Date Published: September 26, 2017
Author(s): Tatevik Balayan, Hacsi Horvath, George W. Rutherford.
Darunavir is a second-generation protease-inhibitor used with ritonavir (DRV/r) and two nucleoside reverse-transcriptase inhibitors as an option in first-line antiretroviral treatment (ART).
We systematically reviewed randomized controlled trials (RCTs) of DRV/r versus other regimens in patients initiating ART. We searched five bibliographic databases and other key resources. We had no language limitations. We assessed bias risk with the Cochrane tool and used GRADE to assess evidence quality. We report findings in terms of risk ratio (RR) with 95% confidence intervals (CI).
Three RCTs met inclusion criteria. In plasma viral load suppression, DRV/r outperformed ritonavir-boosted lopinavir at 48 weeks (RR 1.13, 95% CI 1.03–1.25), 96 weeks (RR 1.11, 95% CI 1.02–1.21), and 192 weeks (RR 1.20, 95% CI 1.07–1.35). DRV/r was similar to dolutegravir at 48 weeks (RR 0.96, 95% CI 0.87–1.06) but less effective at 96 weeks (RR 0.84, 95% CI 0.75–0.93). At 96 weeks, DRV/r underperformed raltegravir (RR 0.94, 95% CI 0.88–0.99) but was similar to ritonavir-boosted atazanavir (RR 1.02, 95% CI 0.96–1.09). Overall bias risk was moderate. Evidence quality was also moderate.
Initial ART regimens using DRV/r should be considered in future World Health Organization guidelines.
Darunavir (DRV) is a once-daily second-generation protease-inhibitor [1, 2] that is administered with low-dose ritonavir (DRV/r) and two nucleoside reverse transcriptase inhibitors (NRTI) for treatment of HIV infection. In vitro studies have shown that resistance to DRV develops much more slowly and that it has a higher genetic barrier for the development of resistance relative to current protease inhibitors . DRV has a very low resistance profile , requires boosting with ritonavir, and is used in combinations with two NRTIs, such as abacavir (ABC) + lamivudine (3TC) or tenofovir (TDF) + emtricitabine (FTC).
We used Cochrane Collaboration methods throughout the review process . We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance in reporting our results . Before beginning our review, we registered its protocol in the PROSPERO online registry (registration number CRD42016040058).
We initially identified 660 articles (605 from bibliographic databases, 14 from conference abstracts, and 41 from registered trials). After removing 230 duplicate records and 50 clearly irrelevant records, we independently reviewed 380 titles and abstracts and excluded 350 clearly irrelevant records. We selected 30 records for full-text review. We then excluded 21 studies reporting results of other background regimens, second-line therapy, pharmacokinetics, and other topics (Figure 1).
We found that DRV/r-containing regimens were associated with a greater proportion of patients being virologically suppressed up to 192 weeks after initiation of therapy compared to LPV/r-based regimens. However, we also found out that DRV/r-based regimens were inferior to DTG- and RAL-based regimens at 96 weeks. There was no difference between DRV/r and ATV/r regimens in terms of virologic suppression.
We found three RCTs that directly compared DRV/r with other regimens for initial treatment of HIV infection in adults and adolescents. DRV/r appears to be superior to LPV/r in terms of durable viral suppression and immunologic recovery, inferior to DTG and RAL and similar to ATV/r. DRV/r-containing regimens should be considered in future international guidelines for initial therapy of HIV infections, but its utility has likely been eclipsed by better performing integrase inhibitor regimens.