Antiretroviral Agents and Their Toxicities ACRN Review Course

ACRN Review Course

Antiretroviral Agents and their Toxicities Christopher Roberson MS, CRNP AAHIVP , Objectives

• Identify the 5 classes of antiretroviral medications • Describe how each class of antiretroviral medications works against the HIV Virus at the level of the CD4 cell • Review key studies related to HAART (highly active antiretroviral medications) • List key toxicities and drug interactions of the antiretroviral classes and individual antiretroviral medications • Review the current guidelines on the administration of antiretroviral medications

MidAtlantic AETC HIV-1 Lifecycle

Entry

RNA RNA Viral protease Proteins Reverse RT transcriptase RNA RNA DNA RT

DNA

DNA Provirus Integrase

MidAtlantic AETC U.S. FDA Approved Antiretroviral Drugs 2016

NRTI/NtRTIs NNRTIs PIs Zidovudine Nevirapine Saquinavir Didanosine Efavirenz Ritonavir Stavudine Rilpivirine Indinavir Lamivudine Nelfinavir Abacavir Lopinavir Emtricitabine Integrase Inhibitors Atazanavir Tenofovir Dolutegravir Fosamprenavir Raltegravir Tipranavir Entry/Fusion Inhibitors Elvitegravir Darunavir

Enfuvirtide Maraviroc

MidAtlantic AETC Effect of HAART on Survival

40 100% Mono/Dual Therapy Introduction of HAART Years

- Deaths 80% 30 60% 20 40%

10 Use of 20%

HAART (% of patient days) 0 0%

Deaths per 100 Person 100 per Deaths 1987 1994 1995 1996 1999 2000 NRTIs PIs NNRTIs Therapy With a Protease Inhibitor a Protease With Therapy AZT dd d4T 3TC SQV RTV DLV ABC LPV/ I IDV NFV APV RTV dd NVP EFV C

MidAtlantic AETC HOPS Cohort: Improved Outcomes With Early Initiation

Mortality (per 1000 person-years) • Prospective cohort (n=4421)of HAART 80 Adherence – 8-year follow-up <95% 60 • Higher pre-HAART CD4 cell count * >95% and >95% adherence 40

Incidence * – Lower incidence of: 20 • Mortality 0 <50 50-199 200-349 350-499 >500 • OIs Pre-HAART CD4 Category (cells/mm3) – Higher percentage achieving OIs (per 1000 person-years) HIV RNA <50 copies/mL 80 Adherence (P<0.01) <95% 60 • These data suggest there are >95% immunologic benefits and less 40

Incidence * toxicity when HAART is initiated 20 * earlier and is continuous * * 0 *P<0.05. <50 50-199 200-349 350-499 >500 Pre-HAART CD4 Category (cells/mm3)

Lichtenstein KA, et al. 13th CROI. Denver, 2006. Abstract 769. Immune Recovery by Baseline CD4+ T-cells in Patients with Sustained Viral Suppression Median CD4+ Cell Count Over Time Stratified by Baseline CD4+ Cell Counts ≤200 cells/µL 201-350 cells/µL >350 cells/µL

µL 900 800 700

600 500

400 300 200

100 0 CD4 lymphocyte count, cells/ CD4 lymphocyte 0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Years after starting HAART

Moore RD, Keruly JC. Clin Infect Dis. 2007;44:441–446.

MidAtlantic AETC CD4+ T-cell Count Associated with Risk of Non–HIV Related Death (D:A:D Study)

• Cohort study of >23,000 patients in Europe, Australia, RR of death according to immune function and specific cause USA 100 Overall • 1248 (5.3%) deaths 2000– HIV 2004 (1.6/100 person-years) Malignanc y Of these, 82% on ART Liver – Heart • Both HIV- and non–HIV- 10 related mortality associated

with CD4+ cell count RR depletion, suggesting role for 1.0

immunosuppression in causes <50 50–99 100–199200–349 350–499>500 of death typically considered not HIV-related* CD4+ Cells/mm3 0.1

Weber R et al. 12th CROI; 2005; Boston. Abstract 595 and AIDS. 2008 Oct 18;22(16):2143-53. *Liver-related: Chronic viral hepatitis, liver failure (other); malignancy-related: malignancy, non-AIDS non-hepatitis; heart-related: MI, other CVD, other heart disease HOPS Cohort: Delay in Initiating HAART Increases Risk of Toxicities Adjusted Odds Ratios (95% CI) • Prospective cohort Pre-HAART Renal Peripheral CD 4 cell count Insufficiency Neuropathy Lipoatrophy (n=4421) (301/2222) (cells/mm3) (113/2156) (176/361) • 8-year follow-up • Higher pre-HAART CD4 cell 200-349 0.5* 0.6* 0.4* (0.3-0.8) (0.5-0.9) (0.2-0.8) count associated with 350-499 0.7 0.6* 0.3* decreased risk of toxicity (0.4-1.2) (0.4-0.9) (0.2-0.6)

• These data suggest that a >500 0.3* 0.7* 0.5* delay in initiating HAART (0.2-0.6) (0.5-0.9) (0.3-0.9) increases the risk of Taking <95% of 1.7* 1.4* 0.6* toxicities prescribed (1.2-2.6) (1.1-1.8) (0.3-0.9) HAART

*P<0.05. Numbers in yellow represent significant increase.

Lichtenstein KA, et al. 13th CROI. Denver, 2006. Abstract 769. Mean Annual Expenditures per Patient by Cost Component and CD4 category

CD4 strata Total ARV Non- Hospital Other Physician/ (cells/mL) ARV Outpt. clinic < 50 $36,532 $10,885 $14,882 $8,353 $1,909 $533

50-199 $23,864 $11,862 $6,685 $3,369 $1,416 $532

200-349 $18,274 $11,935 $3,452 $1,186 $1,365 $336

> 350 $13,885 $9,407 $1,855 $1,408 $930 $285

All $18,640 $10,500 $4,240 $2,342 $1,199 $359

Patients with CD4 counts < 50 expend 2.6 times more health care dollars than those with CD4 counts > 350 (P<0.001)

Chen, et al. Clin Infect Dis. 2006;42(7):1003-10. DHHS: Changing Criteria for Initiating ART

CD4+ 1998 2001 2006 2008 2009 2012 Count, &Beyond cells/mm3 Offer if Consider if Consider in Offer if > 500 VL VL certain Consider Treat VL > 20,000 > 55,000 ≥ 100,000 groups Consider if Consider if Consider in Offer if 350-500 VL VL certain Treat Treat VL > 20,000 > 55,000 ≥ 100,000 groups Offer, but Offer after Offer if 200-350 controversy discussion Treat Treat Treat VL > 20,000 exists with patient < 200 or symptomatic Treat Treat Treat Treat Treat Treat disease

MidAtlantic AETC When to Start ART When the Patient is Ready Considerations in Starting ART:

• Age • OIs/Co-morbidities • CD4/Viral Load – Mental health • Social – Substance Abuse – Unstable housing – Hepatitis B and C – Major life crises – Renal - HIVAN – Perceived stress – Cardiovascular – Stigma/Denial – Malignancies – Neurologic

MidAtlantic AETC “It’s much more important to know what sort of patient has a disease than what sort of disease a patient has.” William Osler

“Drugs don’t work if people don’t take them.”

C. Everett Koop

MidAtlantic AETC Need to Individualize • One regimen does not fit all

• Multiple treatment options

• Factors Which Impact Regimen Durability – Non-adherence • Side effects/toxicities • Pill burden • Life schedule • Social situation – Resistance – Pharmacokinetics

MidAtlantic AETC HIV-1 Lifecycle

Entry

RNA RNA Proteins RT RNA RNA DNA RT

DNA

DNA Provirus

MidAtlantic AETC Fusion Inhibitors

GP41 GP41 GP120 GP120 inhibitor GP120 CD4 GP41

GP-41 HR-1 CC HR-2 T-20 T-1249

Doms R. State of the Art Lecture. 8th CROI, Chicago, 2001. #14

MidAtlantic AETC O

O HN

HO O OH H N NH NH 2 O O HO O NH O 2 HN N H NH HN O N O O O H NH NH NH O O OH HN HN H O N O H NH N N NH HO O O HN HN H 2N O O NH NHHO O O O HN HN OH O O NH O NH HO O O O OH O HN ZIDOVUDIN HN SAQUINAVIR O OH O NH E NH MESYLATE H 2N O O O O HN M.W. 267 HO HN M.W. 767 O O HO O H N O O NH 2 NH O H 2N O NH H O 2 O N H H O O N N N N N O H H H O O NH 2

H N O 2 HO O

NH 2 ENFUVIRTIDE (T-20) M.W. 4,492

MidAtlantic AETC TORO 1 + 2: Injection site reactions • ISRs are the most common AE associated with T-20 – Occur in 98% of patients • Only 3% discontinued T-20 due to ISRs • Most common signs/symptoms – pain/discomfort, most mild to moderate – induration, most < 50 mm – erythema, most < 50 mm – nodules or cysts, most < 3 cm • 1% of patients had infections at site of injection • Mean duration of individual ISR ≤ 7 days

Clotet et al., Barcelona, ‘02 Henry et al., Barcelona, ‘02

MidAtlantic AETC T-20 Related ISR

MidAtlantic AETC T-20: Other Adverse Events

• Limited evidence for differences in most clinical and laboratory endpoints • Eosinophilia > 700/mm3 in 10%, > 1400 1.8% • Hypersensitivity – 3 cases confirmed with rechallenge – Other possibly related cases GBS, glomerulonephritis • Pneumonia approx 6 times higher with T-20 in Toro studies – One case in OB prior to switch – T-20 rate similar to cohort and natural history studies

MidAtlantic AETC Maraviroc is a CCR5 Antagonist

• Selective small-molecule antagonist of the interaction between the human chemokine CCR5 co-receptor and HIV-1 gp120 • Not active against CXCR4-tropic HIV-1 Binding Conformational Change Inhibition of Viral Entry

Maraviroc binds to the CCR5 CCR5 3-dimensional structure is gp120-CD4 complex cannot transmembrane domain altered bind to modified CCR5

Moore J, et al. Proc Natl Acad Sci U S A. 2003;100:10598-10602. Yost R, et al. Am J Health-Sys Pharm. 2009;66:715-726.

MidAtlantic AETC Defining Co-Receptor Tropism

• CCR5 and CXCR4 are the primary chemokine co-receptors used by HIV to enter CD4+ T cells

CCR5-tropic (R5) HIV that can use CXCR4-tropic (X4) virus enters CD4+ T either CCR5 or virus enters CD4+ T cells via CCR5 CXCR4 is called dual cells via CXCR4 tropic

Virus populations containing a mixture of R5-tropic, X4-tropic, and/or dual-tropic HIV are called mixed tropic

Westby E, et al. Antivir Chem Chemother. 2005;16:339-354.

MidAtlantic AETC Viral Tropism Is Associated With + HIV Co-ReceptorCD4 UsageT (%)-Cell in Patients Count Screened for MOTIVATE by Screening CD4+ T-Cell Count (mean count = 160)

≥ 400 (n=189) 76% 24% 0%

200-399 (n=681) 66% 31% 3%

50-199 (n=887) 59% 38% 3%

0-49 (n=828) 40% 57% 3%

0 10 20 30 40 50 60 70 80 90 100

R5 only D/M X4 only This data is based on the less-sensitive original Trofile assay. Therefore, the data may overestimate the prevalence of CCR5-tropic virus and underestimate the prevalence of D/M and X4-tropic virus. Clax P, et al. 3rd Intl Workshop HIV Entry. 2007.

MidAtlantic AETC Maraviroc Adverse Effects

• Hepatotoxicity • Caution – Associated with allergic – Postural Hypotension reaction or hepatitis – Cardiovascular Events in • Dizziness 1.3% • Cough • Abd pain • Potential Risks – Increase risk of infection • Fever • Higher rate of Upper • Musculoskeletal respiratory tract infections vs. placebo symptoms (20 vs. 11.5 %) • Rash • Lower rate of pneumonia (2.1 vs. 4.8%) – Increase risk of malignancy

MidAtlantic AETC Co-administration of Maraviroc With Potent CYP3A Inhibitors and Inducers Affects Dose Selection • Co-administration of potent CYP3A inhibitors and/or inducers with maraviroc must be considered when constructing multidrug regimens:

– Potent CYP3A inhibitors → ↑ maraviroc plasma level – Including: efavirenz, rifampin, etravirine, carbamazepine, phenobarbital, phenytoin

– Dose MVC 150 mg PO BID – Potent CYP3A inducers → ↓ maraviroc plasma levels – The effect of CYP3A inhibition on maraviroc levels is dominant when potent CYP3A inhibitor is co-administered with an inducer

– Including: efavirenz, rifampin, etravirine, carbamazepine, phenobarbital, phenytoin

– Dose MVC 600 mg PO BID

SELZENTRY [prescribing information]. New York, NY: Pfizer Inc; 2009. Entry Inhibitor Resistance Mutations • Enfuvirtide – Mutations in First Heptad Repeat (HR-1) of envelope gene – 36, 37, 38, 39, 40, 42, 43 – Polymorphisms and mutations in HR-2 or other regions and coreceptor usage/density may also affect susceptibility

• Maraviroc – Outgrowth of DM/X4 virus – Mutations in gp120

MidAtlantic AETC HIV-1 Lifecycle and Mechanisms of Action of Antiretroviral Agents

RNA RNA Proteins Reverse RT transcriptase RNA RNA DNA RT

DNA

DNA Provirus

MidAtlantic AETC Currently Approved Nucleoside/tide Reverse Transcriptase Inhibitors (NRTI/NtRTIs) in the U.S.

Drug Other Names Year Approved

Zidovudine (AZT, Retrovir) 1987 Didanosine (ddl, Videx) 1991 Zalcitabine (ddC, Hivid) 1992 Stavudine (d4T, Zerit) 1994 Lamivudine (3TC, Epivir) 1995 Abacavir (1592, Ziagen) 1998 Tenofovir (PMPA, Viread) 2001 Emtricitabine (FTC, Emtriva) 2003 Mechanism of NRTI Function

Nucleotide Incorporation

P N P N dNTP

AZTMP Incorporation

P N P N

dNTP AZT AZT N N 3 3

MidAtlantic AETC Case 1

• 58 y.o. African American man referred to IHV in November 2001 • PMH: HTN, hand surgery • FH: DM, HTN • SH: no IVDU • CD4 401, RNA not detectable • Meds: ddI, d4T, Lopinavir/ritonavir

MidAtlantic AETC Case 1

• January 2002 – Seen in ER 3 times in 2 week period for recurrent nausea, vomiting, abd pain – Told he had an “inflamed pancreas” • February 2002 – Routine clinic appt – Still with abd pain, Lipase >700 – Antiretrovirals discontinued – Symptoms resolved within several weeks

MidAtlantic AETC Case 1

• July 2002 - CD4 241 – Restarted antiretrovirals (TDF, ABC, LPV/r) • October 2002 – Asymptomatic – Glucose 500, Avandia started for diabetes – Medications discontinued • March 2003 - CD4 193, glucose controlled – Restarted TDF, ABC, LPV/r • July 2003 – CD4 330, RNA 63 – Glucose 110-140

MidAtlantic AETC Mitochondrial Toxicities Related to NRTIs • Neuropathy • Myopathy • Myocarditis • Pancreatitis • Hepatic steatosis • Lipodystrophy • Lactic Acidosis • Renal tubular defects • Pancytopenia

MidAtlantic AETC Inhibition of Mitochondrial DNA Content After 9 Days of NRTI Liver Exposure Skeletal Muscle Cells 140 (HepG2 Cells) 3TC 140 TDF ABC 120 120 ABC TDF 100 Control 100 3TC ZDV 80 80 ZDV 60 60 d4T d4T 40 40

mtDNA Content (%) mtDNA ddI Content (%) mtDNA ddI ddC 20 20 ddC

0 0 0.1 1.0 10 100 1000 0.1 1.0 10 100 1000 NRTI (µM) NRTI (µM)

Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723.

MidAtlantic AETC Lactic Acidosis Symptoms and Laboratory Findings Symptoms Laboratory Findings • Nausea and • Increased anion gap vomiting • Increased lactic acid • Abdominal pain levels • Weight loss • Increased • Malaise lactate/pyruvate • Dyspnea/tachypnea

MidAtlantic AETC Adverse Effects of NRTIs • Bone Marrow Suppression • Lactic Acidosis – All – Zidovudine (anemia) • Myopathy • Flatulence – Zidovudine – tenofovir • Palmar Hyperpigmentation • Fatigue – emtricitabine • Pancreatitis Zidovudine (all) – – ddI, d4T, ddC • GI effects • Peripheral Neuropathy – All – ddI, d4T, ddC • Headache • Renal – tenofovir – All • Stomatitis • Hypersensitivity – ddC – abacavir

MidAtlantic AETC Description of Hypersensitivity Reactions to Abacavir • Symptoms of multiorgan system involvement • Four most common symptoms: Major – Fever, rash, GI, malaise/fatigue/headache • Less common (<10%): Minor – Edema, musculoskeletal, respiratory symptoms, mucous membrane, constitutional • Resolves on stopping abacavir • More severe symptoms, including life-threatening hypotension and death, have occurred on rechallenge • Rechallenge must not be attempted

MidAtlantic AETC Time to Onset of ABC HSR in Clinical Trials (n=206)

15 Median time to onset 9 days

10 89% of cases occurred within 6 weeks of ABC initiation

Number of Cases 5

0 1 5 9 13 17 21 25 29 33 37 41 45 49 53 Days from First Dose of ABC Data on file, GlaxoSmithKline. Data on file, GlaxoSmithKline.

MidAtlantic AETC Most Common (>10%) Symptoms with ABC HSR in 9 Clinical Trials

n=206

MidAtlantic AETC Overlapping Drug Toxicities • Peripheral neuropathy – didanosine, isoniazid, linezolid, stavudine, zalcitabine • Bone marrow suppression – cidofovir, cotrimoxazole, dapsone, zidovudine, gancyclovir, hydroxyurea, PEG-interferon, ribavirin • Hepatotoxicity – efavirenz, isoniazid, NRTIs, nevirapine, protease inhibitors, isoniazid, rifampin, fluconazole • Pancreatitis – didanosine, stavudine, zalcitabine, pentamidine, ritonavir, cotrimoxazole

MidAtlantic AETC D:A:D Study: NRTI Use and Risk of MI • D:A:D study Relative Risk P Recent use (95% CI) Value – 33,347 HIV patients on HAART • 517 patients developed MI over Zidovudine 0.97 0.82 157,912 person-years of follow-up (0.76- 1.25) – Recent didanosine use (n=124) Stavudine 1.00 0.93 – Recent abacavir use (n=192) (0.76-1.32) – Recent other NRTI use (n=237) Lamivudine 1.25 0.10 (0.96-1.62) • Recent use of abacavir and didanosine (but not cumulative or Abacavir 1.90 0.001 past use) associated with increased (1.47-2.45) risk of MI Didanosine 1.49 0.003 – Risk persists regardless of length (1.14-1.95) of use Implications:Use caution in the interpretation of – Risk was reversible with these preliminary findings and await further studies discontinuation of drugs – Most MIs occurred in patients with existing cardiovascular risk factors

Sabin C, et al. 15th CROI. Boston, 2008. Abstract 957C.

MidAtlantic AETC ABC Not Associated With MI in FHDH After Controlling for CV Risk Factors

. • In earlier analysis of French Hospital Factors associated with MI in the HIV population include CV risk factors Database on HIV, recent exposure including cocaine and IV drug use, to ABC associated with increased having a detectable HIV-1 RNA, risk abnormal CD4+/CD8+ cell ratio of MI[1] Factor OR (95% CI) – OR: 1.97 (95% CI: 1.09-3.56; P = .025) CV risk factors* • After controlling for additional CV 0 1 (Ref) risk factors and factors associated 1-2 16.8 (5.9-48.4) with HIV and ART, association no ≥ 3 49.4 (16.4-149.0) longer observed[2] HIV-1 RNA – OR: 0.97 (95% CI: 0.86-1.10) ≤ 50 c/mL 1 (Ref) > 50 c/mL 1.6 (1.1-2.1) – Risk factors included HTN, smoking, family history of premature CAD, use CD4+/CD8+ ratio of cocaine and/or IV drug use, plasma ≥ 1 1 (Ref) HIV-1 RNA level, CD4/CD8+ cell ratio, < 1 1.8 (1.0-3.0) and exposure to FTC, ATV, RTV, and TPV *Man > 50 yrs or woman > 60 yrs, current smoker or smoking cessation < 3 yrs, family history of premature CAD, hypertension, 1. Lang M, et al. CROI 2009. Abstract 43 LB. hypercholesterolemia, diabetes and cocaine and/or IV drug use 2. Costagliola D, et al. IAS 2009. Abstract MOAB201. clinicaloptions.com/hiv Nucleoside/tide Resistance Mutations • Zidovudine 41, 67, 70, 210, 215, 219 • Didanosine 65, 74 or 3 or more TAMs • Zalcitabine 65, 69, 74, 184 • Stavudine 41, 65, 67, 70, 210, 215, 219 • Lamivudine 65,184 • Emtricitabine 65,184 • Abacavir 65, 74, 115, 184(+ 2-3 TAMs ↓, 4+ TAMs 0) • Tenofovir 65, ≥ 3 TAMS with 41 or 210

Multinucleoside Resistance

• Multiple TAMs/NAMs 41, 67, 70, 210, 215, 219 • 69 insertion complex 41, 62, 69, 70, 210, 215, 219 • 151 complex1 62, 75, 77, 116, 151

1. Tenofovir retains activity MidAtlantic AETC Predicted NRTI activity based on median phenotypes by genotype*

# Mutations RT genotype ZDV d4T ddI 3TC/F ABC TDF TC

1 184V/I 65R 2 65R + 184V/I 74V/I + 184V/I 41L + 184V/I 3 67N + 70R + 184V/I 215Y/F* +184V/I 4 67N + 70R +219E/Q + 184V/I 41L + 215Y/F* + 184V/I 5 41L + 210W + 215Y/F* + 184V/I

*215Y and 215F both require 2 mutations from wild type Resistant Susceptible

Lanier R, et al. 10th CROI, Boston 2003, #586 Partial

MidAtlantic AETC HIV-1 Lifecycle and Mechanisms of Action of Antiretroviral Agents

RNA RNA Proteins Reverse RT transcriptase RNA RNA DNA RT

DNA

DNA Provirus

MidAtlantic AETC Currently Approved Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in the U.S. Drug Other Names Year Approved

Nevirapine (Viramune) 1996 Delavridine (Rescriptor) 1996 Efavirenz (Sustiva) 1998 Etravirine (Intelence) 2008 Rilpivirine (Edurant) 2011 Crystal Structure of HIV Reverse Transcriptase

pol RNase H active active site fingers p66 thumbsite

Nucleoside drug binding site

Non-nucleoside drug binding site p51 Adverse Effects of NNRTIs • Rash – Occurs in 15-30% of patients – Discontinuation of therapy due to rash • Nevirapine - 7% • Delavirdine - 4% • Efavirenz - 1.7% • Etravirine – 2% • Rilpivirine – 0.1%

• Hepatotoxicity – With NVP, seen in higher incidence and contraindicated in • Men CD4 > 400 • Women CD4 > 250 – Can see in Efavirenz and Etravirine • Especially in Hep B/C co-infection

• CNS side effects with Efavirenz

MidAtlantic AETC NNRTI Resistance Mutations Low Mutation Theshold • Nevirapine 100, 101, 103, 106, 108, 181, 188, 190 • Delavirdine 103, 106, 181, 188, 236 • Efavirenz 100, 101,103, 106, 108, 181, 188, 190, 225 • Etravirine 90, 98, 100, 101, 106, 138,179, 181, 190, 230 • Rilpivirine 90, 100, 101, 138, 179, 181, 189, 190, 221, 227, 230

MidAtlantic AETC TMC125-C223 Etravirine - Number of NNRTI Mutations and Virologic Response at Week 24

Baseline NNRTI mutations TMC125 Active in TMC125 800 mg bid 800 mg bid control 0* 1 2 ≥3 c/ml) 0

10 N=7 N=40 N=1 N=1 N=1 N=2 9 5 8 7 9 – –0.5 0.19

– –1.0 0.66 – – 1.00 –1.5 1.18 Relevant NNRTI – Mutations: –2.0 – 1.65 Mean change in viral load (log 1.82 K101P, V179E, V179F, *All subjects had NNRTI mutations from prior genotyping Y181I, Y181V, G190S,

Vingerhoets J, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 154 M230L HIV-1 Lifecycle and Mechanisms of Action of Antiretroviral Agents

RNA RNA Proteins RT RNA RNA DNA RT

DNA

DNA Provirus Integrase

MidAtlantic AETC Currently Approved Integrase Inhibitors (INSTIs) in the U.S.

Drug Other Names Year Approved Raltegravir (Isentress) 2007

Elvitegravir (Viteka) (Coformulated with TDF/FTC and cobicistat only as a STR Stribild) 2012 (Coformulated with TAF/FTC and cobicistat only as a STR Genvoya) 2015

Dolutegravir (Tivicay) (Coformulated with ABC/3TC as well as STR Triumeq) 2013 Raltegravir Adverse Effects

• Diarrhea • Toxicities Seen in Trials with • Nausea Unknown Relationship – Malignancies • Headache – Myopathy • Fever – Rhabdomyolysis • Fatigue Abd pain – Hypersensitivity • Dizziness • Able to rechallenge • Higher rate of worsening AST, ALT or bilirubin vs. placebo • Rash

MidAtlantic AETC Elvitegravir + TDF/FTC/Cobicistat Adverse Effects

• Diarrhea • Renal abnormalities • Nausea – Cobicistat • Increases serum creatinine • Abnormal dreams and decrease estimated • Headache creatinine clearance (through inhibition of • Fatigue tubular secretion of creatinine) • Dizziness • No effect on actual GFR • Rash • Upper respiratory tract infection

MidAtlantic AETC Dolutegravir Adverse Effects

• Diarrhea • Renal abnormalities • Nausea – 9-13% decrease in Creatinine clearance • Headache – No change in actual GFR by • Fever Iohexol • Fatigue • Abd pain • Dizziness • Increased AST, ALT or bilirubin

MidAtlantic AETC HIV-1 Lifecycle and Mechanisms of Action of Antiretroviral Agents

RNA RNA Viral protease Proteins RT RNA RNA DNA RT

DNA

DNA Provirus

MidAtlantic AETC Protease Inhibitors are Competitive Inhibitors of the Protease

54 53 53 54 46 46

82 82 84 84 20 20 63 63 10 24 2410 90 90 71 71

Kempf D, et al. Abstract 129, First IAS Conference on HIV Pathogenesis and Treatment, July 8-11, 2001.

MidAtlantic AETC Currently Approved Protease Inhibitors in the U.S.

Drug Other Name Year Approved

Saquinavir (Invirase) 1995 Ritonavir (Norvir) 1996 Indinavir (Crixivan) 1996 Nelfinavir (Viracept) 1997 Amprenavir (Agenerase) 1999 Lopinavir/ritonavir (ABT378, Kaletra) 2001 Atazanavir (BMS232632,Reyataz) 2003 fosAmprenavir (GW433908, Lexiva) 2003 Tipranavir (Aptivus) 2005 Darunavir (TMC-114, Prezista) 2006 Atazanavir/cobicistat (Evotaz) 2014 Darunavir/cobicistat (Prezcobix) 2014 Lopinavir and Lopinavir/r single dose pharmacokinetics in humans

Lopinavir alone 10 Lopinavir from Kaletra Ritonavir from Kaletra

1 g/mL) µ

0.1

0.01 Concentration (

0.001 0 6 12 18 24 30 36 42 48 Time (hours)

MidAtlantic AETC Reasons to Use a Boosted PI

• Potency • High Barrier to Resistance – May also protect other agents in combination regimen • Pharmacokinetics • Durability • May protect against apoptosis • May decrease immune activation

MidAtlantic AETC Mutations Acquired with Virologic Failure in Boosted vs. Non-boosted PIs % Virologic Failures with Resistance

50 NAMs 40 3TC/FTC PI 30

0 d4T/3TC/LPV/r d4T/3TC/NFV ABC/3TC/fAPV ABC/3TC/NFV ABC/3TC/fAPV/r ABC/3TC/NFV d4T/3TC/ATV/r d4T/3TC/ATV

Kempf, et al, 10th CROI, Abstract 600, Macmanus, et al, 10th CROI, Abstract 598, Malan N, et al. IAS 2007. Abstract WEPEB024 Pharmacokinetic and Genetic Barriers to Resistance

Non-Boosted NNRTIs Boosted PIs High Drug Levels Small Change per Mutation PIs BUT AND Small Change per Mutation Large Change per Mutation High Drug Levels BUT Low Drug Levels High High Trough Troug h

Low Trough

Increasing EC50 EC50 EC50

Increasing Number of Mutations

MidAtlantic AETC Boosted vs. Unboosted PIs?

Desirable Factors Boosted Unboosted Potency x Durability x Prevent Resistance x High Drug Levels x Once Daily in Naives* x x (ATV) RTV(↓apoptosis/Immun Act) x Undesirable Factors RTV (side effects/toxicities) x Drug-drug Interactions xx x

* Applies to LPV/r, fAPV/r, SQV/r; No data with ATV/r in naives. ATV only unboosted QD PI Medications That Interact with Protease Inhibitors

• Meperidine, Piroxicam • Corticosteroids (including some • Clarithromycin, Erythromycin, nasal steroids) Flagyl • Ergot alkaloids • Coumadin • Estrogens • Phenytoin, Phenobarbital • Cimetidine, Cisapride • Azoles (i.e., fluconazole) • Quinine • Astemizole, Terfenadine • Alfentanil, Fentanyl, • Clofibrate Methadone • Isoniazid, Rifampin, Rifabutin • Clozapine, Desipramine, Sertaline • Anthracyclines, Tamoxifen • Alprazolam, Clorazepate, • Amiodarone,Amlodipine, Diazepam, Flurazepam, Diltiazem, Flecainide, Midazolam, Triazolam, Zolpidem Nifedipine, Propafenone, Quinidine, Verapamil • Sildenafil, Tadalafil, Vardenafil

MidAtlantic AETC Drug-drug Interactions with Atazanavir • Decreased ATV levels • Increased Drug levels – Proton pump inhibitors – Antiarrhythmics – Antacids/H2 Blockers – Benzodiazepines – Calcium Channel Blockers – Rifampin – Cisapride – St. John’s Wort – HMG CoA Reductase inhibitors – Pimozide – Tenofovir – PDE5 Inhibitors – Didanosine – Tricyclic antidepressants – NVP, EFZ – Warfarin

MidAtlantic AETC Nasal Steroid Metabolism

• P450 Metabolism • Not P450 Metabolized • RTV Contraindicated • Safe with RTV – Budesonide – Beclomethasone

– Fluticasone – Flunisolide

– Mometasone – Triamcinolone

MidAtlantic AETC Case 2 • 32 y.o. African woman who was brought in by sisters for evaluation of HIV • Diagnosed 3 years before with pregnancy • CD4 390, RNA 194,000

• Started on ZDV/3TC, IDV, RTV • RNA suppressed rapidly • 1 year later – CD4 650, RNA < 50 – Complains of clothes not fitting and changes in body appearance

MidAtlantic AETC Case 2

• Switched therapy to Trizivir (ZDV, ABC, 3TC)

• 2 years later – CD4 660, RNA < 50 – Clothes size/appearance returned to baseline

MidAtlantic AETC Metabolic and Morphologic Complications of HIV and HAART Wasting Metabolic Morphologic • Dyslipidemias • Fat accumulation -hypercholesteremia • Fat loss -hyperlipidemia -hypertriglyceridemia Others • Impaired glucose • Osteoporosis tolerance/diabetes • Osteopenia • Lactic acidosis • osteonecrosis

MidAtlantic AETC Physical Manifestations of Lipodystrophy

MidAtlantic AETC Other Adverse Effects of Protease Inhibitors

• Headache • Rash • Insomnia – Fosamprenavir • Paresthesias – Darunavir • Increased LFTs – Atazanavir – Ritonavir • Increased Bilirubin – Tipranavir (Black Box warning) • Diarrhea – Indinavir, Atazanavir – Nelfinavir • Nephrolithiasis • GI toxicities (anorexia, nausea, – Indinavir, Atazanavir vomiting, abd pain) • Intracranial Hemorrhage – Tipranavir (Black box warning)

MidAtlantic AETC Protease Resistance Mutations • Indinavir 10, 20, 24, 32, 36, 46, 54, 71, 73, 76, 77, 82, 84, 90 • Nelfinavir 10, 30, 36, 46, 71, 77, 82, 84, 88, 90 • Ritonavir 10, 20, 32, 33, 36, 46, 54, 71, 77, 82, 84, 90 • Saquinavir 10, 24, 48, 54, 62, 71, 73, 77, 82, 84, 90 • Fosamprenavir 10, 32, 46, 47, 50V, 54, 73, 76, 82, 84, 90 • Lopinavir/r 10, 20, 24, 32, 33, 46, 47, 50, 53, 54, 63, 71, 73, 76, 82,84, 90 • Atazanavir 10, 16, 20, 24, 32, 33, 34, 36, 46, 48, 50L, 53, 54, 60, 62, 64, 71, 73, 82, 84, 85, 88, 90, 93 • Tipranavir/r 10, 13, 20, 33, 35, 36, 43, 46, 47, 54, 58, 69,74, 82, 83, 84, 90 • Darunavir/r 11, 32, 33, 47, 50, 54, 74, 76, 84, 89

MidAtlantic AETC Pregnancy Risk(categories no longer used)

Category Example Description

A None (Controlled studies…no risk in humans)

B ddI, TDF, FTC, NFV (Animal studies…no DRV, RTV, SQV, ATV abnormalities but no human MVC, ETV, RPV, EVG studies) Cobicistat, DTG

C ZDV, ddC, d4T, 3TC (Animal studies reveal fetal ABC, N VP, DLV, abnormalities but no human IDV, APV, fAPV, LPV/r studies, use only if benefit TPV, RAL > risk)

D EFV Human fetal risk but benefit > Hydroxyurea risk Summary • Knowledge of how agents work can help understand their limitations/toxicities

• Some toxicities can occur across all classes – GI disturbances – Headache – Fatigue

• Careful choice of agents can minimize the impact of toxicities on adherence/treatment success

MidAtlantic AETC Antiretrovirals 2016 Guidelines – What to Start

NRTI NNRTI PI/Integrase/Entry Guideline Preferred Alternative Preferred Alternative Preferred Alternative

DRV/r QD ATV/r QD TDF/FTC RPV RAL BID ATV/colbicistat DHHS ABC/3TC* EFV# ‡ EVG/Colbicistat DRVcolbicistat TAF/FTC DTG

DTG TAF/FTC EFV# DRV/r RAL BID IAS-USA ABC/3TC* RPV DRV/cobicistat EVG/Cobicistat

ATV/r QD ATV/c QD ABC/3TC* EFV# RAL BID TDF/3TC RPV DRV/r QD EACS TDF/FTC NVP‡ EVG/Cobicistat DRV/c QD LPV/r BID

ATZ/R ARV/R BHIVA TDF/FTC ABC/3TC* RPV EFV# DTG RAL EVG/Cobicistat

*Use only if HLA-B*5701 negative. Use with caution in patients with cardiovascular risk or HIV-1 RNA > 100,000 copies/mL. #Excep during first trimester of pregnancy or in women with high pregnancy potential. Use caution in patients with unstable psychiatric disease. ‡Only in women with CD4+ cell count < 250 cells/mm3 or in men with CD4+ cell count < 400 cells/mm3 +May be acceptable but use with caution DHHS Guidelines. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 7/26/16. EACS guidelines. Available at http://www.eacsociety.org/guidelines/guidelines-guiidelines.html. Accessed 7/26/16 British HIV Association. Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2015/2015-treatment-guidelines.pdf Current Recommended Therapies DHHS Guidelines

Truvada, Isentress: • 3 meds (2 NRTI, 1 Integrase Inhibitor) • 3 pill, taken twice daily • Potential Rash, runny nose

Stribild (Truvada, elvitegravir, cobicistat) • 4 meds (2 NRTI, 1 integrase, 1 non-viral booster) • 1 pill, taken once daily with food • Minimal CNS, possible n, v, d

Genvoya (Descovy, elvitegravir, cobicistat) • 4 meds (2 NRTI, 1 integrase, 1 non-viral booster) • 1 pill, taken once daily with food • Minimal CNS, possible n, v, d Note: There are many other effective drugs use to treat HIV. Finding the best option requires discussion with your provider

MidAtlantic AETC Current Recommended Therapies

Dolutegravir, Truvada

Triumeq (Epzicom,Dolutegravir) • 3 med – integrase inhibitor, 2NRTI • 1 pill, taken daily with or without food

Truvada, Prezista, Norvir: • 3 pills (2 NRTI, 2 PI) • Taken once daily • Potential Rash, nausea, loose stool

MidAtlantic AETC Alternative Therapies DHHS Guidelines Atripla: • 3 meds (2 NRTI, 1 NNRTI) • 1 pill, taken once daily • Potential Rash, CNS effects • NOT used in pregnancy

Truvada, Reyetaz, Norvir: • 3 pills (2 NRTI,2 PI) • Taken once daily • Potential Rash, nausea, loose stool, yellowing of eyes Complera (Truvada, rilpivirine) • 3 meds (2 NRTI, 1 NNRTI) • 1 pill, taken once daily with meal • Less CNS than Atripla Odefsey (Descovy, rilpivirine) • 3 meds (2 NRTI, 1 NNRTI) • 1 pill, taken once daily with meal • Less CNS than Atripla Note: There are many other effective drugs use to treat HIV. Finding the best option requires discussion with your provider

MidAtlantic AETC Considerations When Selecting First-line Antiretroviral Therapy

Patient/Viral Factors Antiretroviral Drug Factors

. Baseline CD4+ cell count/ . Efficacy HIV-1 RNA level . Baseline drug susceptibility/ . Age resistance . Sex . Tolerability . Occupation (eg, work schedule) . Long-term toxicity, metabolic effects . Comorbid conditions (eg, CV risk) . Drug interactions . Plans for pregnancy . Dosing frequency . Access to care . Pill burden . Concurrent medications . Pharmacokinetics . Adherence to other medications . Cost . Genetics (eg, HLA-B*5701) . Viral tropism

MidAtlantic AETC Antiretroviral Therapy: Primary Goals

• Maximal and durable suppression of viral load • Restoration and preservation of immune function • Improvement in quality of life • Reduction of HIV-related morbidity/mortality • Prevent vertical HIV transmission • Treatment as a part of prevention

DHHS; October 2011Guidelines for use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

MidAtlantic AETC When to Start Therapy: Balance Now Favors Early ART

. Drug toxicity . ↑ potency, durability, simplicity, . Preservation of limited Rx safety of current regimens options . ↓ emergence of resistance . Risk of resistance (and . ↓ toxicity with earlier therapy transmission of resistant virus) . ↑ subsequent treatment options . Risk of uncontrolled viremia at all CD4 levels . ↓ transmission

Delayed ART Early ART

MidAtlantic AETC Potential Adverse Effects of HAART

Alopecia

Insomnia, Headache In some cases, depression only a certain drug Breast hypertrophy Anemia induces the effect; Cardiomyopathy the risk for and Hepatotoxicity Nausea, vomiting severity of adverse Nephrolithiasis effects also can Pancreatitis Central adiposity Thinning extremities differ among drugs within the same Diarrhea

class Skin rash Pruritic skin

Lactic acidosis Osteoporosis

Peripheral neuropathy Ingrown toenails

Montessori V, et al. CMAJ. 2004;170:229-238.

MidAtlantic AETC Challenging Cases in HIV Management

Supported by educational grants from multiple commercial supporters. Case 3: 22-Yr-Old Man Recently Diagnosed With HIV • 22-yr-old black man presents with newly diagnosed HIV infection, after testing positive on routine screening • Tested HIV seronegative 6 months ago • No significant medical problems, no medication use • Initial laboratory studies, including lipids, renal, and hepatic function are normal • CD4+ cell count 726 cells/mm3 (40%), HIV-1 RNA 2130 copies/mL • HIV genotype WT, HBV immune, HCV negative, HLA-B*5701 negative • He is unsure if he should start antiretroviral therapy

Slide credit: clinicaloptions.com

MidAtlantic AETC Case 3: Current Presentation

• Pt expresses concern about having to take medicines every day and is worried about adverse events • He is a nonsmoker and has no family history of heart disease • He has multiple sex partners, but says he “almost always” uses condoms when he has sex

Slide credit: clinicaloptions.com

MidAtlantic AETC Would you recommend antiretroviral therapy for this pt? A. Yes B. No C. Unsure

. 22-yr-old black man with recent HIV seroconversion . HIV-1 RNA 2130 copies/mL, CD4+ cell count 726 cells/mm3 . No medical problems . Labs normal, HIV GT WT, HBV immune, HCV negative, HLA-B*5701 negative . Multiple sex partners

Slide credit: clinicaloptions.com

MidAtlantic AETC DHHS Recommendations for Early HIV Infection • ART recommended for early HIV infection – Although no definitive data confirming whether this approach has long-term virologic, immunologic, or clinical benefits • ART recommended for pregnant women with early HIV infection – To prevent perinatal transmission • ART can start before drug resistance test results are available – Boosted PIs + 2 NRTIs recommended to prevent resistance in this setting

DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com

MidAtlantic AETC Which regimen would you recommend? A. Dolutegravir/abacavir/ F. Dolutegravir + lamivudine tenofovir DF/emtricitabine B. Elvitegravir/cobicistat/ G. Raltegravir + tenofovir DF/emtricitabine tenofovir DF/emtricitabine C. Elvitegravir/cobicistat/ H. Darunavir + ritonavir + tenofovir tenofovir alafenamide/emtricitabine DF/emtricitabine D. Efavirenz/ I. I would recommend a different tenofovir DF/emtricitabine regimen E. Rilpivirine/ tenofovir DF/emtricitabine

. 22-yr-old black man with recent HIV seroconversion, multiple sex partners . HIV-1 RNA 2130 copies/mL, CD4+ cell count 726 cells/mm3, no medical problems . Labs normal, HIV GT WT, HBV immune, HCV negative, HLA-B*5701 negative

Slide credit: clinicaloptions.com

MidAtlantic AETC Discussion Question: Would your choice change if the pt… • Was HLA-B*5701 positive? • Was HBsAg positive? • Had high viral load? • Was a woman?

Slide credit: clinicaloptions.com

MidAtlantic AETC Potential Advantages and Disadvantages of Single-Tablet Regimens

Advantages Disadvantages . Simplicity . Inability to adjust dosages of . Convenience components if needed due to . Fewer copays drug–drug interactions or . Reduces selective tolerability issues, eg, renal nonadherence to components insufficiency of regimen . Not available for all ART regimens . Not available for all NRTI pairings

Slide credit: clinicaloptions.com

MidAtlantic AETC Available Single-Tablet Regimens

Agent Type Year of FDA Approval Efavirenz/tenofovir DF/ NNRTI + dual NRTI 2006 emtricitabine (EFV/TDF/FTC) Rilpivirine/tenofovir DF/ NNRTI + dual NRTI 2011 emtricitabine (RPV/TDF/FTC) Elvitegravir/cobicistat/ INSTI + booster + dual NRTI 2012 tenofovir DF/emtricitabine (EVG/COBI/TDF/FTC)*

Dolutegravir/abacavir/lamivudine INSTI + dual NRTI 2014 (DTG/ABC/3TC)* Elvitegravir/cobicistat/ INSTI + booster + dual NRTI 2015 tenofovir alafenamide/emtricitabine Today? (EVG/COBI/TAF/FTC)*

*DHHS recommended regimen for initial ART. Slide credit: clinicaloptions.com

MidAtlantic AETC Case 4: 53-Yr-Old Man With HIV Infection and Multiple Medical Problems

• 53-yr-old man presents with newly diagnosed HIV infection • Tested for HIV infection by his PCP, who has been treating him for hyperlipidemia and DM for 12 yrs • Hospitalized 2 yrs earlier for chest pain and diagnosed with NSTEMI • Reports he has been better in the last yr at sticking to his medical regimen and now rarely misses a dose of his prescribed medications (metformin, glipizide, aspirin, metoprolol, and atorvastatin) • He is an ex-smoker and denies use of illicit drugs

Slide credit: clinicaloptions.com

MidAtlantic AETC Case 4: Laboratory Analysis

• CD4+ count 423 cells/mm3 (27%), HIV-1 RNA 69,554 copies/mL • HIV genotype K103N (resistant to EFV, NVP, DLV) • HLA-B*5701 negative • Cr/BUN 1.6/20, eGFRCG 53 mL/min • ALT/AST normal, HBV immune, HCV negative • Last recorded A1c 6.5; last LDL 105 mg/dL • His hyperlipidemia and DM are relatively well controlled • He is interested in starting ART

Slide credit: clinicaloptions.com

MidAtlantic AETC Which NRTI combination would you recommend? A. Abacavir/lamivudine B. Tenofovir DF/emtricitabine C. Tenofovir alafenamide/emtricitabine (as E/C/F/TAF) D. I would use a different NRTI combination E. I would use lamivudine or emtricitabine without other NRTIs F. I would not use NRTIs in this pt G. Unsure

. 53-yr-old man recently diagnosed with HIV infection . HIV-1 RNA 69,554 copies/mL, CD4+ count 423 cells/mm3 . Hyperlipidemia and DM controlled on medication, history of NSTEMI . Cr/BUN 1.6/20, eGFR 53 mL/min, HbA1c 6.5, LDL 105 mg/dL . HIV GT: K103N, HBV immune, HCV negative, HLA-B*5701 negative

Slide credit: clinicaloptions.com

MidAtlantic AETC Which other agents would you use in the regimen? A. Boosted PI B. INSTI C. Boosted PI + INSTI D. Other E. Unsure

Slide credit: clinicaloptions.com

MidAtlantic AETC Considerations for Pts With Renal Impairment

CrCl (mL/min) EVG/COBI/FTC/TAF[1] EVG/COBI/FTC/TDF[2]

No adjustment needed No adjustment needed ≥ 70

50-70 No adjustment needed Initiation not recommended

Initiation not recommended; 30-49 No adjustment needed Discontinue if CrCl declines to this level during treatment

Initiation not recommended < 30 Initiation not recommended Discontinue if CrCl declines to this level during treatment

1. EVG/COBI/FTC/TAF [package insert]. 2. EVG/COBI/FTC/TDF [package insert]. Slide credit: clinicaloptions.com

MidAtlantic AETC If you were considering an ABC, TDF, and TAF– sparing regimen, which would you most strongly consider? A. Boosted PI monotherapy B. Boosted PI + INSTI ± 3TC (or FTC) C. Boosted PI + 3TC (or FTC) D. DTG + 3TC E. I would not consider an ABC, TDF and TAF–sparing regimen in this type of pt F. Other

Slide credit: clinicaloptions.com

MidAtlantic AETC Recommendations on the Use of NRTI-Sparing Regimens in First-line ART

• Regimens using < 2 NRTIs should only be used in pts who cannot take ABC or TDF • These regimens can be considered when ABC or TDF cannot be used: – DRV + RTV + RAL (only for pts with HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3) – LPV/RTV (BID) + 3TC (BID)

DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com

MidAtlantic AETC Case 4: 53-Yr-Old Man With HIV Infection and Multiple Medical Problems

Slide credit: clinicaloptions.com

MidAtlantic AETC Case 4: Laboratory Analysis

Slide credit: clinicaloptions.com

MidAtlantic AETC Which other agents would you use in the regimen? A. Boosted PI B. INSTI C. Boosted PI + INSTI D. Other E. Unsure

Slide credit: clinicaloptions.com

MidAtlantic AETC Rising Rates of Comorbidities at HIV Diagnosis in USA

Medicare (> 65 Yrs) Medicaid 100 100

80 80

60 60 Pts(%) 40 Pts(%) 40

20 20

0 0 All CV HTN DM Renal All CV HTN DM Renal

2003 (n = 177; mean age 72.2 yrs) 2003 (n = 3008; mean age 34.7 yrs) 2013 (n = 436; mean age 72.9 yrs) 2013 (n = 1632; mean age 39.2 yrs)

Meyer N, et al. IAS 2015. Abstract MOPEB157. Slide credit: clinicaloptions.com

MidAtlantic AETC IAS-USA: Recommendations for Initial ART in the Settings of Specific Conditions

• In pts with or at high risk of CVD, consider avoiding ABC, LPV/RTV, or FPV + RTV • In pts with reduced renal function, TDF should generally be avoided, especially with a boosted PI • In pts at elevated fracture risk (eg, HCV coinfection, postmenopausal women, osteoporosis), it may be prudent to avoid TDF, especially with a boosted PI

Günthard HF, et al. JAMA. 2014;312:410-425. Slide credit: clinicaloptions.com

Slide credit: clinicaloptions.com

MidAtlantic AETC Recommendations on the Use of NRTI-Sparing Regimens in First-line ART • Regimens using < 2 NRTIs should only be used in pts who cannot take ABC or TDF • These regimens can be considered when ABC or TDF cannot be used: – DRV + RTV + RAL (only for pts with HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3) – LPV/RTV (BID) + 3TC (BID)

DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com

MidAtlantic AETC Case 5: 40-Yr-Old Woman With An OI • A 40-yr-old woman presents to the ED with L arm weakness, difficulty walking, and dysarthric speech • Prior history of positive HIV serology, but she is homeless and has neither entered into care for HIV nor received ART • CT scan shows R frontoparietal mass with extensive edema; no hydrocephalus or midline shift • Toxoplasma IgG is positive • Pt is started on sulfadiazine, pyrimethamine and folinic acid with improvement in her neurological status

Slide credit: clinicaloptions.com

MidAtlantic AETC Case 5, Laboratory Analysis

• HIV-1 RNA 175,000 copies/mL, CD4+ count 65 cells/mm3 (4%) • HIV genotype is pending • Coinfection with HCV (HCV RNA positive) and HBV (HBsAg positive) • HLA-B*5701 negative • No known history of heart disease or renal insufficiency • History of injection drug use • She smokes 1 pack/day and uses methamphetamine and opiates when she can get them

Slide credit: clinicaloptions.com

MidAtlantic AETC When would you recommend starting antiretroviral therapy? A. Start ART within 2-3 weeks B. Defer ART until the pt completes treatment for toxoplasmic encephalitis C. Defer ART until the pt is in a stable living situation D. Defer ART until the pt starts a drug treatment program E. Unsure

. 40-yr-old woman with untreated HIV infection and new dx of toxoplasmic encephalitis . HIV-1 RNA 175,000 copies/mL, CD4+ cell count 65 cells/mm3 . HIV GT pending, HBsAg positive, HCV RNA positive, HLA-B*5701 negative . History of injection drug use . Homeless

Slide credit: clinicaloptions.com

MidAtlantic AETC Recommendations for ART in Pts With Selected Opportunistic Infections

Opportunistic Infection DHHS Recommendation for ART

Pneumocystis pneumonia . Start ART within 2 wks of PCP diagnosis

Toxoplasma gondii encephalitis . Many clinicians start ART within 2-3 wks . Based on A5164 study, in which the 282 pts with OIs included 13 pts (5%) with toxoplasmosis

Mycobacterium tuberculosis . Start ART within 2 wks if CD4+ < 50 cells/mm3, by 8-12 wks for all others . Consider DDIs, adherence support

Cryptosporidiosis . Start ART as part of OI management

Cryptococcal meningitis . Consider delaying ART until after antifungal induction (2 wks) or induction/consolidation (10 wks)

DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com

MidAtlantic AETC Which regimen would you recommend if starting ART prior

A. Dolutegravir/abacavir/lamivudineto discharge? B. Dolutegravir + tenofovir DF/emtricitabine C. Elvitegravir/cobicistat/tenofovir DF/emtricitabine D. Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine E. Raltegravir + tenofovir DF/emtricitabine F. Boosted darunavir + tenofovir DF/emtricitabine G. NNRTI-based regimen H. Something else

Slide credit: clinicaloptions.com

MidAtlantic AETC Prevalence of Drug Resistance Mutations in Treatment-Naive Pts, 2000-2013

• Baseline plasma samples from 4 • Little evidence of transmitted phase III trials (GS 903, 934, 104, INSTI resistance over period 111; N = 2531) – Mostly T97A polymorphism – 1617 samples analyzed for integrase mutations 10 8.7 2000 (GS-903) – 2531 analyzed for protease or 8 2003 (GS-934) RT mutations 2013 (GS-104/GS-111) • Substantial ↑ in prevalence of 6 NNRTI resistance, modest ↑ in PI 4.2 4 3.2 2.9 resistance 2.6 2.6 2.4 • Stable prevalence of NRTI 2 1.4 1.2 1.0 resistance (mostly TAMs) 0.5

Pts Pts With at Mutations (%) BL 0 0 – M184V/I ≤ 0.2%; K65R ≤ 0.1% NNRTI NRTI PI INSTI

Margot NA, et al. CROI 2014. Abstract 578. Slide credit: clinicaloptions.com

MidAtlantic AETC Summary

• Randomized trial data support ART initiation in pts with CD4+ cell count > 500 cells/mm3 • ART guidelines recommend ART for all pts regardless of CD4+ cell count • Recommended regimens for ART initiation have been revised • ART selection should be individualized according to pt requirements, the evidence base, and practice guidance

Slide credit: clinicaloptions.com

MidAtlantic AETC Switch strategies Reasons to Switch ART in Suppressed Pts • Simplification of complex therapies • Improve tolerability and ease of administration • Avoid or minimize drug–drug interactions • Reduce toxicity or avoid future toxicity • Change in clinical status – Pregnancy or planned pregnancy, chemotherapy, organ transplant • Reduce costs or decrease copayments

Slide credit: clinicaloptions.com

MidAtlantic AETC Principles of Switching Therapy in Suppressed Patients • Essential to get a complete ARV treatment history and resistance tests results – Archival HIV DNA resistance testing may be helpful • Maintain viral load suppression – Complex history, missing information, and previous resistance increase risk • Within class switching likely has lowest risk – TDF → TAF, EFV → RPV, RAL → DTG, RTV → COBI • Cross-class switching or from high to low barrier agents has greater risk – b-PI → RPV, DTG → EVG, ETR → RPV (?)

Slide credit: clinicaloptions.com

MidAtlantic AETC STRIIVING: Outcomes at Wk 24

• Switch to DTG/3TC/ABC noninferior • No cases of protocol-defined to continued BL ART virologic failure • Treatment difference (95% CI): – 3 pts in DTG/3TC/ABC arm (1%) and 4 pts in BL ART arm (1%) had – ITT-exposed (E): -3.4 (-9.1 to 2.3) HIV-1 RNA > 50 but < 100 – Per protocol (PP): -0.3 (-4.9 to 4.4) copies/mL through Wk 24 • 10 pts discontinued for AEs in 100 93 93 ITT-E: 88 DTG/3TC/ABC arm vs 0 in baseline 85 DTG/3TC/ABC (n = 274) 80 ART arm Baseline ART (n = 277) 60 PP: • However, significantly greater DTG/3TC/ABC (n = 220) increase in treatment satisfaction 40 Baseline ART (n = 215) score from baseline to Wk 24 in 1 RNA < < RNA1 50 (%) c/mL

- DTG/3TC/ABC arm vs baseline ART 20 14 10 6 5 arm (P < .001) HIV 1 1 < 2 0 Virologic Virologic1 No Virologic Success Nonresponse Data

Trottier B, et al. ICAAC 2015. Slide credit: clinicaloptions.com

MidAtlantic AETC Prevention Prevention Opportunities

Cohen et al, JCI, 2008 Cohen IAS 2008

UNEXPOSED UNEXPOSED EXPOSED INFECTED

Behavioral Interventions • condoms • decrease # partners, abstinence • know partners status • needle exchange PrEP* TasP* • precautions in HCW PEP* Vaccines PMTCT* Biological Interventions Microbicides • circumcision • STI treatment • screening blood

Consistent Condom Use: - 25% in heterosexuals *ARV Based Prevention - 16% in MSM Khawcharoenporn T. AIDS Patient Care STDS. 2012;26:222-233. Herbenick D. J Sex Med. 2013;10:474-483 TasP

Partners Linked (+) Partner on ART working* infected (from + to - ) ART

Delayed 59 43 5 0

Early 19 3 3 0 Cumulative probability of infection infection of probability Cumulative

# years since starting study N Engl J Med 2011; 365:493-505 N Engl J Med 2016;375;9:830-839

MidAtlantic AETC PEP vs PrEP

PEP PrEP Definition POST Exposure PRE Exposure Target population Anyone accidentally exposed to HIV Those at high risk for exposure to HIV - Not meant to be used repeatedly - MSM, transwomen - HCW (oPEP) - Ongoing IDU - Sexual exposures (nPEP) - Serodiscordant couples - 1 time or single high risk IDU (nPEP)

Time frame to start Within 72 hours after At least 1 week before Duration 28 days Ongoing, ‘seasons of risk’ Medication Full HIV regimen (3 medications) NOT a full HIV regimen (2 medications = Truvada) Analogy Plan B Birth control pills Malaria prophylaxis

MidAtlantic AETC PEP

123 Occupational Post Exposure Prophylaxis

 600,000-800,000 needlestick or other percutaneous exposures/year in US  Risk of HIV transmission ~0.3%  58 transmissions reported through 2013

Infect Control Hosp Epidemiol 2007; 28:10 Curr Med Res Opin 2007; 23:2093 cdc.gov/HAI/organisms/hiv/Surveillance-Occupationally-Acquired-HIV-AIDS.html

MidAtlantic AETC Animal Data in favor of PEP

Day Rx-3 Placebo 100 Day Rx-10 100 Hour Rx 12 100% Day Rx-28 Hour Rx 36 80 80 Hour Rx 72 75% 60 60

50% 40 40 SIV (%) Infected SIV (%) Infected 20 20 25% 0% 0% 0% 0 0

Tsai CC et al. J Virol 1998;72:4265-73. Otten RA et al. J Virol 2000;74:9771-5.

MidAtlantic AETC Post Exposure Prophylaxis

• The preferred PEP regimen for sexual assault and for other types of non-occupational exposures and occupational exposures: • Tenofovir 300 mg PO daily + Emtricitabine 200 mg PO daily Plus • Raltegravir 400 mg PO twice daily or Dolutegravir 50 mg PO daily • See HIV Prophylaxis Following Non-Occupational Exposure for regimen considerations when the source is known to be HIV- infected, dose adjustments for patients with renal insufficiency, drug-drug interactions, and recommended alternative regimens.

MidAtlantic AETC Side Effects

 Possibly more common in those un-infected  Limit completion of 4 wks  Early/worst regimens: 41% stop  Current regimens: 2% stop  Some drugs not preferred for this reason  Common/ recommended regimens chosen based on side effect profiles

MidAtlantic AETC HIV RNA Testing & PEP

• Plasma HIV RNA testing of the source person is recommended in addition to HIV serologic screening in the following settings; nPEP should be initiated and continued in these situations until results of the plasma HIV RNA assay are available: – If the source person’s HIV screening result is negative but there has been a risk for HIV exposure in the previous 6 weeks – If the source person’s HIV screening result is positive but the confirmatory antibody-differentiation assay is nonreactive or indeterminate

MidAtlantic AETC PreP

129 1 3 PrEP: Results from Clinical Trials 0

mITT a efficacy of % Adherence-adjusted efficacy reduction in acquisition based on TDF detection in blood c Clinical trial Participants Number Drug of HIV infection b

% (95% CI) % (95% CI)

Men who have sex iPrEx 2499 TVD 42 (15-63) 92 (40-99) with men (MSM)

Partners HIV discordant TDF 67 (44-81) 86 (67-94) 4747 PrEP couples TVD 75 (55-87) 90 (58-98) Heterosexually TDF 2 active men and 1200 TVD 63 (22-83) 85d NS women Bangkok Tenofovir IDU 2413 TDF 49 (10-72) 74 (17-94) Study Heterosexually Fem-PrEP 1951 TVD NR ----- NR ----- active women Heterosexually VOICE 5029 TVD NR ----- NR ----- active women

a. Modified Intent to Treat b. Excluded only those enrolled patients later found to be infected at randomization and those with no follow-up visit or HIV test c. The percentage of reduction in HIV incidence among those with TFV detected in blood, compared with those without detectable TFV d. Finding not statistically significant

US Public Health Services. Preexposure Prophylaxis For The Prevention Of HIV Infection In The United States, 2014. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf.

MidAtlantic AETC CDC 2014 PrEP guidelines

 Truvada indicated to decrease risk of transmission in:  MSM and heterosexual men and women at substantial risk of HIV acquisition  IVDU at substantial risk of HIV acquisition  Serodiscordant couples (especially pregnancy)  Insufficient data on adolescents  Tenofovir alone is an option for:  IVDU, heterosexual men and women  Must exclude acute HIV infection, and test regularly for HIV acquisition

MidAtlantic AETC HIV Guideline Pearls

2017 Continued Improvement in Currently Available ART Classes • Dolutegravir – Once-daily, unboosted integrase inhibitor – Limited drug interactions, high barrier to resistance – Use in renal dysfunction (CrCl down to 50 mL/min for DTG/3TC/ABC) • Tenofovir alafenamide – Equal efficacy with TDF-containing therapies, less bone toxicity and renal tubular effects – Smaller mg dosing (10 mg to 25 mg) – Use in renal dysfunction (CrCl down to 30 mL/min) • 2-drug therapy – Less expensive, fewer toxicities?

Slide credit: clinicaloptions.com

MidAtlantic AETC HIV Guidelines Pearls

• The Panel recommends that HIV-infected partner(s) in HIV-seroconcordant and HIV-serodiscordant couples planning pregnancy attain maximum viral suppression before attempting conception (AIII). • The Panel notes that periconception administration of ARV pre-exposure prophylaxis (PrEP) for HIV-uninfected partners may offer an additional tool to reduce the risk of sexual transmission (CIII).

MidAtlantic AETC HIV Guidelines Pearls

• All HIV-infected patients should be screened for Hepatitis C virus (HCV) infection. Patients at high risk of HCV should be screened annually and whenever HCV infection is suspected. • Antiretroviral therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. For most HIV/HCV-co-infected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury (DILI). Therefore, ART should be initiated in most HIV/HCV-co-infected patients, regardless of CD4 T lymphocyte (CD4) cell count (BII).

MidAtlantic AETC HIV Guidelines Pearls

• Combined treatment of HIV and HCV can be complicated by drug-drug interactions, increased pill burden, and toxicities. Although ART should be initiated for most HIV/HCV-coinfected patients regardless of CD4 cell count, in ART-naive patients with CD4 counts >500 cells/mm3 some clinicians may choose to defer ART until HCV treatment is completed (CIII). • In patients with lower CD4 counts (e.g., <200 cells/mm3), ART should be initiated expeditiously (AI) and HCV therapy may be delayed until the patient is stable on HIV treatment (CIII).

MidAtlantic AETC HIV Guidelines Pearls

• Initial ART combination regimens recommended for most HIV/HCV-co-infected patients are the same as those recommended for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, consideration of potential drug-drug interactions and overlapping toxicities should guide ART regimen selection or modification

MidAtlantic AETC Guidelines for the Use of ARV agents in Pediatric HIV infection

• Updated March 5, 2015 • Confirmation of HIV infection in children 18-24 months who are HIV antibody-positive should be based on a nucleic acid test (NAT) (AII) • Recommends that absolute CD4 T lymphocyte (CD4) cell count should be used for monitoring immune status in children of all ages, with CD4 percentage as an alternative (AII).

MidAtlantic AETC Guidelines for the Use of ARV agents in Pediatric HIV infection

• Added integrase inhibitors Raltegravir can be used in children age 2 years and older and dolutegravir in children aged 12 years and older. • The Panel has added a new section about ART for neonates to address specific issues raised by the ability to diagnose HIV infection within a few days of birth in conjunction with growing discussion and reports of early intensive ART of HIV- infected infants and infants at high risk of HIV infection.

MidAtlantic AETC MidAtlantic AIDS Education and Training Center - Contact Information

Regional Partner: Headquarters: Abby Plusen, MSSW MidAtlantic AIDS Education and University of Maryland Training Center MidAtlantic AIDS Education and Department of Infectious Diseases Training Center and Microbiology, 22 S. Greene Street, Box 175 Graduate School of Public Health, Baltimore, MD 21201 University of Pittsburgh o-410.328.2436 412-624-1895 c-410.960.3262 [email protected] [email protected] www.pamaaetc.org

Linda Rose Frank, PHD, MSN, ACRN, FAAN Principal Investigator and Program Director Associate Professor of Public Health, Medicine & Nursing University of Pittsburgh

MidAtlantic AETC