Johns Hopkins HIV Guide

Initial Regimen

Joel E. Gallant, M.D., M.P.H.

DEFINITION

  • First drug regimen in ART-naive patient

INDICATIONS[Top]

DHHS Guidelines (10/14/11): Preferred Regimens

  • 2-NRTI backbone + NNRTI or PI (preferably RTV-boosted) or INSTI (integrase strand transfer inhibitor)
  • 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.
  • NNRTI-based regimen: EFV/TDF/FTC (AI).
  • PI-based regimens (alphabetical order): (1) ATV/r + TDF/FTC (AI) or (2) DRV/r + TDF/FTC (AI).
  • INSTI-based regimen: RAL + TDF/FTC (AI)
  • Preferred regimen for pregnant women: LPV/r (twice-daily) + AZT/3TC (AI)

DHHS Guidelines (10/14/11): Alternative regimens

  • Alternative regimens: Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. May be the preferred for some pts.
  • NNRTI-based regimens (alphabetical order): (1) EFV + ABC/3TC (BI) or (2) RPV/TDF/FTC (BI) or (3) RPV + ABC/3TC (BIII)
  • PI-based regimens (alphabetical order): (1) ATV/r + ABC/3TC (BI) or (2) DRV/r + ABC/3TC (BIII) (3) FPV/r (once- or twice-daily) + (ABC/3TC or TDF/FTC) (BI) or (4) LPV/r (once- or twice-daily) + (ABC/3TC or TDF/FTC) (BI)
  • INSTI-based regimen: RAL + ABC/3TC (BIII)

DHHS Guidelines (10/14/11): Acceptable regimens

  • Acceptable regimens: regimens that may be selected for some pts but are less satisfactory than preferred or alternative regimens
  • NNRTI-based regimens: (1) EFV + AZT/3TC (CI) or (2) NVP + (ABC/3TC or TDF/FTC) (CI)
  • PI-based regimens: (1) ATV + (ABC or AZT)/3TC (CI), or (2) ATV/r + AZT/3TC (CI) or (3) FPV/r + AZT/3TC (CI) or (4) LPV/r + AZT/3TC (CI)
  • CCR5 antagonist-based regimens: MVC + AZT/3TC (CI).

DHHS Guidelines (10/14/11) Regimens that may be acceptable but more definitive data are needed

DHHS Guidelines (10/14/11): Regimens that may be acceptable but should be used with caution

DHHS Guidelines (10/14/11): 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
  • Do not use EFV during 1st trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception
  • ABC should not be used in patients who test positive for HLA-B*5701; use with caution in patients with high risk of cardiovascular disease or with pretreatment VL >100,000
  • LPV/r + AZT/3TC is the preferred regimen for pregnant women. Once-daily LPV/r not recommended in pregnant women
  • Use RPV with caution in patients with pre-treatment VL >100,000. Use of PPIs contraindicated with RPV
  • 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
  • SQV/r assoc. w/ PR and QTc prolongation in healthy volunteer study; see DHHS guidelines regarding ECG criteria for use

IAS-USA Guidelines (7/21/10): 

  • 2-NRTI backbone
    • Recommended: renal dysfunction, decreased bone mineral density affect choice
    • Alternative: ABC/3TC screen with HLA B*5701 assay to reduce risk of hypersensitivity reaction; may have less activity that TDF/FTC in pts w/ VL >100,000; may increase cardiovascular risk
  • 3rd agent
    • Recommended: EFV: major psychiatric illness, 1st trimester pregnancy, or intention to become pregnant affect choice
    • Recommended: ATV/r (300/100 mg once-daily): hyperbilirubinemia, need for acid-reducing agents, and risk of nephrolithiasis affect choice
    • Recommended: DRV/r (800/100 mg once-daily): limited experience in naive patients, availability of other options, and efficacy in experienced pts with multi-drug resistant virus affect choice
    • Recommended: RAL (400 mg twice-daily): limited experience in naive patients, availability of other options, and efficacy in experienced pts with multi-drug resistant virus affect choice
    • Alternatives: LPV/r (200/50 mg tabs, 4 once-daily or 2 tabs twice-daily), FPV/r (700/100 mg twice-daily or 1400/200 or 1400/100 mg once-daily), or MVC (300 mg twice-daily if used only with NRTIs)

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 LPV/r in ACTG 5142 despite superior virologic suppression
  • EFV: Advantages: the gold standard; coformulated with TDF/FTC; antiviral activity as good or better than all comparators to date. Disadvantages: CNS side effects, rash, likelihood of NNRTI resistance with failure, teratogenicity. Avoid EFV in pregnant women (esp. 1st trimester) or women with pregnancy potential.
  • RPV: Advantages: coformulated with TDF/FTC; better tolerated than EFV with fewer CNS effects, less rash and lipid effects. Disadvantages: less effective at VL >100,000 with greater resistance at failure, including cross-resistance to ETR.
  • 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; preferred 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: acceptable in pregnancy (LPV/r preferred). 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 and better tolerated in STARTMRK trial through 156 wks, with more rapid virologic suppression. Disadvantages: Twice-daily dosing, barrier to resistance more similar to NNRTI- than PI/r-based regimens.

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)
  • d4T + (3TC or FTC): Advantages: well studied; well tolerated; resistance to d4T (TAMs) occurs gradually; M184V increases d4T activity. Disadvantages: more toxic than other NRTIs (neuropathy, lipoatrophy, hyperlipidemia, lactic acidosis/hyperlactatemia, hepatic steatosis). Not recommended.
  • AZT/3TC/ABC: Potential for use in combination with 4th agent. In ACTG 5095 AZT/3TC/ABC + EFV not more effective than AZT/3TC + EFV. Therefore, triple NRTI backbone + NNRTI not recommended for initial regimen in pts w/ wild-type virus.
  • ABC + ddI, TDF + ddI, ABC + TDF: Avoid in naive pts (minimal data, possible increased selective pressure for resistance). Sometimes used in pts with NRTI resistance, but minimal data; TDF increases ddI levels and toxicity and may decrease CD4 count: if used, reduce ddI dose.
  • ddI + d4T: Avoid (toxicity, lower efficacy)
  • AZT + d4T: Avoid (antagonism)

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, 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.
  • If ART indicated for woman’s health, start ART as soon as possible. If indicated only to prevent perinatal transmission, consider delaying until after 1st trimester.
  • 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.
  • LPV/r preferred PI in pregnant women. Always use twice-daily dosing; consider increasing dose (3 tabs twice-daily) in 3rd trimester due to decreased LPV levels. ATV/r also approved in pregnancy (class B).
  • Avoid EFV, especially in 1st trimester (teratogenicity)
  • Avoid ddI/d4T (toxicity); DLV (teratogenicity in animals); liquid APV (contains propylene glycol)
  • Avoid NVP in women with CD4 >250 (hepatotoxicity). Single-dose NVP not associated with hepatotoxicity.
  • RPV class B, but no clinical data.
  • Little experience with ENF, MVC, RAL, ETR in pregnancy.
  • See Perinatal Guidelines (ref) for information on prevention of perinatal transmission.

References[Top]

  1. Thompson MA et al: Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 304:321, 2010 July 21  [PMID:20639566]

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

  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 Sep. 5  [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. 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 April 1  [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.

  4. Sax PE et al: Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 361:2230, 2009 Dec. 3  [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.

  5. 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 Aug. 23  [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.

  6. 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 July 31  [PMID:18614861]

    Comment:

  7. Riddler SA et al: Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358:2095, 2008 May 15  [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.

  8. 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 April 26  [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.

  9. 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 Jan. 1  [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).

  10. 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 Aug. 5  [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.

  11. 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 Aug. 16  [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.

  12. 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 March 21  [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.

  13. Gallant JE et al: Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354:251, 2006 Jan. 19  [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.

  14. 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 Oct. 1  [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.

  15. 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.

  16. 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.

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Initial Regimen
Last updated: March 30, 2012
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