Johns Hopkins HIV Guide

Initial Regimen

DEFINITION

  • First drug regimen in ART-naive patient

INDICATIONS[Top]

DHHS Guidelines (10/30/13): Preferred Regimens

  • Preferred regimens: regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use. Preferred regimens for non-pregnant pts listed in order of FDA approval of non-NRTI components, thus, by duration of clinical experience.

DHHS Guidelines (10/30/13): Alternative regimens

  • Alternative regimens: Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. May be the preferred for some patients.

DHHS Guidelines (2/12/13): Other regimens

DHHS Guidelines (2/12/13): Notes on specific agents

  • 3TC may be substituted for FTC and vice versa
  • 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
  • EFV is teratogenic in non-human primares. Strongly consider non-EFV-containing regimen in women who are planning to become pregnant or are sexually active and not using effective contraception.
  • TDF should be used with caution in patients with renal insufficiency.
  • RPV is not recommended in patients with pre-treatment VL >100,000 c/mL. Higher rate of virologic failure reported in patients with pre-ART CD4 count < 200. Use of PPIs contraindicated.
  • ABC should not be used in patients who test positive for HLA-B*5701; use with caution in patients with known high risk of cardiovascular disease or with pretreatment VL >100,000
  • Once-daily LPV/r not recommended in pregnant women
  • NVP should not be used (1) in patients with moderate-to-severe hepatic impairment (Child-Pugh B or C); in women with pre-ART CD4 >250; or (3) in men with pre-ART CD4 >400
  • ATV/r generally preferred over unboosted ATV, which may be used when RTV boosting not possible. Do not use unboosted ATV with TDF
  • AZT can cause bone marrow suppression, lipoatrophy, and rarely lactic acidosis with hepatic steatosis
  • Perform toprism test before initiation of MVC therapy. MVC may be considered in patients who have only CCR5-tropic virus
  • Use NVP and ABC together with caution because both can cause HSRs within the first few weeks of therapy
  • EVG/COBI/TDF/FTC should not be started in patients with estimated CrCl < 70 mL/min and should be change to alternative agent if CrCl falls to < 50 mL/min. Should not be used with other ARV drugs or with nephrotoxic drugs. COBI is a potent CYP3A4 inhibitor, and can increase the concentration of other drugs metabolized by this pathway.
  • SQV/r assoc. w/ PR and QTc prolongation in healthy volunteer study; see DHHS guidelines regarding ECG criteria for use
  • Perform tropism testing before initiation of therapy with MVC. MVC may be considered in patients who have only R5-tropic virus.

IAS-USA Guidelines (7/2012): 

  • NNRTI + 2 NRTIs
  • PI/r + 2 NRTIs
  • InSTI + 2 NRTIs
  • Notes on specific agents
    • NVP: Severe hepatoxocity and rash more common in initial therapy when CD4 >250 in women, >400 in men
    • ABC: Consider avoiding in patients with or at high risk for cardiovascular disease
    • LPV/r: Consider avoiding in patients with or at high risk for cardiovascular disease
    • AZT: AZT/3TC is an alternative NRTI component, but toxicity profile reduces its utility

CLINICAL RECOMMENDATION[Top]

NNRTI-Based Regimens

  • Advantages: simplicity, tolerability, relative lack of long-term toxicity, single tablet regimens available, better virologic suppression with EFV than LPV/r in ACTG 5142, efficacy at all VL & CD4 strata
  • Disadvantages: lower genetic barrier to resistance: greater resistance consequences with failure than with PI/r; CNS side effects (EFV); hepatotoxicity and skin rash (NVP); lower CD4 response with EFV than with most comparators
  • EFV: Advantages: has been gold standard; coformulated with TDF/FTC; long-term tolerability. Disadvantages: CNS side effects, rash, likelihood of NNRTI resistance with failure, teratogenicity.
  • RPV: Advantages: coformulated with TDF/FTC; better tolerated than EFV with fewer CNS effects, less rash and lipid effects. Disadvantages: may be 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: an acceptable NNRTI in women with CD4 < 250 and men with CD4 < 400. Advantages: 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 CD 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, though may eventually have role for pts infected with EFV/NVP-resistant virus

PI-Based Regimens

  • Advantages: typically no PI resistance with failure of PI/r-based regimen; ATV/r had similar efficacy to EFV in ACTG 5202; greater CD4 increase w/ LPV/r than EFV in ACTG 5142; once-daily regimens with 100 mg/d of RTV (ATV/r, FPV/r, DRV/r) better tolerated with less hyperlipidemia than regimens with higher doses of RTV.
  • Disadvantages: greater pill burden than with EFV or RPV coformulations; more GI side effects.
  • ATV +/- RTV: Advantages: lowest pill burden (2/d); well tolerated; less hyperlipidemia than LPV/r; does not require RTV boosting. Best choice if RTV boosting not possible (with ABC/3TC, not TDF/FTC). Disadvantages: potential for jaundice; requirement for gastric acidity (decreased absorption with proton pump inhibitors, H2 blockers, antacids); food requirement. RTV boosting preferred, and essential with TDF or EFV; cannot be combined with NVP
  • DRV/r : Advantages: DRV/r 800/100 mg once-daily 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); Disadvantages: Greater pill burden than ATV/r (3 vs. 2); potential for rash.
  • LPV/r: Advantages: convenience (coformulated with RTV); no food restriction with tablet formulation; best stuided 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 in DHHS guidelines; minimal data; nephrotoxicity; fluid requirement; elevated indirect bilirubin; dermatologic changes
  • NFV: Advantages: None. Disadvantages: not recommended in DHHS or IAS-USA guidelines; 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

Integrase Inhibitor-Based Regimens 

  • RAL: Advantages: RAL + TDF/FTC non-inferior to EFV/TDF/FTC (superior at 4-5 years) and better tolerated in STARTMRK trial, with more rapid virologic suppression. Disadvantages: Twice-daily dosing, barrier to resistance more similar to NNRTI- than PI/r-based regimens.
  • EVG: Advantages: Available as once-daily, single-tablet coformulation (EVG/COBI/TDF/FTC); non-inferior and better tolerated than TDF/FTC/EFV. Disadvantages: No stand-alone tablet, so TDF required; COBI inhibits tubular secretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (but not actual GFR). Not recommended if eGFR < 70, and should be stopped if eGFR falls to < 50.
  • DTG: Advantages: Once-daily administration, few drug interactions, may have higher barrier to resistance than RAL or EVG, superior to EFV and DRV/r (primarly based on tolerability advantages), likely to be combined with ABC/3TC in first non-TDF-based single-tablet regimen; Disadvantages: Currenlty not available in a single-tablet regimen, inhibits tubular excretion of creatinine, causing early increase in serum creatinine and decrease in eGFR (like COBI).

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. Disadvantages: nephrotoxicity, esp. in pts with pre-existing renal dysfunction and in pts on PI-based regimen; cross-resistance to ABC and ddI with K65R/M184V; greater loss of bone mineral density during initial therapy than with other NRTIs
  • 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; possible association with increased risk of MI; cross-resistance to ddI (L74V, K65R), TDF (K65R)
  • AZT/3TC: Advantages: well studied; resistance to AZT (TAMs) occurs gradually; M184V increases AZT activity. Disadvantages: 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 (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.
  • AZT/3TC preferred NRTI backbone (established efficacy with AZT, experience with AZT/3TC), but use regimen most likely to suppress viral load. TDF appears safe in pregnancy registry and is an alternative NRTI backbone in perinatal guidelines.
  • LPV/r (twice daily) or ATV/r preferred PIs in pregnant women. Consider LPV/r 3 tabs twice-daily in 3rd trimester or ATV/r 400/100 mg once daily in 2nd and 3rd trimester due to decreased PI levels.
  • Avoid EFV in 1st trimester (teratogenicity). Women found to be pregnant on EFV do not need to change therapy.
  • Avoid starting NVP in women with CD4 >250 (hepatotoxicity).
  • RPV class B, but no clinical data.
  • Little experience with ENF, MVC, RAL, ETR, EVG in pregnacy.
  • See Perinatal Guidelines (ref) for information on prevention of perinatal transmission.

References[Top]

  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. 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.

  6. 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).

  7. 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.

  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 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.

  13. 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.

  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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