Guidelines for the Clinical Management of HIV Infection in Adults and Adolescents

National AIDS-STD control programme Department of Health, Ministry of Health Myanmar

Second Edition

July 2007

Table of Contents List of experts who developed the guidelines...... 3 List of abbreviations...... 4 Introduction and Objectives...... 6 HIV testing...... 8 Two test Strategy for use in the general population...... 8 Three test Strategy for use in Pregnant Women ...... 9 Voluntary confidential counselling and testing...... 10 Clinical Assessment ...... 11 WHO Clinical Staging of HIV Disease...... 11 Medical History and symptom check list ...... 12 Physical examination checklist ...... 13 Management and follow up plan based on WHO staging...... 14 Visit schedule and follow up for patients commencing ART ...... 15 Assessment of Patients’ readiness for therapy...... 15 Initiating Antiretroviral Therapy ...... 16 Goals of Antiretroviral therapy...... 16 Mechanisms of action of antiretrovirals ...... 16 Classification of antiretrovirals by class ...... 16 When to start antiretroviral therapy in adults and adolescents...... 17 CD4 testing not available...... 17 CD4 testing available...... 17 Commencing ART in the presence of active opportunistic infections...... 17 Managing opportunistic infections before starting antiretroviral therapy...... 18 Recommended first line antiretroviral regimens ...... 19 Starting ARV – What to expect and what to do...... 20 Triple NRTI-based regimens ...... 20 Use of protease inhibitors (PIs) in initial therapy...... 20 Starting and stopping NNRTIs ...... 21 ARV combinations not recommended ...... 21 Immune reconstitution inflammatory syndrome (IRIS) ...... 21 Adherence ...... 23 Clinical and laboratory monitoring prior to commencing and on first line ART...... 25 Antiretroviral drug toxicities...... 26 Class adverse drug reactions to nucleoside reverse transcriptase inhibitors ...... 26 Class adverse drug reactions to non-nucleoside reverse transcriptase inhibitors...... 26 Class adverse drug reactions to protease inhibitors (PIs)...... 26 Symptom directed toxicity management table...... 28 Individual drug substitutions for toxicity and intolerance ...... 29 Notes on Stavudine (d4T) ...... 29 Considerations for specific patients...... 31 ART for women of childbearing potential or who are pregnant ...... 31 Interaction between ART and hormonal contraceptives ...... 32 Initiating ART in pregnant women...... 32 ART in Tuberculosis/HIV co-infection...... 33 Initiating ART in patients with active TB...... 33 Recommendations for patients on ART who develop active TB...... 33 Second line ART for patients with TB indicating first-line ART failure...... 33 Antiretroviral therapy for IDUs ...... 35 Viral hepatitis and chronic liver disease ...... 36 Opiod substitution therapy ...... 36 HIV and Hepatitis Co-infection...... 38 Hepatitis B infection...... 38 Hepatitis C infection...... 39 ART failure and when to switch therapy...... 40 Defining failure...... 40 Immunological criteria for failure ...... 41 Choice of second-line regimens for treatment failure ...... 42 Boosted PI/NRTI combinations...... 42 Symptom directed toxicity management table for SECOND line ARVs...... 42 Prevention of Mother to Child Transmission...... 44 The comprehensive strategic approach ...... 44

2 Counselling for PMCT ...... 45 ARV prophylaxis for PMCT ...... 45 Nevirapine resistance and its prevention...... 46 Doses of antiretroviral prophylaxis drugs for PMCT ...... 47 Post exposure prophylaxis ...... 50 Occupational and non-occupational exposure prophylaxis...... 50 Occupational post exposure prophylaxis...... 51 Components of occupational PEP ...... 51 Antiretrovirals for PEP ...... 54 Non-occupation post exposure prophylaxis (nPEP)...... 54 Summary of recommendations for occupational and non-occupational PEP...... 56 Syndromic approach to the management of opportunistic infections...... 57 Annexes ...... 75 Annex 1 Criteria for HIV-Related Clinical Events in Adults and Adolescents...... 75 Annex 2 Dosages of antiretroviral drugs for adults and adolescents ...... 79 Annex 3 Storage of Antiretrovirals ...... 81 Annex 4 Drugs that interact with ART...... 82 Annex 5 Clinical diagnosis and management of common opportunistic infections ...... 86 References...... 89

List of experts who developed the guidelines

1. Dr Min Thwe National AIDS programme manager 2. Dr Win Maung National TB programme manager 3. Dr Htin Aung National AIDS programme 4. Dr Aung San C. S. Specialist Hospital, Waibargi, N Okkalapa, Yangon 5. Dr Chit Htun Lecturer/Consultant Physician 6. Dr Htin Aung Saw C. S. Specialist Hospital, Waibargi, N Okkalapa, Yangon 7. Dr Khin Yi Oo Head/Consultant Virologist, National Health Laboratory, Yangon 8. Dr Phyu Noe National TB programme 9. Prof Rai Mra Yangon General Hospital 10. Prof Samuel Kyaw Hla Consultant Paediatrician, Thingangyun Hospital 11. Dr Win Myat Aye Consultant Paediatrician, Magway 12. Prof Khin May Ohn Head, Department of Medicine, Institute of Medicine 2 13. Dr Riitta Dlodlo HIV programme coordinator, IUATLD 14. Dr Yasuda Tadashi UNICEF, Myanmar 15. Dr Angela Bailey AZG, Myanmar (REPLACE) 16. Dr Anorla Bailei AZG, Myanmar 17. Dr Lianne Kuppens WHO Myanmar 18. Dr Ying Ru Lo WHO South EAST Asia Regional Office (SEARO) 19. Mrs Phavady Bollen WHO Myanmar 20. Dr Oscar Barreneche WHO Myanmar 21. Dr Catrina Casalini WHO TB group 22. Dr Chris Duncombe WHO Consultant (Editor)

Acknowledgement The authors wish to acknowledge the contribution of the WHO South EAST Asia Regional Office (SEARO) for the source material used in these guidelines: Management of HIV infection and antiretroviral therapy in adults and adolescents: A clinical Manual WHO South East Asia Regional Office (2006)

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List of abbreviations TC lamivudine AB antibody ABC abacavir AFB acid-fast bacilli AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ANC Absolute Neutrophil count ART antiretroviral therapy ARV antiretroviral (drug) AST aspartate aminotransferase ATS amphetamine type stimulants ATV atazanavir AZT zidovudine (also known as ZDV) b.d. twice daily CD4 count CD4+ T-lymphocyte CMV cytomegalovirus CNS central nervous system CSF cerebrospinal fluid CTX co-trimoxazole CXR chest X-ray d4T stavudine ddI didanosine DOT directly observed therapy EC enteric-coated EFV efavirenz FBC full blood count FDA Food and Drug Administration FDC fixed-dose combination FPV fos-amprenavir FTC furthicitibine GI gastrointestinal HDL high-density lipoprotein Hb haemoglobin HBV hepatitis B virus HCV hepatitis C virus hgc hard gel capsule HIV human immunodeficiency virus HSV herpes simplex virus IDV indinavir INH isoniazid IRIS immune reconstitution inflammatory syndrome LPV lopinavir MTCT mother-to-child transmission (of HIV) NFV nelfinavir NNRTI non-nucleoside reverse transcriptase inhibitor nPEP Non-occupational post exposure prophylaxis NRTI nucleoside reverse transcriptase inhibitor NVP nevirapine OHL oral hairy leukoplakia OST opioid substitution treatment PCP Pneumocystis pneumonia PEP Post exposure prophylaxis PGL persistent generalized lymphadenopathy

4 PI protease inhibitor PK pharmacokinetic PML progressive multifocal leukoencephalopathy PMTCT prevention of mother-to-child transmission (of HIV) PPE pruritic papular eruption /r low-dose ritonavir RBV Ribavirin RTI reverse transcriptase inhibitor RTV ritonavir SEARO World Health Organization, South East Asia Regional Office SJS Stevens-Johnson syndrome SDN Single dose nevirapine SQV saquinavir TB tuberculosis TDF tenofovir disoproxil fumarate TLC total lymphocyte count VL viral load US United States of America WBC white blood cell count WHO World Health Organization

5 Introduction and Objectives This is the second edition of the Guidelines for the Clinical Management of HIV Infection in Adults and Adolescents and is fully updated from the first edition published in 2004. It was developed by an expert writing committee in collaboration with the National AIDS-STD Control Programme (NAP), Department of Health, Ministry of Health, Myanmar, for use by health facilities at state-divisional, district and township levels as well as by the private medical sector in Myanmar. It reflects consensus obtained after a series of working meetings with NAP experts, medical and laboratory specialists, NGOs and the World Health Organization (WHO).

It is the intention of the writing committee to produce a single guideline applicable for use by the public, private and NGOs sectors in Myanmar. The guidelines include flexibility in the recommendations to accommodate different treatment strategies depending on individual program resources and the capacity to deliver care. Material and recommendations contained in this second edition have undergone peer review by expert clinicians in Myanmar and by external reviewers.

Antiretroviral therapy (ART) is now considered an integral part of the comprehensive response to HIV prevention, care and support. These guidelines employ a public health approach to the delivery of comprehensive HIV care, including ART, using standardized ARV regimens provided through a simplified approach and supported by clinical and basic laboratory monitoring.

There are three broad sections to the guidelines: • Initial Assessment and patient management planning • Using antiretroviral therapy • Prevention and treatment of opportunistic infections

In 2006, WHO (Head Quarters, Geneva) published Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings: Towards Universal Access: Recommendations for a Public Health Approach as part of a series of updates on HIV care for adults and children, new recommendations on the use of cotrimoxazole prophylaxis, HIV disease staging and the prevention of mother to child transmission. Revised guidlines for post exposure prophylaxis are in preparation.

The WHO South East Asia Regional Office (SEARO) has also produced two new publications for use in the region. These are: Management of HIV infection and antiretroviral therapy in children: A clinical Manual Management of HIV infection and antiretroviral therapy in adults and adolescents: A clinical Manual These global and regional WHO publications and recommendations from expert physicians and program managers in Myanmar are the basis of information included in this second guideline edition.

6 Key new recommendations are: • Choices for first-line ARVs have been broadened • Dosing of stavudine (d4T) is changed following new WHO recommendations that 30mg BID should be given to all patients irrespective of body weight. The previous recommendation was 40 mg BID for those ≥ 60kg and 30mg BID for those< 60 kg1 • Recognition and management of the toxicities of Stavudine (d4T) • Recognition and management of Immune Reconstitution Inflammatory Syndrome (IRIS) • Clear guidlines on how to safely stop NNRTIs in chronic HIV infection and in the setting of PMCT to limit the development of resistance • Earlier initiation of ART before CD4 count drops below less 200 cells/mm3 • The use of cotrimoxazole prophylaxis to prevent bacterial infections and malaria in addition to the “classic” prevention of PCP and toxoplasmosis • Expanded PMCT interventions • Updated guidelines for occupational and non-occupation post exposure prophylaxis

7 Chapter HIV testing Two test Strategy for use in the general population

PRE-TEST education and/or counseling Ensure Informed Consent 1

First HIV test (screening)

Positive test result* NEGATIVE test result: Counsel for negative

Second HIV test

POSITIVE test result: Negative test result Counsel for positive result

INCONCLUSIVE result** Repeat HIV test in 6 weeks

Positive test result NEGATIVE test result: Counsel for negative result

Second HIV test

POSITIVE test result: Negative test result Counsel for positive result

Notes The second test should use a different principle. When the population tested has an HIV prevalence of less than 10% the WHO/UNAIDS advise a third confirmatory test to reduce the risk of false positives. In the context of late pregnancy or labour, it is advised to give a single dose of nevirapine on the basis of a single positive rapid test. Where a result is inconclusive, this should be reported to the person being tested. Post-test counselling should focus on the possibility of the test being performed during the “window period”, i.e., when antibodies have not yet formed after exposure to HIV. Three test Strategy for use in Pregnant Women

Pre-test education and/ or counseling and ensure informed consent

First HIV antibody test a

Positive test result Negative test result Counsel for negative result

Second HIV antibody test a

Positive test result Negative test result

Person has b signs/symptoms In the setting of Inconclusive result consistent with PMCT Repeat HIV test in 6 HIV weeks

Positive test result: Counsel Confirm by third for positive specific HIV test result

Positive test result: Negative Counsel for positive result

Follow assessment and Indeterminate management procedures Recheck 6 weeks after HIV diagnosis is confirmed

9 Chapter Voluntary confidential counselling and testing VCCT is an integral part of HIV prevention and care for people who want to know their HIV status in order to make an informed decision to be tested for HIV

Pre test counselling All clients who request HIV testing should receive information: 2 • The risks for transmission and how HIV can be prevented. • The benefits and consequences of HIV testing • The testing process • Assurance about confidentiality • The meaning of the test results in understandable language

Post test counselling • Clients should be counselled for a positive or a negative result and have the result explained • Clients should be assured of confidentiality

In case of positive results, the counsellor needs to: • Provide emotional support • Assess the individual’s ability to cope • Assess the social support available • Explain how to prevent HIV transmission to uninfected or untested partners • Encourage individuals to share their HIV status with their sexual partners • Refer the individual for clinical monitoring and follow up and to evaluate the need for ART

In case of negative results, the counsellor needs to: • Encourage the HIV negative individual to adopt safe practices (condom use) • Explain that the individual has to be tested again in 6 to 8 weeks in case if the first test was performed during the “window period”. • Explain that a negative test performed during “window period” may not mean that the individual is definitively uninfected.

Clinical Assessment Chapter WHO Clinical Staging of HIV Disease The revised WHO clinical classification of HIV-associated disease is designed to be used in patients with confirmed HIV infection. Along with CD4 count testing, where available, the staging system is used to guide decisions on when to start opportunistic infection (OI) prophylaxis and when to start and switch ART. 3 Clinical stage 1 (Asymptomatic) Asymptomatic Persistent generalized lymphadenopathy Clinical stage 2 (Mild disease) Moderate unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis) Herpes zoster Angular chelitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections Clinical stage 3 (Moderate disease) Unexplained severe weight loss (>10% of presumed or measured body weight ) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (intermittent or constant for longer than one month) Persistent oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis Severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Unexplained anaemia (<8 g/dl ), neutropaenia (<0.5 x 109 /L) and or chronic thrombocytopenia (<50 X 109 /L3) Clinical stage 4 (Severe disease) HIV wasting syndrome Pneumocystis pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi's sarcoma Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Penicilliosis Chronic cryptosporidiosis Chronic isosporiasis Disseminated mycosis (extrapulmonary histoplasmosis, coccidiomycosis) Recurrent septicaemia (including non-typhoidal Salmonella) Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy Source: Revised WHO Clinical Staging and Immunological Classification of HIV and case definition of HIV for surveillance, May 2006

Medical History and symptom check list The following checklist is a guide to key information to ask the patient at the initial (and subsequent) visits. The information will guide in deciding the need for HIV testing if HIV status is unknown and allow disease staging (WHO Clinical Staging of HIV Disease) which is the basis of the management and follow up plan HIV Testing HIV Risk Ever tested for HIV in the past? Unprotected sexual contact Date and place of first HIV test Injection drug use Reason for the test Occupational exposure Documentation of the result Perinatal transmission Date of any negative HIV test Recipient of blood products Prior CD4+ cell counts (if available) Unknown System Review Past history of HIV-Related Illnesses Oral candidiasis or Candida esophagitis Unexplained weight loss Persistent diarrhea Swollen lymph nodes Varicella zoster (shingles) Night sweats and fever Oral hairy leukoplakia Unusual headaches or poor concentration Pneumocystis jiroveci pneumonia (PCP) Changes in appetite Recurrent bacterial pneumonia Skin rashes Cryptococcal meningitis Sores or white spots in mouth Toxoplasmosis Painful swallowing Kaposi's sarcoma Chest pain, cough or shortness of breath Disseminated Mycobacterium avium complex Stomach pain or Vomiting or Diarrhea Cytomegalovirus (CMV) infection Numbness or tingling in hands or feet Tuberculosis Muscle weakness and changes in vision Invasive cervical cancer Tuberculosis History Sexually Transmitted Infections Last chest X-ray History of past TB Genital ulcer or other lesion Treatment given (drugs and duration) Genital discharge History of exposure to TB BCG and PPD skin test and result Gynecologic History General Medical History Last PAP smear Any other past medical condition such as diabetes, Menstrual irregularities hypertension, cardiovascular disease Hepatitis B, Pelvic pain or discharge Hepatitis C Pregnancy and Contraception history Vaccination History Previous pregnancies and terminations Living children and HIV status of children BCG Exposure to ARV during pregnancy Hepatitis A vaccine Drugs and duration of ART Hepatitis B vaccine Contraception used Last menstrual period Medication Allergies Past drugs and reasons for taking them Current drugs and reasons for taking them Known allergies to drugs or other substances or Include traditional remedies materials Opioid substitution therapy ART History Psycho Social History Family history, e.g. other immediate family Current and past exposure to ART member with known HIV infection Which drugs taken and for how long Social history, e.g. marital status, education, Understanding and readiness to commence occupation, source of income ART if never taken Financial and family support status Disclosure status, readiness to disclose Substance use Functional status Able to work, go to school, do housework Alcohol, stimulant, opiate and other drug use Ambulatory but not able to work Smoking history Amount of day to day care needed

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Physical examination checklist

Record body weight, temperature, blood pressure, pulse rate, respiratory rate

Wasting weight loss Rapid loss is more suggestive of active OI, especially if associated with fever Gradual weight loss (not caused by malnutrition or other obvious Appearance illness) is more suggestive of HIV infection Gradual loss, fever and anaemia are common presentations of MAC infection “Track marks” and soft tissue infections which are common to IDUs Malaria, tuberculosis, syphilis, gastrointestinal infections, bacterial Consider other conditions pneumonia, viral hepatitis Look for signs of HIV related and other skin problems. These include diffuse dry skin, typical lesions of PPE, especially on the legs, Skin seborrhoeic dermatitis on face and scalp Look for herpes simplex and herpes zoster or the scarring of previous herpes zoster Start with posterior cervical nodes. PGL (Persistent Glandular Lymphadenopathy) typically presents as multiple bilateral soft, non-tender mobile cervical nodes. Similar Lymph nodes nodes may be found in the arm pits and groin Tuberculous lymph nodes typically present as unilateral, painful, hard, enlarging nodes with constitutional symptoms such as fever, night sweats and weight loss Look for signs suggestive of HIV infection including white plaques on tongue, cheeks and roof of moth (oral candida), white stripped Mouth lesions on the side of the tongue (OHL) and cracking at the corners of the mouth (angular chelitis) The most common problems will be PCP and TB Signs and symptoms are cough, shortness of breath, haemoptysis, Chest weigh loss, fever, congestion or consolidation. Perform a chest X-ray if possible Hepato-splenomegaly, masses and local tenderness Abdomen Jaundice may indicate viral hepatitis Difficulty swallowing is commonly caused by oesophageal candida Herpes simplex and other genital sore/lesions, vaginal or penile Ano-genital discharge Perform PAP smear if possible Focus on visual fields and the signs of neuropathy (bilateral Neurological examination peripheral or localised mono neuropathies) Assess focal neurological deficit

13 Management and follow up plan based on WHO staging WHO Management Clinical Stage Patients are followed up every 3-6 months Check for clinical signs of progression Informed of the clinical signs of progression that would alert them to go back to their medical doctor. • enlargement of lymph glands • fever lasting more than 2 weeks Stage 1 • weight loss • diarrhoea for more than 2 weeks • cough lasting more than 3 weeks or shortness of breath • persistent headache Total lymphocyte count or CD4 cell count if available Diagnosis and treatment of sexually transmitted infections STIs Counsel on safer sexual practices and contraception Patients are followed up every 3-6 months Check for any symptom of disease progression (stage III symptoms) • Fever lasting more than 2 weeks • weight loss >10% of body weight • diarrhoea lasting of more than 2 weeks • oral thrush • persistent headache • persistent cough • mucocutaneous manifestations (seborrheic dermatitis, prurigo, recurrent oral ulceration) Symptom directed laboratory evaluation (if available) • Full blood count • ALT Stage 2 • Sputum smear for TB when productive cough • Total lymphocyte count or CD4 cell count Follow up STI management counselling as for stage 1 patients Cotrimoxazole prophylaxis Start prophylaxis in all patients with WHO stage 2, 3 and 4 disease If CD4 testing is available, start prophylaxis in patients with: • Any WHO clinical stage and CD4 < 200 cells/mm3 where the aim of cotrimoxazole prophylaxis is the prevention of PCP and toxoplasmosis. • Any WHO clinical stage CD4< 350 cells/mm3 where the aim of cotrimoxazole prophylaxis is the reduction of morbidity and mortality associated with malaria, bacterial diarrhoeal disease and bacterial pneumonias in addition to the prevention of PCP and toxoplasmosis Dose One double strength tablet or two single strength tablets once daily Total daily dose is 960 mg (800 mg SMZ + 160 mg TMP) Frequency of follow up depends on the patient’s individual condition. Frequent visits are recommended at initiation of ART (1-2 weekly) then 1-3 monthly once the patient is stable on ART. The main objectives of examination are to detect signs and symptoms of Immune Inflammatory Reconstitution Syndrome (IRIS) and OIs including pulmonary or extra pulmonary tuberculosis. Symptom directed laboratory evaluation (if available) Stage III and IV • Full blood count • ALT • Sputum smear for TB when productive cough • Total lymphocyte count or CD4 cell count Start opportunistic infections (OI) prophylaxis Start cotrimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg) P0 daily if symptom of stage III or stage IV.

14 Visit schedule and follow up for patients commencing ART

Visit ART medically indicated (any time if new problems CD4 count < 350 especially close to 200 occur) CD4 <200 WHO stage 3 or 4 Medical History and symptom check list History Examination Document WHO clinical stage First visit Start cotrimoxazole prophylaxis Tretatmen preparedness and understanding of HIV/AIDS, transmission, risk reduction, treatment options Adherence counseling (more than one session may be needed prior to commencing ART) History (new problems) Commence ART if stable on cotrimoxazole and patient is ready Week 2 Commence lead in dose of NVP 200mg OD plus two NRTIs Liver function testing if available if signs /symptoms of NVP hepatoxicity History (new problems) Examination If on NVP, any side effects (rash, fever, signs of liver toxicity) Week 4 Symptom directed liver function testing if available Dose escalation on NVP to 200 mg BID Adherence assessment/support Reassess WHO clinical T stage History (new problems) Symptom checklist Week 8 Examination Adherence assessment/support Reassess WHO clinical T stage History (new problems) Symptom checklist Examination Follow-up Adherence assessment/support Psychosocial support Visits every 1-3 months and more often as needed CD4 count every 6 months if available

Assessment of Patients’ readiness for therapy • Build confidence and assess knowledge • Explain ART and the objectives of the treatment o to avoid occurrence of OI o to restore immunity • Ensure the patient has understood o The treatment does not kill the virus o The treatment only suppresses the virus o The treatment has to be taken regularly to avoid resistance o It is a life long-treatment • Advise and encourage the patient to disclose his diagnosis to his/ her partner or family and support testing of the partner if status is unknown.

15 Chapter Initiating Antiretroviral Therapy Goals of Antiretroviral therapy • Maximal and durable suppression of replication of HIV • Restoration and/or preservation of immune function • Reduction of HIV-related morbidity and mortality • Minimization of drug related side effects 5 • Improvement of quality of life

Mechanisms of action of antiretrovirals Antiretroviral agents act by blocking fusion of the virus with the cell, and by blocking the enzymes responsible for the reproduction and functioning of HIV. Currently available antiretroviral drugs belong to three classes: 1. Fusion inhibitors – these drugs block the fusion of HIV with the CD4 cell membrane and hence prevent the entry of HIV RNA into the cell. There is only one fusion inhibitor available, T20 other wise known as enfuvirtide 2. Reverse transcriptase inhibitors (RTIs) – these drugs block HIV reverse transcriptase and prevent the copying of the viral genetic code (RNA) into the genetic code (DNA) of infected host cells. There are three types of reverse transcriptase inhibitors. a. Nucleoside reverse transcriptase inhibitors (NsRTIs)-e.g. AZT, 3TC D4T b. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)–There are three NNRTIs available - efavirenz, nevirapine and delavirdine. Delavirdine is rarely used. c. Nucleotide reverse transcriptase inhibitors (NtRTIs). Tenofovir is the only example in this class 3. Protease inhibitors (PIs) – these drugs block the enzyme protease and prevent the assembly and release of HIV particles from infected cells. Examples are indinavir and nelfinavir

Classification of antiretrovirals by class Nucleoside Reverse Non-nucleoside Reverse Protease Inhibitors Transcriptase Inhibitors Transceriptase Inhibitors

Zidovudine (ZDV, AZT) Nevirapine (NVP) Saquinavir (soft gel cap) Didanosine (ddI) Efavirenz (EFV) Saquinavir (hard gel cap) Stavudine (d4T) Saquinavir tablets Lamivudine (3TC) Ritonavir (RTV, r)1 Abacavir (ABC) Indinavir (IDV) Nelfinavir (NFV) Fos-amprenavir (f-APV) Nucleotide Reverse Fusion Inhibitors Lopinavir/ritonavir (LPVr) Transcriptase Inhibitors Tenofovir (TDF) Enfuvirtide (T20) Darunavir Fixed Combination Antiretrovirals2 Zidovudine + Lamivudine Zidovudine + Lamivudine +Abacavir Stavudine + Lamivudine + Nevirapine Tenofovir + lamivudine + efavirenz 1. Ritonavir is only recommended as a booster of other protease inhibitors 2. Other combinations may be available in some countries

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When to start antiretroviral therapy in adults and adolescents Starting ART by clinical staging WHO Clinical Stage Recommendation 1 Do not treat 2* Do not treat 3 Treat 4 Treat *Consider treatment in WHO stage II disease and total lymphocyte count < 1200 cells/mm3

Starting ART by CD4 count WHO Clinical Staging CD4 testing available 1 Treat if CD4 cell count 2 < 200 cells/mm3

General principles • Consider treatment if CD4 cell count < 350 cells/mm3 • Start ART before CD4 cell count drops below 200 cells/mm3 In the case of pregnancy or TB 3 • Start ART in all pregnant women with WHO stage 3 disease and CD4 < 350 • Start ART HIV infected patients with CD4 < 350 and pulmonary TB (WHO stage 3) or severe bacterial disease

Treat irrespective of CD4 count 4 (Note: extrapulmonary TB is WHO stage 4)

The decision to initiate ART in adults and adolescents is based on clinical and immunological assessment. In many resource limited settings, only clinical staging will be available to guide the decision of when to start ART. Viral Load is not recommended to guide decisions on when to start ART. The process of initiating ART involves assessment of patient readiness to commence therapy and an understanding of its implications (life-long therapy, adherence, toxicities). Access to nutritional and psychosocial support and family and peer support groups is important when making decisions about the initiation of ART. CD4 testing not available In the absence of CD4 testing, all patients with WHO stage 3 and 4 disease should start ART. Those with WHO stage 1 and 2 disease should be monitored carefully, with a minimum of 3 monthly clinical review and anytime if new symptoms develop.

CD4 testing available The optimum time to commence ART is prior to patients becoming unwell or presenting with their first opportunistic infection. Disease progression is greater in patients who commence ART with a CD4 cell count <200/mm3 compared to those persons who start therapy above this level.2 3 4 5 6 7 If CD4 testing is available, ART should be commenced before the CD4 count drops below 200 cell/mm3. The optimum time to initiate ART with a CD4 cell count 200-350 cells/mm3 remains unknown and patients with CD4 counts in this range require regular clinical and immunological evaluation. Initiation of ART is recommended for all patients with pulmonary TB or severe bacterial infections and CD4 count < 350/mm3. It is also recommended that all pregnant women with any stage 3 disease and CD4< 350 initiate ART.

Commencing ART in the presence of active opportunistic infections Do not commence ART in the presence of an active OI. In general, OI should be treated or stabilized before commencing ART. For details on starting ART in patients with HIV/TB co- infection, see section on the management of HIV/TB. An exception is Mycobacterium Avium Complex (MAC) when commencing ART may be the preferred treatment, especially in

17 situations where specific MAC therapy is not available. Other conditions which may regress following the commencement of ART include candidiasis and cryptosporidiosis. The following opportunistic infections and HIV-related illnesses need treatment or stabilization before commencing ART.

Managing opportunistic infections before starting antiretroviral therapy Clinical situation Action Any undiagnosed active infection with Diagnose and treat first; start ART when stable fever and patient is unwell TB Treat TB first; start ART as recommended in TB section Pneumocystis pneumonia (PCP) Treat PCP first; start ART when PCP treatment is completed Invasive fungal diseases: Treat esophageal candidiasis first; start ART as soon oesophageal candidiasis, cryptococcal as the patient can swallow comfortably meningitis, penicilliosis, histoplasmosis Treat cryptococcal meningitis, penicilliosis, histoplasmosis first; start ART when treatment completed Bacterial pneumonia Treat pneumonia first; start ART when treatment completed Malaria Treat malaria first; start ART when malaria treatment is completed Drug reaction Do not start ART during an acute reaction Significant acute diarrhoea which may Diagnose and treat acute diarrhoea first; start ART reduce absorption of ART when diarrhoea stabilized or controlled Non-severe anaemia (Hb > 8 g/L) Start ART if no other causes for anaemia are found (HIV is often the cause of the anaemia). Avoid AZT Skin conditions such as PPE and Start ART (ART may resolve these problems) seborrhoeic dermatitis, psoriasis, HIV- related exfoliative dermatitis Suspected MAC, cryptosporidiosis and Start ART (ART may resolve these problems) microsporidiosis Cytomegalovirus infection Treat if drugs available. If not available, start ART

18 Recommended first line antiretroviral regimens Recommendation Regimen Comments AZT + 3TC + (NVP or EFV) AZT may cause anaemia and WHO recommends Hb monitoring EFV is substituted for NVP intolerance and if patients are receiving rifampicin. Both NVP and EFV should be used with caution and careful monitoring in patients with known or suspected hepatic dysfunction. (AZT* or d4T) NVP should not be used in women with CD4 >250 + If EFV is not available, option in patients First line regimens 3TC receiving rifampicin are NVP, a PI based or a tripled nucleoside regimen. + EFV may be used in women if they use (NVP or EFV) consistent and reliable contraception EFV may be used on the second and third trimester of pregnancy d4T may continue to be used by many programs due to its availability and no requirements for laboratory monitoring. d4T has significant toxicities (lipoatrophy, lactic acidosis, peripheral neuropathy)

TDF is unavailable in many countries but this TDF + 3TC + (NVP or EFV) * may change

Other options Inferior virological response but keeps 2 Triple NRTI classes to second line

Note * Preferred NRTIs ABC is not available in Myanmar and is not included in the first line recommendations

19 Starting ARV – What to expect and what to do Drug What to expect When What to do Hepatitis Anytime Stop and change when Didanosine (ddI) Pancreatitis Anytime stable Lactic acidosis 3-12 months Lamivudine (3TC) Generally well tolerated Peripheral neuropathy 6-12 months Stop, consider dose reduction Lipoatrophy (fat loss) Stop d4T before and progressive weight 6-24 months lipoatrophy is severe Stavudine (d4T) loss since it is usually not reversible Lactic acidosis Anytime Stop if acidosis

At commencement Nausea, headache, Take with food often resolves after 2 fatigue Paracetamol weeks Zidovudine (AZT) Anemia, neutropaenia Anytime Check CBC 2-4 weeks after starting and regularly Myopathy – muscle 6-24 months Stop AZT if severe pain and muscle loss Try to treat through with Efavirenz (EFV) Rash often self limiting 2-4 weeks antihistamines At start of NVP or at Rash Nevirapine (NVP) time of dose escalation Stop if moderate -severe Hepatitis at 2 weeks

Note: Lead in NVP dosing at 200 mg once daily for the first 2 weeks produces adequate NVP drug levels. Due to enzyme auto induction, NVP levels decline over 2 weeks and dose escalation to 200 mg BID is required to maintain adequate levels. Starting NVP 200 mg BID without lead in dosing results in high serum concentrations of NVP and increased risk of rash and hepatoxicity. If nevirapine is restarted after more than 14 days of treatment interruption, lead-in dosing (200mg OD for 2 weeks, then200mg BID) is again necessary. Triple NRTI-based regimens Triple NRTI regimens are inferior to NRTI/NNRTI regimens.8 9 10 11 AZT+3TC+ABC may be considered in patients with intolerance or resistance to NNRTIs when PI-based regimens are unavailable, to preserve second-line options, for the treatment of HIV-2 infection and for the treatment of HIV/TB co-infected patients receiving rifampicin. Use of protease inhibitors (PIs) in initial therapy PIs are not recommended in first line regimens because the use of PIs in an initial treatment regimen essentially rules out second-line options in the setting of limited drug availability. PIs may be considered in first line regimens (with a standard dual NRTI backbone) for the treatment of HIV-2 infection, in women with CD4 count of 250-350 cells/mm3 who require ART and who cannot take efavirenz or in patients with NNRTI intolerance.

20 Starting and stopping NNRTIs Starting Nevirapine AM PM (AZT or d4T) + 3TC Lead in NVP dose for the first FDC One separate pill each 2 weeks (AZT or d4T + 3TC + NVP) OR One pill FDC (AZT or d4T +3TC) One pill FDC FDC Escalate to full NVP dose after (AZT or d4T + 3TC + NVP) (AZT or d4T + 3TC + NVP) 2 weeks One pill One pill Stopping either NVP or EFV Stop NVP or EFV Continue NRTI backbone (2 drugs only) for 7 days then stop all drugs. This is to cover the long half life of NNRTI decay and reduce the risk of NNRTI resistance

ARV combinations not recommended ARV combinations Reason not to use Monotherapy or dual therapy to treat chronic HIV Rapid development of resistance infection d4T + AZT Antagonism (reduced levels of both drugs) d4T + ddI Overlapping toxicities (pancreatitis, hepatitis, lipoatrophy) Deaths reported in pregnant women 3TC + FTC Interchangeable, but should not be used together TDF + 3TC + ABC or TDF + 3TC + ddI Select for K65R mutation and are associated with high incidence of early virological failure TDF + ddI + any NNRTI High incidence of early virological failure

Immune reconstitution inflammatory syndrome (IRIS) A reaction against a foreign antigen (alive or dead) in patients who have started ART and have undergone a reconstitution of their immune responses against this Definition antigen. MTB accounts for approximately 1/3 of all IRIS events 10% of all patients initiating ART Frequency Up to 25% among patients initiating ART with a CD4 cell count < 50 cells/mm3.12 13 Timing Typically within 2-12 weeks of initiation of ART but may present later Unexpected deterioration of clinical status soon after commencing ART Signs and Unmasking of subclinical infections such as TB, which present as new active symptoms disease Worsening of co-existing infections such a flare of hepatitis B or C Most common 60% of IRIS events are M.Tuberculosis, MAC or cryptococcal disease 14 IRIS events IRIS may be mild and resolve without treatment. Continue ART if possible. Treat unmasked active OI, such as TB. This may mean temporary interruption of ART until the patient is stable on TB drugs, then reintroduction of ART. Corticosteroid treatment to suppress exaggerated inflammatory response may be Management indicated. For example, an acute hepatic flare where viral hepatitis coinfection is known or suspected. If the patient is taking nevirapine, clinical hepatitis and/or rising hepatic enzymes in association with rash and fever is more likely to be due to nevirapine than IRIS and switching to efavirenz is recommended. Prednisone 0.5mg/kg/day for 5-10 days is suggested in moderate to severe cases of IRIS.15

21 Unexpected deterioration in clinical condition with signs and symptoms of inflammation/infection soon after commencing ART (Typically 2-12 weeks)

a. A paradoxical reaction against a Suspect foreign antigen (alive or dead) in a IRIS patients who have started ART and have undergone a reconstitution of their immune responses against this antigen. MTB accounts for approx.

Reported IRIS Events 1/3 of all IRIS events

Cryptococcal meningitis TB meningitis or abscess CNS symptoms Toxoplasmosis PML CMV Lymphoma Management Principles Reported IRIS Events

Hepatobiliary Flare of hepatitis B or C Continue ART if possible symptoms Visceral leishmaniasis Diagnose and treat the TB abscess specific pathogen in order to decrease the antigen load Consider corticosteroids in Reported IRIS Events moderate to severe cases of

Disseminated TB IRIS (Prednisolone (or Fever without prednisone) at 0.5 mg/kg/ Invasive fungal disease localizing signs day orally or IV for five to MAC CMV ten days or longer depending on the severity of the inflammation Discontinue ART and Reported IRIS Events Extra pulmonary TB prioritize treatment of the Focal pathogen in patients who are adenopathy MAC Kaposi’s sarcoma severely unwell Histoplasmosis Aspiration and drainage of lymph nodes and abscesses (may need to be repeated

several times) Respiratory Reported IRIS Events Emergency surgical symptoms with Pulmonary TB decompression in cases of worsening Invasive fungal pneumonia trachea or intestinal CXR changes PCP (if not on cotrimoxazole) obstruction

Reported IRIS Events Herpes zoster and helped simplex HPV infection (warts) Muco- Molluscum contagiosum cutaneous Kaposi’s sarcoma conditions Psoriasis Eczema, folliculitis, PPE Leprosy Muco cutaneous leishmaniasis

Reported IRIS Events Auto immune Sarcoidosis Graves disease diseases Guillain Barré Syndrome Reiter’s syndrome

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Adherence The most common reason for ART failure is poor adherence. Adherence should be assessed and routinely reinforced at every clinic visit. A high degree of adherence to ARV drugs is necessary for optimal virological suppression. Studies indicate that 90-95% of the doses should be taken for optimal suppression and lesser degrees of adherence are more often associated with virological failure.16 Maintaining this level of adherence is difficult. Imperfect adherence is common and surveys indicate that one- third of patients missed doses within 3 days of survey.17 Factors that are associated with poor adherence include poor patient-clinician relationship, high pill burden, forgetfulness, mental depression, lack of patient education, inability of patients to identify their medications, drug toxicity and being too ill.18

Key Elements of treatment adherence counselling • Establishing trusting relationship with health workers • Providing necessary information and advice • Encouraging peer participation and help identify treatment support persons/organizations • Developing individual treatment plan fitting ART into patient’s lifestyle/daily events and identifying treatment reminders • Assessing readiness and commitment of patients for ART. Readiness to commence ART may be assessed by: − past ability to attend regular clinic visits and not miss appointments − past ability to take OI prophylaxis, such as cotrimoxazole − past ability to complete full course of TB therapy − adequate understanding • Treatment adherence should be strict and adherence to recommended regimens should be greater than 95% to avoid resistance. This means that missing more than 3 doses per month is associated with increased risk of drug resistance and failure • If regular dose are missed or lat, reinforce adherence counselling. Enlist community outreach teams and PLHA peer support groups as appropriate • Treatment has to be continued for life. • Timing of drug intake is critical (e.g. drugs taken twice daily must be taken every 12 hours+/- one hour). • Missed doses can be taken up to 6 hours in a BID regimen. If > 6 hours late, skip dose and take next normal dose • Some drugs are taken with food, some drugs are taken on an empty stomach, and some require an increase intake of water. • Drug side effects have to be understood and explained to the patient in advance of commencing ART • People on ART need to continue to use condoms regularly and practice safe injecting use. • Other medications, including herbal products, may interact with ART. Patients need careful counselling about which medications are allowed and which are not permitted with their ART • Regular clinic attendance for monitoring of efficacy and adherence is essential • If patient cannot make clinic appointment, they need to call or make home visit

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The treatment regimen should be simplified by reducing the number of pills, reducing the frequency of therapy such as twice daily dosing, and minimizing side effects. Simplified regimens improve adherence. Adherence may be measured by patient self-report, pill count, and the report of the primary care provider.

The pre-enrolment information and counselling process The process of offering information, counselling and adherence support must be carried out by staff (counsellors and/or PLHA) who understands the problems in the lives of PLHA. There are 3 steps in this process. In some cases all 3 steps may be carried out during one session. Step 1 – Giving information Clients are given basic information enabling them to understand the need for a high level of commitment to treatment and adherence. Information can be provided to a group of PLHA if the facilitator has some understanding of group dynamics and is able to stimulate group discussion. Step 2 – Counselling – in one or more individual sessions Help the client explore his/her feelings. Many clients will be preoccupied with problems related to family, job, relationships etc, and cannot focus on strict adherence until they have released negative feelings about these problems Many will have no private place to store their medicines and will not be able to take them in secret. Not wanting others to know their HIV status is by far the commonest reason providers come across for poor adherence. The client needs to be realistic about who needs to know their HIV status and how to tell them. Step 3 – Solving practical problems and creating a treatment plan Where will the ARV drugs be stored? At what time will it be taken? Who will remind the clients to take it if he or she forgets? What will the client do if her or his normal routine is interrupted? A time should be arranged to meet or telephone the client within a few days in order to discuss any problems.

Checklist to assess treatment adherence once ART is commenced • Number of doses missed in the last 3 days • Number of doses missed since last visit • If dose taken at correct time (if no, ask for delay in hours/days) • If correct dose taken • Specification of reasons for interruption or modification/failure to take doses • Estimated proportion of doses taken using visual analogue scale

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Clinical and laboratory monitoring prior to commencing and on first line ART Before or Every W W As Evaluation at ART W 2 W 4 W 8 6 12 24 needed start Mnths Clinical Clinical evaluation Weight Concomitant medications Check ART adherence Laboratory HIVAB test1 CD4 count Haemoglobin2 Pregnancy test3 VDRL/RPR Chemistry Serum lactate Viral Load4 1. Historical documented HIV antibody test is sufficient to commence ART. In the absence of documented, confirmed HIV antibody test, testing prior to commencing of ART is recommended 2. For patients receiving AZT; Haemoglobin monitoring prior to commencing AZT and at weeks 4, 8 and 12 and as required when taking AZT 3. Pregnancy testing for women initiating a first-line regimen containing EFV. Do not commence EFV if pregnancy test is positive and the woman is in the fist trimester 3. Pregnancy testing if pregnancy is suspected in women who are receiving an EFV-based regimen. Change to a non –EFV based regimen if the if the pregnancy test is positive and the woman is in the first trimester 4. chemistry includes liver and renal functions 5. HIV-RNA measurement is currently not recommended for decision-making on initiation or regular monitoring of ART in resource-limited settings. It may be considered to make the diagnosis of treatment failure earlier or to assess discordant clinical and CD4 findings in patients suspected of failing ART.

25 Antiretroviral drug toxicities Class adverse drug reactions to nucleoside reverse transcriptase inhibitors Acute lactic acidosis and severe hepatomegaly with steatosis during NsRTI use occur at a low frequency, but with a high risk of fatality. The incidence of lactic acidosis seems to be around 1%, while an increase in serum lactate levels can be found in as many as 5–21% of patients treated with NsRTI-containing regimens. While uncommon, lactic acidosis is associated with a high fatality rate (33–57%). The initial clinical manifestations of lactic acidosis are variable and may include non-specific gastrointestinal symptoms (weight loss, anorexia, nausea, vomiting, abdominal pain, diarrhoea) without dramatic increase of hepatic enzymes and, in some cases, dyspnoea and/or fatigue. Evaluation shows lactic acidosis with possibly elevated creatine phosphokinase (CPK), alanine transaminase (ALT), and/or lactate dehydrogenase (LDH), low bicarbonate and increased anion gap. All NsRTIs and tenofovir have been implicated but the syndrome is consistently reported at higher rates with the use of d4T or ddI. The combination of d4T and ddI is not recommended. The most important therapeutic intervention appears to be NsRTI withdrawal; the safety of substituting alternative drugs in this class is not known. This adverse event has been attributed to mitochondrial toxicity caused by NsRTIs. Other clinical expressions of mitochondrial toxicity include myopathy (AZT-related), dilated cardiomyopathy (AZT), peripheral neuropathy (d4T, ddI), pancreatitis (ddI, d4T, 3TC), bone marrow suppression (AZT) and/or lipoatrophy (d4T, AZT, ddI). Liver toxicity manifested as asymptomatic increases in liver transaminases, with normal bilirubinaemia, occurs in 5–15% of patients receiving NsRTIs.

Class adverse drug reactions to non-nucleoside reverse transcriptase inhibitors Skin rash occurs most commonly with the NNRTI class of drugs. Most cases are mild-to- moderate in nature, occurring within the first few weeks of therapy. Management of NNRTI- related skin rashes depends on the severity of the rash. In general, mild (grade1) and moderate (grade 2) rashes can be managed with symptomatic therapy (antihistamines) and careful monitoring (daily visits or daily telephone progress reports). If patients experience severe (grade 4) or life-threatening (grade 4) skin reactions, the drugs need to be stopped immediately. More serious cutaneous manifestations such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis should result in the prompt and permanent discontinuation of the NNRTI or other offending agents. Most cases of skin rash are confined to cutaneous reactions. However, a severe or even life- threatening syndrome of drug rash with eosinophilia and systemic symptoms (DRESS) has also been described. The systemic symptoms may include fever, haematological abnormalities and multiple organ involvement. Among the NNRTIs, skin rash occurs more frequently and is greater in severity with NVP. Using a two-week lead-in dose escalation schedule when initiating NVP therapy may reduce the incidence of rash. Acute symptomatic hepatitis with jaundice, liver enlargement, gastrointestinal symptoms, fatigue and anorexia may occur. Hypersensitivity may manifest as rash, fever and other systemic symptoms, usually within 6–8 weeks of starting therapy. Lactic acidosis may occur. If adverse reactions occur, discontinue all ARVs until symptoms resolve. Transaminase and bilirubin levels should be monitored if possible. NVP should not be re- administered in the future but ART should be restarted using alternative ARVs.

Class adverse drug reactions to protease inhibitors (PIs) Hyperglycaemia New-onset diabetes mellitus, diabetic ketoacidosis, and exacerbation of existing diabetes mellitus, as well as hyperglycaemia, insulin resistance or glucose tolerance have all been reported in patients receiving PIs. Insulin resistance occurs in up to 40% of patients treated with PIs, while hyperglycaemia has been reported in 3–17% of patients receiving PIs with 1% of these patients develop clinical evidence of diabetes. The reversibility of these events is currently unknown, due to limited data and still limited follow up of patients. Some patients were able to continue PI therapy and initiated treatment with oral hypoglycaemic agents or insulin.

26 Fat redistribution Modifications in body fat distribution, lipodystrophy syndrome, fat redistribution syndrome are frequently (13–84%) observed in patients treated with PIs. These changes have also been described with NsRTI therapy (particularly with d4T-containing regimens). The most typical clinical findings include central obesity and peripheral fat wasting. The observed changes include visceral fat accumulation, dorsocervical fat accumulation (known as "buffalo hump"), extremity wasting with venous prominence, loss of buttock fat, facial thinning, breast enlargement and lipomatosis. Hyperlipidaemia Changes in blood levels of triglycerides and/or cholesterol have been observed very frequently, even in the absence of fat redistribution. Although all PIs have been implicated, RTV produces substantial increases in triglycerides and cholesterol most frequently, which reach higher blood levels than with other PIs. Monitoring serum triglycerides and cholesterol at regular intervals during treatment can be an option for the assessment of cardiovascular risk. However, a complete evaluation of all other independent cardiovascular risk factors (e.g. smoking, diet, weight, etc.) is necessary, and it should be suggested to patients to reduce these as much as possible. Intervention is usually recommended for triglyceride levels >750–1000 mg/dl and/or low- density lipoprotein (LDL) cholesterol levels >130 mg/dl (in individuals without known coronary disease and with two or more coronary risk factors) or >160 mg/dl (in individuals without known coronary disease and with fewer than two coronary risk factors). However, the effectiveness of dietary modifications and lipid-lowering drugs is not yet clear. In some cases, discontinuation of PIs was found to be beneficial; but such a decision requires a careful risk– benefit analysis.

Time Side Effects and Toxicities Common causes Gastrointestinal toxicities including nausea and vomiting, AZT, TDF, PIs diarrhoea NVP Rash EFV Most rashes occur within the first Short term Abacavir 2-3 weeks (the first few PIs (rarely) weeks) Hepatoxicity NVP, EFV More common in hepatitis B or C co-infection PIs Drowsiness, dizziness, confusion, and vivid dreams are associated with the use of efavirenz. EFV Normally self-resolving but can take weeks to months Anaemia and neutropaenia Sudden and acute AZT bone marrow suppression can AZT occur within the first weeks of therapy or present as a slow onset of progressive anaemia over months Medium term Hyperpigmentation of skin, nails and mucous membranes AZT (the first few Lactic acidosis can occur at any time months) More common after the first few months d4T, ddI, AZT Most commonly associated with d4T Peripheral neuropathy can occur at any time d4T,ddI More common after the first few months Pancreatitis can occur at any time ddI Lipodystrophy and lipoatrophy d4T, ddI, AZT PIs Long term Dyslipidaemia d4T,EFV,PIs (after 6-18 Diabetes months) IDV Skin hair an nail abnormalities PIs, especially IDV

27 Symptom directed toxicity management table Toxicity Causative ARVs Recommendations Acute pancreatitis d4T and ddI Discontinue ART. Supportive treatment and laboratory monitoring. Resume ART with an NRTI with low pancreatic toxicity risk. (AZT, ABC, TDF) Diarrhea ddI (buffered Usually self-limited, without need to discontinue formulation), NVF, ART. Symptomatic treatment should be offered. LPV/r SQV/r Drug eruptions (mild to NVP, EFV (rarely) In mild cases, antihistamines severe, including Moderate rash, non- progressing and without Stevens-Johnson mucosal involvement or systemic signs, consider syndrome or toxic a single NNRTI substitution (i.e., from NVP to epidermal necrolysis) EFV). In moderate and severe cases, discontinue ART and give supportive treatment. After resolution, resume ART with 3 NRTI or 2 NRTI + PI regimens. Dyslipidaemia, insulin PIs Consider replacing the suspected PI by drugs resistance and EFV with less risk of metabolic toxicity hyperglycemia GI intolerance All ARVs Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. Hematological toxicities AZT If severe (Hg<6.5 g% and /or Absolute (particularly anemia and Neutrophil Count [ANC] <500 cells/mm3) leucopenia) replace by an ARV with minimal or no bone marrow toxicity (e.g. d4T, ABC or TDF) and consider blood transfusion. Hepatitis All ARVs If ALT >5-fold the basal level, discontinue ART (particularly with and monitor. After resolution, replace the drug NVP and PI/r) most likely associated. Hyperbilirubinaemia ATV Generally asymptomatic, but can cause scleral (indirect) icterus (without ALT elevations). Replace ATV for other PI. Hypersensitivity ABC Discontinue ABC and do not restart. reaction Symptomatic treatment. Reexposure may lead to a severe and potentially life-threatening reaction. Lactic acidosis All NRTIs Discontinue ART and give supportive treatment. (particularly d4T After clinical resolution, resume ART, replacing and ddI) the offending NRTI. ABC, TDF and 3TC are less likely to cause this type of toxicity. Lipoatrophy and All NRTIs Early replacement of the suspected ARV drug lipodystrophy (particularly d4T) (e.g., d4T for TDF or ABC). Consider esthetic treatment and physical exercises. Neuropsychiatric EFV Usually self-limited, without need to discontinue changes ART. Renal toxicity IDV If using IDV, interrupt IDV and offer hydration, (nephrolithiasis) laboratory monitoring and symptomatic treatment (50% recurrence rate). Consider replacing IDV for another PI. Renal toxicity ( renal TDF Discontinue TDF and give supportive treatment. tubular dysfunction) After clinical resolution, resume ART, replacing the offending drug. Peripheral neuropathy d4T and ddI Consider replacement by an NRTI with minimal or no neurotoxicity (AZT, TDF or ABC). Symptomatic treatment should be considered.

28 Individual drug substitutions for toxicity and intolerance ARV drug Common associated toxicity Suggested substitute Severe anaemia or neutropaenia TDF or d4T Severe gastrointestinal intolerance AZT TDF Boosted PI + NNRTI if TDF Lactic acidosis not available (eg IDV/r + EFV) TDF Lactic acidosis Boosted PI + NNRTI TDF not d4T Lipoatrophy / metabolic syndrome available (eg IDV/r + EFV) Peripheral neuropathy AZT or TDF TDF Renal toxicity (renal tubular dysfunction) AZT or d4T Persistent and severe central nervous NVP or TDF system toxicity EFV Potential teratogenicity (first trimester of pregnancy or women not using adequate NVP contraception) Hepatitis EFV • Substitute EFV for NVP following a non-severe NVP rash and/or Non severe (grade 1 or 2) moderate hepatotoxicity with careful NVP hypersensitivity reaction monitoring. • TDF • PI based regimen if TDF not available Severe or life-threatening rash (Stevens- Cease all ARV until stable Johnson syndrome) g TDF or PI based regimen

Notes The general principle is that single-drug substitution for toxicity should be made within the same ARV class. [e.g., substitution of AZT or TDF for d4T (for neuropathy), TDF or d4T for AZT (for anaemia) or NVP for EFV (for CNS toxicity or in pregnancy)] If a life-threatening toxicity occurs, all ART should be stopped until the toxicity has resolved and a revised regimen commenced when the patient has recovered.

Notes on Stavudine (d4T) d4T is the NRTI most associated with lactic acidosis, lipoatrophy and peripheral neuropathy.19 Because of the current wide availability as FDC and lower price, d4T- containing regimens may be most accessible option for people in resource-limited settings. While safer first-line ART choices become available, closer monitoring for d4T toxicities is recommended. In February, 2007, WHO reviewed evidence for the use of stavudine (d4T) at reduced doses. Previously, the preferred d4T dosing was weight-based. Dosing for patients >60 kg was recommended at 40 mg twice daily; dosing for patients <60 kg was recommended at 30 mg twice daily. A systematic review of nine randomized trials and six observational cohort studies strongly suggests that stavudine-containing regimens maintain clinical and virologic efficacy when stavudine is dosed at 30 mg twice daily, and that this reduced dose is associated with lower rates of toxicity, especially peripheral neuropathy, compared to the 40 mg twice daily dose. Complementary studies have also demonstrated a significant reduction of mitochondrial DNA depletion in patients on the 30 mg twice daily dose. 20,21 Some countries (such as Thailand) and some treating physicians have adopted the principle of commencing a d4T-based regimen and switching to an AZT-based regimen after 6-12 months. The rationale for this is two-fold. AZT may be contraindicated in patients with anaemia at the time of commencement ART (common in those with advanced HIV disease). These patients can be commenced d4T and then switched to AZT once the anemia improves on ART. Secondly, switching from an initial

29 d4T-based regimen to AZT as soon as signs of lipoatrophy or peripheral neuropathy present is an appropriate way to manage these side effects. While no clinical trial data are available to support this strategy, such trials are being planned.

Strategies to maximize the safe use of d4T Consider d4T 30 mg BID for all patients irrespective of body weight Error! Bookmark not defined. Training health care workers to recognize Adequately educating patients in the early the signs and symptoms of lactic acidosis, recognition of d4T side effects and when to lipoatrophy and peripheral neuropathy. expect them

Switching to an alternative NRTI (such as The role of dose reduction in limiting d4T AZT, TDF or ABC) as soon as side effects toxicity is uncertain. Some data suggest that occur may reduce the severity of d4T toxicities dose reduction may be associated with a lower incidence of adverse event without Commence with d4T in anaemia patients and compromising virological control.22 switch to an alternative NRTI (such as AZT, TDF or ABC) if anaemia improves on ART Dose reduction to 30 mg twice daily irrespective of weight has been adopted in some county programs.

30 Chapter

Considerations for specific patients

6 ART for women of childbearing potential or who are pregnant Clinical Situation Guiding Principles Recommendations Recommended first-line regimen is a NVP-based plus 2 NRTIs EFV plus 2 NRTIs may be Treatment decisions are based solely on All women used if women have access to the women’s medical need consistent and reliable barrier methods of contraception or after the first trimester of pregnancy Some experts recommend that all pregnant woman with ART is recommended for pregnant WHO clinical stage 3 disease women according to the same eligibility and CD4 count < 350 criteria as for non-pregnant adults cells/mm3 should initiate Initiating ART in ART should be initiated in pregnant ART pregnant women women with WHO clinical stage 3 or 4 Recommended regimen is 2 disease, or those with WHO clinical NRTIs plus and NNRTI stage 1 or 2 disease with CD4 count The preferred regimen is before drops below 200 AZT+3TC+NVP with careful monitoring women with higher CD4 counts (>250) NVP is substituted for EFV with close monitoring in Women who are women with higher CD4 pregnant, are in the EFV should be discontinued and counts first trimester and are replaced with another drug Alternatively a PI-based or a taking EFV triple NRTI regimen could be substituted ART is recommended for postpartum Women who are breastfeeding women who meet the The preferred regimen is breast feeding WHO criteria for initiation of therapy for AZT+3TC+NVP their own health Women who have previously received single-dose NVP prophylaxis for SDN > 6 months prevention of MTCT should be NNRTI-based regimen Women who received considered eligible for NNRTI-based SDN <6 months ART as part of PMCT regimens. Alternatives may be A triple NRTI regimen or PI- intervention considered for women whose exposure based regimen also can be to single dose NVP (SDN) was <6 considered months before ART was initiated

31 Notes on Nevirapine Women with CD4 counts between 250 and 350 are at increased risk of NVP hypersensitivity with fatal hepatic toxicity. This applies to pregnant and non-pregnant women. NVP should be used with caution and with careful clinical and monitor liver function monitoring in this population Interaction between ART and hormonal contraceptives NVP, RTV, NFV, LPV/r and SQV/r result in reduced ethinyl oestradiol levels. 23 24 Oestrogen levels are slightly increased by ATV and IDV and EFV. Consistent use of condoms is recommended women in all HIV-infected women also when taking ART. Limited data show no interaction between medroxyprogesterone acetate and NVP, EFV, or NFV.25

Initiating ART in pregnant women When to start ART in pregnant woman WHO Stage CD4 testing not available CD4 testing available 1 Do not treat Treat if CD4 count 2* Do not treat < 200 cells/mm3

3 Treat Treat if CD4 count < 350 cells/mm3 4 Treat Treat irrespective of CD4 cell count

Recommendations only differ from general adult guidelines in that ART should be initiated in pregnant women with a CD4 count < 350. Many women with a CD4 200-350 will require ART within the first year postpartum and efficacy of NNRTI-based ART initiated less than 6 months following exposure to single-dose NVP viral suppression may be compromised due to NVP resistance. Once initiated, ART should be continued post-partum. Close monitoring of AST/ALT is recommended during the first few months after commencing NVP-containing ART in pregnant women. Recommended testing schedule is at weeks 0, 2, 4, 6, 8 and then monthly until delivery. NVP should be discontinued if ALT >2.5X ULN, a lower threshold than normally recommended in adults.

Preferred NRTIs for use in pregnant women are AZT and 3TC. The combination of d4T/ddI should not be used. There are no data on use of FTC in pregnancy. Studies have associated TDF with decreased foetal growth and bone demineralization. 26 27

The preferred NNRTI is NVP, due to extensive clinical experience with this drug in pregnant women and its proven efficacy in reducing mother to child HIV transmission. SQV/r and NLF are the preferred PIs if women cannot tolerate NVP .EFV may be considered after the first trimester

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ART in Tuberculosis/HIV co-infection Initiating ART in patients with active TB Timing of ART in relation CD4 Cell Count ART recommendations1 the start of TB treatment CD4 < 200 Recommend ART Between 2-8 weeks CD4 between 200-< 350 Recommend ART After 8 weeks Re-evaluate patient at 8 CD4 > 350 Defer ART weeks and at the end of TB treatment CD4 not available Recommend ART 2-8 weeks Choice of NRTI This is the same as for all HIV infected persons. Choice of NNRTI EFV is the preferred NNRTI. EFV blood levels are decreased in the presence of rifampicin. There is evidence standard EFV dosing of 600 mg/daily in patients with a weight <60 kg is adequate. 28 29 30 31 32 Pending more data on EFV dosing for those ≥60 kg, WHO also recommends the standard 600 mg dose of EFV. NVP levels are also decreased in the presence of rifampicin. However, standard NVP dosing is recommended.33 34 35 36 37 Due to concerns about hepatotoxicity, nevirapine-containing regimens should only be used when no alternative is available for women on rifampicin- containing regimens, with CD4 cell count 250-350 cells/mm3 who need to start ART. A triple NRTI regimen (AZT+3TC+ABC or AZT+3TC+TDF) can be used with rifampicin. AZT, 3TC and TDF have no or minimal interactions with rifampicin but triple NRTI regimens are less potent than NNRTI-based regimens Recommendations for patients on ART who develop active TB First or second line ART regimen at the time ART Options ART TB occurs 2 NRTI + EFV Continue with 2 NRTI + EFV Substitute to EFV or First line 2 NRTI + NVP Substitute to triple NRTIs or Continue with 2 NRTI + NVP Triple NRTI Continue triple NRTI Substitute to or continue ( if already Second line 2 NRTI + PI being taken) LPV/r or SQV/r containing regimen and adjust dose of RTV

Notes: Switching back to NVP after rifampicin completed can be considered. When switching back from EFV to NVP no lead-in dose is required. If a pregnant woman develops active TB and she is in the second or third trimester, an EFV containing ART regimen can be considered. An alternative in women with active TB in the first trimester is a triple NRTI regimen or a NVP containing regimens, with careful monitoring in women with higher CD4 counts or when CD4 count is unknown. Second line ART for patients with TB indicating first-line ART failure

33 Unboosted PIs cannot be used with rifampicin-containing regimens because protease inhibitor levels are sub-therapeutic. 38 39 If a patient needs to switch to or is already on a PI-based regimen, lopinavir 400 mg/ritonavir 400 mg twice daily in combination with rifampicin could be considered under close clinical and laboratory supervision for hepatic toxicity. An alternative is SQV 400 mg/RTV 400 mg with close clinical and laboratory monitoring, Recommendations and precautions for the use of PI-based regimens in combination with rifampicin in women of childbearing potential and pregnant women are the same as for other TB patients.

34

Antiretroviral therapy for IDUs Criteria for initiating ART in substance using patients are the same as all patients with HIV Before starting ART, specific factors which may affect the timing of initiation and the choice of ART should be considered. These include, social instability, active use of illicit drugs and presence of co-morbidities such as mental problems and Initiating hepatitis viruses co-infections ART Unavailability of OST or active use of illicit drugs should not preclude access to ART for those IDUs in need Effective links between ART and harm reduction programs are essential Unless the person is severely unwell, initiation of ART is not urgent Adequate time spent preparing to start ART, understanding treatment goals, adherence and the nature of life long ART will maximize treatment outcomes WHO-recommended regimens can be chosen for the majority of IDUs Choice of The choice of specific antiretroviral drugs depends on: ART • Co-morbidities (especially hepatitis B/C and psychiatric disorders) • Drug interactions (methadone, buprenorphine) • Adherence (fixed dose combinations Preferred first line AZT + 3TC + (EFV or NVP) regimen Hepatitis C (and hepatitis B) infection are extremely common in IDUs. Monitoring hepatotoxicity is strongly recommended in IDUs receiving NNRTI based ART, especially NVP EFV EFV is recommended by some experts due to the high prevalence of hepatitis B and C infection in IDUs and less risk of hepatic complications with EFV compared to NVP.40 Choice of EFV is preferred in patients with clinical and/or laboratory evidence of significant NNRTI (grade 3 or 4) hepatic dysfunction. EFV should not be used or used with caution in patients with depression or other significant psychiatric conditions NVP NVP is recommended in patients with no other significant comorbidities. Specifically, patients with no clinical signs of hepatic dysfunction or elevation of hepatic transaminases (grade 3 or 4). If NVP is the only NNRTI available, use with careful clinical and laboratory (liver enzyme) monitoring TDF + (3TCor FTC) + (EFV or NVP) Alternative Patients who are HBsAg +ve and TDF is available first line AZT may be replaced by d4T in any regimen in case of toxicity or regimen contraindication Second line Recommendations are the same as for all patients with HIV regimen (ddI or TDF) + ABC+ PI/r or TDF + 3TC (± AZT) + PI/r or ddI +TDF + PI/r With experienced staff and adequate support, IDUs can adhere to ART and have Adherence clinical outcomes comparable to those of HIV patients who do not use drugs 41 42 Administration of methadone with EFV, NVP or RTV decreases plasma levels of Methadone methadone which may precipitate opiate withdrawal.43 Patients receiving methadone and commencing ART may require increased doses of methadone

Choice of NNRTI component Patients, particularly women, with increased CD4+ cell count at initiation of NVP therapy (>250 cells/mm3 in women and >400 cells/mm3 in men) are at higher risk for the development of symptomatic hepatic events, often associated with rash. The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non- specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver

35 tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels Patients who have infection with hepatitis B or C and/or increased liver function tests at the start of therapy with NVP are at greater risk of later symptomatic events (6 weeks or more after starting NVP) and asymptomatic increases in AST or ALT. Serious psychiatric adverse experiences have been reported in patients treated with EFV. These include severe depression (2.4%, 0.9%), suicidal ideation, aggressive behavior, paranoid reactions and manic reactions. Viral hepatitis and chronic liver disease Co-infection with Hepatitis C is common in HIV infected IDUs. Chronic active infection with Hepatitis B and alcoholic liver disease are also common. Hepatotoxicity associated with these conditions complicates the choice of ART. The NRTIs with most hepatotoxicity are AZT, ddI or d4T. Both available NNRTIs can cause hepatotoxicity. NVP is more commonly associated with severe hepatotoxicity and should be avoided if possible in all patients with chronic liver disease.44 Efavirenz can be administered at full doses in patients with liver insufficiency. Protease inhibitors are also associated with hepatotoxicity. PI dosing is complex in patients with hepatic insufficiency 45. If drugs are available, the recommended treatment for HIV/HBV co-infection is TDF alone or in combination with 3TC or FTC as part of the ART regimen. 3TC should not be used alone due to rapid development of HBV resistance. Fatal cases of acute flare of HBV have been documented in HIV/HBV coinfected patients who discontinue 3TC monotherapy.46 47 Drugs for treating hepatitis C normally are not available in resource limited settings. Treatment is with pegylated interferon and ribavirin. There is no other treatment for hepatitis C. Patients should be stable on ART with CD4 >200 before pegylated interferon and ribavirin are commenced. AZT levels are increased by ribavirin and patients should be closely monitored for hepatic toxicity, neutropaenia, and anaemia. Other causes of hepatic dysfunction need to be considered in addition to viral hepatitis. Alcohol use/dependency has the same implication for treatment options and monitoring as does viral hepatitis. Where possible, the least hepatotoxic ARV should be used and hepatic enzymes monitored in all patients with hepatic dysfunction. Opiod substitution therapy OST is the most effective treatment for opioid dependence with substantially higher retention rates, suppression of drug use and improved psychosocial functioning. Its use in the context of HIV treatment has been associated with improved adherence and outcomes to treatment. Detoxification and abstinence based programs are unlikely to achieve similar levels of clinical effectiveness and may prove counterproductive in the context of ART. If possible, stabilization of substance use with substitution treatment is recommended prior to commencement of ART. Where substitution therapy is available, consideration should be given to offering HIV care and dispensing HIV medication at the same site where substitution therapy is delivered. This approach can achieve maximal levels of treatment supervision

36 which should enhance efficacy and reduce the risk of HIV drug resistance. In addition co- location of these services facilitates management of the drug-drug interactions between methadone and ART. Outcomes of OST in a structured program include: • Decreased heroin use and reduced chaotic drug taking • Decreased needle sharing • Stabilization of client’s lives • Improved quality of life and the chance to lead a productive life in the community • Improved ability to commence and adhere to ART

37

HIV and Hepatitis Co-infection Hepatitis B infection Choice of Drugs with anti-HBV therapy should be included in first line ART regimen for ART HIV-infected patients who are HBsAg+ (and HBeAg+ if known) Preferred first line TDF + (3TC or FTC) + EFV ART Alternatives (AZT or d4T) + (3TC or FTC) + EFV if TDF is (AZT or d4T) + (3TC or FTC) + NVP (See Choice of NNRTI below) unavailable In this case, 3TC (or FTC) will be the only drug with activity against hepatitis B • EFV is the preferred NNRTI option • NVP should be used with care and regular monitoring in patients who have Choice of known HIV/HBV coinfection and grade 1, 2 or 3 elevation of ALT/AST NNRTI • NVP is not recommended for patients with grade 4 or greater elevations of ALT/AST Second line 3TC be continued as part of second-line ART following initial ART failure, even regimen if it was used in first-line regimen • Ideally, 3TC should be used either with TDF or not at all • This may not be feasible in resource limited settings HBV • HBV resistance to 3TC will develop in 50% of patients after two years and in Resistance 90% after four years of treatment if 3TC is the only active anti-hepatitis B drug in the ART regimen. Therapy HBV seroconversion (loss of HBeAg and development of HBeAb) occurs in outcomes 11-22% of HBeAg-positive HIV-infected patients treated with 3TC for one year • Soon after initiation of ART as part of IRIS Hepatic flares • Discontinuation of 3TC also may result in hepatic flares

Hepatic flares Hepatic flares may occur • Following initiation of ART as part of the immune reconstitution inflammatory syndrome (IRIS). • When ART is stopped Flares typically present as unexpected increase in ALT/AST and symptoms of clinical hepatitis (fatigue, nausea, abdominal pain and jaundice) within 6-12 weeks of commencing ART. Flares may be difficult to distinguish from ART-induced hepatic toxicity. Drugs active against HBV should preferably be continued during a suspected flare. If it is not possible to distinguish a serious hepatitis B flare from grade 4 drug toxicity, all ART should be stopped until the patient stabilizes.

38 Hepatitis C infection No ARVs are directly active against HCV. However, ART has been shown to delay progression of HCV liver disease in HCV/HIV coinfection HCV therapy The only effective treatment is pegylated interferon and ribavirin which are generally not available in resource limited settings48 Clinical trial outcomes Therapy • HCV genotype 1: 15-28% sustained virological response rates outcomes • HCV genotype 2 and 3: 60-70% virological response rates Side effects Up to 60% of individuals treated with IFN will experience mental health issues, of interferon mostly commonly depression. Monitor mental health closely. • Commence anti-HCV therapy before CD4 count drops to levels where ART is required Timing of HCV therapy • If ART is required in HCV-positive patients, they should be stable on ART with a CD4 count >200 cells/mm3 before anti-HCV therapy is considered 40 • NRTI choice is the same as for HCV uninfected patients • EFV is the preferred NNRTI option Preferred • NVP should be used with care and regular monitoring in patients who have first line known HIV/HBV coinfection and grade 1, 2 or 3 elevation of ALT/AST ART • NVP is not recommended for patients with grade 4 or greater elevations of ALT/AST • Ribavirin and d4T/ddI - pancreatitis/lactic acidosis o do not co-administer • Ribavirin and AZT - anaemia Drug interactions o monitor closely • Interferon and EFV - depression o Monitor closely Hepatic Soon after initiation of ART as part of IRIS flares

39 Chapter

ART failure and when to switch therapy

7 Work with the patient to resolve issues causing non- Does the patient have adherence. Continue the same first line regimen, good adherence to ART? give OI prophylaxis of necessary and follow closely. [a] No Start second line therapy only after good adherence can be assured Yes

Patient has Signs or been on ART symptoms of for at least 6 IRIS or OI months especially TB

Manage IRIS or OI Monitor response Obtain CD4 count if possible before diagnosing failure Patient Yes improves after IRIS /OI management Prepare the patient for second Continue first line line regimen No ART The regimen is like to be more complex Make sure the patient Diagnose treatment understands the new drugs, how failure if OI present to take them and possible side and on ART >6 effects months with Reinforce adherence good adherence

40 Defining failure New or recurrent WHO stage 4 condition after at least 6 months on ART Clinical failure Exceptions are TB, oesophageal candidiasis and severe bacterial infections which may not always represent ART failure Review response to therapy first and if response is good, do not switch Virological failure Viral load >10,000 copies after at least 6 months on ART

Notes: ART failure cannot be diagnosed on clinical criteria grounds in the first 6 months on ART. Clinical events that occur before the first 6 months of therapy often represent IRIS and not failure. Immunological criteria for failure

CD4 count

Pattern 3

Pattern 2

50 or 100

Pattern 1

6 months 12 months

Pattern 1 CD4 count < 100 cells/mm3 (some experts recommend <50 cells/mm3) after one year of therapy Pattern 2 Return to or a fall below the pre-therapy CD4 baseline after one year of therapy Pattern 3 50% decline from the on-treatment peak CD4 value (if known). CD4 cell count can also be used to determine when not to switch therapy. For example, in a patient with a new clinical stage 3 event for whom switch is being considered switching is not be recommended if the CD4 cell count is >200 cells/mm3. Virological criteria for failure are included here as some countries in the region (such as India and Thailand) have increasing capacity to perform affordable viral load testing. Viral load remains the most sensitive indicator of ART failure. Recognizing early failure facilitates switching before multiple resistance mutations have developed to drugs in the first line regimen. The optimal viral load value at which ART should be switched has not been defined.

41 However, values of more than 5,000-10,000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline 49 50 51 52 53 Choice of second-line regimens for treatment failure Second Line Regimen First Line Regimen RTI Component* PI Component

ddI + ABC or

TDF + ABC or AZT or d4T + 3TC Preferred regimens +(NVP or EFV) TDF + 3TC (± AZT) PI/r

(or ddI + TDF ) (AZT or d4T) + 3TC Alternative regimen EFV or NVP ± ddI + (TDF or ABC) The entire treatment regimen needs be changed in the setting of treatment failure. Boosted PI/NRTI combinations A ritonavir-boosted PI (PI/r) such as ATV/r, FPV/r, IDV/r, LPV/r or SQV/r is the backbone of all second line regimens. Unboosted PIs are not recommended with the exception of NFV if no ritonavir is available. Nelfinavir is less potent than a boosted PI. 54 55 Two unused NRTIs are added to the PI/r and ddI is a preferred NRTI.56 *If AZT or d4T are used in the first line regimen (as may be the case in many countries), TDF or ABC are included in all preferred second line regimens. If these drugs are not available, options are limited. ddI + 3TC (± AZT) may be the only option if ABC and TDF are not available. If preferred NRTIs are not available, some experts recommend supporting the boosted PI component of the second line regimen with ddI plus retaining 3TC (+/-AZT), even though it was used in the first line.3TC reduces HIV fitness even if 3TC resistance is present. The combination of TDF and ddI plus and NNRTI is not recommended due to reports of early virological failure57, falling CD4 counts despite undetectable viral load58 59 and safety concerns. TDF increases ddI exposure by 60% and intracellular ddI levels two fold60. There are also reports of renal and pancreatic toxicity. Although ddI and TDF are not recommended anymore, the combination is still mentioned as the drugs are still widely available in the public health sector. For those who received a triple NRTI first line regimen, the recommended combination is a boosted PI plus an NNRTI with the option to add ddI and/or 3TC to the boosted PI/NNRTI combination. 61 62

Symptom directed toxicity management table for SECOND line ARVs Toxicity Causative ARVs Recommendations Discontinue ART. Supportive treatment and Acute pancreatitis ddI laboratory monitoring. Start new regimen replacing ddI with ABC or TDF if available Usually self-limited, without need to discontinue NVF, ddI (buffered ART. Symptomatic treatment should be offered. Diarrhea formulation), LPV/r NFV is most commonly associated with SQV/r diarrhoea. Replace NFV with another PI

42 Chol and TG elevations to grade 1or 2 Monitor, diet , exercise Chol and TG elevations to grade 3 or 4 Treat elevated TG with fibrates (fenofibate 600 Dyslipidaemia PIs mg 1-2 times per day Treat elevated chol with statins. Avoid simvastatin due to interactions with PIs (Annex 4) Insulin resistance and Indinavir Switch to a different PI hyperglycemia Renal colic and calculi Indinavir Drink 3l of fluid per day. Consider switching PIs Usually self-limited, without need to discontinue GI intolerance All ARVs ART. Symptomatic treatment should be offered. Hematological toxicities If severe (Hg<6.5) stop AZT and consider blood (particularly anemia and AZT transfusion. leucopenia) LPV/r and other PIs If ALT >5-fold the basal level, discontinue ART Hepatitic dysfunction less commonly and monitor. After resolution, try a different PI Generally asymptomatic, but can cause scleral Hyperbilirubinaemia ATV, IDV icterus (without ALT elevations). Replace ATV (indirect) or IDV with another PI. Discontinue ABC and do not restart. Hypersensitivity ABC Symptomatic treatment. Reexposure may lead to reaction a severe and potentially life-threatening reaction. Discontinue ART and give supportive treatment. All NRTIs After clinical resolution, resume ART, replacing Lactic acidosis (particularly d4T the offending ITRN. ABC, TDF and 3TC are and ddI) less likely to cause this type of toxicity. All NRTIs Lipoatrophy and (particularly d4T) Early replacement of the suspected ARV drug. lipodystrophy and PIs Discontinue TDF and give supportive treatment. Renal toxicity ( renal TDF After clinical resolution, resume ART, replacing tubular dysfunction) the offending drug. Consider replacement by an NRTI with minimal Peripheral neuropathy d4T and ddI or no neurotoxicity (AZT, TDF or ABC). Symptomatic treatment should be considered.

43 Chapter Prevention of Mother to Child Transmission Objective Mother to child transmission is one of the important preventable causes of HIV infection. This guideline aims to provide guidance to assist the health workers in different settings including hospitals and 8 primary health care facilities for the selection and provision of ARV for pregnant women, either for their own health or prophylaxis for the prevention of mother to child transmission (PMCT), taking into account the needs and constraints on health systems in various settings. The comprehensive strategic approach The comprehensive strategic approach to the prevention of HIV infection in infants and young children consists of four components: o primary prevention of HIV infection among women of reproductive age o prevention of unintended pregnancies among women living with HIV o prevention of HIV transmission from mothers living with HIV to their infants o care, treatment and support for mothers living with HIV, their children and families

Although this document primarily describes the third component, it is always important to make sure the other components are appropriately addressed. Background Transmission Rate without intervention Most children living with HIV acquire the infection through mother-to-child transmission (MTCT), which can occur during pregnancy, labour and delivery or during breastfeeding. In the absence of any intervention the risk of such transmission is 15–30% in non-breastfeeding populations. Breastfeeding by an infected mother increases the risk by 5–20% to a total of 20– 45%. Transmission rate with intervention The risk of MTCT can be reduced by 50% with the administration of single dose Nevirapine to mother and baby. But this can be further reduced to below 2% by more potent antiretroviral (ARV) prophylaxis given to women during pregnancy and labour and to the infant in the first weeks of life followed by complete avoidance of breastfeeding. Risk Factors MTCT risk factors during pregnancy High maternal viral load (new or advanced HIV/AIDS) Viral, bacterial, and parasitic placental infection (especially malaria) Sexually transmitted infections Maternal malnutrition (indirectly)

MTCT risk factors during labour and delivery High maternal viral load (new or advanced HIV/AIDS) Rupture of membranes for more than 4 hours before labour begins Invasive delivery procedures (vacuum, forceps, episiotomy) First infant in a multiple birth Chorioamnionitis (inflammation of the membranes covering the foetus)

MTCT risk factors during breastfeeding High maternal viral load (new or advanced HIV/AIDS) Duration of breastfeeding Early mixed feeding of infant (breast milk with replacement feeding) Breast abscesses/inflammation or cracked nipples Maternal malnutrition

44 Infant oral disease (eg, thrush or mouth sores) Counselling for PMCT Counselling is an essential part of PMCT programs to provide informed choice so that pregnant women are able to decide on: o HIV testing o Choosing ART treatment or ARV prophylaxis, with commitment to good adherence o safe delivery options o appropriate infant feeding practice Another important aspect is that PMCT can be a useful means for HIV prevention as HIV- negative pregnant mothers can be thoroughly counseled to maintain their negative status, and their spouses will also be encouraged for testing.

Safe delivery Interventions that reduce MTCT risk in labour and delivery include: o Universal precautions o Minimal use of cervical examinations o Avoidance of: Prolonged labour Routine rupture of membranes Unnecessary trauma such as episiotomies and foetal scalp monitoring o Minimise risk of postnatal haemorrhage o Safe transfusion practices

Regarding mode of delivery, elective Cesarean section, when performed before the onset of labour or membrane rupture, has been associated with reduced MTCT. But it needs to be considered individually that the benefits and risks of vaginal delivery versus elective caesarean section, including the safety of the blood supply and the risk of complications from operation.

ARV prophylaxis for PMCT Following are the potential case scenarios of HIV positive pregnant women : A. Women who become pregnant while receiving ARV treatment B. Pregnant women with indications for ARV treatment C. Pregnant women not yet indicated for ARV treatment [ARV prophylaxis for preventing HIV prevention in infants] D. Women living with HIV who are in labour and who have not received ARV prophylaxis E. Infants born to women living with HIV who have not received ARV drugs during pregnancy or labour

A. Women who become pregnant while receiving ARV treatment For women who become pregnant while receiving antiretroviral therapy, the treatment should be continued. o However, if she is on an EFV-containing regimen and is in the first trimester of pregnancy, NVP should be substituted for EFV. Alternatively a triple NRTI- or PI-based regimen could be used. o Women who are receiving EFV and are in the second or third trimester of pregnancy can continue the current regimen. o Exposure to EFV during pregnancy is not an indication for abortion.

Infants born to women who are receiving antiretroviral therapy should receive AZT for seven days. B. Pregnant women with indications for ARV treatment

45 Recommended and alternative prophylactic ARV regimens for pregnant women who have indication for ART depends on the capacity of the staff, resources and facilities in addition to clinical criteria.

If there is access to ARV treatment for pregnant women If she meets the criteria and conditions, initiate ARV using the same principles as in no pregnant women. Preferred regimen: AZT +3TC +NVP

If there is no access to ARV treatment for pregnant women, Follow the recommendations in Scenario C. C. Pregnant women no indications for ARV treatment- ARV prophylaxis for preventing HIV transmission to the infants Single dose NVP is the simplest regimen to administer but less effective and at high risk of resistance to NVP. On the other hand, longer and more complex regimens are more effective and lower risk of NVP resistance but costly and more complex to deliver. The decision is based on the availability, capacity, resource as well as the informed choice of pregnant women. A new recommendation in this guideline is the AZT/3TC “tail”. This refers to the administration of AZT/3TC “tail” for seven days following single dose nevirapine given to the mother to reduce the development of resistance to NVP.

Time Of Administration Ranking Pregnancy Labour Postpartum Mother: AZT AZT/3TC × 7 days a Sd-NVP a Recommended (>28 weeks Infant: + AZT/3TC gestation) Sd-NVP a

+ AZT × 7 days b AZT Sd-NVP Infant: Alternative (>28 weeks Sd-NVP+ AZT × 7 days b

gestation) Mother: Sd-NVP + Minimum AZT/3TC × 7 days - AZT/3TC Infant:

Sd-NVP Minimum Sd-NVP Infant: - Sd-NVP a If the woman receives at least four weeks of AZT during pregnancy, omission of the NVP dose for mothers may be considered. In this case the NVP dose must be given to the infant immediately after birth, AZT is recommended for four weeks instead of one week, and the mother will not require 3TC during labour as well as AZT and 3TC postpartum. b If the mother receives less than four weeks of AZT during pregnancy, AZT is recommended for four weeks instead of one week.

Nevirapine resistance and its prevention NVP has a prolonged half-life, with detectable levels persisting in some women who have received Sd-NVP for up to 21 days postpartum. The prolonged half-life is beneficial in that, in addition to preventing intrapartum transmission, NVP can prevent MTCT occurring postnatally during the first few weeks of life. However, the woman is also exposed to a prolonged period of non-suppressive drug levels, promoting the development of resistance to NVP. Studies have shown that resistance to NVP may occur in as many as 60–89% of women given Sd-NVP. In addition, resistance to NVP usually confers cross-resistance to EFV. Viral resistance was also detected among 33–53% of infants with HIV when both they and their mothers were exposed to Sd-NVP.

46 The most important method of preventing resistance to NVP is to give combination therapy to those women who require it. However, accumulating data suggest that the incidence of resistance may be decreased if dual NRTI drugs are administered intrapartum and for a short period postnatally as a “tail” following Sd-NVP. By adding the “tail” with AZT and 3TC during labour and postpartum, the risk of developing resistance to NVP can be reduced from 60% to about 10%.

Doses of antiretroviral prophylaxis drugs for PMCT All regimens are administered by mouth. Dosage is summarized in the below table. Paediatric formulations exist for the main drugs used in current prophylactic regimens to prevent MTCT (AZT, NVP and 3TC). For Mothers During pregnancy AZT 300 mg twice a day starting at 28 weeks or as soon as possible thereafter

During labour Sd-NVP 200 mg at onset of labour AZT 600 mg at onset of labour OR 300 mg at onset of labour and every 3 hours until delivery 3TC 150 mg at onset of labour and every 12 hours until delivery.

After delivery AZT 300 mg twice a day for 7 days 3TC 150 mg twice a day for 7 days

For Infants Sd-NVP: 2 mg/kg oral suspension (or 6 mg) at once immediately after birth (within 72 hours) AZT 4 mg/kg twice a day for 7 days OR 4 weeks* 3TC 2 mg/kg twice a day for 7 days

* If the mother receives less than four weeks of AZT during pregnancy, AZT is recommended for four weeks instead of one week.

D. Women living with HIV who are in labour and who have not received ARV prophylaxis If the pregnant women are in labour without receiving ARV prophylaxis, the recommended regimen is as shown below. If delivery is expected imminently, the NVP dose for the mother should be omitted and the same recommendations and considerations apply as for infants under scenario E. When delivery occurs within two hours of the woman taking NVP, the infant should receive Sd-NVP immediately after delivery and AZT for four weeks.

47

Selection of prophylactic ARV regimens depends on the capacity of the staff, resources, facilities as well as the informed choice of pregnant women.

Time Of Administration Ranking Labour Postpartum Mother Sd-NVP + Recommended AZT/3TC × 7 days AZT/3TC Infant:

Sd-NVP + AZT × 4 weeksa Mother Alternativeb AZT/3TC AZT/3TC × 7 days Infant AZT/3TC × 7 days Mother Sd-NVP + Minimum AZT/3TC × 7 days AZT/3TC Infant

Sd-NVPa Minimum Infant Sd-NVP Sd-NVP a Data on added efficacy of four weeks of infant AZT in this situation are limited. bEquivalent efficacy to Sd-NVP alone intrapartum/postpartum and no risk of resistance to NVP in women or infants should they become infected E. Infants born to women living with HIV who have not received ARV drugs during pregnancy or labour Sd-NVP immediately after delivery and AZT for four weeks are recommended for infants born to women living with HIV who do not receive any ARV prophylaxis, because this regimen results in a greater reduction in transmission than just Sd- NVP for the infant. ARV prophylaxis for infants should begin immediately after delivery or within 12 hours after delivery, if possible. Selection of prophylactic ARV regimens depends on the capacity of the staff, resources, facilities and well-informed choice of the mother.

Time Of Administration Ranking Postpartum Recommended Infant: Sd-NVP immediately after birth + AZT × 4 weeksa Alternative Infant: Sd-NVP immediately after birth + AZT × 1 week Minimum Infant: Sd-NVP immediately after birth

a NVP administered immediately after birth, if possible within 12 hours after delivery, is likely to result in a larger reduction in transmission than starting it later. Data on added efficacy of four weeks of AZT for infants in this situation are limited 2. Cotrimoxazole prophylaxis It is recommended for all HIV-exposed children born to mothers living with HIV, and pregnant women living with HIV who fulfil the criteria. For details please refer to OI prophylaxis for adult (Chap##) and children (Chap ##).

48

3. Diagnosis of HIV exposed babies Early diagnosis of exposed babies helps to guide the infant feeding option and OI prophylaxis, as well as introduction to ART. However, testing at young month does not provide reliable results due to the presence of maternal antibody in the infants. • Final confirmation should be made at 18 months by antibody test. • Negative result at 9 months by antibody test can confirm as negative, but positive result needs to be confirmed at 18 months. • Antigen testing by PCR after 6 weeks can provide more than 95% sensitivity and specificity. However, it has to be confirmed by antibody test at 18 months. 4. Referral for care and support The needs of HIV infected mother and their families are diverse and change over time. The need is not limited to medical. Health care staff should try to link with appropriate service available in the locality, either by public or private and continuously follow up with strict confidentiality.

49 Chapter Post exposure prophylaxis

9 Occupational and non-occupational exposure prophylaxis

What type of exposure has occurred?

Exposure with Exposures with the potential for no or negligible HIV potential for HIV transmissiona transmission

≤ 72 hours >72 hours PEP not since exposure since exposure recommended b

PEP recommended

a. PEP should be provided following exposure of non-intact skin (through percutaneous sharps injury or other exposure) or mucous membranes (through sexual exposure or splashes to the eyes, nose, or oral cavity) to a potentially infected body fluid from an HIV positive or unknown HIV status source. Body fluids which may transmit HIV include blood, genital secretions, and cerebrospinal, amniotic, peritoneal or pleural fluids. b. While PEP will be less effective or ineffective if delayed > 72 hours, it may be considered in circumstances where a significant potential exposure has occurred

50 Occupational post exposure prophylaxis Prevention of occupational exposure in health facilities Since PEP is not 100% effective, the importance of primary prevention in all settings where HIV could be transmitted should be reinforced as part of all programs that provide PEP. Health facilities should implement and strengthen primary prevention measures including safety training the workplace and universal precautions for the prevention of exposure to potentially contaminated material. Universal precautions include: • Training of all employees in handling and disposal of infectious material • Provision of guidelines for prevention and control of infections • Provision of equipment necessary for prevention and control of infections, such as, educational materials, disposable gloves, disposable syringes and needles and sharps bins • Monitoring mechanism to ensure implementation

Risk of Exposure The risk of occupational transmission of HIV varies with the type and severity of exposure.63 It is estimated that the transmission rate of HIV from an infected patient to an exposed person through significant needle stick accidents is approximately 0.3% (3 in a 1000) and approximately 0.09% in the case of mucous membrane exposure.64

Components of occupational PEP • Treatment of exposure site • Assessment of risk and counseling of the exposed person • Discussion of PEP and provision based on informed consent (not necessarily written) and understanding of the benefits and possible side effects of ARVs • Provision of voluntary counselling and testing • Providing antiretrovirals if indicated • Follow up and documentation of the incident Treatment of exposure site Wash skin with soap and water. Do not rub the Skin exposed area Eyes Rinse eyes immediately with eye wash fluid Spit out immediately Rinse mouth immediately several times with clean Oral exposure water Do not use antiseptics

Assessment of risk If available, give PEP for deep skin injuries, large hollow-bore needle and blood visible on needle or sharp instrument if source patient is known to have HIV. Ascertain the HIV status of the patient and the injured health worker after providing appropriate counseling. Risk fluids and exposure

51 Deep skin injury (Needle stick, cut with sharp object) Contact with mucous membranes and non-intact skin Types of exposure (eyes, skin rash present, scratch, abrasion) with potentially infectious body fluid Blood is a high risk fluid Risk fluids Other high risk body fluids are semen vaginal secretions CSF, synovial, pleural, peritoneal pericardial amniotic fluids Saliva and urine are low risk fluids Contact with normal skin with no injury is not a risk for HIV transmission

Assessment of source patient If the status of source patient is unknown, provide counseling and encourage HIV testing if appropriate. If it is not possible to determine the HIV status of the source patient, PEP should be given if the exposure is assessed as a potential risk for HIV transmission If the source patient is HIV negative, no post-exposure prophylaxis is necessary for the exposed health worker. If the source patient is confirmed HIV positive, the risk of exposure to the HCW is higher if the source patient has advanced HIV disease, a known high viral load or is not on ART. If the source patient is on ART and known to be failing or has previously failed ART, the choice of PEP provided to the HCW will depend on a detailed ART history and review if the source patient’s medical record if available. In this scenario, as viral resistance is probably present, addition of a 3rd drug (a boosted PI) to the PEP regimen is recommended for the exposed person. Assessment of exposed person Baseline HIV testing should be performed on all persons seeking evaluation PEP. Rapid tests are recommended. If PEP is indicated, it should be commenced before test results for the exposed person or the source are available. The need to continue nPEP can be reviewed based in the test results. If the exposed person is HIV positive, no post-exposure prophylaxis is necessary but the person should be referred for further counseling and management on a long-term basis for his/her HIV infection. If the person is HIV negative and the source patient is HIV positive then continue antiretrovirals for a period of 28 days; repeat the person’s HIV tests at 3 months and at 6 months after the initial test. PEP, if indicted, should be commenced immediately and not delayed pending the result of the HIV status of the exposed person. If the HCW subsequently is found to be HIV positive, a 2 drug PEP regimen should be stopped and the person’s clinical and immunological (if available) status and the need to commence ART assessed. Two drug PEP should be stopped because resistance will rapidly develop if the HCW is already infected. A three drug PEP regimen may be continued if it is required for the medical needs of the person. If the person should seroconvert during this time then provide appropriate care and counseling and refer for expert opinion and management.

52 Counselling • Give health care worker pre test counseling • Test the health care worker (baseline tests) o HIV o Hepatitis B and hepatitis C • Counsel HCW that they must not give blood and must practice safer sex and safer injecting practices until outcome is known • Review HCW (post test counseling) and give baseline results • Offer hepatitis B vaccination if HBsAg negative and HBsAg negative • Provide counselling on further HIV transmission including condom use, avoiding breast feeding and not donating blood until the person is tested HIV negative three moths after the exposure Documentation of the incident • Record date and time of exposure • Details of the event • Exposure source if known • Details of PEP treatment if given • Follow up

53

Antiretrovirals for PEP A limited number of studies have shown that immediate administration of antiretrovirals reduces the risk of transmission following exposure to HIV. ARVs should be started as soon possible and at the latest within 72 hours of the exposure. Persons presenting after 72 hours of exposure could also be considered for post exposure prophylaxis. ARV should be continued for one month.64 The drugs used in PEP should be aligned with the formulary adopted in the country. AZT, 3TC and boosted PIs are the most common ARV drugs used in these situations. Alternative NRTIs that can be considered are d4T and ddI. NRTIs (NVP and EFV) should not be used for PEP. Nevirapine is NOT recommended for PEP due to the risk of severe reactions reported in these situations. Efavirenz should be avoided due to CNS side effects and should not be given to pregnant women or women of child bearing potential. There is also no evidence that a three drug regimen is superior to a two drug regimen in the setting of PEP. 65 • two drug regimen (for all potential exposures) • three or more drug regimen (for potential exposures where source is known or suspected to have ART resistance)

Non-occupation post exposure prophylaxis (nPEP)

Situations where nPEP may be provided Unprotected sexual exposure including rape Needle sharing by IDUs Injuries from needles discarded in public places. 66 Human bite injuries Situations where nPEP should not be provided nPEP should not be provided in case of persistent potential exposure to HIV such as discordant sex partners who rarely use condoms, repeated unprotected sex with sex workers or other non regular partners or injection-drug users who often share injection equipment. Persons who engage in frequent, recurrent risk exposure behavior should be counseled and provided with appropriate risk-reduction interventions. Antiretrovirals for nPEP The choice is the same for occupational and non-occupation PEP Counselling • Assess extent of risk exposure, frequency of exposure and timing • Try to ascertain the HIV status if the source (often unknown) • Evaluate for sexually transmitted infections • Assess the need for emergency contraception (“morning after pill”) • Give pre HIV test counseling

54 • Test the individual (baseline tests) o HIV o Hepatitis B and hepatitis C o Swabs and cultures for gonorrhea and Chlamydia if available o VDRL and TPHA o Pregnancy test (if available) following appropriate counselling • Counsel the individual that they must not give blood and must practice safer sex and safer injecting practices and not breast feed until outcome is known • Review and give baseline results • Offer hepatitis B vaccination if HBsAg negative and HBsAg negative

55 Summary of recommendations for occupational and non-occupational PEP As soon as possible after exposure and within one hour if possible Starting PEP Not more the 72 hours after exposure if possible Consider PEP > 72 hours after a high risk exposure Duration of PEP 28 days

2 NRTIs which are the same as the recommended NRTI backbone Which regimen to choose in the standard first line WHO ART in the country AZT 250mg or 300 mg BID or d4T 30/40mg BID Preferred two drug Plus regimens 3TC 150 mg BID Alternative two drug TDF 300mg OD + (3TC 300mg OD or FTC 200mg OD) regimens This ARVs can all be given once daily Some counties have already implemented 3 drug PEP regimens. There are no prospective data regarding the relative efficacy of 2 or 3 drugs. The potential advantages of using 2 drugs include relative ease of administration potentially resulting in better adherence, fewer side effects, lower cost, and ease of procurement, storage and dispensing. In most cases where the Three drug regimens source in unlikely to have ART-resistant HIV infection, 2 drugs are likely to be sufficiently potent to prevent HIV transmission with only incremental increase in potency with the addition of a third drug. In cases where the source is known or suspected to have ART resistance two NRTIs plus a protease inhibitor (PI) can be considered. 2 NRTIs as listed above + Ritonavir boosted PI chosen according to availability Preferred 3 drug OR regimens Nelfinavir 1250 mg twice daily or IDV 800mg TID if RTV not available If a third drug is used, an NNRTI should NOT be used. Nevirapine is contraindicated for PEP due to risk of toxicities NNRTIs in PEP and the potential for development resistance. Efavirenz should not be used in women who are pregnant or are of child-bearing age. PEP should be provided if indicated. Pregnant women should not receive efavirenz, tenofovir or the PEP in pregnant women combination of d4T + ddI The preferred PI in pregnancy is saquinavir/r.

56 Chapter Syndromic approach to the management of opportunistic infections

10

Dysphagia [a]

Treat presumptively for oesophageal candidiasis [b]

Improved Treat Improved after 7 presumptively after 7 Esophagoscopy days for HSV [c] days for diagnosis No [c] No Yes Yes

Continue fluconazole 14 days Continue acyclovir 14 days Recurrence is likely unless Recurrence is likely unless ART is commenced ART is commenced Consider prophylaxis with Consider prophylaxis with fluconazole 200mg twice acyclovir 400mg twice daily weekly

Notes: a. Oesophageal candida Candidiasis may infect the oesophagus in immune compromised patients, causing difficulty and pain on swallowing. Diagnosis is based on clinical symptoms and response to systemic antifungal therapy. Endoscopy is not required unless the patient fails to respond to treatment. b. Systemic treatment Fluconazole 200 mg daily for 14 days or Itraconazole 200 mg daily for 14 days or Ketoconazole 200 mg daily for 14 days c. Acyclovir 400mg every 4 hours d. Failure of treatment Other causes of oesophagitis are cytomegalovirus (CMV), Kaposi’s sarcoma and lymphoma. Non –HIV related causes include acid reflux. Endoscopy is required for diagnosis

57

Lymphadenopathy

[a]

Characteristics of the lymphadenopathy

Single node or Generalized nodes asymmetrical nodes

HIV associated Persistent generalized lymphadenopathy Lymph node (PGL) biopsy available No specific treatment required Assess for clinical or CD4

Yes count criteria for commencing ART No Treat according to biopsy results (tuberculosis or

fungal or bacterial infection ) Clinical presentation suggestive of extra pulmonary TB

Yes Treat for TB Notes: a. Persistent generalized lymphadenopathy is common in HIV-infected patients. In an asymptomatic patient no further investigation or treatment is required. However, in patients with recently symptomatic lymphadenopathy, rapidly enlarging nodes, marked nodal asymmetry, and constitutional symptoms, further evaluation and treatment is necessary. Causes of lymphadenopathy (other than HIV) include tuberculosis, cryptococcosis, histoplasmosis, lymphoma and Kaposi’s sarcoma. Extra pulmonary tuberculosis is common in HIV-infected patients. Clinical suspicion of tuberculosis is raised by the following signs and symptoms: fever, weight loss, unilateral nodes increasing in size, matted nodes, fluctuant nodes. Treat according to the national TB guidelines.

58

Chronic diarrhea [a]

Dehydrated [b]

Correct with oral fluids and rehydration salts or IV fluids and symptomatic antidiarrhoeal treatment [g]

Empirical treatment with Stool No quinolones microscopy & (eg. norfloxacin) or TMP- culture SMZ for 7 days available [d] [e]

Yes No Treat according to improvement specific diagnosis [f]

Empirical treatment with metronidazole 400-500 mg TID for 7 days [g] Notes: a. Definition of chronic diarrhea: liquid stool three or more times a day, continuously or episodically or for more than one month Causes: Cryptosporidiosis Campylobacter spp Isospora belli Entamoeba histolytica Giardia lamblia Strongyloides stercoralis Salmonella spp Shigella flexneri Microsporidium Mycobacterium avium complex Cytomegalovirus Lymphoma HIV (no other pathogens) b. Assessment of dehydration General appearance Restless, irritable Pulse Rapid Respiration Deep, may be rapid Skin elasticity Pinch retracts slowly Eyes Sunken Mucous membranes Dry Urine flow Reduced amount & dark c. In the case of moderate dehydration, correct with oral fluids and rehydration salts (ORS), prescribe intravenous fluids in the case of severe dehydration.

59 Supplemental feeding should be given slowly with multiple and divided feeding, and supplemented with intravenous fluids (minimum 1.5 liter of water a day) d. Multiple stool examinations (each day for 3 days) increases the diagnostic yield. e. Empirical treatment Norfloxacin (400mg BID) or ciprofloxacin (500mg BID) or cotrimoxazole (2 tablets BID) +/- metronidazole 400mg TID for seven days. Relapse may be due to the short duration of initial treatment. One prolonged course of treatment, for 3 weeks, is justified. f. Specific treatments Salmonellosis and shigellosis: Ciprofloxacin 500 mg, 1 tablet bid for 7 days or Ofloxacine or Ceftriaxone 1g, IM or IV, 1 injection each day, for 5 days. Campylobacter spp: Erythromycin (tablet 500mg) 3 tablets daily for 5 days. Giardiasis: Metronidazole tablet 250 mg, 2 tablets tid for 5 days. Entamoeba histolytica: Metronidazole tablet 250mg, 2 tablets tid for 7-10 days. Isospora belli: TMP-SMX tablet 480 mg, 2 tablets 4 times daily for 7 days. Strongyloidiasis: Thiabendazole 25 mg/kg, 3 times daily for 3 days. Cryptosporidiosis: there is currently no established effective treatment. ART is the only effective treatment. Maintenance of fluid and electrolyte balance is of greatest importance, and constipating agents may also be useful. Mycobacterium avium complex infection: drugs to be given are Ethambutol (single daily dose of 15mg/kg/day) and Clarithromycin (500mg BID), or/and Azithromycin (500 mg fourth hourly). Salmonellosis, shigellosis, campylobacteriosis and isosporiasis in HIV-infected patients often relapse. If relapse occurs after an initial course of antimicrobial therapy, a 6-12 weeks course therapy should be administered g. Symptomatic treatment Loperamide, 4 mg initially, followed by further 2 mg after each unformed stool (maximal daily dosage 16 mg) Constipating agents should not be used in patients with bloody diarrhea, because of the risk of inducing toxic mega colon.

60

Respiratory Symptoms

Sputum microscopy & AFB stain Induced sputum examination is necessary for PCP diagnosis [c]

Treat TB according to National

AFB Yes TB Guidelines positive Give cotrimoxazole PCP prophylaxis to all HIV positive

patients diagnosed with TB

No

Chest X ray Clinical consistent with: presentation TB [d] suggestive of PCP [e] PCP [b] Bacterial pneumonia [f] Fungal pneumonia [g] Empirical treatment for PCP and bacterial Successful pneumonia with treatment of PCP cotrimoxazole is followed by secondary cotrimoxazole prophylaxis

Notes: a. Respiratory symptoms which commonly present in patients with HIV infection and immunodeficiency are fever, dry cough (typical of PCP), productive cough with sputum and/or haemoptysis (typical of pneumonia and TB), shortness of breath and severe respiratory distress Causes of respiratory symptoms Infections: Mycobacterium tuberculosis (cough > 2-3 weeks) Pneumocystis jiroveci pneumonia (cough often 1-2 moths) Bacterial pneumonia Fungal infection (cryptococcus, histoplasmosis) Atypical mycobacteria (MAC) CMV pneumonitis Malignancies Lymphoma, Kaposi’s sarcoma Others Pleural effusion/empyema (tuberculosis, bacterial infection or malignancies) Pneumothorax (tuberculosis, or pneumocystis jiroveci pneumonia) Pericardial effusion (often associated with tuberculosis)

b. PCP typically presents with slow onset over weeks to months of dry cough, fever and shortness of breath

61 c. Sputum examination for acid-fast bacteria (AFB) is indicted inpatients with cough for more than 2 weeks.Three separate sputums are recommended. For diagnosis of PCP, induced sputum examination is essential. Clinical diagnosis supported by CXR findings is preferred for the diagnosis of PCP. Cough and sputum production is induced by inhalation of normal saline by nebulizer. Training of staff in safe induced sputum collections is necessary. d Tuberculosis: No chest X-ray pattern is absolutely typical of pulmonary TB. The classical pattern is more common in HIV-negative patients; the atypical pattern is more common in HIV positive patients. Pleural effusion is a prominent feature. Pleural tap and microscopic examination of pleural fluid may be helpful for diagnosis. Treat according to national TB guidelines. Classical Pattern Atypical Pattern Upper lobe infiltrates Interstitial infiltrates (especially lower zones) Cavitation Bilateral infiltrates Pulmonary fibrosis No cavitation e. PCP: The chest X-ray is abnormal in more than 90% cases of pneumocystis jiroveci pneumonia, typically showing bilateral interstitial infiltrates. Typical clinical presentation is with non-productive cough, shortness of breath and fever for 1-2 months. PCP treatment: Trimethoprim-sulfamethoxazole, (Cotrimoxazole- TMP 15 mg plus SMZ 75 mg/kg) daily in 4 divided doses, orally or intravenously, for 21 days. Treatment should be IV in severally ill patients. Cotrimoxazole, 4 vials in 500 ml of Glucose 10% by slow IV infusion (over one hour) three times a day. Cotrimoxazole cannot be administrated IV directly. Patient can switch to oral Cotrimoxazole if clinically improved. Total course of cotrimoxazole is 21 days. Oral doses are: • TMP-SMZ 480 mg, 2 tablets 4 times daily (patient <40 kg) • TMP-SMZ 480 mg, 3 tablets 4 times daily (patient >40 kg) Alternative treatment: Clindamycin 600mg IV or 450mg orally TID + primaquine 15mg orally OD for 21 days if allergy to sulphonamides. Prednisolone, 20 mg 4 times daily, reducing slowly over 7-10 days depending on response to therapy is recommended for severely ill patients. Prevention of relapse with cotrimoxazole 2 tablets daily should be given after the first phase of treatment and needs to be continued life- long (secondary prophylaxis). Dapsone 100mg OD is an alternative for allergic patients. f. Bacterial pneumonia: Typical presentation is with productive cough, purulent sputum and fever for 1-2 weeks. PCP presents more slowly and there is normally no sputum. Typical CXR finding is lobar consolidation. Gram-positive pyogenic bacteria will be the most probable cause of bacterial pneumonia. Cotrimoxazole as above will successfully treat most community acquired bacteria and PCP. Amoxycillin/clavulanate, 625mg 3 times daily or Azithromycin 250 mg, 3 tablets 3 times daily, for 7 days are an alternative if the clinical presentation suggests bacterial pneumonia and not PCP. g. Fungal pneumonia: Amphotericin B 0.7 mg/kg daily by intravenous injection for 4-6 hours for 6 weeks. Alternative: Fluconazole 400 mg daily for 10 weeks.

62

Neurological signs and symptoms [a]

Focal Clinical No Treat for neurological signs of Cryptococcal signs [b] meningeal meningitis [d] irritation

Yes Yes CSF examination available Cerebral CT available Treat for cryptococcal Bacteria, meningitis, bacterial WBC, meningitis, [e] Yes No AFBs, tuberculous Indian-ink meningitis, syphilitic meningitis

Treat based on clinical examination and CT Treat for findings toxoplasmosis [c]

Notes: a. Causes of headache include cryptococcal meningitis, tuberculous meningitis, cerebral toxoplasmosis, chronic HIV meningitis, bacterial meningitis, and lymphoma • Causes of headache not related to HIV infection include migraine, syphilis, malaria, tension, sinusitis, refractive disorders, dental disease, anaemia, and hypertension. And other infectious diseases such as malaria, typhoid fever, dengue fever, and rickettsiosis. b. Neurological examination • Evidence of meningeal irritation (photophobia, neck stiffness) or raised intracranial pressure (high blood pressure, and show pulse in the presence of fever). • Changes in metal state • Focal neurological deficits including paresis, cranial nerve palsies, movement disorders ataxia, and aphasia. Seizures c. Toxoplasmosis Pyrimethamine loading dose 75-100 mg, then 25-50 mg daily plus Sulfadiazine, 4 g daily in 4 divided doses for 6 weeks followed by chronic suppressive therapy with Pyrimethamine, 25 mg daily plus Sulfadiazine, 2 g daily in 4 divided doses. Alternative therapy is pyrimethamine as above plus clindamycin 300mg four times per day for 6 weeks. d. Cryptococcal meningitis Primary treatment Maintenance treatment Amphotericin B 0.7-1 mg/kg/day, IV, for 14 days 1. Amphotericin B, 0.7-1 mg/kg /week followed by Itraconazole 200 mg 2 times daily Itraconazole 200 mg/day for 8 weeks, or Fluconazole 400 mg daily. or Fluconazole 200mg/day Fluconazole 400 mg daily for 8 to 12 weeks Fluconazole 200 mg/day

63 e. Bacterial meningitis Benzyl-penicillin 1.2-2.4 million IU daily be intravenous injection in divided doses every 4 hours. Treat for a minimum of 7 days or for 4-5 days after the patient becomes afebrile. If allergic with Penicillin, ampicillin or chloramphenicol or ceftriaxone can be used.

Skin conditions: Differential diagnosis table ☺ Clinical diagnosis preferred. Diagnostic test normally not required *Highly suggestive of HIV infection. HIV counseling and testing if HIV status unknown Skin Conditions 1. Pruritic (itchy) rashes Diagnostic tests Diagnosis Clinical features in favour of diagnosis (if available) Erythematous, pruritic, follicular Eosinophilic papules/pustules on face, upper trunk, upper Clinical diagnosis folliculitis arms, intense itching Hyperpigmented, hyperkeratotic papules and Papular pruritic nodules which often appear symmetrically on Clinical diagnosis eruptions* arms, legs, lower back, buttocks Rash and excoriations on torso; burrows in Scabies Microscopy of skin web space and wrist; face spared. scrapings Extensive crusting (psoriatic like lesions) with KOH or mineral oil Norwegian Scabies thick, hyperkeratotic scales overlying the preparations elbows, knees, palms, and soles. Eczema Wet, oozing sores or excoriated, thick patches. Clinical diagnosis Dry and rough skin, sometimes with fine Xerosis Clinical diagnosis cracks. 2. Erythematous rashes Limited to area in contact with problem substance Contact dermatitis Clinical diagnosis Early: redness and blistering Later: thick, dry, scaly. Serology for HIV-RNA Primary HIV Generalized maculo- papular rash usually with or HIV-DNA infection* fever and systemic symptoms May be negative in early primary HIV infection Generalized erythematous pruritic rash with or without fever and signs of hepatoxicity. Severe Drug reaction drug reactions (Stevens Johnson Syndrome) Clinical diagnosis with dlisters of skin and/or mucous membranes Typically in the first days to weeks of commencing the new drug 3. Blisters, sores, nodules and pustules Typical painful blisters in clusters along dermatomes. Can involve the eye. HIV infection should be suspected if lesions are multidermatomal or episodes of H. Zoster are Herpes zoster* recurrent Clinical diagnosis Pre-pressional symptoms include parasthesiae and/ or pain in the dermatome a few days before the rash appears. Fever, malaise, and headache may precede the outbreak of blisters Typical blisters, with pain and tingling, usually in genital area or face. Chronic HSV presents Herpes simplex Clinical diagnosis as a progressive, shallow, clean-based ulcer on genitalia, perianal, perioral areas Impetigo and Microscopy Red, tender, warm crusts or small lesions folliculitis Gram positive cocci

64

Diagnostic tests (if Diagnosis Clinical features in favour of diagnosis available) Generalized papulo-necrotic skin lesions resembling molluscum contagiosum associated Cryptococcus* with fever and other symptoms of disseminated cryptococcosis such as meningitis, lung Microscopic of skin infection biopsy lymph node Papulo-necrotic skin lesions associated with aspirate or CSF India Ink, systemic disease of fever, lung involvement, Wright’s stain or Cotton cough, weight loss, anaemia, hepato- blue stain splenomegaly and lymphadenopathy. 70% of Blood culture Penicilliosis* patients with disseminated Penicillium Chest x-ray marneffei infection will have skin lesions. It is endemic in Northern Thailand, Southern China, Vietnam, Indonesia, and Hong Kong Tissue biopsy results Pustules, nodules, ulcers and papules in a Yeast forms on Histoplasmosis* patient with systemic symptoms including lung, hematoxylin and eosin CNS, gastrointestinal and ocular involvement staining Blood or tissue culture Microscopy of Papules or nodules resembling pyogenic Bacillary Warthin-Starry silver or granuloma, nodules or plaques resembling angiomatosis* Grocott-silver Kaposi sarcoma. Splenomegaly, anaemia methenamine stain Papulo-pustular eruptions on trunk and Mycobacterium extremities. Systemic symptoms including Acid-fast bacilli on skin avium complex fever and pulmonary symptoms, biopsy (MAC) * lymphadenopathy, diarrhea, weight loss, night Blood culture sweats Dark field microscopy or immunofluorescent Painless indurated genital ulcer (chancre) with staining Primary syphilis localized lymphadenopathy. Other locations for RPR, VDRL not positive chancres include mouth and anus until 7-10 days after appearance of chancre Macula, papular or pustular rash on entire RPR, VDRL, TPHA body, especially on palms and soles CSF examination shows Secondary syphilis 40 percent of these patients will have CNS increased protein and involvement with headache and meningism lymphocytic pleocytosis Tissue smear testing/slit- Hypopigmented macules with a raised border. skin smears Leprosy Plaques are also common. Necrosis, Ziehl-Neelsen acid-fast neuropathies stain Ulcerations of oral mucosa and anogenital area Signs and symptoms GI CMV disease include Cytomegalovirus* Biopsy nausea, vomiting, dysphagia, epigastric pain, jaundice, and watery diarrhea. TB verrucosa cutis: Asymptomatic warty papules on hands or extremities often mistaken for verruca vulgaris. Lesions may evolve and Cutaneous Acid-fast bacilli in persist for years. tuberculosis stained tissue Disseminated tuberculosis presents as papulo- necrotic lesions (indistinguishable from penicilliosis, histoplasmosis, cryptococcosis).

65

4. Skin rashes with few or no symptoms Erythematous plaques with greasy scaling on Seborrhea Clinical diagnosis the scalp, face, post auricular area, and chest. Raised dome shaped pedunculated lesions Molluscum usually on face and neck and genital area and Clinical diagnosis contagiosum armpits Condyloma Multiple raised irregular lesions with a Clinical diagnosis accuminata cauliflower appearance typically in genital area Dermatophytosis Hyper- or hypopigmented patches that are ringworm, itchy, with or without a ring pattern and with Clinical diagnosis onychomycosis scaling Extensive plaques that have well-demarcated borders and are covered with thick silvery white scales. It is often mistaken for a fungal Psoriasis Clinical diagnosis skin infection. Lesions are often bilateral and favor the scalp, elbow, knees, hairline and intertriginous areas. HIV-associated Itchy generalized maculo-papular Clinical diagnosis skin rash 5. Severe soft tissue or muscle infection Pyomyositis and Abscess or affected area is fluctuant and warm. Gram stain or culture skin abscess There may be discharge

66 Details of selected common HIV-related skin conditions Pruritic rashes Eosinophilic folliculitis Cause The exact cause of eosinophilic folliculitis is not clear. It is most likely an autoimmune process.67 Physical Examination Areas of erythematous papules and pustules and involves the face in 85% of patients. Patients with HIV present with widespread urticarial lesions or large erythematous plaques with excoriations. Other conditions to consider Acne, eczema, other causes of folliculitis (bacterial, fungal, or dermatophytic), psoriasis scabies, reactions to bites and stings Treatment Treat mild disease with topical steroids and oral antihistamines.68 Treat moderate to severe disease with oral itraconazole, isotretinoin, or phototherapy. Papular pruritic eruptions Cause This condition is considered to be a hypersensitivity reaction to the bites of mosquitoes, fleas, bedbugs, and other insects. Physical examination Papules may occur on any body part, but they tend to be grouped on exposed areas, particularly the extensor surfaces of the extremities (legs). Scratching may produce erosions and ulcerations. Secondary bacterial infection is common. Other conditions to consider Impetigo, insect bites Treatment Treatment includes mild topical steroids and systemic antihistamines for relief of the itching that often accompanies this condition. If secondary impetigo occurs, topical or systemic antibiotics may be needed. The condition improves with immune recover on ART but scarring form old lesions may be permanent. Scabies Cause Sarcoptes scabiei mite Physical Examination Classic scabies presents with burrows in the skin, typically in the web spaces of the fingers, flexor aspects of the wrists, axilla, umbilicus, buttocks, and feet. In men, red papules or nodules on the penile glans, shaft, and scrotum are almost pathognomonic of scabies.69 Norwegian (or crusted) scabies presents with extensive, widespread, crusted lesions appear with thick, hyperkeratotic scales over the elbows, knees, palms, and soles. Secondary infection bacterial be present.70 The mite is same the same as “regular” scabies. The difference is the host, with those developing Norwegian scabies usually having a compromised immune system and a higher parasitic burden. The skin manifestations are much more severe, with thick, hyperkeratotic crusts that can occur on almost any area of the body. Clinically, Norwegian scabies differs from regular scabies in two ways: more severe skin manifestations and often not very pruritic. The decreased pruritis observed in Norwegian scabies is due host's compromised immune response. Treatment 1. Gammabenzene hexachloride once a week for 2-3 weeks or until lesions are cleared. 2. Permethrin cream 5% Apply from chin to toes and shower off 10-12 h later; repeat in 1 week 3. 25% benzylbenzoate solution71. Apply the lotion from head to toe. The application is left on the skin to dry and then repeated the next day. Treatment should be repeated weekly until all lesions are clear. Itching can be relieved by chlorpheniramine 4 mg, 3-4 tab/day. Clothes and beddings should also be washed and kept separately for 3 days to prevent re- infestation. Household contacts should be treated. After treatment, all the clothes and bed linen should be washed and dried. Household and other close contacts require the same

67 treatment. In severe cases, Ivermectin (if available), administered in a single oral dose of 200 micrograms per kilogram, may be considered 72 Xerosis Cause The cause is not known. Xerosos (dry skin) is common, with up to 75% of patients with HIV infection experiencing dry skin. 73 74 Physical examination Lesions consist of a diffuse, pruritic, scaly rash, involving mainly the limbs and the back. Other conditions to consider Scabies Treatment Treatment is with moisturising skin lotion and antihistamines for itch (chlorpheniramine 4 mg TID or hydoxyzine 10 mg BID). The condition improves with immune restoration or ART.75

Erythematous rashes Primary HIV infection Cause The acute retroviral syndrome typically occurs 2-4 weeks after primary infection with HIV Physical examination The rash is usually generalized erythematous and maculopapular with or without itch. Other symptoms are fever, arthralgia, lymphadenopathy, headache pharyngitis and oral candida. HIV antibody tests may still be negative. HIV-RNA or HIV DNA will be positive Treatment No specific treatment is indicated for the rash or for primary HIV infection. Patient counseling, education and behaviour modification are necessary. Bacillary angiomatosis Cause Bacillary angiomatosis (BA) is the vascular proliferative form of infection with Bartonella infection. Cats are the reservoirs of Bartonella henselae, which may be transmitted by cat bites or scratches. It is more common on patients with CD4 counts<200.76 Physical examination Cutaneous lesions are solitary or multiple red, purple, flesh-colored, or colorless papules (hemangioma-like lesions) or nodules or large, friable, polypoid masses. Other internal organs that may be involved include the brain, bone marrow, heart, lungs, pleura, larynx, oropharynx, tongue, esophagus, stomach, colon, kidneys, adrenal glands, pancreas, uterine cervix, and vulva. Systemic symptoms include fever, chills, malaise, night sweats, anorexia, and weight loss, abdominal pain, nausea, vomiting (peliosis hepatis), jaundice and gastrointestinal bleeding Other conditions to consider Pyogenic granuloma, common wart, haemangioma, MAC, Kaposi’s sarcoma Treatment Erythromycin (500 mg QID) is the drug of choice. Doxycycline (100 mg BID) is an alternative. Rifampicin (300 mg BID) may be added to erythromycin or doxycycline in patients with severe disease who are immunocompromised. Drug reactions Causes Drugs most frequently involved include NNRTIs (nevirapine and efavirenz), abacavir, cotrimoxazole and dapsone. Typically, drug reactions present within days to weeks of commencing the drug. Physical examination Itchy morbilliform rash with or without fever Severe drug reaction may present as Stevens-Johnson syndrome with extensive blistering, ulceration, and necrosis Although lesions may occur anywhere, the palms, soles, dorsum of hands, and extensor surfaces are most commonly affected. Systemic symptoms include fever tachycardia, hypotension, mucosal and corneal ulceration, seizures and coma

68 Other conditions to be considered Burns, Erythema Multiforme, staphylococcal scalded skin syndrome, Toxic Epidermal Necrolysis, toxic shock syndrome Treatment Stop the causative drug. Antihistamines and topical moisturizing creams. Hospitalization with cardio-respiratory support may be needed for patients with Stevens-Johnson syndrome. Most experts recommend the use of short course systemic steroids in severe case of drug reactions.77 Commence with prednisone 0.5mg/kg per day reducing over 5-10 days.

Blisters sores nodules and pustules Herpes simplex Cause Herpes simplex viruses (HSV-1 or HSV-2) Physical examination Typical blisters (often with pain, tingling and itch) usually in genital area (HSV-2) or face (HSV-1) Other conditions to consider Candidiasis, chancroid, hand-foot-and-mouth disease, syphilis Treatment Local lesion care, such as Burow’s solution wet compression 15 minutes 4-5 times/day or gentian violet or chlorhexidine. If available, acyclovir 200-400 mg 5 times daily for 7 days. In cases of frequent recurrences, long-term suppressive therapy with acyclovir 400 mg bid may be necessary. In immunosuppressed patients herpes simplex can be chronic and invasive (e.g esophagitis, encephalitis). Secondary Prophylaxis in cases of frequent recurrences, long-term suppressive therapy with acyclovir 400 mg twice daily may be necessary. Alternative is famciclovir: 500 mg BID for 7 days with suppressive therapy of 250 mg OD. Herpes Zoster Cause Varicella zoster virus Physical examination Typical painful blisters in clusters along dermatomes. Can involve the eye Treatment Local lesion care, such as with gentian violet and chlorhexidine. Acyclovir 800 mg 5 times daily for 7 days, commenced within 72 hours of onset of blisters. Famciclovir and valaciclovir are alternatives. Acyclovir ointment applied into eye every 4 hours for ophthalmic Herpes zoster. Pain management is with paracetamol 1Gm 6th hourly or stronger analgesics if necessary. Amitriptyline 25-50mg before bed is useful in the control of the neuropathic pain associated with Herpes Zoster and for post herpetic neuralgia which may persist for months after an episode of Herpes Zoster. Cryptococcus Cause Cryptococcus neoformans Physical examination Umbilicated papules (resembling Molluscum contagiosum), pustules, nodules, ulcers, or draining sinuses. In immunosuppressed patients skin involvement is considered evidence of disseminated disease, which commonly affects lung and CNS (meningitis). Patients present with headaches, nausea, fever, fatigue, altered mental status, seizures, coughing, and shortness of breath. Other manifestations include myocarditis, retinitis, hepatitis, peritonitis, renal abscess, prostatitis and myositis Other conditions to consider Pyogenic abscess, Nocardia, Aspergillus species, lymphomas, Mycobacterium Tuberculous Histoplasmosis, acne Treatment Preferred: IV amphotericin B (0.7mg/kg daily) + flucytosine (25mg/kg 4 times a day) for 2 weeks then fluconazole (400mg daily) for 8 weeks.

69 Alternatives: IV amphotericin B (0.7mg/kg daily) for 2 weeks then fluconazole (400mg daily) for 8 weeks. Secondary Prophylaxis is with Fluconazole (200mg daily) life long or until evidence of immune recover on ART (CD4 cell count > 100 cells/mm3) Notes on the use of amphotericin B Amphotericin B is given by slow IV infusion over 45 minutes 4 times per day. Patient needs careful observation, especially with initial doses as fever and chills can occur. The other main side effects of Amphotericin B are electrolyte disturbances (especially hypokalaemia) and hypoglycemia. Frequent monitoring of electrolytes and blood sugar are required, with 5% dextrose co- infusion and potassium supplements to maintain normal levels Penicilliosis Cause Penicillium marnefei - a fungus endemic in Northern Thailand, Southern China, Vietnam, Indonesia, and Hong Kong. Physical examination This disease presents as typical papulo-necrotic skin lesions and often as systemic disease with fever, lung involvement and cough, weight loss, anaemia, lymphadenopathy over 3-4 weeks. It usually presents with advanced HIV disease and a CD4 cell count < 100 cells/mm3 Other conditions to consider Molluscum contagiosum Treatment IV amphotericin B (0.7mg/kg daily) for 2 weeks then itraconazole 400 mg orally daily for 10 weeks In mild cases: Itraconazole 400 mg orally daily for 8 weeks. Secondary prophylaxis is with itraconazole 200mg per day for life or until immune recovery on ART. Histoplasmosis Cause Histoplasma capsulatum (fungus) Physical examination Cutaneous lesions are present in 10% of patients with disseminated Histoplasmosis. These are erythematous maculopapular lesions, with ulceration and purpura. Oropharyngeal lesions may also be present. Systemic manifestations include CNS mass lesions, encephalopathy, meningitis hepatosplenomegaly and lymphadenopathy Other conditions to consider Aspergillosis, Lymphoma, mycoplasma infections, PCP, other Pneumonias (bacterial, fungal, viral) Sarcoidosis Tuberculosis Treatment Amphotericin B (0.7mg/kg daily) minimum total dose should be 2 g.78 Secondary prophylaxis is with itraconazole 200mg per day for life or until immune recovery on ART. Primary and secondary syphilis Cause The spirochete Treponema pallidum Physical examination The chancre of primary syphilis usually is a single, painless papule that rapidly becomes eroded and indurated. Chancres usually are located on the genitals but may be found in the anal canal, mouth. The primary lesion usually is associated with regional lymphadenopathy Secondary syphilis may present in many different ways but usually includes a localized or diffuse mucocutaneous rash which may be macular, papular, pustular, or mixed and generalized non-tender Constitutional symptoms of secondary syphilis include malaise, sore throat, headache, fever and anorexia. Secondary syphilis presents years to decades after the initial infection Other conditions to consider Primary genital syphilitic lesion: Herpes simplex, chancroid, carcinoma, granuloma inguinale, lichen planus, psoriasis, fungal infection

70 Cutaneous eruption of secondary syphilis: Drug eruptions, pityriasis rosea, psoriasis, lichen planus, viral exanthem Treatment Primary, secondary, and early latent syphilis (<1 y duration) Single dose of benzathine penicillin G, 2.4 million U IM Alternative treatments (only for nonpregnant, penicillin-allergic patients) - 2-week course of doxycycline 100 mg BID, tetracycline 500 mg QID, or erythromycin base 500 mg QID. Late latent syphilis (>1 y duration), syphilis of undetermined duration, and late syphilis Benzathine penicillin G, 2.4 million U IM once weekly for 3 consecutive weeks Alternative treatment - Doxycycline 100 mg PO bid or tetracycline 500 mg QID daily for 4 weeks Neurosyphilis Aqueous crystalline penicillin G, 2-4 million U IV q4h for 10-14 days Alternative treatment - Procaine penicillin, 2.4 million U IM OD, plus probenecid 500 mg QID for 10-14 days Cutaneous tuberculosis Cause Mycobacterium Tuberculosis Physical exam Asymptomatic warty papules on hands or extremities often mistaken for verruca vulgaris Lesions may evolve and persist for years. Treatment: Treatment should follow the national TB Guidelines

Skin rashes with few or no symptoms Seborrhea Cause Seborrheic dermatitis occurs on the sebum-rich areas of the scalp, face, and trunk. In addition to sebum, this dermatitis is linked to the fungus Malassezia furfu. Physical examination Scalp appearance varies from mild, patchy scaling to widespread, thick, adherent crusts. From the scalp, seborrheic dermatitis can spread onto the forehead, eyebrows, naso-labial folds, the posterior part of the neck, and the postauricular skin. Skin lesions are greasy and scaling over red, inflamed skin. Other conditions to be considered Xerotic (dry skin) eczema, exfoliative dermatitis, scaling drug eruptions, psoriasis, staphylococcal blepharitis, tinea, Vitamin B and/or zinc deficiency Treatment In mild cases, use 1% hydrocortisone cream or 0.1% triamcinalone cream or similar topical steroid cream .This condition also responds to topical antifungals. Use 2% ketoconazole shampoo to wash hair and scalp and spread shampoo lather over face eyebrows etc. Leave on for 5 minutes and wash off. Repeat daily until cleared and once weekly to prevent recurrence. Ketoconazole cream can also be used on the face. Whitfield's ointment twice a day or gentian violet twice a day or miconazole 2% cream twice daily. For refractory cases oral ketoconazole 200 mg/day during 7-14 days can be used.

71 Molluscum contagiosum Cause A large DNA poxvirus Physical examination Firm, smooth, umbilicated papules, may be present in groups or widely disseminated on the skin and mucosal surfaces. Some lesions become confluent to form a plaque. Other conditions to be considered Histiocytoma, herpes zoster, cryptococcosis Treatment Removal by enucleation (with forceps) or cryotherpy, prick the centre and apply Phenol. Condyloma accuminata Cause Human papillomavirus (HPV) Physical examination Cauliflower-like lesions typically on genital and facial areas. HPV cause cervical and anal dysplasia and caner. Treatment Removal by cryotherapy, cauterization or application of podophylline 25% solution (2-3 times weekly). Annual pap smears as the risk of invasive cervical cancer is increased. Dermatophytosis (cutaneous ringworm, onychomycosis) Cause Microsporum spp, Trichophyton spp, Epidermophyton Physical examination Irregular plaques with spreading raised edge and central clearing. Nail infections Treatment Topical antifungal creams. For extensive, intractable and recurrent deep (nail bed) infections use terbinafine 250 mg/day 6 weeks for finger nails, 12 weeks for toe nails, Itraconazole 200 mg/day/3-5 months or 400 mg/day for one week per month for 3-4 consecutive months or fluconazole 150-300 mg/ wk until cure (6-12 months) or griseofulvin 500-1000 mg/day until cure (12- 18 months) HIV-associated skin rash Cause HIV, especially with advanced immunosuppression and low CD4 count Physical examination Itchy generalized maculo-papular skin rash; erythroderma A generalized pruritic maculopapular skin rash due to eosinophilic folliculitis is typical of HIV. Treatment No specific cause has been identified. Treatment is mainly symptomatic such as antihistamines and emollient creams The condition may improve with immune recovery on ART Severe soft tissue and muscle infection Causes Staphylococcal and streptococcal infections Physical examination Folliculitis and furunculosis present as painful, hot, fluctuant, sometimes discharging, lesions Pyomyositis, caused most commonly by Staphylococcus aureus, is a suppurative infection of striated muscle characterized by localized muscle pain, swelling, and tenderness. Cellulitis and erysipelas are streptococcal infections of the subcutaneous tissue, and are a result from contamination of minor wounds. Other conditions to be considered Pyomyositis may resemble muscle strain, contusion, cellulitis, hematoma, perinephric abscess, deep vein thrombophlebitis, osteomyelitis, synovitis, septic arthritis, or soft tissue sarcoma. Treatment Flucloxacillin 500 mg QID orally for 10 days or 1-2 g IV QID intravenously for10 days. In the case of pyomyositis surgical drainage may be necessary.

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Herpes zoster Local lesion care, such as with gentian violet and chlorhexidine. If available and indicated, acyclovir 800 mg 5 times daily for 7 days. Famciclovir and valaciclovir are alternatives. Herpes simplex Local lesion care, such as Burow’s solution wet compression 15 minutes 4-5 times/day or gentian violet or chlorhexidine. If available, acyclovir 200-400 mg 5 times daily for 7 days. In cases of frequent recurrences, long-term suppressive therapy with acyclovir 400 mg bid may be necessary. Molluscum contagiosum Pick each lesion with a needle or sharpened orange stick and touch with phenol. Alternative treatments are electrocautery, application of liquid nitrogen or simple enucleation of the molluscum body with forceps. Human papilloma virus (warts) Treat with podophyllin 20% solution 1-2 times per week, until cleared or use electrocautery or application of liquid nitrogen. Oral Hairy Leucoplakia (OHL) OHL is caused by Epstein Barr Virus (EBV). It occurs on the side of the tongue, is usually asymptomatic and requires no treatment. If the tongue is painful, OHL responds to oral acyclovir 800 mg 5 times per day. Resolves with ART Candidiasis Local lesion care is with 1% aqueous solution of gentian violet or nystatin or clotrimazole 1% cream twice daily, until lesions are cleared. In severe cases, systemic therapy may be required. Preferred treatment is fluconazole, 200 mg once daily for 14 days. Alternative treatment is ketoconazole, 200 mg twice daily for 14 days. Ketoconazole should not be co- administered with nevirapine Dermatophytosis Treat with topical broad-spectrum antifungal cream such as 1% clotrimazole for 4-8 weeks. Widespread dermatophytosis may necessitate systemic treatment with griseofulvin, 500 mg to 1000 mg daily for 4 to 8 weeks. Alternatives are ketoconazole 200 mg daily for 14 days or itraconazole 400 mg daily for 3 months. Systemic mycoses Cutaneous lesions of systemic cryptococcosis or disseminated histoplasmosis are rare. Systemic cryptococcosis is treated with fluconazole 400 mg OD for 10-12 weeks, followed by maintenance therapy with fluconazole 200 mg OD. Histoplasmosis is treated with itraconazole 400 mg OD for 12 weeks in uncomplicated cases. Bacterial infections Local skin care with antiseptic solution, and cloxacillin or erythromycin tablet 250 mg, 2 tablets, 3 times daily, for 7 to 10 days. In severe cases, intravenous antibiotics may be required. In non-responding cases, choice of antibiotic should depend on culture and sensitivity results. Scabies 1. Gammabenzene hexachloride once a week for 2-3 weeks or until lesions are cleared. 2. 25% benzylbenzoate solution. Apply the lotion from head to toe. The application is left on the skin to dry and then repeated the next day. Treatment should be repeated weekly until all lesions are clear. Clothes and beddings should also be washed and kept separately for 3 days to prevent re- infestation. Household contacts should be treated. Drug eruptions Withdraw drug. Local lesion care with moisturizing cream. Symptomatic treatment with antihistamines to relieve itching. Short course systemic corticosteroids such as prednisolone 10 mg bid for 3 days and then 5 mg bid for 3 days should be given in severe cases. Malignancies Kaposi’s sarcoma may respond to local surgical excision or liquid nitrogen therapy. In severe cases and in the treatment of lymphoma, systemic chemotherapy is required. Pruritic papular eruptions This condition responds poorly to any treatment. High potency topical corticosteroids and oral anti-histamines are needed. Resolves with ART

73 Seborrhoeic dermatitis In mild cases, use 1% hydrocortisone cream or 0.1% triamcinalone cream or similar topical steroid cream . In severe cases with coexistent candidiasis, topical ketoconazole cream or shampoo is beneficial. Systemic ketoconazole 200 mg OD for 14 days is useful in severe and recurrent cases.

Primary HIV Infection 50% to 90% of patients acutely infected with HIV will develop a “flu-like” illness typically within 1-3 weeks following initial infection. However, many patients acquire HIV infection “silently” without the typical syndrome. The syndrome can be difficult to diagnose due to the non-specific clinical picture and the difficulty of obtaining a laboratory diagnosis in resource limited countries. Treatment is symptomatic only

Presentation of Acute Retroviral Syndrome • Generalized maculo- papular rash usually with fever and systemic symptoms • Lymphadenopathy • Pharyngitis • Erythematous maculopapular with lesions on face and trunk and sometimes extremities, including palms and soles. • Mucocutaneous ulceration involving mouth, esophagus or genitals • Myalgia or arthralgia • Diarrhea • Headache • Nausea and vomiting • Hepatosplenomegaly • Weight Loss ( • Thrush • Neurologic symptoms • Meningoencephalitis or aseptic meningitis • Peripheral neuropathy or radiculopathy • Facial palsy • Guillain-Barré syndrome • Brachial neuritis • Cognitive impairment or psychosis

74 Annexes Annex 1 Criteria for HIV-Related Clinical Events in Adults and Adolescents Clinical event Clinical diagnosis Definitive diagnosis Clinical Stage 1 No HIV related symptoms reported and no signs on Asymptomatic examination. Not applicable

Persistent generalized Painless enlarged lymph nodes >1 cm, in two or Histology lymphadenopathy more non-contiguous sites (excluding inguinal), in

(PGL) absence of known cause & persisting for ≥3 months Clinical Stage 2 Moderate unexplained Reported unexplained weight loss. In pregnancy Documented weight loss weight loss (<10% of body failure to gain weight. <10% of body weight. weight)

Recurrent bacterial upper Symptom complex, e.g. unilateral face pain with Laboratory studies where respiratory tract infections nasal discharge (sinusitis), painful inflamed available, e.g. culture of (current event plus one or eardrum (otitis media), or tonsillo-pharyngitis suitable body fluid. more in last six-month without features of viral infection (e.g. coryza,

period) cough). Painful vesicular rash in dermatomal distribution of Clinical diagnosis Herpes zoster a nerve supply does not cross midline.

Splits or cracks at the angle of the mouth not due to Angular chelitis iron or vitamin deficiency, and usually respond to Clinical diagnosis. antifungal treatment. Recurrent oral ulcerations Aphthous ulceration, typically painful with a halo (two or more episodes in of inflammation and a yellow-grey Clinical diagnosis. last six months) pseudomembrane. Papular pruritic lesions, often with marked post- Papular pruritic eruption Clinical diagnosis. inflammatory pigmentation. Itchy scaly skin condition, particularly affecting Seborrhoeic dermatitis Clinical diagnosis. hairy areas (scalp, axillae, upper trunk and groin). Paronychia (painful red and swollen nail bed) or onycholysis (separation of the nail from the nail Fungal culture of nail/nail Fungal nail infections bed) of the fingernails (white discolouration - plate material. especially involving proximal part of nail plate – with thickening & separation of nail from nail bed).

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Clinical event Clinical diagnosis Definitive diagnosis Clinical Stage 3 Severe unexplained weight Reported unexplained weight loss (>10% of body Documented loss of more loss (more than 10% of weight or body mass index <18.5). In pregnancy than 10% of body weight. body weight) weight loss may be masked. Unexplained chronic Chronic diarrhoea (loose or watery stools three or Not required but diarrhoea for longer than more times daily) reported for longer than one confirmed if one month month. three or more stools observed and documented as unformed, and two or more stool tests reveal no pathogens Unexplained persistent Reports of fever or night sweats for more than one Documented fever >37.6. fever month, either intermittent or constant with reported with negative blood (intermittent or constant lack of response to antibiotics or antimalarials, culture, negative Ziehl- and lasting for longer than without other obvious foci of disease reported or Nielsen (ZN) stain, one month) found on examination. Malaria must be excluded in negative malaria slide, malarial areas. normal or unchanged chest X-ray (CXR) and no other obvious focus of infection. Oral candidiasis Persistent or recurring creamy white curd-like Clinical diagnosis plaques which can be scraped off (pseudomembranous), or red patches on tongue, palate or lining of mouth, usually painful or tender (erythematous form). Oral hairy leukoplakia Fine white small linear or corrugated lesions on Clinical diagnosis lateral borders of the tongue, which do not scrape off. Pulmonary TB Chronic symptoms: (lasting ≥2-3 weeks) cough, Isolation of M. (current) haemoptysis, shortness of breath, chest pain, tuberculosis on sputum weight loss, fever, night sweats, PLUS either culture or histology of lung positive sputum smear biopsy (together with OR compatible symptoms). Negative sputum smear AND compatible chest radiograph (including but not restricted to upper lobe infiltrates, cavitation, pulmonary fibrosis and shrinkage). No evidence of extrapulmonary disease Severe bacterial infection Fever accompanied by specific symptoms or signs Isolation of bacteria from (e.g. pneumonia, that localize infection, and response to appropriate appropriate clinical meningitis, empyema, antibiotic. specimens (i.e. usually pyomyositis, bone or joint sterile sites). infection, bacteraemia, severe pelvic inflammatory disease ) Acute necrotizing Severe pain, ulcerated gingival papillae, loosening Clinical diagnosis. ulcerative gingivitis or of teeth, spontaneous bleeding, bad odour, and necrotizing ulcerative rapid loss of bone and/or soft tissue. periodontitis

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Clinical event Clinical diagnosis Definitive diagnosis Clinical Stage 4 Documented weight loss Reported unexplained weight loss (>10% body >10% of body weight; weight), with obvious wasting or body mass index plus <18.5. two or more unformed PLUS EITHER stools negative for unexplained chronic diarrhoea (loose or watery pathogens stools three or more times daily) reported for longer HIV wasting syndrome or than one month. Documented temperature OR of > 37.6 oC or more with Reports of fever or night sweats for more than one no other cause of disease, month without other cause and lack of response to negative blood culture, antibiotics or antimalarials. Malaria must be negative malaria slide and excluded in malarial areas. normal or unchanged

CXR. Cytology or Dyspnoea on exertion or nonproductive cough of immunofluorescent recent onset (within the past 3 months), tachypnoea microscopy of induced Pneumocystis pneumonia and fever; AND Chest x-ray evidence of diffuse sputum or bronchoalveolar bilateral interstitial infiltrates AND No evidence of lavage (BAL), or histology a bacterial pneumonia. Bilateral crepitations on of lung tissue. auscultation with or without reduced air entry.

Recurrent bacterial Current episode plus one or more previous episodes pneumonia in last 6 months .Acute onset (<2 weeks) of Positive culture or antigen (this episode plus one or symptoms (e.g. fever, cough, dyspnoea, and chest test of a compatible more episodes in last 6 pain) PLUS new consolidation on clinical organism. months) examination or CXR. Response to antibiotics. Chronic herpes simplex Painful, progressive anogenital or orolabial Positive culture or DNA virus (HSV) infection ulceration; lesions caused by recurrent HSV (by PCR) of HSV or (orolabial, genital or infection and reported for more than one month. compatible anorectal) of more than History of previous episodes. Visceral HSV cytology/histology. one month duration requires definitive diagnosis. Macroscopic appearance at Recent onset of retrosternal pain or difficulty on endoscopy or Oesophageal candidiasis swallowing (food and fluids) together with oral bronchoscopy, or by candidiasis. microscopy/histology. Systemic illness (e.g. fever, night sweats, weakness M. tuberculosis isolation and weight loss). Other evidence for or compatible histology extrapulmonary or disseminated TB varies by site: from appropriate site, Pleural, pericardial, peritoneal involvement, together with compatible meningitis, mediastinal or abdominal symptoms/signs (if Extrapulmonary TB lymphadenopathy, osteitis. culture/histology is from

Miliary TB diffuse uniformly distributed small respiratory specimen then miliary shadows or micronodules on CXR. must other have evidence Discrete cervical lymph node M. tuberculosis of extra pulmonary infection is usually considered a less severe form of disease). extra pulmonary tuberculosis. Typical appearance in skin or oropharynx of Macroscopic appearance at persistent, initially flat, patches with a pink or endoscopy or Kaposi’s sarcoma blood-bruise colour, skin lesions that usually bronchoscopy, or by develop into violaceous plaques or nodules. histology. Positive serum toxoplasma Recent onset of a focal neurological abnormality or antibody AND (if reduced level of consciousness AND response CNS toxoplasmosis available)single/multiple within 10 days to specific therapy. intracranial mass lesion on

neuro-imaging Clinical finding of disabling cognitive and/or motor dysfunction interfering with activities of daily Diagnosis of exclusion: living, progressing over weeks or months in the and (if available) neuro- HIV encephalopathy absence of a concurrent illness or condition other imaging (CT or MRI) than HIV infection which might explain the findings.

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Clinical event Clinical diagnosis Definitive diagnosis Isolation of Cryptococcus Extrapulmonary Meningitis: usually sub acute, fever with increasing neoformans from cryptococcosis (including severe headache, meningism, confusion, extrapulmonary site or meningitis) behavioural changes that responds to cryptococcal positive cryptococcal therapy. antigen test (CRAG) on CSF/blood. Diagnosed by finding Disseminated non- atypical mycobacterial tuberculous mycobacteria No presumptive clinical diagnosis. species from stool, blood, infection body fluid or other body tissue, excluding lung. Progressive neurological disorder (cognitive dysfunction, gait/speech disorder, visual loss, limb Progressive multi focal weakness and cranial leukoencephalopathy No presumptive clinical diagnosis nerve palsies) together (PML) with hypodense white PML matter lesions on neuro- imaging or positive polyomavirus (JCV) PCR on CSF. Cysts identified on Cryptosporidiosis (with modified ZN microscopic diarrhoea lasting more than No presumptive clinical diagnosis. examination of unformed one month) stool. Chronic isosporiasis No presumptive clinical diagnosis. Identification of Isospora Disseminated mycosis Histology, antigen (coccidiomycosis, detection or culture from No presumptive clinical diagnosis. histoplasmosis) clinical specimen or blood culture. Recurrent non-typhoid No presumptive clinical diagnosis. Blood culture. salmonella bacteraemia Lymphoma (cerebral or B Histology of relevant cell non-Hodgkin) or other No presumptive clinical diagnosis specimen or for CNS solid HIV associated tumours neuroimaging tumours. techniques Invasive cervical carcinoma No presumptive clinical diagnosis. Histology or cytology.

Diagnosed by histology (amastigotes visualized) or Visceral leishmaniasis No presumptive clinical diagnosis. culture from any

appropriate clinical specimen. HIV-associated No presumptive clinical diagnosis Renal biopsy nephropathy Cardiomegaly and evidence of poor left HIV-associated No presumptive clinical diagnosis ventricular function cardiomyopathy confirmed by echocardiography. Source: Revised WHO Clinical Staging and Immunological Classification of HIV and case definition of HIV for surveillance, May 2006

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Annex 2 Dosages of antiretroviral drugs for adults and adolescents Generic name Dose Nucleoside RTIs Abacavir (ABC) 300 mg twice daily or 600 mg once daily Zidovudine (AZT) 250 mg or 300 mg twice daily1 Emtricitabine (FTC) 200 mg once daily Didanosine (ddI)2 >60 kg: 400 mg once daily buffered tabs or enteric coated <60 kg: 250 mg once daily (EC) caps 150 mg twice daily or Lamivudine (3TC) 300 mg once daily

Stavudine (d4T)b 30 mg twice daily Nucleotide RTIs Tenofovir 300 mg once daily Non-nucleoside RTIs Efavirenz (EFV) 600 mg once daily Nevirapine (NVP) 200 mg once daily for 14 days, followed by 200 mg twice daily Proteases inhibitors Atazanavir/ritonavir (ATV/r) 300 mg/100 mg once daily Fos-amprenavir/ritonavir (FPV/r) 700mg/100 mg twice daily Indinavir/ritonavir (IDV/r)4 800 mg/100 mg twice daily three capsules twice daily Capsule (400/100mg twice daily) Lopinavir 133.3mg + four capsules twice daily when ritonavir 33.3mg combined with EFV or NVP (533/133,33 mg twice daily) Treatment naïve patients Lopinavir/ritonavir (LPV/r) 5 Two tablets twice daily irrespective of Tablet (heat stable coadministration with EFV or formulation) NVP (400/100 mg twice daily) Lopinavir 200mg + Treatment experienced patients ritonavir 50mg Three tablets twice daily when combined with EFV or NVP (600/150 mg twice daily) Nelfinavir (NFV) 1250 mg twice daily Saquinavir/ ritonavir (SQV/r)5 1000/100 mg twice daily 1. AZT 250mg BID is included as an option in the 2006 WHO guidelines for adult ART and is available as the FDC of AZT 250mg/3TC 150mg/NVP 200mg (GPOVIR-Z). New data from Thailand may support a dose of 200mg BID in a Thai population79 2. ddI dose should be adjusted when coadministered with tenofovir. If weight >60 kg, the recommended dose is 250 mg once daily. If weight <60 kg, there is no data to make a recommendation (some preliminary PK studies suggest 125-200 mg once daily)80. Buffered ddI need to be taken with an empty stomach. 3. Other dose regimens in clinical use are 600mg/100mg 81 and 400mg/100mg 82 4. See TB section for TB-specific dose modifications of lopinavir/r and saquinavir/r

79 daily doses are in tablets / capsules for solid forms and in ml for liquid forms

3TC 150mg + 3TC 150mg + 3TC 150 mg d4T 30mg + NVP 200 mg EFV 200 mg EFV 600 mg first line adults d4T 30mg + AZT 300 NVP 200mg tablets tablets tablets tablets mg tablets tablets

LAMIVUDINE (3TC) 150mg + STAVUDINE (d4T) 30mg + NEVIRAPINE (NVP) 200mg 2 ZIDOVUDINE (AZT) 300 mg + LAMIVUDINE (3TC) 150 mg + NEVIRAPINE (NVP) 200 mg 22 ZIDOVUDINE (AZT) 300 mg + LAMIVUDINE (3TC) 150 mg + EFAVIRENZ (EFV) 600 mg 21 LAMIVUDINE (3TC) 150mg + STAVUDINE (d4T) 30mg + EFAVIRENZ (EFV) 600 mg 2 1 EFAVIRENZ (EFV) 200 mg for TB patients(50% of new patients for 6 months) 1

3TC NVP AZT d4T 15mg d4T 20mg d4T 30mg NVP 200mg EFV 50 mg EFV 200 mg AZT 100 mg AZT 300 mg first line children 50mg/5ml, oral 50mg/5ml, oral 50mg/5ml tablets tablets tablets tablets capsules capsules capsules tablets solution solution oral solution

LAMIVUDINE (3TC) + STAVUDINE (d4T) + NEVIRAPINE (NVP) < 1 y. old (10kg) 81 14 LAMIVUDINE (3TC) + STAVUDINE (d4T) + NEVIRAPINE (NVP) > 1 and < 5 y. old (15kg) 12 2 1 LAMIVUDINE (3TC) + STAVUDINE (d4T) + NEVIRAPINE (NVP) > 5 y. old (25kg) 20 1 1 1 ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) < 1 y. old (10kg) 81420 ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) > 1 and < 5 y. old (15kg) 12 1 1 ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + NEVIRAPINE (NVP) > 5 y. old (25kg) 20 1 21 LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) < 1 y. old (10kg) (not recommended) LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) > 1 and < 5 y. old (15kg) 12 2 11 LAMIVUDINE (3TC) + STAVUDINE (d4T) + EFAVIRENZ (EFV) > 5 y. old (25kg) 20 1 1 31 ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) < 1 y. old (10kg) (not recommended) ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) > 1 and < 5 y. old (15kg) 12 11 1 ZIDOVUDINE (AZT) + LAMIVUDINE (3TC) + EFAVIRENZ (EFV) > 5 y. old (25kg) 20 31 21

LPV/r LPV/r AZT 300 mg TDF 300 mg ddI 25 mg ddI 100 mg ddI 200 mg ddI 250 mg ABC 300 mg RTV 100 mg SQV 200 mg second line adults 133.3/33.3 200/50 mg +3TC 150 tablets tablets tablets tablets tablets tablets capsules capsules mg capsules capsules mg

Tenofovir (TDF) 300 mg + Abacavir (ABC) 300mg + Lopinavir /Ritonavir (LP/r) 200/50 mg 124 Tenofovir (TDF) 300 mg + Abacavir (ABC) 300mg + Saquionavir /Ritonavir (SQV/r) 200/100 mg 12210 Tenofovir (TDF) 300 mg + AZT 300 mg +3TC 150 mg + Lopinavir /Ritonavir (LP/r) 200/50 mg 1 42 Tenofovir (TDF) 300 mg + AZT 300 mg +3TC 150 mg + Saquinavir /Ritonavir (SQV/r) 200/100 mg 1 2 10 2 Tenofovir (TDF) 300mg + Didanosine (ddI) 125mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 mg <60kg 111 6 Tenofovir (TDF) 300mg + Didanosine (ddI) 250mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 mg >60kg 1 16 Tenofovir (TDF) 300mg + Didanosine (ddI) 125mg + Saquinavir/Ritonavir (SQV/r) 200/100mg <60kg 111 299 Tenofovir (TDF) 300mg + Didanosine (ddI) 250mg + Saquinavir/Ritonavir (SQV/r) 200/100mg >60kg 1 1299 Abacavir (ABC) 300mg + Didanosine (ddI) 250mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 <60kg 162 Abacavir (ABC) 300mg + Didanosine (ddI) 400mg + Lopinavir/Ritonavir (LPV/r) 133.3/33.3 >60kg 2 62 Abacavir (ABC) 300mg + Didanosine (ddI) 250mg + Saquinavir/Ritonavir (SQV/r) 200/100mg <60kg 12299 Abacavir (ABC) 300mg + Didanosine (ddI) 400mg + Saquinavir/Ritonavir (SQV/r) 200/100mg >60kg 2 2299

Lopinavir/riton ABC = Ziagen ddI 25 mg ddI 50 mg NFV 250mg second line children avir 80 mg / 20 100mg/5ml tablets tablets tablets mg per 5 mL

ABACAVIR (ABC) + DIDANOSINE (ddI) + NELFINAVIR (NFV) < 1 year (10kg) 42 2 ABACAVIR (ABC) + DIDANOSINE (ddI) + NELFINAVIR (NFV) > 1 and < 5 y. old (15kg) 6113 ABACAVIR (ABC) + DIDANOSINE (ddI) + NELFINAVIR (NFV) > 5 y. old (25kg) 10 1 2 5 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r]7 to <15 kg, <1 Yr (not recommended) ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r]7 to 10 kg, <1 Yr 4 2 2.5 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 10 to 15 kg, >1yr=<5yr 6 1 3.5 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 15 to 40 kg, >1yr=<5yr (not recommended) ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 15 to 20 kg, >1yr=<5yr 6 1 4.5 ARVs_3DF_Aug 07.MM Page 1 of 2 10/24/2007 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 20 to 25 kg, >1yr=<5yr 6 1 5.5 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 25 to 30 kg, > 5yr old (25 kg) 10 1 7 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 30 to 35 kg, > 5yr old (25 kg) 10 1 8 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] 35 to 40 kg, > 5yr old (25 kg) 10 1 9.5 ABACAVIR (ABC) + DIDANOSINE (ddI) + LOPINAVIR/RITONAVIR [LPV/r] >40 kg, > 5yr old (25 kg) 10 1 10

PMTCT (for Mother) AZT 300 mg NVP 200mg recommend tablets tablets ed days ZIDOVUDINE (AZT) 300 mg (during pregnancy) 2 196 ZIDOVUDINE (AZT) 300 mg + NEVIRAPINE (NVP) 200 mg (during labour) 217 ZIDOVUDINE (AZT) 300 mg + NEVIRAPINE (NVP) 200 mg (after delivery) 227

NVP AZT 3TC recommend PMTCT (for Infants) 50mg/5ml, oral 50mg/5ml oral 50mg/5ml, ed days solution solution oral solution

NEVIRAPINE (NVP) 50mg/5ml, oral solution 0.2 1 ZIDOVUDINE (AZT) 50mg/5ml oral solution 0.8 7 ZIDOVUDINE (AZT) 50mg/5ml oral solution(during pregnancy receives < 28 days) 0.8 28 LAMIVUDINE (3TC) 50mg/5ml, oral solution 0.4 7

PEP AZT 300 mg d4T 30mg recommend tablets tablets ed days

ZIDOVUDINE (AZT) 300 mg + STAVUDINE (d4T) 30mg 2228

PEP (for pregnancy woman) RTV 100 mg SQV 200 mg recommend capsules capsules ed days

Saquinavir/Ritonavir (SQV/r) 200/100mg 2 228

ARVs_3DF_Aug 07.MM Page 2 of 2 10/24/2007 Annex 3 Storage of Antiretrovirals Generic name Storage requirements Nucleoside RTIs Abacavir (ABC) Room temperature Zidovudine (AZT) Room temperature Room temperature for tablets and capsules. Reconstituted buffered powder should be Didanosine (ddI) refrigerated; oral solution for children is stable after reconstitution for 30 days if refrigerated. Emtricatabine (FTC) Room temperature Lamivudine (3TC) Room temperature Room temperature. After reconstitution, oral Stavudine (d4T) solution should be kept refrigerated; if so, it is stable for 30 days. Stavudine (d4T)+Lamivudine (3TC) Room temperature + Nevirapine (NVP) Zidovudine (AZT) + Lamivudine Room temperature (3TC) + Abacavir (ABC) Zidovudine (AZT) + Lamivudine Room temperature (3TC) + Nevirapine (NVP) Nucleotide RTIs Tenofovir (TDF) Room temperature Non-nucleoside RTIs Efavirenz (EFV) Room temperature Nevirapine (NVP) Room temperature Proteases inhibitors Atazanavir (ATV) Room temperature Indinavir (IDV) Room temperature Fos-amprenavir (FPV) Room temperature Refrigerate for long term storage Lopinavir/Ritonavir (LPV/r) capsules At room temperature: stable for 30 days Lopinavir/Ritonavir (LPV/r) heat Room temperature stable tablets Nelfinavir (NFV) Room temperature Refrigerate capsules until dispensed; Stable at room temperature for 30 days Ritonavir (RTV) Room temperature for oral solution (do not refrigerate) Saquinavir – hard gel caps. (SQVhgc) Room temperature Room temperature is defined as 15-30 deg C. Refrigeration is defined as 2-8deg C

81 Annex 4 Drugs that interact with ART ARV NVP EFV LPV/r NFV SQV Antimycobacterium ↓NVP level by 20-58%. Virological consequences are uncertain; the ↓SQV level by 84% potential of additive ↓EFV level by 25% Severe liver impairment ↓LPV AUC by 75% ↓NFV level by 82% Rifampicin hepatotoxicity exists. Co- Standard dosing of EFV with co-administer Should not co-administer Should not co-administer administration is recommended reported recommended only be Should not co-administer done with careful monitoring Levels: EFV unchanged; Levels: Rifabutin AUC ↑ Levels: SQV↓40%. Rifabutin ↓ 35% 3-fold. 25 Levels: NFV ↓ 82%. Contraindicated unless Levels: NVP↓ 16%. Dose: ↑ rifabutin dose to Decrease rifabutin dose to Should not be co- SQV/RTV. Rifabutin No dose adjustment.* 450-600 mg 150 mg once daily or administered. Dose: Rifabutin 150 mg Once daily or 600 mg 3x/week once daily or 3x/week 3x/week. LPV/r: Standard. EFV: Standard Without RTV, ↑clarithromycin level by 45%, ↑SQV level 177% ↑Clarithromycin AUC by RTV can ↑Clarithromycin ↓Clarithromycin by 39% 75%, adjust Clarithromycin none Monitor for efficacy or No data level by 75% clarithromycin dose if use alternative drugs No clarithromycin dose renal impairment adjustment needed for unboosted SQV. For boosted SQV if renal impairment – no data Antifungal ↑Ketoconazole level by ↑SQV level by 3 fold ↑LPV AUC 63% No dose adjustment No significant changes in ↑Ketoconazole level 3- ↑NVP level by 15-30% No dose adjustment necessary if given Ketoconazole ketoconazole or EFV fold Do not recommend co- necessary unboosted. levels Do not exceed 200mg/day administer For RTV-boosted SQV – ketoconazole no data (RTV treatment

82 ARV NVP EFV LPV/r NFV SQV dose can increase ketoconazole level 3-fold) ↑NVP Cmax, AUC, Cmin by 100% No change in fluconazole level Fluconazole Possible increase No data No data No data No data hepatotoxicity with co- administer requiring monitoring of NVP toxicity Bidirectional interaction has been observed. May ↑Itraconazole level No data but potential for need to decrease Itraconazole No data No data Do not exceed 200mg/day bidirectional inhibition, itraconazole dose. itraconazole monitor toxicities Consider monitor SQV level (especially if given unboosted with RTV) Oral contraceptives No data for unboosted ↓Ethinyl oestradiol by ↓Ethinyl oestradiol level ↑Ethinyl oestradiol by ↓levels of norethindrone SQV. 20%. by 42% Ethinyl oestradiol 37%. Use alternative or by 18% and ethinyl RTV treatment dose can Use alternative or Use alternative or additional methods oestradiol by 47% ↓level of ethinyl additional methods additional methods oestradiol by 41% Anticonvulsants Many possible interactions: Unknown, but may Carbamazepine ↑ levels Unknown, but may Use with caution. One decrease NFV levels when co-administered markedly ↓ SQV levels. case report showed low Unknown. Use with substantially. Carbamazepine with RTV. Use with Monitor anticonvulsant EFV concentrations with caution. Monitor anticonvulsant Phenytoin caution. Monitor levels and consider phenytoin. levels and virological anticonvulsant levels. obtaining SQV level. response. Phenytoin: ↓levels of

LPV, RTV, and↓ levels of phenytoin when

83 ARV NVP EFV LPV/r NFV SQV administered together. Avoid concomitant use or monitor LPV level.

Opiod Substitution Treatment (OST) Levels: NVP unchanged. methadone ↓ Methadone AUC ↓ 20%. Levels: methadone ↓ NFV may decrease significantly. Opiate Methadone AUC ↓ 53%. When co-administered 60%. Opiate withdrawal methadone levels, but withdrawal common Opiate withdrawal may with SQV/RTV 400/400 common, increase opiate withdrawal when this combination is occur. Monitor and titrate mg BID. Methadone methadone dose often rarely occurs. Monitor used. Increased dose if needed. No adjustment for this PI necessary. Titrate and titrate dose if needed. methadone dose often May require↑ methadone regimen, but monitor and methadone dose to effect. May require necessary. Titrate dose. titrate to methadone ↑ methadone dose. methadone dose to effect. response as necessary.

Buprenorphine levels ↓ 50% nut no withdrawals Buprenorphine Not studied reported. No dose No significant interactions No significant interactions No significant interactions adjustment is recommended Lipid lowering agents ↓ Simvastatin level by 58% ↑ Simvastatin AUC by EFV level unchanged Potential large ↑ statin 505% Potential large ↑ statin Simvastatin, No data Adjust simvastatin dose level Potential large ↑ level Lovastatin according to lipid Avoid concomitant use lovastatin AUC Avoid concomitant use response, not to exceed Avoid concomitant use the maximum recommended dose ↓Atorvastatin AUC by ↑ Atorvastatin level by 43% ↑Atorvastatin AUC 5.88 ↑Atorvastatin AUC 74% 450% when use as EFV level unchanged fold No data Use lowest possible SQV/RTV Atorvastatin Adjust atorvastatin dose Use lowest possible starting dose with careful Use lowest possible according to lipid starting dose with careful monitoring starting dose with careful response, not to exceed monitoring monitoring maximum recommended

84 ARV NVP EFV LPV/r NFV SQV dose ↑Pravastatin AUC 33% ↓Pravastatin level by 50% Pravastatin No data No data No dose adjustment No data No dose adjustment needed needed Anticonvulsants ↑Carbamazepine from Use with caution. One Unknown but may Unknown for unboosted Unknown. Use with RTV case report showed low decrease NFV level SQV but may markedly ↓ Carbamazepine, caution Both phenytoin and EFV levels with substantially SQV level Phenobarbital, Monitor anticonvulsant LPV/r levels ↓ phenytoin Monitor Monitor phenytoin levels For all, avoid concomitant Monitor anticonvulsant NFV/anticonvulsant SQV/anticonvulsant use or monitor and EFV levels levels levels LPV/anticonvulsant levels Proton pump inhibitors. All the PIs and EFV can ↑ levels of cisapride and non sedating antihistamines (aztemizole, terfenedine) which can cause cardiac toxicity. Co administration is not recommended

Abbreviations: AUC: area under the curve, Cmax: maximum concentration, Cmin: minimum concentration. Note: Concomitant use of fluticasone with RTV results in significant reduced serum cortisol concentrations. Coadministration of fluticasone with RTV or any RTV-boosted PI regimen is not recommended unless the potential benefit outweighs the risk of systemic corticosteroid side effects. (Adapted from the Guidelines for the use of antiretroviral agents in HIV infected Adults and Adolescents, May 4, 2006, www.aidsinfo.nih.gov.)

85

Annex 5 Clinical diagnosis and management of common opportunistic infections Opportunistic Clinical Features Diagnosis Treatment Infection

Preferred treatment Cotrimoxazole (Trimethoprim-sulfamethoxazole, TMP 15 mg plus SMZ 75 mg/kg daily) in 4 divided doses, orally or intravenously, for 21 days. Chest X-ray is abnormal in more Treatment should be IV in severally ill patients. Patients can Dry cough Pneumocystis than 90% cases of pneumocystis switch to oral cotrimoxazole if clinically improved. Shortness of breath jiroveci jiroveci pneumonia, typically Oral doses are 480 mg, 2 tablets 4 times daily (patient <40 kg) Fever (previously know as showing bilateral interstitial and 3 tablets 4 times daily (patient >40 kg) Night sweats carinii) infiltrates Alternative treatment Subacute presentation over 1-2 months Clindamycin 600mg IV or 450mg orally TID + primaquine 15mg orally OD for 21 days if allergy to sulphonamides. Prednisolone, 20 mg 4 times daily, reducing slowly over 7-10 days depending on response to therapy is recommended for severely ill patients.

Typical clinical appearance on physical examination Oral candida Clotrimazole or nystatin lozenges, to be sucked every 4 hours for

White mucosal plaques +/- erythema in 7 days or Microscopic demonstration of oral cavity Nystatin oral suspension 100,000 IU, three times a day for 7 days Candida psuedohyphae on potassium hydroxide preparation

Oesophageal Candida Typical clinical presentation and Fluconazole 200 mg daily for 14 days or Dysphagia response to antifungal therapy Ketoconazole 200 mg daily for 14 days +/- retrosternal chest pain Endoscopy if available

86 Opportunistic Clinical Features Diagnosis Treatment Infection

Occipital headache Preferred treatment meningeal irritation photophobia, neck IV Amphotericin B (0.7 mg/kg/day) for 2 weeks followed by stiffness or raised intracranial pressure Elevated intracranial pressure CSF Itraconazole 200 mg 2 times daily or fluconazole 400 mg daily for Fever and protein on lumbar puncture 8 weeks Cryptococcosis Changes in mental state Organism demonstrated from CSF Alternative treatment Disseminated disease with papulo- or skin legions with India Ink stain Fluconazole 400 mg daily for 8 to 12 weeks necrotic skin lesions resembling and light microscopy Maintenance treatment molluscum contagiosum associated with Itraconazole 200 mg/day or Fluconazole 200mg/day fever and pulmonary infiltrates

Papulo-necrotic skin lesions associated Preferred treatment with systemic disease of fever, lung Microscopy of skin biopsy or lymph IV amphotericin B (0.7mg/kg daily) for 2 weeks followed by involvement, cough, weight loss, node aspirate itraconazole 400 mg orally daily for 8-10 weeks. Penicilliosis anaemia, and lymphadenopathy. Organism demonstrated with 70% of patients with disseminated Wright’s stain or Cotton blue stain Maintenance therapy Penicillium marneffei infection will Itraconazole 400 mg daily have skin lesions

Preferred treatment Pyrimethamine loading dose 75-100 mg, then 25-50 mg daily plus Headache Focal neurological signs Sulfadiazine, 4 g daily in 4 divided doses Drowsiness Single or multiple ring-enhancing Folinic acid 10 mg per day if available Toxoplasmosis Fever lesions on CT (if available) Treat for 6 weeks Focal neurologic abnormality Response to presumptive treatment Maintenance therapy Seizures can be used to support the diagnosis Pyrimethamine, 25 mg daily plus Sulfadiazine, 2 g daily in 4 divided doses

Clusters of typical blisters, usually in Usually self-limiting and may not require treatment. Herpes simplex genital area or face Typical clinical appearance Local lesion care, such as with gentian violet and chlorhexidine. virus (HSV) Systemic involvement (such as HSV If indicated, acyclovir 200-400 mg 5 times daily for 7 days. oesophagitis, encephalitis) is possible

87 Opportunistic Clinical Features Diagnosis Treatment Infection

Local lesion care, such as with gentian violet and chlorhexidine. Acyclovir 800 mg 5 times daily orally for 7 days, commenced Herpes zoster virus Typical painful blisters in clusters along Clinical appearance within 72 hours of onset of blisters. Famciclovir and valaciclovir (HZV) dermatomes. Can involve the eye are alternatives. Acyclovir ointment applied into eye every 4 hours for ophthalmic H. zoster

Sputum examination for AFB Chest X-ray Classic chest X-ray pattern Pulmonary TB Upper lobe infiltrates Cavitation Cough, fever, weight loss, fatigue Atypical Pattern Mycobacterium Bilateral Interstitial infiltrates Treat according to national TB guidelines. tuberculosis Infiltrates, pleural effusion Pleural tap for AFBs

Unilateral nodes increasing in size, Extra pulmonary TB matted nodes, fluctuant nodes, fever, Enlarged lymph nodes or spleen weight loss, splenomegaly CNS or gastro-intestinal symptoms Diarrhoea and abdominal pain

Preferred therapy Azithromycin (500-600mg once a day) or clarithromycin (500mg twice a day) plus ethambutol (15mg/kg/day) plus rifabutin Mycobacterium Chronic or recurrent fever Isolation of organism from blood or (300mg once a day) Avium Complex Weight loss other sites ART may resolve the condition (MAC) Fatigue Unexplained anaemia Maintenance therapy Clarithromycin (500mg twice a day) or azithromycin (500mg once a day) plus ethambutol (15mg/kg once a day)

Chronic diarrhea Modified AFB stain on stool Cryptosporidium Cramps and vomiting ART is the preferred treatment specimen Right upper quadrant pain

88

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