Anti-Retroviral Therapy

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

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II. 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

III. 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. Each agent has specific GFR-related containdications below which they should not be used (30-60 ml/min)
    3. Preferred agent if baseline Genotypic Antiretroviral Resistance Testing not yet available
      1. Biktarvy: Bictegravir (BIC) AND Tenofovir Alafenamide (TAF) AND Emtricitabine (FTC)
      2. Dolutegravir (Tivicay) based TXF/XTC regimens
  2. First-Line regimens: Integrase Strand Transfer Inhibitor Based Therapy
    1. Bictegravir AND Tenofovir Alafenamide AND Emtricitabine (Biktarvy)
      1. Avoid if Creatinine Clearance <30 ml/min
    2. Dolutegravir AND Abacavir AND Lamivudine (Triumeq)
      1. Avoid if HLA-B*5701 positive (due to Abacavir)
      2. Avoid if Creatinine Clearance <50 ml/min
    3. Dolutegravir (Tivicay) AND one of the following TXF/XTC regimens
      1. Tenofovir alefenamide/Emtricitabine (Descovy) or
      2. Emtricitabine/Tenofovir disopoxil fumarate (Truvada) or
      3. Lamivudine/Tenofovir disopoxil fumarate (Cimduo)
  3. Alternative regimens: Integrase Strand Transfer Inhibitor Based Therapy with two medication combinations
    1. Dolutegravir (DTG) and Lamivudine (3TC, Dovato)
      1. Contraindications
        1. Hepatitis B coinfection (or results not available yet)
        2. Genotypic Antiretroviral Resistance Testing not yet available
        3. HIV RNA >500k copies on initial viral load
        4. GFR <50 ml/min
  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 one of the following
      1. Emcitrabine AND Tenofovir disopoxil fumarate or
      2. Emcitrabine AND Tenofovir Alafenamide or
      3. Lamivudine AND Tenofovir disopoxil fumarate
  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)

IV. 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. Preferred Pregnancy Protocol (triple ART)
    1. First 2 Agents: Dual nRTI (TXF + XTC)
      1. TXF: Either the preferred Tenofovir Alafenamide (TAF) or alternatively, Tenofovir disoproxil Fumarate (TDF)
      2. XTC: Either Emtricitabine (FTC) or Lamivudine (3TC)
    2. Third Agent (choose 1)
      1. Preferred (InSTI): Dolutegravir (DTG, evidence rating A1a)
      2. Alternative (InSTI): Raltegravir (RAL, evidence rating A2a)
      3. Alternative (PI): Atazanavir/r (ATV/r, evidence rating B2a)
      4. Alternative (PI): Darunavir/r (DRV/r, evidence rating B2a)
      5. Alternative (NNRTI): Rilpivirine (RPV, evidence rating B2a)
  4. Agents to avoid in pregnancy due to lack of evidence
    1. Bictegravir (BIC, in Biktarvy)
    2. Doravirine
    3. Cabotegravir
    4. Dual therapy with Dolutegravir (DTG) and Lamivudine (3TC)
    5. Dual therapy with Dolutegravir (DTG) and Rilpivirine (RPV)
    6. Cobicistat boosted regimens
      1. Cobicistat does not reach adequate drug levels in pregnancy
  5. Precautions
    1. Efavirenz (EFV) is contraindicated in first trimester pregnancy or in women with unreliable Contraception
    2. Dolutegravir
      1. Preferred Integrase Strand Transfer Inhibitor in pregnancy (as of 2022, includes first trimester)
      2. Initial data with risk of Neural Tube Defects (and had been avoided at conception and first trimester)
        1. However further study demonstrates no increased risk compared with other ART
        2. Patel (2022) N Engl J Med 387(9):799-809 +PMID: 36053505 [PubMed]
    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)

V. Approach: Preferred Antiretroviral Regimens during Tuberculosis Treatment

  1. TXF/XTC Triple Agent Regimens
    1. First 2 Agents: Dual nRTI (TXF + XTC)
      1. TXF: Either the preferred Tenofovir Alafenamide (TAF) or alternatively, Tenofovir disoproxil Fumarate (TDF)
      2. XTC: Either Emtricitabine (FTC) or Lamivudine (3TC)
    2. Third Agent (choose 1)
      1. InSTI: Dolutegravir (DTG)
      2. InSTI: Raltegravir (RAL)
      3. NNRTI: Efavirenz (EFV)
      4. Alternatively, if no other option, Protease Inhibitor boosted with Ritonavir may be used
        1. Substitute Rifabutin 150 mg should be used instead of Rifampin for Tuberculosis
  2. Agents to avoid with Rifampin in Tuberculosis treatment
    1. Bictegravir (BIC)
    2. Boosted Darunavir (DRV with either Cobicistat or Ritonavir)
    3. Doravirine
    4. Elvitegravir (EVG) boosted with Cobicistat
    5. Long-Acting Cabotegravir with Ripivirine
    6. Etravirine (Intelence)
    7. Rilpivirine (RPV, Endurant)
    8. Dual therapy with Dolutegravir (DTG) and Lamivudine (3TC)

VI. Medications: Single Agents and Classes

  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, also referred to as TXF)
    9. Additional abbreviations
      1. TXF: Either Tenofovir Alafenamide (TAF) or Tenofovir disoproxil Fumarate (TDF)
      2. XTC: Either Emtricitabine or Lamivudine
  2. Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)
    1. Delavirdine (Rescriptor)
    2. Doravirine (Pifeltro)
    3. Efavirenz (Sustiva, EFV)
      1. Efavirenz (EFV) is absolutely contraindicated in first trimester pregnancy (or if unreliable Contraception)
    4. Etravirine (Intelence)
    5. Nevirapine (Viramune, NVP)
    6. Rilpivirine (Endurant, RPV)
  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. SaquinavirMesylate (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. Bictegravir (BIC)
    2. Cabotegravir
    3. Dolutegravir (Trivicay, DTG)
    4. Elvitegravir (EVG) used with Cobicistat (Ritonavir-like booster)
    5. Raltegravir (Isentress, RAL)

VII. Medications: 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

VIII. Precautions

  1. Start Antiretroviral therapy (ART) as soon after diagnosis as possible (within 7-14 days)
    1. Ideally, start on the same day as diagnosis or wthin 7 days (if concurrent opportunistic infection is not suspected)
    2. Ideally, start within 14 days for new HIV diagnosis and comorbid opportunistic infections (with Consultation)
  2. Obtain Genotypic Antiretroviral Resistance Testing (GART) before starting therapy (and if failing therapy)
    1. See Genotypic Antiretroviral Resistance Testing
    2. Consider repeating resistance testing if failure to reach or maintain HIV RNA <200 copies/ml
    3. Indications for initial Genotype testing before starting ART
      1. HIV Preexposure Prophylaxis with TXF/FTC
        1. If Genotype not yet available, may start TXF/XTC with BIC or DTG
      2. Cabotegravir preexposure prophylaxis
        1. Obtain InSTI genotyping before InSTI based regimen start
        2. If Genotype not yet available, may start boosted Darunavir with TXF/XTC
  3. Despite HIV Antiretroviral therapy high efficacy (see below), it is underutilized
    1. Only half of the 1.2 million patients with HIV in U.S. (2015) were adequately treated with Antiretrovirals
    2. Woodring (2015) Natl Health Stat Report (83):1-13 [PubMed]
  4. 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
  5. 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

IX. 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
  7. Consider monthly injection in those achieving stable viral suppression
    1. Cabenuva (Cabotegravir and Rilpivirine) IM monthly

X. Labs: Initial (before starting treatment)

  1. HIV Viral Load (HIV-1 RNA)
  2. CD4 Cell Count
  3. Pregnancy Test
  4. HIV Genotype for NRTI, non-NRTI, Protease Inhibitors
  5. Screening for active Viral Hepatitis (Hepatitis A, Hepatitis B, Hepatitis C)
    1. Many of the Combination Medications when stopped, risk a flare of coinfected Hepatitis B or Hepatitis C
  6. Screening for Sexually Transmitted Infection (e.g. Gonorrhea PCR, Chlamydia PCR, Syphilis)
  7. Tuberculosis Screening (and repeat annually depending on risk)
  8. Adverse effects of HIV Medications
    1. Lipid Profile
    2. Compled blood count
    3. Comprehensive metabolic panel
      1. Serum Glucose (or Hemoglobin A1C)
      2. Hepatic profile
      3. Serum Creatinine
  9. Other labs
    1. HLA-B*5701 Allele (if prescribing Abacavir)

XI. Labs: Monitoring

  1. Obtain viral load 1 month (2-8 weeks) after initiating therapy and after any treatment change
    1. Repeat every 4-8 weeks until viral load undetectable
    2. When on stable therapy, repeat every 3-4 months for 2 years, then every 6 months
  2. Obtain CD4 Count 3 months after initiating Antiretroviral therapy
    1. Then obtain CD4 Count every 3-6 months for 2 years, and then every 12 months if CD4>300 cells/uL
    2. CD4 Count is optional if CD4 Count is consistently >500 cell/uL for 2 years, and suppressed viral load
  3. Other lab monitoring
    1. Comprehensive metabolic panel (renal profile, hepatic profile, Serum Glucose, Serum Albumin)
      1. Obtain at baseline, at 2-8 weeks and then at 3-6 months
      2. Consider Hemoglobin A1C yearly
    2. Complete Blood Count with differential
      1. Obtain at baseline, 3-6 months, then every 12 months (if not monitoring CD4 Counts)
    3. Fasting Lipid Profile
      1. Obtain at baseline and then yearly
  4. 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
  5. 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. See Genotypic Antiretroviral Resistance Testing
    5. Consider repeat Genotypic Antiretroviral Resistance Testing if unable to maintain HIV RNA <200 copies/ml
  6. 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
  7. Reference
    1. Kitchen (2001) Clin Infect Dis 33:466-72 [PubMed]

XII. Efficacy: Retroviral therapy payoff is excellent

  1. Antiretroviral therapy results in excellent key clinical outcomes
    1. Near normal Life Expectancy
    2. Prevents clinical progression to advanced HIV disease or AIDS
    3. Reduces transmission risk
  2. Dollars denote cost per life saved
    1. Antiretroviral therapy: $10,000 to $18,000
    2. HMG CoA Reductase Inhibitors: $21,000
    3. Mammogram: $30,000
    4. Flexible Sigmoidoscopy and FOBT: $43,000
    5. Hemodialysis: $50,000
    6. Warfarin for Atrial Fibrillation: $110,000
    7. Prostate Cancer Screening: $113,000
    8. Coronary Artery Bypass Graft: $113,000

XIII. 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

XIV. Adverse Effects

  1. See Immune Reconstitution Inflammatory Syndrome
  2. See specific agents for contraindications, adverse effects and required monitoring

XV. Resources

  1. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults
    1. https://jamanetwork.com/journals/jama/fullarticle/2799240
  2. HIV-AIDS Treatment Information Website (NIH)
    1. https://hivinfo.nih.gov/home-page
  3. Stanford HIV Drug Resistance Database
    1. https://hivdb.stanford.edu/
  4. Perinatal HIV/AIDS
    1. https://nccc.ucsf.edu/clinician-consultation/perinatal-hiv-aids/

XVI. References

  1. (2019) Am Fam Physician 99(6): 395-6 [PubMed]
  2. (2018) JAMA 320(4): 379-96 [PubMed]
  3. (1995) Med Lett Drugs Ther 37: 959 [PubMed]
  4. Carpenter (2000) JAMA 283:381-90 [PubMed]
  5. Gandhi (2023) JAMA 329(1): 63-84 +PMID: 36454551 [PubMed]
  6. GoldSchmidt (2016) Am Fam Physician 94(9): 708-16 [PubMed]
  7. GoldSchmidt (2021) Am Fam Physician 103(7): 407-16 [PubMed]
  8. Lesho (2003) Am Fam Physician 68(4):675-86 [PubMed]
  9. Paterson (2000) Ann Intern Med 133-21-30 [PubMed]
  10. Sherin (2014) Am Fam Physician 89(4): 265-72 [PubMed]
  11. Yeni (2002) JAMA 288:222-35 [PubMed]

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Cost: Medications

cart (on 9/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
CARTEOLOL HCL 1% EYE DROPS Generic $1.19 per ml
CARTIA XT 120 MG CAPSULE Generic $0.14 each
CARTIA XT 180 MG CAPSULE Generic $0.20 each
CARTIA XT 240 MG CAPSULE Generic $0.24 each
CARTIA XT 300 MG CAPSULE Generic $0.30 each
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