October 30, 2013
In the February 12, 2013, version of the Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, the Panel recommendations on initial combination regimens for the antiretroviral therapy (ART)-naive, HIV-infected patient include raltegravir (RAL) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as the preferred integrase strand transfer inhibitor (INSTI)-based regimen, and elvitegravir (EVG)/cobicistat (cobi)/TDF/FTC as an alternative regimen for patients with estimated creatinine clearance (CrCl) ≥70 mL/min. Since the release of the Guidelines, a new INSTI, dolutegravir (DTG), was approved for use in ART-naive and ART-experienced patients. Additionally, long-term follow-up data (up to 144 weeks) from randomized clinical trials have demonstrated the durable safety and efficacy of EVG/cobi/TDF/FTC.
On the basis of these new findings, the Panel now recommends the following 4 INSTI-based regimens as preferred regimens for ART-naive patients (arranged in order of drug approval):
Since the inclusion of co-formulated EVG/cobi/TDF/FTC as an alternative INSTI in the February 2013 guidelines, 96 week data from 2 Phase 3 clinical trials have been published,1,2 and additional data through 144 weeks have been presented.3,4 In these studies, EVG/cobi/TDF/FTC remained non-inferior to co-formulated efavirenz (EFV)/TDF/FTC3 and to ritonavir-boosted atazanavir (ATV/r) plus TDF/FTC at Week 144.4 No additional occurrences of proximal renal tubulopathy were reported in the EVG/cobi/TDF/FTC-treated participants in either study beyond 24 weeks. Additionally, following early, modest increases in serum creatinine observed with EVG/cobi/TDF/FTC therapy, there were no further increases in creatinine levels through Week 144.3,4 These data, along with post marketing clinical experience with the co-formulated product, are the basis for the Panel's decision to recommend EVG/cobi/TDF/FTC as a preferred regimen for ART-naive patients.
In 3 Phase 3 randomized controlled trials, DTG 50 mg once daily plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) was compared to 3 Guidelines-designated preferred regimens:
The primary endpoint for these trials was the proportion of patients with HIV RNA <50 copies/mL at Week 48. DTG was found to be non-inferior to RAL at Week 48 and also at Week 96.5,8 DTG-based regimens were also found to be superior to DRV/r- and EFV-containing regimens, largely because of more discontinuations for adverse events or other reasons in the comparator arms. No emergent DTG resistance has been observed thus far in clinical trials of DTG in treatment-naive patients.
Overall, DTG was well tolerated in clinical trials, with insomnia and headache of moderate to severe intensity (in 3% and 2% of patients, respectively) being the most commonly reported adverse effects. Cases of hypersensitivity reaction have been reported in clinical trials. DTG decreases tubular secretion of creatinine without affecting glomerular function, with increases in serum creatinine observed within the first 4 weeks of treatment (mean change from baseline in serum creatinine of 0.11 mg/dL after 48 weeks); no discontinuations due to drug-related renal adverse events have been seen to date.9
In summary, all three approved INSTIs have been shown in randomized clinical trials to be non-inferior to other preferred ART regimens for treatment-naive patients. Each INSTI-based regimen has distinctive characteristics; certain clinically relevant features are summarized below and in Table 1.
|Table 1. Comparison of 4 INSTI-Based Regimens|
|RAL + TDF/FTC||EVG/cobi/TDF/FTC||DTG + ABC/3TC||DTG + TDF/FTC|
|Comparators in Randomized Trials||EFV/TDF/FTC||EFV/TDF/FTC|
ATV/r + TDF/FTC
DRV/r + 2 NRTI
RAL + 2 NRTI
|DRV/r + 2 NRTI|
RAL + 2 NRTI
|Follow-Up Data||>5 years||144 weeks||48-96 weeks||48-96 weeks|
|Post-Marketing Experience||6 years||1 year||Minimal||Minimal|
|Dosing Frequency||Twice daily||Once daily||Once daily||Once daily|
|Numbers of Tablets Per Day||3||1||2||2|
|Meal Consideration||None||Take with a meal||None||None|
|CYP 3A4 Interactions||No||Yes||No||No|
|CrCl and Dosing||Dosage adjustment for TDF and FTC if CrCl <50 mL/min||Not recommended if CrCl <70 mL/min||Dosage adjustment for 3TC if CrCl <50 mL/min||Dosage adjustment for TDF and FTC if CrCl <50 mL/min|
|HLA B*5701 (+) Patients||No concern||No concern||Do not use this regimen||No concern|
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; cobi = cobicistat; CrCl = creatinine clearance; DRV/r = ritonavir-boosted darunavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; RAL = raltegravir; TDF = tenofovir disoproxil fumarate.
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