Meta-analysis: Dolutegravir and raltegravir produce better viral suppression than efavirenz

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The integrase inhibitor, dolutegravir or low-dose efavirenz, were associated with higher rates of long-term viral suppression than standard-dose efavirenz in patients with HIV, a meta-analysis indicated.

“The combination of (Atripla, Bristol-Myers Squibb/Gilead Sciences (efavirenz, tenofovir, and emtricitabine) is the preferred option for first-line therapy, although a ritonavir-boosted protease inhibitor or an integrase strand transfer inhibitor-based regimen can also be used in a first-line regimen in patients with complex diseases or contraindications, or both,” Steve Kanters, of Precision Global Health and the School of Population and Public Health, University of British Columbia, and colleagues wrote. “Results of our analysis showed that [Tivicay, ViiV Healthcare (dolutegravir)] and [Sustiva, Bristol-Myers Squibb (low-dose efavirenz)] were not only more tolerable than [Sustiva, Bristol-Myers Squibb (standard-dose efavirenz)], but that they were also more effective, albeit with dolutegravir doing slightly better with respect to viral suppression efficacy and tolerability.”

To evaluate the safety and efficacy of available ART regimens among ART-naive patients with HIV, researchers conducted a network meta-analysis using 126 manuscripts from 71 trials, including patients in 161 treatment groups (n = 34,032). At 48 weeks, Kanters and colleagues reported, dolutegravir produced superior viral suppression vs efavirenz (OR = 1.87; 95% credible interval [CrI], 1.34-2.64). Raltegravir also had better viral suppression than efavirenz (OR = 1.4; 95% CrI, 1.02-1.96). The drug with the “most protective effect,” the researchers wrote, was dolutegravir (OR = 0.26; 95% CrI, 0.14-0.47). Low-dose efavirenz also was more effective than standard-dose efavirenz (OR = 0.39; 95% CrI, 0.16-0.92). Kanters and colleagues did not report any conclusions about adverse effects, citing insufficient data.

In an accompanying editorial, Dr Anton L Pozniak and Dr Andrew M Hill, both of the S Stephen’s AIDS Trust, Chelsea and Westminster Hospital, London, wrote that the dramatic price difference between generic ART and newer drugs may outweigh the benefits.

“Generic combination treatment with tenofovir, lamivudine and efavirenz is available in low-income countries for between US $110 and $184 per person-year,” Pozniak and Hill wrote. “The launch price for the patented combination of [Triumeq, ViiV Healthcare (abacavir, lamivudine and dolutegravir)] in the USA was $32,000 per person-year (average wholesale price).”

They also wrote that the meta-analysis “has a methodological issue, which limits the applicability of the results,” pointing to the SINGLE trial, in which researchers reported dolutegravir had a slightly higher virological failure rate than efavirenz at 144 weeks.

“National health authorities need to carefully assess how universal access programmes for HIV prevention, testing, treatment and care can be achieved within realistic budgets,” Pozniak and Hill wrote.

Summary
Background: New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART regimens for HIV in ART-naive patients.
Methods: For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV. We extracted data on trial and patient characteristics, and the following primary outcomes: viral suppression, mortality, AIDS defining illnesses, discontinuations, discontinuations due to adverse events, and serious adverse events. We synthesised data using network meta-analyses in a Bayesian framework and included older treatments, such as indinavir, to serve as connecting nodes. We defined network nodes in terms of specific antivirals rather than specific ART regimens. We categorised backbone regimens and adjusted for them through group-specific meta-regression. We used the GRADE framework to interpret the strength of inference.
Findings: We identified 5865 citations through database searches and other sources, of which, 126 articles related to 71 unique trials were included in the network analysis, including 34 032 patients randomly assigned to 161 treatment groups. For viral suppression at 48 weeks, compared with efavirenz, the odds ratio (OR) for viral suppression was 1•87 (95% credible interval [CrI] 1•34–2•64) with dolutegravir and 1•40 (1•02–1•96) with raltegravir; with respect to viral suppression, low-dose efavirenz was similar to all other treatments. Both low-dose efavirenz and integrase strand transfer inhibitors tended to be protective of discontinuations due to adverse events relative to normal-dose efavirenz. The most protective effect relative to efavirenz in network meta-analyses was that of dolutegravir (OR 0•26, 95% CrI 0•14–0•47), followed by low-dose efavirenz (0•39, 0•16–0•92). Owing to insufficient data, we could make no conclusions about serious adverse events. Low event rates also limited the quality of evidence with regard to mortality and AIDS defining illnesses.
Interpretation: The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings.

Authors
Kanters S, Vitoria M, Doherty M, Socias ME, Ford N, Forrest JI, Popoff E, Bansback N, Nsanzimana S, Thorlund K, Mills EJ

Healio report
The Lancet article summary
The Lancet editorial comment


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