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Anti-Retroviral Therapy

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Anti-Retroviral Therapy, Anti-Retroviral Agents, HIV Treatment, HIV Medication, Antiretroviral, Anti-retroviral, Combination Antiretroviral Therapy, CART, Highly Active Antiretroviral Therapy

  • Precautions
  1. Obtain Genotypic Antiretroviral Resistance Testing (GART) before starting therapy (and if failing therapy)
    1. See Genotypic Antiretroviral Resistance Testing
  2. Compliance is critical to suppress viral load (<500 c/ml)
    1. Adherence of 95% to drug regimen: 81% success rate
    2. Adherence of 90-95% to drug regimen: 64% success rate
    3. Adherence of 80-90% to drug regimen: 50% success rate
    4. Adherence of 70-80% to drug regimen: 24% success rate
    5. Adherence of <70% to drug regimen: 6% success rate
  3. Hospitalizations are high risk for Antiretroviral medication errors (85% of HIV patients)
    1. HIV Patients should be encouraged to bring their Antiretrovirals to hospital
    2. Many Antiretrovirals are substituted during admission for formulary options
    3. Consider infectious disease Consultation
    4. Adjust adntiretroviral doses for reduced Renal Function (esp. GFR <50 ml/min)
    5. On hospital discharge, arrange phone follow-up at 2 days, and clinic visit at 7-14 days
    6. Be aware of antiretroviral Drug Interactions
      1. Azole Antifungals
      2. Anticoagulants
      3. Anticonvulsants
      4. Antacids
      5. Calcium, Magnesium or Zinc
    7. References
      1. (2017) Presc Lett 24(5): 26-7
  • Pearls
  • Better compliance
  1. Compliance is critical to prevent drug resistance
    1. Set up reminders to take medications
      1. Alarm clock
      2. Pill box
      3. Place medication on night stand
    2. Anticipatory guidance that adverse effects are common
    3. Emphasize risks of nonadherence (drug resistance, fewer treatment options later)
  2. Patient forgets to take dose
    1. Take dose as soon as remembered
    2. Take next dose if time (do not double dose)
  3. Patient experiences adverse effects
    1. Call primary doctor or pharmacist
    2. Do not stop just one Anti-retroviral medication
      1. Stop all Anti-retrovirals, or stop none
      2. Prevents developing resistance to Antiretrovirals
    3. Antiretrovirals may taste awful
      1. Pediatric HIV patients may require Gastrostomy Tubes to stay on regimen
  4. Patient traveling
    1. Gradually adjust dosing to the next time zone
    2. Ritonavir may be un-refrigerated for 30 days
  5. Understand that cost is very expensive: $1000/month
  6. Consider combination pills that reduce number per day
    1. See combinations listed below
    2. Truvada or Descovy (Tenofovir-TDF or TAF 300 mg AND Emtricitabine-Emtriva-FTC 200 mg) once daily
    3. Combivir (AZT/3TC) bid with Efavirenz qhs
    4. Trizavir (AZT/3TC/Abacavir) one orally twice daily
  • Preparations
  1. Nucleotide-Nucleoside Reverse Transcriptase Inhibitor (nRTI)
    1. Abacavir (Ziagen, ABC)
      1. Contraindicated in HLA-B*5701 positive patient
      2. Relatively contraindicated if high cardiovascular risk or HIV RNA >100,000 copies/ml pre-treatment
    2. Didanosine (Videx EC, ddI)
    3. Emtricitabine (FTC)
    4. Lamivudine (Epivir, 3TC)
    5. Stavudine (Zerit, d4T)
    6. Zalcitabine (Hivid, ddC)
    7. Zidovudine (Retrovir, ZDV or AZT)
    8. Tenofovir (Viread, TDF or TAF)
  2. Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
    1. Delavirdine (Rescriptor)
    2. Efavirenz (Sustiva, EFV)
      1. Efavirenz (EFV) is absolutely contraindicated in first trimester pregnancy (or if unreliable Contraception)
    3. Etravirine (Intelence)
    4. Nevirapine (Viramune, NVP)
    5. Rilpivirine (Endurant)
  3. Protease Inhibitor (PI) - suffix '/r' added when combined with Ritonavir
    1. Amprenavir (Agenerase)
    2. Atazanavir (Reyataz, ATV or ATV/r)
      1. Contraindicated in high dose Proton Pump Inhibitor (e.g. Omeprazole >20 mg daily)
    3. Darunavir (DRV or DRV/r)
    4. Fosamprenavir (FPV or FPV/r)
    5. Indinavir (Crixivan)
    6. Lopinavir with Ritonavir (Kaletra, LPV/r)
    7. Nelfinavir (Viracept)
    8. Ritonavir (Norvir, r)
    9. Saquinavir (Fortovase)
    10. Saquinavir mesylate (Invirase)
    11. Tiprinavir (Aptivus)
  4. Entry Inhibitor (Coreceptor Antagonist)
    1. Maraviroc (Selzentry)
  5. Fusion Inhibitor
    1. Enfuvirtide (Fuzeon)
  6. Integrase Strand Transfer Inhibitor (InSTI)
    1. Raltegravir (Isentress, RAL)
    2. Elvitegravir (EVG) used with Cobicistat (Ritonavir-like booster)
    3. Dolutegravir (Trivicay, DTG)
    4. Bictegravir (BIC)
  • Preparations
  • Combination
  1. Atripla
    1. Efavirenz (EFV), Emtricitabine (FTC) and Tenofovir (TDF)
  2. Combivir
    1. Lamivudine (3TC) and Zidovudine (ZDV)
  3. Epzicom
    1. Abacavir (ABC) and Lamivudine (3TC)
  4. Trizivir
    1. Abacavir (ABC), Lamivudine (3TC), and Zidovudine (ZDV)
  5. Triumeq
    1. Dolutegravir (Trivicay) AND Epzicom (Abacavir and Lamivudine)
  6. Dovato
    1. Dolutegravir (Trivicay) and Lamivudine (3TC)
  7. Descovy (or Truvada)
    1. Emtricitabine (FTC) and Tenofovir (TAF in Descovy, or TDF in Truvada)
    2. TAF formulation in Descovy is preferred due to less renal and BMD toxicity
  8. Genvoya (or Stribild)
    1. Elvitegravir/Cobicistat (EVG) and Emtricitabine (FTC) and Tenofovir (TAF in Genvoya, or TDF in Stribild)
    2. Creatinine Clearance must be >70 ml/min/1.73m2 (especially due to Cobicistat which increase Serum Creatinine)
    3. TAF formulation in Genvoya is preferred due to less renal and BMD toxicity
  9. Biktarvy
    1. Emtricitabine (FTC), Bictegravir (BIC) and Tenofovir (TAF)
    2. Fewer Drug Interactions than Genoya and no Genetic Testing needed before use
    3. Contraindicated for Creatinine Clearance <30 ml/min
    4. Avoid with high dose NSAIDS (Nephrotoxicity Risk), and within 2 hours of Antacid salts (Mg, Ca, Al)
  10. Juluca
    1. Combines the InSTI, Dolutegravir (Tivicay) with the NNRTI, Rilpivirine (Endurant) taken once daily
  • Indications
  • Initiation of Antiretroviral therapy (Combination Antiretroviral Therapy or CART)
  1. Indications: Early Therapy
    1. Combination Antiretroviral Therapy (CART) is now recommended at initial diagnosis
      1. Regardless of CD4 Count, age, comorbidity or HIV Viral Load
      2. Based on International Antiviral Society (2012, U.S.) Guidelines
    2. Benefits of early therapy
      1. Lowers HIV Viral Loads to nearly undetectable levels
      2. Community-based prevention (decreased transmission rates)
    3. Risks of early initiation of therapy
      1. Increased Antiretroviral drug resistance due to noncompliance
      2. Greater risk of longterm Antiretroviral therapy adverse effects and Drug Interactions
    4. Thompson (2012) JAMA 308(4): 387-402 [PubMed]
  2. Other indications based on labs
    1. CD4 Count < 350 (<500 per prior IAS guidelines)
    2. Rapid decline in CD4 Count >100/year
    3. Viral load >100,000 copies/ml
  3. Other indications based on comorbidity
    1. AIDS Defining Illness (start within 2 weeks)
      1. Exception: Tuberculosis and Cryptococcal Meningitis require a delayed start and tailored CART therapy
        1. Increased risk of Immune Reconstitution Inflammatory Syndrome
        2. Severe inflammatory response to infection when immune response is Restored to HIV patients
    2. Pregnancy
    3. HIV Associated Nephropathy
    4. Hepatitis B coninfection (also for Hepatitis C per IAS )
    5. Symptomatic HIV
    6. Age over 60 years
    7. Cardiovascular disease
    8. High risk for HIV Transmission
  • Labs
  • Before starting treatment
  1. HIV Viral Load (HIV-1 RNA)
  2. CD4 Cell Count
  3. HIV Genotype for NRTI, non-NRTI, Protease Inhibitors
  4. Screening for active Viral Hepatitis
  5. Adverse effects of HIV Medications
    1. Lipid Profile
    2. Serum Glucose
    3. Hepatic profile
    4. Serum Creatinine
  6. Other labs
    1. HLA-B*5701 Allele (if prescribing Abacavir)
  • Approach
  • Preferred agents for therapy-naive non-pregnant patients
  1. Based on strong quality data from randomized controlled trials (A-I as of 2018)
    1. Many other protocols supported by non-AI level evidence are available (see resources below)
  2. First-Line regimens: Integrase Strand Transfer Inhibitor Based Therapy
    1. Bictegravir AND Tenofovir Alafenamide AND Emtricitabine (Biktarvy)
    2. Dolutegravir AND Abacavir AND Lamivudine (Triumeq)
    3. Dolutegravir (Tivicay) AND Tenofovir alefenamide/Emtricitabine (Descovy)
  3. Alternative regimens: Integrase Strand Transfer Inhibitor Based Therapy with two medication combinations
    1. Dolutegravir and Lamivudine (Dovato)
  4. Alternative regimens: Integrase Strand Transfer Inhibitor Based Therapy
    1. Elvitegravir AND cobicistat AND Tenofovir alefenamide AND Emtricitabine (Genvoya)
      1. Genvoya is preferred over Stribild
      2. Less renal and Bone Mineral Density (BMD) toxicity (see above)
    2. Elvitegravir AND cobicistat AND Tenofovir disopoxil fumarate AND Emtricitabine (Stribild)
    3. Raltegravir (Isentress) AND Tenofovir disopoxil fumarate AND Emtricitabine
    4. Raltegravir (Isentress) AND Tenofovir Alafenamide AND Emtricitabine
  5. Alternative regimens: Protease Inhibitor-Based
    1. Darunavir/cobicistat (Prezcobiz) AND
      1. Tenofovir alefenamide/Emtricitabine (Descovy) OR
      2. Tenofovir disopoxil fumarate/Emtricitabine (Truvada)
    2. Darunavir (Prezista) AND Ritonavir (Norvir or /r) AND
      1. Tenofovir alefenamide/Emtricitabine (Descovy) OR
      2. Tenofovir disopoxil fumarate/Emtricitabine (Truvada)
  6. Alternative regimens: NNRTI-Based
    1. Efavirenz AND Tenofovir disopoxil fumarate AND Emtricitabine (Atripla)
      1. NNRTI based therapy with Atripla was previously first-line therapy prior to 2015
  7. Other NNRTI-Based Alternative Regimens (if HIV RNA <100,000 and CD4 Count >200 cells/ul)
    1. Rilpivirine AND Tenofovir Alafenamide AND Emtricitabine (Odefsey)
    2. Rilpivirine AND Tenofovir disopoxil fumarate AND Emtricitabine (Complera)
  • Approach
  • Preferred agents for therapy-naive pregnant patients
  1. Consult perinatal specialist (also see resources below)
  2. Antiretroviral therapy should be used in pregnancy for benefit of both the mother and the fetus
  3. Based on strong quality data from randomized controlled trials (A-I, as of 2014)
  4. Agent 1: Nucleoside-Nucleotide Reverse Transcriptase Inhibitor (NRTI)
    1. Lamivudine (3TC)
  5. Agent 2: Nucleoside-Nucleotide Reverse Transcriptase Inhibitor (NRTI)
    1. Zidovudine (ZDV)
  6. Agent 3: Protease Inhibitor (see precautions below)
    1. Lopinavir with Ritonavir (LPV/r)
  7. Precautions
    1. Efavirenz (EFV) is contraindicated in first trimester pregnancy or in women with unreliable Contraception
    2. Dolutegravir
      1. Risk of Neural Tube Defects (avoid in preconception and first trimester)
      2. Preferred Integrase Strand Transfer Inhibitor AFTER first trimester due to safety, efficacy
    3. Darunavir/cobicistat and atazanavir/cobicistat are NOT recommended for use in pregnancy (high failure rates)
    4. Many older Protease Inhibitors are not recommended in pregnancy (lower efficacy, toxicity risk)
  • Monitoring
  1. Obtain viral load 1 month after initiating therapy and after any treatment change
  2. Goal optimal viral suppression
    1. Viral load falls by >0.5 log copies/ml OR falls below detectable level (20-75 copies/ml)
    2. Typically achieved by 8-24 weeks
    3. Brief rises in viral load may occur, but consider resistance or noncompliance if sustained
  3. Failure to decrease viral load to undetectable levels by 8-24 weeks
    1. Address compliance (see above)
    2. Consider change in therapy
    3. Consult HIV specialist
  4. Predictors of decreased HIV progression
    1. Viral load decreases by >0.5 log copies/ml or becomes undetectable
    2. CD4 Count increases >200 cells/mm3
      1. CD4 Count lags viral load in response to therapy
      2. Expect CD4 Count increases of 50 to 150 cells/mm3 per year until reaching steady state
  5. Reference
    1. Kitchen (2001) Clin Infect Dis 33:466-72 [PubMed]
  • Efficacy
  • Retroviral therapy payoff is excellent
  1. Dollars denote cost per life saved
  2. Antiretroviral therapy: $10,000 to $18,000
  3. HMG CoA Reductase Inhibitors: $21,000
  4. Mammogram: $30,000
  5. Flexible Sigmoidoscopy and FOBT: $43,000
  6. Hemodialysis: $50,000
  7. Warfarin for Atrial Fibrillation: $110,000
  8. Prostate Cancer Screening: $113,000
  9. Coronary Artery Bypass Graft: $113,000
  • Drug Interactions
  1. Antiretroviral Drug Interactions are common (a few examples listed below)
    1. Protease Inhibitors and Simvastatin, Lovastatin, apixiban, Rivaroxaban
    2. OTC medication interactions (e.g. iron, Antacids, Proton Pump Inhibitors)
  2. Interactions often lower Antiretroviral concentrations
  3. Drug Interactions frequently cause viral resistance
  4. Address potential interactions when starting new agent
  • Adverse Effects
  1. See Immune Reconstitution Inflammatory Syndrome
  2. See specific agents for contraindications, adverse effects and required monitoring
  • Resources
  1. Guidelines for use of Antiretroviral agents in HIV-1 Infected Adults and Adolescents
    1. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
    2. Updated 1/10/11 and accessed 10/8/2011
  2. HIV-AIDS Treatment Information Service Website
    1. http://www.hivatis.org
  3. Stanford HIV Drug Resistance Database
    1. http://hivdb.stanford.edu/pages/links.html
  4. UCSF National HIV/AIDS Clinicians Consultation Center
    1. http://www.nccc.ucsf.edu/about_nccc/warmline/
    2. Phone (warmline): 800-933-3413
  5. NIH AIDS Info Site
    1. http://www.aidsinfo.nih.gov/
  6. Perinatal HIV/AIDS
    1. http://nccc.ucsf.edu/clinician-consultation/perinatal-hiv-aids/