HIV Updates Abdi Mohamed, Pharm.D Assistant Professor o Pharmacy Practice Husson University School of Pharmacy

Objectives Review of the history and epidemiology of HIV/AIDS Diagnosis of HIV infection When to initiate therapy Overview of antiretroviral medications New DHHS adult and adolescent antiretroviral treatment guidelines. Importance of adherence

What is HIV? HIV is a lentivirus HIV = Human Immunodeficiency Virus It destroys CD4 cells (T-cells and macrophage) AIDS = Acquired immunodeficiency Syndrome CD4 count < 200/mm3 or CD4 % < 14%

History of HIV First cases of AIDS were identified in 1981 in Los Angeles, CA Believed to be a zoonosis (transmitted from animal) HIV is a descendant of a Simian Immunodeficiency Virus (SIV) SIVs bear a very close resemblance to HIV-1 and HIV-2 (two types of HIV). HIV-2 is similar to SIVsm, a strain of SIV found in the sooty mangabey (also known as the White-collared monkey), which is indigenous to western Africa. HIV-1, was recently discovered to relate to SIVcpz, the SIV strain found in chimpanzees Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996 Jun;70(6):3617-27

Etiology HIV was identified as the etiologic agent of AIDS until 1983 Two types HIV-1 HIV-2 Both them cause similar condition They differ in transmission and progression HIV-1 more virulent and more easily transmissible Barre-Sinoussi F, Chermann JC, et al. Science. 1983 May 20;220(4599):868-71.

Transmission

G.J. Stine. AIDS update 2012. Mc Graw Hill p152 Epidemiology 2012 US HIV data Annually HIV infection 60,000 People living with HIV 1.62 million HIV patients not in care ~55% 1 in 5 (20%) are unaware of their infection By race, blacks/African Americans face the most severe burden of HIV G.J. Stine. AIDS update 2012. Mc Graw Hill p152

Progression of HIV Death 2007 The Hopkins HIV guide 2-3 wks 2-3 wks Viral transmission Viral transmission Acute retroviral syndrome Recovery + seroconversion Avg. 1.5yrs Death Avg. 8 yrs Asymptomatic chronic HIV inf Symptomatic HIV/AIDS 2007 The Hopkins HIV guide

Diagnosis & Testing HIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA) If positive repeat the test Use Western blot (WB) to confirm Rapid immunoassy (e.g OraQuick) Resistance test genotype (detects mutations that confers HIV drug resistance) Phenotype (culture based on viral replication assays in the absence or presence of drugs)

Use of CD4 Cell Levels to Guide Therapy Decisions CD4 count The major indicator of immune function Most recent CD4 count is best predictor of disease progression A key factor in determining urgency of ART or need for OI prophylaxis Important in determining response to ART Adequate response: CD4 increase 50-150 cells/µL per year CD4 monitoring Check at baseline (x 2) and at least every 3-6 months* * May consider every 6-12 months in clinically stable patients on ART with sustained HIV RNA suppression and CD4 status well above threshold for opportunistic infection risk. February 2013 www.aidsetc.org

Use of HIV RNA Levels to Guide Therapy Decisions May influence decision to start ART and help determine frequency of CD4 monitoring Critical in determining response to ART Goal of ART: HIV RNA below limit of detection (ie, <20-75 copies/mL, depending on assay) Commercially available assays do not detect HIV-2 February 2013 www.aidsetc.org

Other Test HLA-B*5701 Screening Coreceptor tropism assay Recommended before starting any regiment containing abacavir, to reduce risk of hypersensitivity reaction (HSR) Positive patient should not receive ABC and ABC allergy should be recorded in file Coreceptor tropism assay Should be performed to detect whether HIV-1 isolates use CCR5 or CXR4 or both. Requires plasma HIV RNA ≥ 1000 copies/mL Maraviroc is considered for patient with virologic failure

DHHS: Changing Criteria for Initiating ART CD4+ Count, cells/mm3 1998 2001 2006 2008 2009 2012 > 500 Offer if VL > 20,000 Offer if VL > 55,000 Consider if VL ≥ 100,000 Consider in certain groups Consider Treat 350-500 Consider if VL > 55,000 200-350 Offer, but controversy exists Offer after discussion with patient < 200 or symptomatic disease clinicaloptions.com/hiv

Current Guidelines for Initiating ART Symptomatic/ AIDS CD4+ Count < 200 CD4+ Count 200-350 CD4+ Count 350-500 CD4+ Count > 500 DHHS (2/2012) Yes IAS-USA (7/2012) British HIV Association (9/2012) Defer* European AIDS Clinical Society (11/2012) Consider Defer WHO (7/2010) No† Not addressed *If a patient with CD4+ count > 350 cells/mm³ wishes to start ART to reduce the risk of transmission to partners, that wish should be respected and ART started. †With the exception of an HIV-positive partner in a serodiscordant relationship, who should be offered antiretroviral therapy at CD4+ count > 350 cells/mm³ to prevent transmission to the uninfected partner. clinicaloptions.com/hiv

Recommendations for Initiating ART ART is recommended for treatment “ART is recommended for all HIV-infected individuals to reduce the risk of disease progression.” The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels) February 2013 www.aidsetc.org

Recommendations for Initiating ART: CD4 Count or Clinical Category Recommended for all CD4 counts: CD4 count <350 cells/µL (AI) CD4 count 350-500 cells/µL (AII) CD4 count >500 cells/µL (BIII) February 2013 www.aidsetc.org

Recommendations for Initiating ART: Prevention Perinatal transmission Recommended for all HIV-infected pregnant women (AI) Sexual transmission Recommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups) February 2013 www.aidsetc.org

Potential Benefits of Early Therapy (2) Potential decrease in risk of many complications, including: HIV-associated nephropathy Liver disease progression from hepatitis B or C Cardiovascular disease Malignancies (AIDS defining and non-AIDS defining) Neurocognitive decline Blunted immunological response owing to ART initiation at older age Persistent T-cell activation and inflammation February 2013 www.aidsetc.org

When to Start Therapy Delayed ART Drug toxicity Preservation of limited Rx options Risk of resistance (and transmission of resistant virus) Delayed ART

When to Start Therapy: Balance Now Favors Earlier ART Drug toxicity Preservation of limited Rx options Risk of resistance (and transmission of resistant virus) ↑ potency, durability, simplicity, safety of current regimens ↓ emergence of resistance ↓ toxicity with earlier therapy ↑ subsequent treatment options Risk of uncontrolled viremia at all CD4+ cell count levels ↓ transmission Delayed ART Early ART clinicaloptions.com/hiv

Antiretroviral therapy

History of ART Got is from CCO inPractice

Current ARV Classes HAART Protease inhibitors (PI) Reverse Transcriptase inhibitors (RTI) Entry Inhibitors Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTI) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Integrase Inhibitor

Current ARV Medications NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETR) Rilpivirine (RPV) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC February 2013 www.aidsetc.org

Nucleoside Reverse Transcriptase Inhibitors (NRTI) Backbone of HIV combination therapy HIV-1&2 Minimal drug interactions Renal excreted except ABC Minimal cross resistance patterns

Abacavir(ABC, Ziagen) ABC 300mg PO twice day or 600mg PO daily Part of Epzicom and Trizivir HLA-B*5701-positive patients should not receive ABC Positive status should be recorded as an ABC allergy Life threatening if re-challenged Toxicity Hypersensitivity (HSR) ≈ 4% Fever, rash, fatigue, malaise Occur within 6 weeks Don’t rechallenge HLA-B*5701 300mg tablet or 20mg/ml solution

Zidovudine (AZT, Retrovir) ZDV 300mg BID Part of Combivir and Trizivir First-line regimen for pregnant women Toxicity Nausea, malaise, headache, insomnia, lipoatrophy Anemia and neutropenia are the most frequent dose-limiting adverse effects 100mg tab, 300mg cap, 10mg/ml IV and 10mg/ml solution

Twin Drugs Lamivudine (3TC)/ Epivir Emtricitabine (FTC)/ Emtriva FDA approved for treatment of HIV and HBV Dose 300mg PO daily Toxicity Minimal ≈ placebo headache Hepatitis flare (BB) Approved for HIV but also used to treat HBV Dose 200mg PO daily Toxicity Minimal ≈ placebo headache Hepatitis flare (BB)

Tenofovir (TDF, Viread) FDA approved for HIV and HBV In 2012, Truvada was approved by the FDA for pre-exposure prophylaxis (PrEP) Usually dose 300 mg daily Toxicity Well tolerated but rarely can lead to acute renal failure, Fanconi’s syndrome, proteinuria, May contribute to decrease in bone mineral density

NRTI Co-formulated Regimen Truvada 1 tablet once a daily TDF 300mg + FTC 200mg Combivir 1 tablet twice a day 3TC 150mg + AZT 300 mg Epzicom 1 tablet once daily 3TC 300mg + ABC 600mg Trizivir 3TC 150mg + AZT 300mg + ABC 300 mg

Adverse Effects: NRTIs All NRTIs: Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC) Lipodystrophy (higher incidence with d4T) February 2013 www.aidsetc.org

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) First Generation Delavirdine [DLV, RESCRIPTOR®] Efavirenz [EFV, SUSTIVA®] Nevirapine [NVP, VIRAMUNE®] Second Generation Etravirine [ETR, INTELENCE®] Rilpivirine [RPV, EDURANT]

Non-Nucleoside Reverse Transcription Inhibitors (NNRTI) HIV-2 is resistant Limitation of first generation NNRTI Low genetic barrier to resistance Long half-lives

Efavirenz (EFV, Sustiva) Dosing recommendation 600mg PO once daily at or before bedtime Take on empty stomach to reduce side effects Co-formulated with TDF/FTC (Atripla) No hepatic (caution) or renal dose adjustment Toxicities CNS side effects (4 weeks) drowsiness, insomnia, vivid dreams, and impaired concentration Rash Hyperlipidemia Potentially teratogenicity to humans Pregnancy category D Administration with food especially high fat meal may increase CNS side effects. False positive reported with cannabinoid and benzodiazepine screening

Nevirapine (NVP, Viramune) Extended release formulation was approved in 2011 Dose recommendation 200mg PO QD x 2 weeks; 200mg PO BID Toxicity Rash including SJ syndrome Hepatotoxicity (BB) Female with CD4 > 250 or male with CD4> 400 Liver disease (HBV, HCV or alcoholics) Child Pugh class B or C is contraindicated

Rilpivirine (RPV, Edurant) Approval: FDA-approved May 20, 2011for treatment-naïve adults 25 mg tablet daily Take with 400 Kcal food Fixed dose Tenofovir-Emtricitabine-Rilpivirine (Complera) Toxicity (low): depression, insomnia, headache, and rash Pregnancy : category B

ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Study Design Rilpivirine: 25 mg qd + TDF/FTC (n = 346) Study Features Protocol - Randomized, double-blind trial - Phase 3 - N = 690 (ECHO) and 678 (THRIVE) - Age > 18 - ARV-naïve - HIV RNA > 5,000 copies/ml - No baseline NNRTI mutations - Randomized to one of 2 arms - All given 2 NRTIs* ECHO 1x Efavirenz: 600 mg qd + TDF/FTC (n = 344) Rilpivirine: 25 mg qd + 2NRTIs* (n = 340) THRIVE 1x Efavirenz: 600 mg qd + 2NRTIs* (n = 338) *2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC) THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR) ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Week 48 Results Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR) 84.3% 82.3% 2NRTIs+ Rilpivirine (n = 686) 2NRTIs+ Efavirenz (n = 682) Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

48 Week Data: Virologic Failure ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Virologic Failure All regimens included 2 NRTIs Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

48 Week Data: Discontinuation Due to Adverse Effects ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Discontinuation Due to Adverse Effects All regimens included 2 NRTIs Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results Conclusions: Rilpivirine demonstrated high response rate Rilpivirine virologic failure rate higher than efavirenz (9.0% vs 4.8%) Rilpivirine had significant tolerability advantage over efavirenz Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

NRTI+NNRTI Co-formulated Regimen Atripla EFT 600mg + FTC 200mg + TDF 300mg FTC+TDF= Truvada 1 tablet once daily at or before bedtime Complera RPV 25mg + FTC 200mg + TDF 300mg 1 tablet once daily with a meal Avoid antacids PPI is contraindicated

Adverse Effects: NNRTIs All NNRTIs: Rash, including Stevens-Johnson syndrome Hepatotoxicity (especially NVP) Drug-drug interactions

Protease Inhibitors Atazanavir [ATV, REYATAZ®] Darunavir [DRV, PREZISTA®] Fosamprenavir [FPV, LEXIVA®] Indinavir [IDV, CRIXIVAN®] Lopinavir/Ritonavir [LPV/r, KALETRA®] Nelfinavir [NFV, VIRACEPT®] Ritonavir [RTV, NORVIR®] Saquinavir [SQV, INVIRASE®] Tipranavir [TPV, APTIVUS®]

ARV Components in Initial Therapy: PIs ADVANTAGES Higher genetic barrier to resistance PI resistance uncommon with failure (boosted PI) NNRTIs and II preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) GI intolerance Potential for drug interactions (CYP450), especially with RTV February 2013 www.aidsetc.org

Atazanavir (ATV, Reyataz) Recommended dose Naïve patient 400 mg once daily or 300 mg + 100mg RTV once daily Take with food Avoid acid suppressing agents Toxicity Hyperbilirubinemia PR prolongation Nephrolithiasis, cholelithiasis

Darunavir (DRV, Prezita) Dose ARV naïve or experienced patients with no mutation 800mg + 100 mg RTV once daily ARV experienced patient with at least one mutation DRV must be boosted with RTN Take with food Toxicity DRV contains a sulfonamide moiety, Avoid patients with a sulfa allergy→ Rash GI (N/V/D) Hyperlipidemia

Lopinavir/Ritonavir (LPV/r, Keletra) The only boosted PI that is coformulated with low-dose ritonavir LPV 200mg + RTV 50mg or LPV 100mg + RTV 25mg preferred regimen for pregnant women Toxicities GI (N/V/D) Hyperlipidemia (especially ↑triglycerides) Potential increased MI risk

Ritonavir (RTV, Norvir) Booster for other PI 100-400mg per day in 1-2 divided doses Formulation 100mg soft gel capsules, 100mg tablet 80mg/mL solution 43% alcohol Toxicities GI (N/V/D) Hyperlipidemia Hyperglycemia

Integrase Inhibitors Raltegravir Elvitegravir* (EVG) Currently being studied in phase III clinical trials Dolutegravir (S/GSK1249572) * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

Integrase Inhibitors Virologic response noninferior to EFV appears to be active against HIV2 Fewer adverse events than with EFV RAL has fewer drug-drug interactions than with PIs or NNRTIs (not true of EVG/COBI) NNRTIs and PIs preserved for future use February 2013 www.aidsetc.org

Raltegravir (RAL, Isentress) Indicated for both naïve and experienced pt Dose recommendation 400mg po twice a day with or without food When combined with other ART dose stays same Toxicities Diarrhea, Nausea Fatigue Myalgia Abnormal liver function Low genetic barrier to resistance

Stribild (Quad Pill) Approved August 2012 Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + tenofovir 300mg Stribild PO daily with food Cobicistat is used to increase the levels of elvitegravir AE Decreased CrCl Nausea, diarrhea

EVG/COBI/TDF/FTC: “Alternative” First-line Regimen EVG/COBI/TDF/FTC recommended as “alternative” regimen in treatment-naive patients with ClCr > 70 mL/min (BI)[1] Benefits Noninferior to EFV/TDF/FTC,[2] ATV/RTV + TDF/FTC[3] 1-tablet, once-daily dosing Limitations Potential for drug–drug interactions Limited safety data; limited data in advanced disease, women Possible increased risk proximal renal tubulopathy Food requirement 1. DHHS Panel Statement. September 18, 2012. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet. 2010;379:2429-2438.

DISADVANTAGES II Twice-daily dosing Lower genetic barrier to resistance than PIs COBI has many drug-drug interactions COBI may cause or worsen renal impairment Myopathy, rhabdomyolysis, skin reactions reported with RAL (rare) February 2013 www.aidsetc.org

Entry Inhibitors Enfuvirtide (T-20, Fuzion) Maraviroc (MVC, Selzentry) Use for experienced patients 90mg subcutaneous injection twice a day Reconstitute with 1.1ml sterile water Adverse effects Injection-site reactions HSR Increased risk of bacterial pneumonia Block the binding of gp120 to the chemokine receptor (CCR5) Coreceptor tropism assay CCR5 or CXCR4 Adverse Effects Drug-drug interactions Rash Abdominal pain Upper respiratory tract infections

New DHHS Treatment guidelines Feb, 2013

Initial Treatment: Choosing Regimens 3 main categories: 1 NNRTI + 2 NRTIs 1 PI + 2 NRTIs 1 II + 2 NRTIs Combination of NNRTI, PI, or II + 2 NRTIs preferred for most patients Fusion inhibitor, CCR5 antagonist not recommended in initial ART Few clinical end points to guide choices Advantages and disadvantages to each type of regimen Individualize regimen choice DHHS guideline; February 2013 www.aidsetc.org

Initial Regimen: Recommended/Preferred Agents TDF/FTC + EFV ATV/RTV DRV/RTV RAL DHHS Guidelines . Feb 2013; Thompson MA, et al. JAMA. 2010;304;321-333.

Initial Regimen: Recommended/Alternative TDF/FTC or ABC/3T + RPV LPV/RTV FPV/RTV EVG/COBI/TDF/FTC 9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012. 10. DHHS Panel Statement. September 18, 2012.

CYP450 and Drug Metabolism CYP2E1 CYP3A4 CYP2C CYP2D6 Key points Majority of drugs metabolized by CYP3A4 and CYP2D6 CYP3A4 and CYP2D6 extensively involved with PI/NNRTI metabolism Enzymes can be induced or inhibited Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. 62

Effect of ARV on Drug Metabolism Induced by: RTV, NFV, TPV EFV, NVP Inhibited by: RTV, NFV, IDV, SQV, DLV 3A4 Inhibited by: RTV Induced by: RTV, NFV Inhibited by: EFV, DLV Induced by: RTV, NFV Inhibited by: DLV 2C19 2D6 2C9 Induced by: RTV, NFV ? Induced by: EFV, NVP 1A2 2E1 2A6 2B6 2C8 From Fichtenbaum CJ. Clin Pharmacokinet 2002:41(14):1195-1211. 63

Recommendations for Initiating ART: Considerations “Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.” Patients may choose to postpone ART Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors February 2013 www.aidsetc.org

MMWR / February 4, 2011 / Vol. 60 / No. 4 Immunization MMWR / February 4, 2011 / Vol. 60 / No. 4

ART Approved & Unapproved Drugs

References Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996 Jun;70(6):3617-27 G.J. Stine. AIDS update 2012. Mc Graw Hill 2012 Thompson MA, et al. JAMA. 2012;308:387-402. Williams I, et al. HIV Med. 2012;13(suppl 2):1-85. EACS Guidelines for the Treatment of HIV Infected Adults in Europe. November 2012. WHO Guidelines for Antiretroviral Therapy for HIV Infection in Adults and Adolescents. July 2010. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013 Cohen M, et al. N Engl J Med. 2011;365:493-505. DHHS Panel Statement. September 18, 2012. Sax PE, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2010;379:2429-2438 ww.hivinsite.com www.clinicaloptions.com www.hivguidelines.org www.hopkins-aids.edu 67