive full protection after vaccination, 40 (5.1%) had a poor impairment in adults, but relative viral loads in CSF and response, and 257 (32.6%) had no response. plasma have not been closely studied in youngsters, in whom neurologic opportunistic infections are Children on cART had a median anti-HBs titer of less prevalent than in adults. Many Romanian 725 mIU/mL, compared with a titer of 455 mIU/mL infants became infected with HIV-1 subtype F from in children not on cART. Children receiving cART had 1987 through 1990 through unsafe injection and a 30% higher chance of attaining a response above transfusion practices. They make up the largest part 10 mIU/mL (RR 1.3, 95% CI 1.1 to 1.5, P = 0.0001). of a group of young people studied by Luminita Ene Children with a CD4 percent at or above 15% or a (Dr. Victor Babes Hospital, Bucharest) and colleagues CD4 count at or above 350 cells/mm3 had more than to compare CSF and plasma loads in youngsters

52 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

with and without neurologic complications of HIV. and in 4 of 8 patients with cryptococcal meningitis, The study also aimed to assess the relevance of and (2) significantly lower CSF than plasma CSF load as a marker for central nervous system viral load in patients with PML and subacute complications in adolescents and young adults. measles encephalitis, a difference similar to that in neurologically asymptomatic patients. Of the 132 study participants that had available CSF and plasma samples, 104 (79%) had neurologic Ene and colleagues speculated that HIV RNA may be complications first noted at an average age of 18.7 lower in CSF than plasma in young people with PML years. Median time from HIV diagnosis to neurologic or subacute myoclonic measles encephalitis because complication was 5.5 years (range 0 to 17 years). Most of possible interactions between HIV and the viruses study participants (116 or 88%) were parenterally that causes these diseases. Earlier research found infected, 6 were vertically infected, and 10 acquired evidence that measles may inhibit HIV replication in HIV sexually. plasma.81-83 The investigators suggested that lower viral load in CSF than plasma may be an indirect In the whole study group, median CSF load was marker of PML or subacute myoclonic measles significantly lower than plasma load (2.61 versus encephalitis. 4.23 log10 copies/mL, P < 0.001), though CSF load correlated positively with plasma load (rho 0.68, P < 0.0001), as well as with albumin level (rho 0.22, P = cART may limit EBV load in Ugandan 0.05) and pleocytosis (rho 0.51, P < 0.001). Thirty- children under 5 nine antiretroviral-naive study participants had a Early cART was associated with lower Epstein-Barr significantly higher CSF load than 34 participants virus (EBV) DNA levels in Ugandan children under 5 on cART but with virologic failure (mean 4.28 versus years old, according to results of a 187-child study. 2.95 log10 copies/mL, P < 0.001). Among 20 people Malaria appeared to promote expansion of EBV- previously exposed to cART but not on treatment positive B cells in these children. at the time of evaluation, CSF load averaged 4.01 log10 copies/mL, which was significantly lower than EBV, a herpes virus, infects B lymphocytes and in the group with virologic failure but still on cART (P epithelial cells and can cause serious malignancies = 0.002). such as Burkitt’s lymphoma, immunoblastic lymphoma, and nasopharyngeal carcinoma. Thirty-two study participants had HIV encephalopathy, People infected with HIV run a high risk of EBV- 22 had PML, 8 had cryptococcal meningitis, 6 had related diseases, including non-Hodgkin B-cell cerebral toxoplasmosis, 2 had cytomegalovirus lymphoma. EBV is endemic in Central Africa, with encephalitis, and 2 had TB meningitis. Non-AIDS primary infection occurring during infancy and early neurologic conditions were subacute myoclonic childhood. In Africa EBV is strongly associated with measles encephalitis in 13, viral encephalitis in 9, Burkitt’s lymphoma, which accounts for 75% of seizures in 4, HIV aseptic meningitis in 2, Guillain- malignancies in children. Barré syndrome in 1, and facial palsy in 1. Because there have been no studies of EBV viremia in The investigators described two distinct patterns HIV-positive African children, Maria Raffaella Petrara associated with specific neurologic infections (University of Padova, Padova, Italy) and coworkers (Table 9): (1) higher CSF than plasma HIV RNA in planned this analysis of 187 HIV-positive children half of the 32 patients with HIV encephalopathy up to 14 years old in a Kampala cohort. Of the 103

Table 9. HIV RNA in CSF versus plasma in Romanian youth

n CSF load* Plasma load* P

HIV encephalopathy 32 4.62 4.61 NS

PML 21 3.13 4.68 < 0.001

Subacute myoclonic measles encephalitis 13 2.46 3.78 0.006

No neurologic disease 28 2.55 3.23 0.0001

*Mean log10 copies/mL. Source: Luminita Ene, Dr. Victor Babes Hospital, Bucharest.80

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children (55%) still naive to antiretrovirals, 83% had Regardless of antiretroviral status, EBV viremia was detectable EBV. Among 84 children (45%) receiving nonsignificantly higher in children with clinical malaria cART, 73% had detectable EBV. (P = 0.093), a finding leading Petrara and colleagues to suggest that Plasmodium falciparum malaria may In the entire cohort, 22% had EBV-1, 18% EBV-2, and induce B-cell activation and stimulate EBV-infected 38% both types of EBV. Rates of EBV-1 or EBV-2 or B cells via toll-like receptor 9 (TLR-9) engagement. coinfection with both types did not differ substantially Higher EBV viremia in antiretroviral-naive versus between antiretroviral-naive and experienced treated children under 5 years old prompted the children. EBV levels were significantly higher in investigators to propose that early cART may restrict children coinfected with both EBV types than in EBV replication and expansion of EBV-infected cells those infected only with EBV-1 (P = 0.001) or EBV-2 during primary EBV infection. (P = 0.015). But EBV load did not differ significantly between children with EBV-1 and those with EBV-2.

EBV viremia did not differ significantly between antiretroviral-treated and naive children. But in children younger than 5 years, EBV load was significantly higher in antiretroviral-naive children (P = 0.017).

4 th International Workshop on HIV Pediatrics Washington DC, USA 20 - 21 July 2012

MARK - THE - DATE 4th International Workshop on HIV Pediatrics 20 - 21 July 2012, Washington, DC, USA

Abstracts & Presentations of the 3rd International Workshop on HIV Pediatrics are available online at www.virology-education.com

54 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement 3rd International Workshop on HIV Pediatrics

Reference 1. Hazra R. Growing up with HIV in resource-rich 13. Palumbo P. Pediatric HIV treatment option—resource countries. 3rd International Workshop on HIV limited settings. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Invited lecture. Pediatrics. 15-16 July 2011. Rome, Italy. Invited lecture. 2. Musoke P. The challenge of growing up HIV infected in 14. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral resource-limited settings. 3rd International Workshop treatment for children with peripartum nevirapine on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Invited exposure. N Engl J Med. 2010;363:1510-1520. lecture. Available at http://www.nejm.org/doi/full/10.1056/ 3. Brady MT, Oleske JM, Williams PL, et al; Pediatric NEJMoa1000931. Accessed 23 August 2011. AIDS Clinical Trials Group219/219C Team. Declines in 15. Tudor-Williams G. What have we learned from the mortality rates and changes in causes of death in HIV- PENPACT 1 trial? 3rd International Workshop on HIV 1-infected children during the HAART era. J Acquir Pediatrics. 15-16 July 2011. Rome, Italy. Invited lecture. Immune Defic Syndr. 2010;53:86-94. 16. PENPACT-1 (PENTA 9/PACTG 390) Study Team, 4. Kapogiannis B, Soe M, Nesheim S, et al. Mortality Babiker A, Castro nee Green H, Compagnucci A, et al. trends in the U.S. Perinatal AIDS Collaborative First-line antiretroviral therapy with a protease inhibitor Transmission Study (1986-2004). Clin Infect Dis. 2011; versus non-nucleoside reverse transcriptase inhibitor in press. and switch at higher versus low viral load in HIV- 5. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, infected children: an open-label, randomised phase Gaillard P, Dabis F; Ghent International AIDS Society 2/3 trial. Lancet Infect Dis. 2011;11:273-283. Available (IAS) Working Group on HIV Infection in Women and at http://www.thelancet.com/journals/laninf/article/ Children. Mortality of infected and uninfected infants PIIS1473-3099%2810%2970313-3/fulltext. Accessed born to HIV-infected mothers in Africa: a pooled 8 August 2011. analysis. Lancet. 2004;364:1236-1243. Available at 17. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse http://www.thelancet.com/journals/lancet/article/ of nevirapine in exposed HIV-infected children PIIS0140-6736%2804%2917140-7/fulltext. Accessed after protease inhibitor-based viral suppression: a 18 August 2011. randomized controlled trial. JAMA. 2010;304:1082- 6. UNAIDS. UNAIDS report on the global AIDS epidemic 1090. Available at http://jama.ama-assn.org/ 2010. Geneva: Joint United Nations Programme content/304/10/1082.long. Accessed 8 August 2011. on HIV/AIDS. 2010. Available at http://www.unaids. 18 Coovadia A. Should PI-based therapy be continued org/en/media/unaids/contentassets/documents/ indefinitely? 3rd International Workshop on HIV unaidspublication/2010/20101123_globalreport_ Pediatrics. 15-16 July 2011. Rome, Italy. Invited lecture. en.pdf. Accessed 24 August 2011. 19. Penazzato M, on behalf of the European Pregnancy 7. Sauvageot D, Schaefer M, Olson D, Pujades-Rodriguez and Paediatric HIV Cohort Collaboration—EPPICC. M, O’Brien DP. Antiretroviral therapy outcomes in Treatment efficacy in European children starting cART resource-limited settings for HIV-infected children <5 in infancy: factors associated with viro-immunological years of age. Pediatrics. 2010;125:e1039-e1047. response and 1st-line therapy duration. 3rd 8. Puthanakit T, Vonthanak S, Ananworanich J, et al. International Workshop on HIV Pediatrics. 15-16 July Randomized clinical trial of immediate versus deferred 2011. Rome, Italy. Abstract O_08. antiretroviral therapy initiation in children older than one 20. Anti-retroviral research for watoto. ARROW trial year with moderate immunodeficiency: the PREDICT summary. Available at http://www.arrowtrial.org/trial_ study (NCT00234091). 3rd International Workshop on summary.asp. Accessed 9 August 2011. HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract 21. Mutasa K, Prendergast A, Ntozini R, et al. Predictive O_01. value of six-week viral load on mortality in HIV-infected 9. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Zimbabwean infants. 3rd International Workshop on Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract Team. Early antiretroviral therapy and mortality among O_ 07. HIV-infected infants. N Engl J Med. 2008;359:2233- 22. Malaba LC, Iliff PJ, Nathoo KJ, et al; ZVITAMBO Study 2244. Available at http://www.nejm.org/doi/ Group. Effect of postpartum maternal or neonatal full/10.1056/NEJMoa0800971. Accessed 24 August vitamin A supplementation on infant mortality among 2011. infants born to HIV-negative mothers in Zimbabwe. 10. World Health Organization. Antiretroviral therapy for Am J Clin Nutr. 2005;81:454-560. Available at http:// HIV infection in infants and children: towards universal www.ajcn.org/content/81/2/454.long. Accessed 8 access. 2010 revision. Available at http://www.who. August 2011. int/hiv/pub/paediatric/infants2010/en/. Accessed 8 23. Abrams EJ, Weedon J, Steketee RW, et al. Association August 2011. of human immunodeficiency virus (HIV) load early in 11. Grinsztejn B, Ribaudo H, Cohen MS, et al. Effects of life with disease progression among HIV-infected early versus delayed initiation of antiretroviral therapy infants. New York City Perinatal HIV Transmission (ART) on HIV clinical outcomes: results from the HPTN Collaborative Study Group. J Infect Dis. 1998;178:101- 052 randomized clinical trial. 6th IAS Conference on 108. HIV Pathogenesis, Treatment and Prevention. 17-20 24. Shearer WT, Quinn TC, LaRussa P, et al. Viral load July 2011. Rome, Italy. Abstract MOAX0105. and disease progression in infants infected with 12. Panel on Antiretroviral Therapy and Medical human immunodeficiency virus type 1. Women and Management of HIV-Infected Children. Guidelines Infants Transmission Study Group. N Engl J Med. for the use of antiretroviral agents in pediatric HIV 1997;336:1337-1342. infection. August 11, 2011; pp 1-268. Available at http:// aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf. Accessed 23 August 2011.

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25. Dickover RE, Dillon M, Leung KM, et al. Early 38. Gilks C, Walker S, Munderi P, et al. A single CD4 prognostic indicators in primary perinatal human test with threshold >250 cells/mm3 can markedly immunodeficiency virus type 1 infection: importance reduce switching to second-line ART in African of viral RNA and the timing of transmission on long- patients managed without CD4 or viral monitoring. term outcome. J Infect Dis. 1998;178:375-387. 18th Conference on Retroviruses and Opportunistic 26. Mofenson LM, Harris DR, Rich K, et al. Serum HIV- Infections. 27 February-2 March 2011. Abstract 676. 1 p24 antibody, HIV-1 RNA copy number and CD4 Available at http://www.retroconference.org/2011/ lymphocyte percentage are independently associated PDFs/676.pdf. Accessed 10 August 2011. with risk of mortality in HIV-1-infected children. National 39. Phillips AN, Pillay D, Miners AH, et al. Outcomes Institute of Child Health and Human Development from monitoring of patients on antiretroviral therapy Intravenous Immunoglobulin Clinical Trial Study in resource-limited settings with viral load, CD4 cell Group. AIDS. 1999;13:31-39. count, or clinical observation alone: a computer 27. Compagnucci A, Penta SC. Long-term consequences simulation model. Lancet. 2008;371:1443-1451. of planned treatment interruptions in HIV-infected 40. Bendavid E, Young SD, Katzenstein DA, Bayoumi children: results from the PENTA 11/TICCH trial. 3rd AM, Sanders GD, Owens DK. Cost-effectiveness International Workshop on HIV Pediatrics. 15-16 July of HIV monitoring strategies in resource-limited 2011. Rome, Italy. Abstract O_10. settings: a southern African analysis. Arch Intern Med. 28. Paediatric European Network for Treatment of AIDS. 2008;168:1910-1918. Response to planned treatment interruptions in HIV 41. Bishai D, Colchero A, Durack DT. The cost infection varies across childhood. AIDS. 2010;24:231- effectiveness of antiretroviral treatment strategies in 241. resource-limited settings. AIDS. 2007;21:1333-1340. 29. Davies M, Bolton C, Eley B, et al. Predicting 1-year 42. Kimmel AD, Weinstein MC, Anglaret X, et al; CEPAC- mortality using current CD4 percent and count in International Investigators. Laboratory monitoring order to guide switching therapy in children on ART to guide switching antiretroviral therapy in resource- in southern Africa. 3rd International Workshop on limited settings: clinical benefits and cost-effectiveness. HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract J Acquir Immune Defic Syndr. 2010;54:258-268. O_09. 43. Walensky RP, Ciaranello AL, Park JE, Freedberg KA. 30. Kuhn L. Virologic monitoring should be routine for Cost-effectiveness of laboratory monitoring in sub- children in resource-limited settings. 3rd International Saharan Africa: a review of the current literature. Clin Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Infect Dis. 2010;51:85-92. Italy. Invited lecture. 44. Walker AS, Gibb DM. Monitoring of highly active 31. Gibb D. Viral load monitoring should be routine antiretroviral therapy in HIV infection. Curr Opin Infect for children in resource-limited countries: the case Dis. 2011;24:27-33. against. 3rd International Workshop on HIV Pediatrics. 45. Dicko F, Malateste K, Koueta F, et al. Patterns of first- 15-16 July 2011. Rome, Italy. Invited lecture. line antiretroviral regimen and switch to second-line in 32. Schneider K, Puthanakit T, Kerr S, et al. Economic West African children on ART. The IeDEA paediatric evaluation of monitoring virologic responses to West African Database. 3rd International Workshop on antiretroviral therapy in HIV-infected children in HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract resource-limited settings. AIDS. 2011;25:1143-1151. PP_06. 33. Oliveira R, Krauss M, Essama-Bibi S, et al; NISDI 46. Bunupuradah T, Puthanakit T, Fahey P, et al. Second- Pediatric Study Group 2010. Viral load predicts new line highly active antiretroviral therapy in Asian HIV- World Health Organization stage 3 and 4 events in HIV- infected children. 3rd International Workshop on HIV infected children receiving highly active antiretroviral Pediatrics. 15-16 July 2011. Rome, Italy. Abstract therapy, independent of CD4 T lymphocyte value. Clin PP_05. Infect Dis. 2010;51:1325-1333. 47. Dinh TH, Goga A, Jackson D, et al. Impact of the 34. Sutcliffe CG, Moss WJ. ART for children: what to start national prevention of mother-to-child transmission and when to switch. Lancet Infect Dis. 2011;11:254- (PMTCT) program on mother-to-child transmission 255. of HIV (MTCT), South Africa, 2010. 3rd International 35. Dunn D; HIV Paediatric Prognostic Markers Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Collaborative Study Group. Short-term risk of disease Italy. Abstract O_13. progression in HIV-1-infected children receiving no 48. Lu L, Motswere-Chirwa C, Legwaila K, et al. HIV antiretroviral therapy or zidovudine monotherapy: a incidence in women during the first postpartum meta-analysis. Lancet. 2003;362:1605-1611. year: implications for PMTCT programs Francistown, 36. DART Trial Team, Mugyenyi P, Walker AS, Hakim Botswana, 2010. 3rd International Workshop on HIV J, et al. Routine versus clinically driven laboratory Pediatrics. 15-16 July 2011. Rome, Italy. Abstract monitoring of HIV antiretroviral therapy in Africa O_15. (DART): a randomised non-inferiority trial. Lancet. 49. Humphrey J, Marinda E, Moulton L, et al: Breastfeeding- 2010;375:123-131. associated HIV transmission among women who 37. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. seroconvert during late pregnancy and during PHPT-3: A randomized clinical trial comparing CD4 breastfeeding. XVI International AIDS conference. 14 vs viral load ART monitoring/switching strategies August 2006. Toronto, Canada. Abstract MOPE0384. in Thailand. 18th Conference on Retroviruses and 50. Amzal B, Jourdain G, Cressey T, et al. Maternal and Opportunistic Infections. 27 February-2 March 2011. infant nevirapine for the prevention of mother-to- Boston. Abstract 44. child transmission of HIV in women with <8 weeks of prenatal HAART: a Bayesian analysis. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_16.

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51. Lallemant M, Jourdain G, Le Coeur S, et al; Perinatal 62. Stringer J. PMTCT in 2011: maximizing long-term HIV Prevention Trial (Thailand) Investigators. Single- outcomes through a measured approach. 3rd dose perinatal nevirapine plus standard zidovudine International Workshop on HIV Pediatrics. 15-16 July to prevent mother-to-child transmission of HIV- 2011. Rome, Italy. Invited lecture. 1 in Thailand. N Engl J Med. 2004;351:217-228. 63. Thomas TK, Masaba R, Borkowf CB, et al; for the Available at http://www.nejm.org/doi/full/10.1056/ KiBS study team. Triple-antiretroviral prophylaxis to NEJMoa033500. Accessed 14 August 2011. prevent mother-to-child HIV transmission through 52. Nielsen-Saines K, Watts DH, Joao EC, et al. breastfeeding—the Kisumu Breastfeeding Study, Infectious morbidity, mortality growth of HIV-exposed, Kenya: a clinical trial. PLoS Med. 2011;8(3):e1001015. uninfected, formula-fed infants enrolled in NICHD/ Available at http://www.plosmedicine.org/article/ HPTN 040/ PACTG 1043. 3rd International Workshop info%3Adoi%2F10.1371%2Fjournal.pmed.1001015. on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Accessed 18 August 2011. Abstract O_11. 64. Hargrove JW, Humphrey JH; ZVITAMBO Study 53. Nielsen-Saines K, Watts H, Gonçalves Veloso V, Group. Mortality among HIV-positive postpartum et al. Phase III randomized trial of the safety and women with high CD4 cell counts in Zimbabwe. AIDS. efficacy of 3 neonatal ARV regimens for prevention of 2010;24:F11-F14. intrapartum HIV-1 transmission: NICHD HPTN 040/ 65. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 PACTG 1043. 18th Conference on Retroviruses and Study Team. Prevention of HIV-1 infection with early Opportunistic Infections. 27 February-2 March 2011. antiretroviral therapy. N Engl J Med. 2011;365:493- Boston. Abstract 124LB. Available at http://www.hptn. 505. Available at http://www.nejm.org/doi/full/10.1056/ org/web%20documents/AnnualMeeting2011/Presen NEJMoa1105243. Accessed 18 August 2011. tationJoint/10HPTN040NielsonOK.pdf. Accessed 15 66. Chasela CS, Hudgens MG, Jamieson DJ, et al. August 2011. Maternal or infant antiretroviral drugs to reduce HIV- 54. Marinda E, Humphrey JH, Iliff PJ, et al. Child mortality 1 transmission. N Engl J Med 2010;362:2271-2281. according to maternal and infant HIV status in Available at http://www.nejm.org/doi/full/10.1056/ Zimbabwe. Pediatr Infect Dis J. 2007;26:519-526. NEJMoa0911486. Accessed 18 August 2011. 55. Technau K, de Tolly K, Sherman G, et al. Mobile 67. Severe P, Juste MA, Ambroise A, et al. Early versus text messaging improves PMTCT follow-up in South standard antiretroviral therapy for HIV-infected African public setting. 3rd International Workshop on adults in Haiti. N Engl J Med. 2010;363:257-265. HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract Available at http://www.nejm.org/doi/full/10.1056/ O_12. NEJMoa0910370. Accessed 18 August 2011. 56. Liotta G, Mancinelli S, Gennaro E, et al. Is highly 68. Ramirez-Avila L, Nixon K, Noubary F, et al. Routine HIV active antiretroviral therapy (HAART) in pregnancy testing in adolescents and young adults presenting protective against maternal mortality? Results from to an outpatient site in Durban, South Africa. 3rd a large DREAM cohort in Malawi and Mozambique. International Workshop on HIV Pediatrics. 15-16 July 6th IAS Conference on HIV Pathogenesis, Treatment 2011. Rome, Italy. Abstract O_05. and Prevention. Rome, Italy. 17-20 July 2011. Abstract 69. Rakhmanina N, Johnson B, Souweine K, et al. TUAB0201. Screening of adolescents and young adults for HIV 57. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral in a large urban pediatric emergency department: regimens in pregnancy and breast-feeding in how to do it right? 3rd International Workshop on Botswana. N Engl J Med. 2010;362:2282-2294. HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract Available at http://www.nejm.org/doi/full/10.1056/ O_06. NEJMoa0907736. Accessed 18 August 2011. 70. Branson BM, Handsfield HH, Lampe MA, et al. 58. Kesho Bora Study Group, de Vincenzi I. Triple Revised recommendations for HIV testing of adults, antiretroviral compared with zidovudine and single- adolescents, and pregnant women in health-care dose nevirapine prophylaxis during pregnancy and settings. MMWR Recomm Rep. 2006;55:1-17. http:// breastfeeding for prevention of mother-to-child www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1. transmission of HIV-1 (Kesho Bora study): a randomised htm. Accessed 19 August 2011. controlled trial. Lancet Infect Dis. 2011;11:171-180. 71. Vargas JA, Fears D. At least 3 percent of D.C. Erratum in Lancet Infect Dis. 2011;11:159. residents have HIV or AIDS, city study finds; rate up 59. World Health Organization. Antiretroviral drugs for 22% from 2006. Washington Post. 15 March 2009. treating pregnant women and preventing HIV infection Available at http://www.washingtonpost.com/wp-dyn/ in infants. 2010. Available at http://whqlibdoc.who. content/article/2009/03/14/AR2009031402176.html. int/publications/2010/9789241599818_eng.pdf. Accessed 19 August 2011. Accessed 18 August 2011. 72. Calderon Y, Leu CS, Cowan EA, et al. Project Control. 60. Panel on Treatment of HIV-Infected Pregnant Evaluation of a brief HIV counseling video to improve Women and Prevention of Perinatal Transmission. teenagers risk reduction behavior. 3rd International Recommendations for use of antiretroviral drugs in Workshop on HIV Pediatrics. 15-16 July 2011. Rome, pregnant HIV-1-infected women for maternal health Italy. Abstract O_03. and interventions to reduce perinatal HIV transmission 73. Shiau S, Arpadi S, Strehlau R, et al. Body composition in the United States. May 24, 2010. Available at and metabolic abnormalities of perinatally HIV-infected http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. children in South Africa on long-term ARV treatment. Accessed 18 August 2011. 3rd International Workshop on HIV Pediatrics. 15-16 61. Dabis F. HAART should be used for PMTCT in all July 2011. Rome, Italy. Abstract O_02. pregnant women: the pro side. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Invited lecture.

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74. Navas A, de Mulder M, Gonzalez-Granados I, et al. High drug resistance prevalence among vertically HIV-infected patients transferred from paediatric care to adult units in Spain. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_04. 75. Walters E, Reichmuth K, Rabie H, Cotton MF, Dramowski A, Marais BJ. Virological outcomes in South African children co-treated with highly-active anti-retroviral therapy (HAART) and anti-tuberculosis therapy. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_20. 76. Nachman S, Zeldow B, Dittmer S, et al. Lack of identification of adult TB contacts in infants with microbiologically confirmed or clinically presumed TB (MCCP TB) in clinical trial P1041. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_21. 77. Madhi SA, Nachman S, Violari A, et al; P1041 Study Team. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011;365:21-31. Available at http://www.nejm.org/doi/ full/10.1056/NEJMoa1011214. Accessed 21 August 2011. 78. Musiime V, Cook A, Bakeera-Kitaka S, et al. Bacteraemia in HIV-1 infected children on antiretroviral therapy in Uganda and Zimbabwe in the ARROW clinical trial. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_19. 79. Sophan S, Ung V, Huot C, et al. Prevalence of HBV/ HIV and HCV/HIV coinfections and HB vaccination in HIV-infected children at the National Pediatric Hospital, Phnom Penh, Cambodia. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_17. 80. Duiculescu D, Ene L, Tardei G, Achim CL. Divergent trends in HIV RNA levels in the cerebrospinal fluid of children and adolescents with central nervous system complications. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_22. 81. Moss WJ, Ryon JJ, Monze M, Cutts F, Quinn TC, Griffin DE. Suppression of human immunodeficiency virus replication during acute measles. J Infect Dis. 2002;185:1035-1042. 82. Ruel TD, Achan, J, Gasasira AF, et al. Dramatic reductions in HIV RNA among HIV-infected children with acute measles in Uganda. 14th Conference on Retroviruses and Opportunistic Infections. 25-28 February 2007. Los Angeles. Abstract 707. 83. Duiculescu D, Ene L, Ungureanu E, et al. Subacute measles encephalitis: a new AIDS defining disease in HIV-infected young patients. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 22-25 July 2007. Sydney. Poster WEPDB03. 84. Petrara MR, Penazzato M, Massavon W, et al. Dynamics of Epstein-Barr virus in HIV-1-infected children in Uganda. 3rd International Workshop on HIV Pediatrics. 15-16 July 2011. Rome, Italy. Abstract O_18.

58 Reviews in Antiviral Therapy & Infectious Diseases - volume 3; 2011 - Supplement VACCINATIE Masterclass 2012