Matters of the HAART: An Update on Current Treatment Options for HIV

Matters of the HAART: An Update on Current Treatment Options for HIV Jason Alegro, PharmD, BCPS Assistant Professor of Clinical Sciences, Roosevelt University Infectious Diseases Clinical Pharmacy Specialist, Mount Sinai Hospital

Disclosures Dr. Alegro declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria.

Pharmacist Learning Objectives 1. Describe the pathophysiology of HIV disease and the role of different highly active antiretroviral therapy (HAART) classes in inhibiting the retroviral replication process. 2. Discuss the mechanism of action, adverse effects, drug interactions, and other clinical considerations of HIV treatment options commonly used in practice. 3. Discuss current treatment guidelines, including new updates for HIV treatment and pre-exposure prophylaxis in selected patients.

Pharmacy Technician Learning Objectives 1. Describe the role of antiretroviral therapy in treating HIV/AIDS. 2. Recognize common adverse effects of antiretroviral agents. 3. List examples of patients who would be indicated for pre-exposure prophylaxis with antiretrovirals.

Pre-Assessment Questions 1. Which of the following is TRUE regarding tenofovir alafenamide (TAF)? A. It is more nephrotoxic compared to TDF B. It has less bone mineral density loss compared to TDF C. It has a higher rate of treatment failure compared to TDF D. It should not be considered as a component of first-line combination ART regimens

Pre-Assessment Questions 2. Which of the following is an appropriate first-line treatment option for HIV? A. Dolutegravir + efavirenz + cobicistat B. Emtricitabine + tenofovir alafenamide + elvitegravir + cobicistat C. Darunavir/r + raltegravir + abacavir D. Lamivudine + rilpivirine + atazanavir/r

Pre-Assessment Questions 3. Which of the following patients would be an appropriate candidate for PrEP? A. 35 y.o. HIV-negative heterosexual male with an HIV infected partner B. 22 y.o. intranasal cocaine and heroin user C. 47 y.o. HIV-positive homosexual male with an HIV-negative partner D. 29 y.o. HIV-negative homosexual male with a mutually monogamous relationship with an HIV negative partner

Human Immunodeficiency Virus

Human Immunodeficiency Virus Definitions: Human Immunodeficiency Virus (HIV) See etiology section Acquired Immunodeficiency Syndrome (AIDS) Advanced stage of HIV infection Defined as a CD4 count <200 cells/mm 3, CD4% of < 14%, or presence of an AIDS-defining illness

AIDS-defining illnesses Candidiasis of bronchi, trachea, esophagus, or lungs Coccidioidomycosis Cryptococcosis Cryptosporidiosis, chronic intestinal (greater than 1 month's duration) Cytomegalovirus disease (particularly CMV retinitis) Encephalopathy, HIV-related Histoplasmosis Kaposi's sarcoma Lymphoma, multiple forms Mycobacterium avium complex Tuberculosis Pneumocystis jirovecii pneumonia Toxoplasmosis of brain Wasting syndrome due to HIV Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report, December 18, 1992/41 (RR-17), 1993

HIV Disease RNA retrovirus that attacks CD4+ T-helper cells of the immune system HIV drugs are antiretrovirals (ARV s) and can be seen as antiretroviral therapy (ART), combined antiretroviral therapy (cart) or highly-active antiretroviral therapy (HAART) HIV viral load: indicates response to ART goal is to have an undetectable viral load 11

Epidemiology - Transmission Requires transmission from blood, semen, rectal fluids, vaginal fluids, or breast milk to a mucous membrane/damaged tissue OR via direct bloodstream inoculation Three primary modes Sexual (most common) Parenteral Perinatal

Sexual Transmission of HIV Highest risk in receptive anorectal intercourse (1.4 transmissions per 100 sexual acts) Lower risk in vaginal receptive intercourse and both vaginal and anorectal insertive intercourse Condom use reduces risk of transmission ~80% Concurrent STI increases risk for contracting HIV HIV-infected partner s viral load affects transmission rates

Parenteral Transmission of HIV Needlesticks, IV drug use (sharing needles), receipt of blood products, organ transplants Transmission from sharing needles = 0.67 per 100 episodes Prior to 1985 before HIV antibody testing was available for blood products, recipients of HIV infected blood acquired the virus at a rate of >90% Needlestick from an HIV infected patient = 0.3 per 100 episodes Mucocutaneous exposure (blood splashes eyes, mouth, nose) = 0.09 per 100 exposures

Perinatal Transmission of HIV Most common mode of pediatric HIV transmission Mother-to-child transmission is 25% if no ART Viral suppression with ART can reduce this to <2% Breast feeding 5-10% in the first six months 15-20% through ~24 months

Etiology HIV is an enveloped single-stranded RNA retrovirus HIV-1 (most common in the U.S. and for global epidemic) and HIV-2 (found mostly in Western Africa) Evidence suggests that HIV arose from a zoonosis from primates infected with simian immunodeficiency virus (SIV) Transmission likely occurred through bush meat and keeping animals as pets (chimpanzees and sooty mangabeys)

The Virus 17

The HIV Life Cycle 1. Binding/Attachment ( - ) 2. Fusion ( - ) 3. Reverse Transcription ( - ) 4. Integration (-) 5. Replication 6. Assembly 7. Budding ( - )

The HIV Life Cycle 20

The HIV Life Cycle 21

The HIV Life Cycle 22

Antiretroviral Therapy

Goals of Antiretroviral Therapy Maximum and sustainable suppression of plasma HIV RNA Restoration and preservation of immune function Reduction in morbidity and mortality of HIV disease Improve duration and quality of life Prevention of HIV transmission

Principal Tenets of Antiretroviral Therapy Treatment for HIV requires combination ART Not curative, but can transform HIV disease into a chronic condition What happens if we didn t have ART or patients are non-adherent with their antiretrovirals?? ART is recommended in ALL HIV-infected individuals, regardless of CD4+ count 1,2 1. N Engl J Med. 2015 Aug 27;373(9):808-22. 2. N Engl J Med 2015; 373:795-807. 25

Antiretroviral classes Nuceloside/tide Reverse Transcriptase Inhibitors (NRTI s) Non-Nuceloside Reverse Transcriptase Inhibitors (NNRTI s) Protease Inhibitors (PI s) INtegrase Strand Transfer Inhibitors (INSTI s) Fusion Inhibitors Entry Inhibitors Combination Agents

NRTI s Agents: Abacavir (ABC, Ziagen) Lamivudine (3TC, Epivir) Emtricitabine (FTC, Emtriva) Tenofovir disoproxil fumarate (TDF, Viread) Tenofovir alafenamide (TAF, Vemlidy) Zidovudine (ZDV, AZT, Retrovir)

NRTI s Mechanism of Action: Structural similarity to natural nucleosides/nucleotides necessary to synthesize viral DNA Competitively binds to the enzyme reverse transcriptase, blocking HIV viral RNA-dependent DNA polymerase Results in DNA chain termination and stops further viral DNA synthesis Reverse Transcription Transcription Translation RNA DNA RNA Proteins

NRTI s Adverse Effects Class N/V/D, rash, headache, insomnia Boxed warning for lactic acidosis and hepatomegaly with steatosis (more with zidovudine, stavudine, didanosine) Abacavir Hypersensitivity reactions (can lead to death) Occurs within first six weeks of therapy, median onset 11 days Possible increased risk of myocardial infarction Tenofovir Renal toxicity, including ARF and/or Fanconi syndrome Osteomalacia and decreased bone mineral density TAF presumably has less renal and bone toxicity compared to TDF Emtricitabine Hyperpigementation of the palms/soles Lamivudine Headache, GI upset, diarrhea Hepatitis flare if active HBV infection Zidovudine Hematologic toxicities (macrocytic anemia and neutropenia) Myopathy

TDF vs. TAF Wohl, DA. (2015, February). CROI 2015 Metabolic Report: Vital Organs and HIV. Presented at the 22nd Conference on Retroviruses and Opportunistic Infections, Seattle, WA.

NRTI s Clinical Pearls All first-line treatment regimens contain TWO NRTI s (backbone) Co-formulations of FTC/TDF (Truvada), FTC/TAF (Descovy), and ABC/3TC (Epzicom) are serve as the backbone for most preferred regimens All require renal dose adjustments except abacavir Specific Agents Abacavir: Must screen for HLA-B*5701 allele prior to starting; If positive, use is contraindicated due to increased risk of serious, possibly fatal hypersensitivity reaction. Lamivudine and TDF have activity against Hepatitis B Zidovudine is the only available intravenous antiretroviral Recommended for peripartum administration if viral load >1000 Didanosine and stavudine uncommonly seen in modern practice due to ADE s

Agents: Efavirenz (EFV, Sustiva) Rilpivirine (RPV, Edurant) Nevirapine (NVP, Viramune) Etravirine (ETR, Intelence) NNRTI s

NNRTI s Mechanism of Action: Non-competitive inhibition of HIV reverse transcriptase Blocks HIV viral RNA-dependent DNA polymerase and results in chain termination ADEs: Class: rash, transaminitis (can be life threatening with nevirapine) Efavirenz Rilpivirine Nevirapine Etravirine CNS effects vivid dreams, nightmares, nocturnal dizziness, morning confusion, depersonalization fat redistribution, peripheral fat wasting, does-dependent QTc prolongation higher incidence of rash and severe fulminant hepatitis; SJS/TENS generally well tolerated; rash, GI distress, LFT abnormalities

NNRTI s Clinical Pearls NNRTI s have a low genetic barrier to resistance (i.e. one mutation will confer resistance), therefore not preferred first-line Caution in patients with hepatic insufficiency Efavirenz previously a first-line option in a combination with TDF and FTC (Atripla), however this is no longer a first-line option Rilpivirine absorption decrease with gastric acid suppression, so contraindicated with PPI s

Agents: Darunavir (DRV, Prezista) Atazanavir (ATV, Reyataz) Ritonavir (RTV, Norvir) Fosampreanvir (FPV, Lexiva) Indinavir (IDV, Crixivan) Lopinavir/ritonavir (LPV/r, Kaletra) Nelfinavir (NFV, Viracept) Saquinavir (SQV, Invirase) Tipranavir (TPV, Aptivus) Protease Inhibitors

Protease Inhibitors Adverse Effects Class: GI distress, metabolic changes (increased lipids, insulin insensitivity, changes in fat distribution) Atazanavir: hyperbilirubinemia, jaundice/scleral icterus Darunavir: transaminitis, rash Ritonavir: GI intolerance

Protease Inhibitors Drug Interactions BIG drug interaction class most are CYP 3A4 inhibitors and substrates DOAC s, antiarrhythmics, azole antifungals, oral contraceptives, statins, benzodiazepines, etc. Clinical Pearls Higher genetic barrier to resistance MANY side effects; darunavir and atazanavir improve upon these side effects, however they are still a major concern in use

PK Boosters Drug Interactions! Ritonavir (RTV, Norvir) CYP 3A4 inhibitor Darunavir/r Lopinavir/r Atazanavir/r Cobicistat (COBI, Tybost) CYP 3A4 inhibitor somewhat more selective than ritonavir (less drug interactions) Darunavir/COBI (Prezcobix) Stribild//Genvoya

Integrase Strand Transfer Inhibitors (INSTI s) Agents: Raltegravir (RAL, Isentress) Elvitegravir (EVG, Vitetka) Co-formulated with cobicistat to boost plasma levels Dolutegravir (DTG, Tivicay) Mechanism of Action Bind to HIV integrase and inhibits strand transfer that incorporates proviral DNA into chromosomal DNA

INSTI s ADEs: As a class, overall well tolerated with good long-term safety data Specific agents Dolutegravir: insomnia, headache, rash Elvitegravir: diarrhea, nausea Raltegravir: rash, increased CPK Clinical Pearls Overall well-tolerated Part of all primary treatment regimens in addition to NRTI backbone HIGH barrier to genetic resistance with dolutegravir Raltegravir and dolutegravir have minimal CYP interactions due to metabolism by UGT1A1 Elvitegravir is a major CYP 3A4 substrate and is formulated with cobicistat to optimize drug exposure

CCR5 Antagonist Agent: Maraviroc (Selzentry) Mechanism of Action: HIV requires viral gp120 to bind to CD4 and a surface chemokine co-receptor located on CD4+ cells, either CCR5 or CXCR4 Maraviroc allosterically inhibits gp120-ccr5 binding that blocks HIV attachment Viral tropism assay (Trofile test) must be performed before starting maraviroc. The patient s HIV strain must express CCR5 only ( R5 tropic ) in order to use maraviroc

Maraviroc ADEs: Generally well tolerated Cough, fever, upper respiratory infection Orthostatic hypotension Clinical Pearls CYP 3A4 and pgp substrate, so always check for drug interactions Although a well-tolerated drug, role is in the management of treatment experienced patients Lack of long-term safety data BID dosing Non-viral target Failure to meet non-inferiority to efavirenz

Fusion Inhibitor Agent: Enfuvirtide (Fuzeon) available only as SC injection! Mechanism of Action: HIV binds to the CD4+ cell using viral protein gp120; gp41 is an HIV transmembrane protein which undergoes a conformational change in order to allow fusion of the viral and host (CD4+) cell membrane Enfuvirtide binds to gp41 subunit of the viral envelope and prevents the conformational change necessary for viral fusion and entry into CD4+ cells

Enfuvirtide ADEs: Local injection site reactions (pain, erythema, induration, nodular cysts) Eosinophilia Bacterial pneumonia Clinical Pearls: Difficult dosing regimen to maintain adherence (SC injection q12h) Option for treatment-experienced patients with resistant virus Expensive Time-consuming reconstitution process

Post-Assessment Questions 1. Which of the following is TRUE regarding tenofovir alafenamide (TAF)? A. It is more nephrotoxic compared to TDF B. It has less bone mineral density loss compared to TDF C. It has a higher rate of treatment failure compared to TDF D. It should not be considered as a component of first-line combination ART regimens

HIV Treatment Guidelines

Most Recent Guideline Updates (2017) ART regimens now classified into: Recommended Initial Regimens for Most People with HIV; and Recommended Initial Regimens in Certain Clinical Situations More robust safety data regarding advantages of tenofovir alafenamide (TAF) containing regimens compared to tenofovir disoproxil fumarate (TDF) containing regimens

The NRTI backbone All first-line antiretroviral regimens consist of an NRTI backbone of one of the following combinations: Tenofovir disoproxil fumarate + emtricitabine (Truvada) Tenofovir alafenamide + emtricitabine (Descovy) Abacavir + lamivudine (Epzicom) Emtricitabine (FTC) and lamivudine (3TC) are almost structurally identical, so these are not used together These backbones are effective, relatively safe, and relatively cheap drugs that have been well-studied to suppress viral load in combination with another core agent (INSTI s preferred)

First-line combination ART for treatmentnaïve HIV positive patients INSTI + NRTI combo dolutegravir + Epzicom 2 = Triumeq 1,2 dolutegravir + Truvada or Descovy elvitegravir/cobicistat/truvada = Stribild 1 elvitegravir/cobicistat/descovy = Genvoya 1 raltegravir + Truvada or Descovy PI + NRTI combo (now only first line for certain clinical situations) darunavir/r + Truvada or Descovy 1 Available as one tablet once daily 2 Must be negative for HLA-B*5701 allele 3 Active against Hepatitis B 4 Dose adjustment required if CrCl <50 51

Building blocks of combination first-line ART regimens based on class NRTI (nucleoside reverse transcriptase inhibitor) combos: abacavir 1 (Ziagen) + lamivudine 2, 3 (Epivir) = Epzicom Emtricitabine 2, 3 (Emtriva) + tenofovir disoproxil fumarate 2,3 (Viread, TDF) = Truvada Emtricitabine 2, 3 + tenofovir alafenamide 2 (Vemlidy, TAF) = Descovy INSTI s (Integrase-strand transfer inhibitors): raltegravir (Isentress) elivitegravir (Vitekta) + cobicistat (Tybost) Cobicistat acts as a PK booster (3A4 inhibitor) dolutegravir (Tivicay) PI (Protease Inhibitor) Darunavir (Prezista) + ritonavir (Norvir) Ritonavir acts as a PK booster (3A4 inhibitor) Darunavir/r = darunavir boosted by ritonavir 1 Must be negative for HLA-B*5701 allele 2 Active against Hepatitis B 3 Dose adjustment required if CrCl <50

First-line combination ART for treatmentnaïve HIV positive patients INSTI + NRTI combo dolutegravir + Epzicom 2 = Triumeq 1,2,3 dolutegravir + Truvada 4 or Descovy 4 elvitegravir/cobicistat/truvada = Stribild 3* (If CrCl <70 ml/min, should not initiate) elvitegravir/cobicistat/descovy = Genvoya 1, 4 raltegravir + Truvada 4 or Descovy 4 PI + NRTI combo (now only first line for certain clinical situations) darunavir/r + Truvada 4 or Descovy 4 1 Available as one tablet once daily 2 Must be negative for HLA-B*5701 allele 3 Not recommended if CrCl <50 4 Not recommended if CrCl <30

Juluca (dolutegravir/rilpivirine) NEW two-drug combination agent (INSTI + NNRTI) approved Nov. 2017 FDA approval as the first two-drug complete regimen for treatment of HIV-1 infection in adults to replace current ART regimen in patients who meet the following: Virologically suppressed on their antiretroviral regimen for at least six months Have no history of antiretroviral treatment failure Have no resistance to active components of Juluca https://julucahcp.com/

Post-Assessment Questions 2. Which of the following is an appropriate first-line treatment option for HIV? A. Dolutegravir + efavirenz + cobicistat B. Emtricitabine + tenofovir alafenamide + elvitegravir + cobicistat C. Darunavir/r + raltegravir + abacavir D. Lamivudine + rilpivirine + atazanavir/r

Pre-Exposure Prophylaxis in HIV

Pre-Exposure Prophylaxis (PrEP) Administered to persons who are HIV negative, but are at high risk of being infected by HIV Reduces sexually transmitted HIV risk by 90% and IVDU risk by 70% if adherent Indications* Sexually active MSM at risk for HIV acquisition (IA) Heterosexually active men and women at risk for HIV acquisition (IA) Adult IV drug users at risk for HIV acquisition (IA) HIV discordant couples *At risk: Ongoing relationship with HIV positive partner Non monogamous relationship with HIV negative partner Gay or bisexual man who has had anal sex without a condom or been diagnosed with an STD in the past 6 months Heterosexual man or woman who does not regularly use condoms during sex with partners of unknown HIV status who are at substantial risk for infection Injection drug users who have shared injection equipment or been in drug treatment for IVDU in the past 6 months

Pre-Exposure Prophylaxis (PrEP) Prophylaxis is given with TDF/FTC (Truvada), one pill, once daily Patients on PrEP should follow up with their provider every three months for a repeat HIV test to ensure the patient has not seroconverted In PrEP clinical trials, none of the studies found significant concerns; some mild upset stomach or loss of appetite occurred within the first month of therapy Should test for Hepatitis B prior to initiating PrEP due to concerns for HBV flare if Truvada is discontinued

Post-Assessment Questions 3. Which of the following patients would be an appropriate candidate for PrEP? A. 35 y.o. HIV-negative heterosexual male with an HIV infected partner B. 22 y.o. intranasal cocaine and heroin user C. 47 y.o. HIV-positive homosexual male with an HIV-negative partner D. 29 y.o. HIV-negative homosexual male with a mutually monogamous relationship with an HIV negative partner

References 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Guidelines accessed January 20, 2018. 2. Preexposure Prophylaxis for the Prevention of HIV Infection 2014: A Clinical Practice Guideline.

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