DEFINITION

  • First drug regimen in ART-naive patient

INDICATIONS

DHHS Guidelines (7/14/16): Recommended Regimens

DHHS Guidelines (7/14/16): Alternative regimens

  • Alternative regimens: Regimens that are effective and tolerable but that have potential disadvantages compared with the recommend regimens listed above, have limitations for use in certain patient populations, or have less supporting data from randomized clinical trials. May be the preferred for some patients.

DHHS Guidelines (7/14/16): Other regimens

  • Other regimens: regimens that, in comparsion with Recommended or Alternative regimens, may have reduced virologic activity, limited supporting data from large comparative clinical trials, or other factors such as greater toxicities, higher pill burdern, drug interactions potential, or limitations for use in certain populations.
    • If VL < 100,000 and HLV B*5701-negative: ATV/c + ABC/3TC (CIII); ATV/r + ABC/3TC (CI)EFV + ABC/3TC (CI),RAL + ABC/3TC (CII)
    • Other regimens when TDF or ABC cannot be used: DRV/r + RAL (twice-daily, for pts with VL < 100,000, CD4>200, CI); LPV/r + 3TC (twice daily, CI)

DHHS Guidelines (7/14/16): Notes

  • 3TC may be substituted for FTC and vice versa
  • ABC should not be used in patients who test positive for HLA-B*5701
  • Chronic kidney disease: Avoid TDF (eGFR < 60; use ABC or TAF; TAF may be used if eGFR >30
  • Liver disease: Some ARVs contraindicated or require dose modification in patients with Child-Pugh class B or C disease; see guidelines
  • Bone disease: Avoid TDF with osteoporosis; use ABC or TAF
  • Psychiatric illness: Consider avoiding EFV- and RPV-based regimens
  • HIV-associated dementia: Avoid EFV-based regimens; favor DRV- or DTG-based regimens
  • Narcotic replacement therapy: Consider avoiding EFV-based regimens; increase methadone dose may be required
  • High cardiac risk: Consider avoiding ABC- and LPV/r-based regimens
  • HBV infection: Use either TDF or TAF plus either FTC or 3TC
  • HCV infection: See HCV guidelines
  • Pregnancy: See perinatal guidelines. Consider non-EFV-containing regimen in women who are planning to become pregnant or are sexually active and not using effective contraception. Can continue EFV in a woman who is found to be pregnant. Once daily LPV/r not recommended.
  • Use of gastric acid-reducing agents (PPIs, H2 blockers): ATV/r should not be used in pts who require >20 mg omeprazole equivalent per day. Use with caution in pts on PPIs (any dose), H2-blockers, antacids. Avoid RPV with PPIs
  • Tuberulosis: TAF not recommended with rifamycin. If rifampin used, can use EFV (standard dose, RAL (800 mg twice-daily), DTG (50 mg twice daily). If PI-based regimen used; use dose-adjusted rifabutin instead of rifampin
  • Resistance results not available: use either DRV/r or DTG plus either TAF/FTC or TDF/FTC
  • Single-tablet, once-daily regimens: DTG/ABC/3TC, EFV/TDF/3TC, EVG/COBI/TAF/FTC, EFV/COBI/TDF/FTC, RPV/TAF/FTC, RPV/TDF/FTC
  • Food effects
    • Without regard to food: RAL- or DTG-based regimens
    • With food: ATV/r-, ATV/c-, DRV/r-, DRV/c-, EVG/c-, and RPV-based regimens
    • Empty stomach: EFV-based regimens

IAS-USA Guidelines (7/2016): 

  • Recommended initial ART regimens:
  • Initial therapy options for patients in whom InSTIs are not an option
    • (DRV/r or DRV/c) + (TAF/FTC, TDF/FTC, or ABC/3TC) (AIa)
    • EFV/TDF/FTC (AIa)
    • RPV/TAF (or TDF)/FTC (AIa)
  • Notes:
    • TDF: not recommended in patients with or at risk for kidney or bone disease (BIII). Avoid or dose adjust before eGFR < 60 (AIa)
    • TAF: Not recommended if eGFR < 30 (AIa)
    • ABC: Use only in HLA B*5701-negative pts

CLINICAL RECOMMENDATION

Integrase Inhibitor-Based Regimens 

  • Advantages: Toxicity and efficacy advantages demonstrated for some InSTIs over some PI- and NNRTI-based regimens. All IAS-USA recommended regimens and most DHHS recommended regimens are now InSTI-based.
  • Disadvantages: Potential for resistance with failure (RAL and EVG/c); drug interactions (EVG/c); twice-daily dosing (RAL)
  • RAL: Advantages: RAL + TDF/FTC superior to DRV/r + TDF/FTC and ATV/r + TDFFTC based on tolerability; non-inferior to EFV/TDF/FTC (superior at 4-5 years) and better tolerated in STARTMRK trial, with more rapid virologic suppression. Disadvantages: Barrier to resistance loower than DTG; twice-daily dosing (but two 600 mg tabs once-daily non-inferior and expected to be approved).
  • EVG: Advantages: Available in two once-daily, single-tablet coformulations (EVG/COBI/TDF/FTC and EFV/COBI/TAF/FTC); non-inferior and better tolerated than TDF/FTC/EFV. Disadvantages: Requires boosting with COBI, resulting in more drug interactions than with other INSTIs. COBI inhibits tubular secretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (but not actual GFR). TDF-containing version should be used only if eGFR < 70 mL/min and should be stopped if eGFR falls to < 50 mL/min; TAF-containing version can be used with eGFR >30 mL/min. Barrier to resistance lower than DTG.
  • DTG: Advantages: Once-daily administration, few drug interactions; higher barrier to resistance than RAL or EVG; superior to EFV and DRV/r (primarily based on tolerability advantages), coformulated with ABC/3TC in first non-TDF-based single-tablet regimen. Disadvantages: inhibits tubular excretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (like COBI).

NNRTI-Based Regimens

  • Advantages: simplicity, tolerability, relative lack of long-term toxicity, 3 single-tablet regimens available
  • Disadvantages: lower genetic barrier to resistance: greater resistance consequences with failure than with PI/r; specific drug toxicities
  • EFV: Advantages: has been gold standard for many years; coformulated with TDF/FTC; long-term tolerability; better virologic suppression with EFV than LPV/r in ACTG 5142; efficacy at all VL and CD4 strata. Disadvantages: CNS side effects including possible increased risk of suicidality, rash, likelihood of NNRTI resistance with failure, teratogenicity, greater lipid effects than other preferred regimens; lower CD4 response with EFV than with most comparators. No TAF coformulation available.
  • RPV: Advantages: coformulated with TDF/FTC and TAF/FTC; better tolerated than EFV with fewer CNS effects, less rash and lipid effects; more effective at VL < 100,000. Disadvantages: less effective at VL >100,000 and/or CD4 < 200 with greater resistance at failure, including cross-resistance to ETR; contraindicated with proton pump inhibitors; requires meal for absorption
  • NVP: Advantages: acceptable in women with CD4 < 250 and men with CD4 < 400 well tolerated; safe in pregnancy; less lipid effects than with EFV.Disadvantages: risk of serious skin reactions and hepatotoxicity, especially in women and at higher pre-treatment CD4 counts; not as well studied as EFV with TDF/FTC or ABC/3TC
  • ETR: Advantages: well tolerated; active against most NNRTI-resistant virus, including K103N mutations. Disadvantages: minimal data in ART-naive pts and not recommended for initial therapy, though could have a role for pts infected with EFV/NVP-resistant virus

PI-Based Regimens

  • Advantages: typically no PI resistance with failure of PI/r-based regimen
  • Disadvantages: greater pill burden than with single-tablet regimens; more GI side effects; more lipid effects than INSTIs
  • ATV/r, ATV/c, or ATV: Advantages: well tolerated; similar efficacy to EFV in ACTG 5202; less hyperlipidemia than LPV/r; does not require boosting. Best choice if RTV boosting not possible (with ABC/3TC, not TDF/FTC). Disadvantages: ATV/r inferior to RAL and DRV/r in ACTG 5257 with more GI toxicity; potential for jaundice; associated with nephrolithiasis, cholelithiasis, and kidney toxicity; requirement for gastric acidity (decreased absorption with proton pump inhibitors, H2 blockers, antacids); food requirement. RTV or COBI boosting preferred, and essential with TDF or EFV; greater loss of bone density than DRV/r or EFV
  • DRV/r or DRV/c: Advantages: DRV/r 800/100 mg once-daily superior to ATV/r in ACTG 5257; noninferior to LPV/r, and superior in pts with VL >100,000; well tolerated, with less hyperlipidemia than LPV/r; no jaundice or gastric acid concerns (vs. ATV/r or ATV/c). Disadvantages: potential for rash.
  • LPV/r: Advantages: convenience (coformulated with RTV); no food restriction with tablet formulation; best studied PI/r in pregnancy. Disadvantages: GI side effects; hyperlipidemia, requires 200 mg/d of RTV
  • FPV +/- RTV: Advantages: once- or twice-daily dosing (once-daily with FPVr 1400/100-200 mg only for PI-naive pts); FPV/r twice-daily equivalent to LPV/r twice-daily in KLEAN study; no food restrictions. Disadvantages: No clear advantage of 700/100 mg twice-daily over coformulated LPV/r; less clinical data with better tolerated FPV/r 1400/100 mg once-daily dose compared to ATV/r and DRV/r; potential for rash.
  • SQV/r : Advantages: well tolerated with less diarrhea and more favorable lipid effects than LPV/r. Disadvantages: higher pill burden than other PIs (6/d); no clear advantages over PI/r regimens that include only 100 mg/d of RTV; black box warning for PR and QTc prolongation.
  • IDV +/- RTV: Advantages: None. Disadvantages: not recommended; minimal data; nephrotoxicity; fluid requirement; elevated indirect bilirubin; dermatologic changes
  • NFV: Advantages: None. Disadvantages: not recommended; higher failure rate than other PIs; diarrhea; food requirement; inability to effectively boost with RTV; potential for PI resistance with failure (including L90M)
  • TPV/r: Not recommended for initial therapy

Choice of NRTI Backbone (as component of HAART regimen)

  • TDF/FTC: Advantages: well tolerated; 1 tab once-daily; no food restrictions; no mitochondrial toxicity; superior to AZT/3TC in GS934 with less toxicity, failure, and resistance (M184V); less K65R with TDF/FTC than TDF/3TC, increased AZT susceptibility w/ M184V and/or K65R; coformulated with EFV, RPV, EVG/COBI. Disadvantages: nephrotoxicity, esp. in pts with pre-existing renal dysfunction and in pts on PI- or COBI-based regimen; cross-resistance to ABC and ddI with K65R/M184V; greater loss of bone mineral density during initial therapy than with other NRTIs
  • TAF/FTC: Advantages: Advantages of TDF/FTC listed above but with less kidney and bone toxicity; coformulated with RPV, EVG/COBI and as dual-NRTI combination. Disadvantages: higher lipids than with TDF/COBI because of lower plasma tenofovir levels (tenofovir has lipid-lowering effects).
  • ABC/3TC: Advantages: well tolerated; 1 tab once-daily; no food restrictions; no mitochondrial toxicity. Disadvantages: need for HLA B*5701 testing to decrease risk of ABC hypersensitivity; decreased activity (vs. TDF/FTC) in pts with baseline VL >100,000 in ACTG 5202 (combined with EFV or ATV/r) but not when combined with DTG; possible association with risk of MI; cross-resistance to ddI (L74V, K65R), TDF (K65R); coformulated with DTG.
  • AZT/3TC: Advantages: well studied; resistance to AZT (TAMs) occurs gradually; M184V increases AZT activity. Disadvantages: not recommended; anemia; GI intolerance; mitochondrial toxicity; including lipoatrophy, twice-daily dosing, extensive NRTI cross-resistance when multiple TAMs present; inferior to TDF/FTC in GS934 with more toxicity, failure, and resistance (M184V)

Use of Other Agents

  • MVC: Advantages: R5 virus more common among ART-naive pts; well tolerated; efficacy similar to EFV in MERIT study when enhanced sensitivity tropism assay used. Disadvantages: baseline tropism testing required; twice-daily dosing (once-daily dosing under study), lack of long-term safety data; studied only with AZT/3TC
  • ENF: No role for initial therapy due to high cost, need for twice-daily injection, and lack of data

Chronic Liver Disease/Viral Hepatitis

  • No regimen contraindicated. Use caution with PIs (esp. TPV), NNRTIs (esp. NVP), d4T. Severe liver disease: decrease dose of some PIs (APV, FPV, ATV, IDV) (DHHS reference).
  • Chronic HBV: Use regimen that includes TDF/FTC, TAF/FTC (or TDF+3TC) for dual anti-HBV therapy

Renal Insufficiency

  • Avoid IDV, TDF, and possibly ATV, or use with caution. Dose adjust some NRTIs (ddI, 3TC, FTC, AZT, d4T, TDF)
  • ART recommended for all patients with HIVAN, regardless of CD4 and VL

Pregnancy or Child-bearing Potential

  • ART recommended for all pregnant women with HIV, regardless of VL and CD4. Transmission is less likely, but still possible, with VL < 1000.
  • Start ART as soon as possible.
  • Preferred NRTI backbones: ABC/3TC, TDF/FTC (or TDF + 3TC), AZT/3TC
  • Preferred PIs: ATV/r, DRV/r
  • Preferred NNRTI: EFV (after first 8 wks of pregnancy)
  • Preferred INSTI: RAL
  • Alternative regimens: LPV/r + a preferred NRTI backbone; RPV/TDF/FTC (or RPV + a preferred NRTI backbone)
  • Avoid starting NVP in women with CD4 >250 (hepatotoxicity).
  • See Perinatal Guidelines (ref) for information on prevention of perinatal transmission.

References

  1. Gallant JE et al: Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354:251, 2006  [PMID:16421366]

    Comment: 48-wk data from GS934: large, randomized, controlled trial comparing AZT/3TC + EFV vs. TDF + FTC + EFV, demonstrating greater efficacy of TDF + FTC arm due to lower toxicity (esp. anemia). Subsequently presented 96-wk data: greater virologic rebound, more M184V, and subcutaneous fat loss in AZT/3TC arm. No K65R among TDF + FTC pts at 2 yrs.

  2. Lennox JL et al: Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374:796, 2009  [PMID:19647866]

    Comment: 48-wk results of STARTMRK, a randomized trial comparing TDF/FTC + RAL vs. TDF/FTC/EFV in ART-naive pts. Results demonstrated non-inferiority of RAL with better tolerability and fewer lipid effects. Virologic suppression more rapid with RAL, but no difference at 48 wks.

  3. Johnson M et al: 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 20:711, 2006  [PMID:16514301]

    Comment: 96-week data from BMS-045, a comparison of ATV/r vs. LPV/r in treatment-experienced pts. Efficacy and safety comparable; ATV/r associated w/ better GI tolerability and lipid profiles than LPV/r. Although study did not enroll naive pts, results often extrapolated to support use of ATV/RTV in naives.

  4. Riddler SA et al: Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358:2095, 2008  [PMID:18480202]

    Comment: ACTG 5142: landmark study comparing EFV vs. LPV/r (both + 2 NRTIs) vs. EFV+LPV/r, demonstrating superior virologic efficacy with EFV + 2 NRTIs, but statistically better CD4 response and less resistance with failure with LPV/r.

  5. Ortiz R et al: Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 22:1389, 2008  [PMID:18614861]

    Comment: ARTEMIS: Randomized trial comparing once-daily DRV/r (800/100 mg) vs. LPV/r (gel caps or tablets, once- or twice-daily) in combination with TDF/FTC in 689 ART-naive pts., demonstrating non-inferiority of DRV/r, and superiority in pts with baseline VL >100,000. GI side effects and AEs leading to discontinuation more common with LPV/r; rash more common with DRV/r.

  6. D:A:D Study Group et al: Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 371:1417, 2008  [PMID:18387667]

    Comment: Analysis of data from D:A:D study indicating that current or recent use of either ABC or ddI associated with increased risk of MI. Effects not seen for past or cumulative use of these agents. Risk no longer observed after discontinuation of drug. Increased risk restricted to MI and other coronary heart disease (CHD) outcomes but not stroke. Greatest absolute risk in pts with multiple cardiac risk factors.

  7. Arribas JR et al: Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr 47:74, 2008  [PMID:17971715]

    Comment: Final 3-yr results of GS 934, confirming superior virologic efficacy and long-term safety of TDF/FTC over AZT/3TC, with progressive differences in limb fat (lipoatrophy) over time favoring TDF/FTC arm. Also less NRTI resistance with TDF/FTC (no K65R in either arm and more M184V with AZT/3TC).

  8. DeJesus E et al: Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 39:1038, 2004  [PMID:15472858]

    Comment: CNA 30024: multicenter, double-blind, randomized trial comparing AZT/3TC + EFV vs. ABC/3TC + EFV in 649 naive subjects. ABC/3TC non-inferior to AZT/3TC, w/ significantly higher CD4 response, w/ more AZT side effects (anemia, GI) in AZT arm, more ABC HSR in ABC arm.

  9. Gulick RM et al: Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA 296:769, 2006  [PMID:16905783]

    Comment: ACTG 5095: no additional benefit to 3- vs. 2-NRTI backbone in EFV-containing regimen. AZT/3TC + EFV was as effective as AZT/3TC/ABC + EFV by all criteria and at all VL, CD4 strata.

  10. Thompson MA et al: Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 304:321, 2010  [PMID:20639566]

    Comment: IAS-USA guidelines on antiretroviral therapy, including when to start, choice of initial regimen, monitoring therapy, changing therapy, etc.

  11. Eron J et al: The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 368:476, 2006  [PMID:16890834]

    Comment: KLEAN study: open-label, randomized trial comparing FPV/r (700/100 mg twice-daily) vs. LPV/r (soft-gel caps 400/100 mg twice-daily) in combination w/ ABC/3TC in 878 naive pts. No difference in efficacy, tolerability, or toxicity, including hyperlipidemia, at 48 wks. Note that gel-cap formulation of LPV/r used; tolerability with tablet formulation appears better.

  12. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission ;  Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. May 24, 2010.; http://aidsinfo.nih.gov/guidelines/;

    Comment: PHS guidelines on prevention of maternal-to-child transmission and use of ART in pregnant women.

  13. Panel on Clinical Practices for Treatment of HIV Infection: Dept. of Health and Human Services (DHHS); Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents - January 10, 2011; http://aidsinfo.nih.gov/guidelines;

    Comment: DHHS guidelines on antiretroviral therapy, including when to start, choice of initial regimen, monitoring therapy, changing therapy, etc.

  14. Molina JM et al: Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 372:646, 2008  [PMID:18722869]

    Comment: Randomized clinical trial comparing ATV/r vs. LPV/r (+ TDF/FTC) in ART-naive pts, demonstrating non-inferiority of ATV/r, with fewer GI side effects and more favorable lipid effects but more hyperblirubinemia.

  15. Sax PE et al: Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 361:2230, 2009  [PMID:19952143]

    Comment: Large (N ~1800) study comparing TDF/FTC vs. ABC/3TC and ATV/r vs. EFV in naive pts. Interim review by DSMB noted more rapid time to virologic failure and grade 3/4 toxicity with ABC/3TC arm in pts with baseline VL >100,000.

  16. Walmsley S et al: Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir Immune Defic Syndr 50:367, 2009  [PMID:19214123]

    Comment: Comparison of twice-daily SQV/r vs. LPV/r (+ TDF/FTC) in naive pts., demonstrating non-inferiority of SQV/r. Less diarrhea and more favorable lipid effects with SQV/r.

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Last updated: October 4, 2016