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NRTI-sparing regimens have long been part of investigational regimens in treatment-naive patients. The current version of the IAS-USA guidelines lists 2 regimens for those who cannot receive abacavir, tenofovir AF, or tenofovir DF, pending further data on other strategies: darunavir plus ritonavir plus raltegravir (only if baseline CD4+ cell count > 200 cells/mm3 and HIV-1 RNA < 100,000 copies/mL) or darunavir plus ritonavir plus lamivudine (only if no lamivudine resistance is present). The DHHS guidelines now include dolutegravir/lamivudine as a recommended regimen for most people with HIV, except for individuals with HIV-1 RNA > 500,000 copies/mL, potential HBV coinfection, or those with no HIV genotype resistance testing results for reverse transcriptase. The DHHS also lists the regimens darunavir plus ritonavir plus raltegravir, and darunavir plus ritonavir plus lamivudine as part of “First-line Regimens to Be Used in Certain Clinical Situations,” specifically when abacavir, tenofovir DF, and tenofovir AF cannot be used. The EACS guidelines include dolutegravir/lamivudine as a recommended regimen and list darunavir plus ritonavir plus raltegravir and cobicistat/darunavir plus raltegravir as part of their alternative regimen recommendations.
This section reviews the clinical trial evidence of the efficacy of many of these regimens in comparison with standard 3-drug regimens.
Darunavir plus ritonavir plus raltegravir has been investigated in 2 prospective studies. The combination used in all cases was darunavir plus ritonavir 800/100 mg once daily plus raltegravir 400 mg twice daily. ACTG A5262 was a small single-arm study of 112 patients. This regimen resulted in an unexpectedly high rate of virologic failure at both Week 24 (16%) and Week 48 (24%). The risk of virologic failure was nearly 4 times higher in patients with baseline HIV-1 RNA > 100,000 copies/mL. Among 25 patients with genotypic resistance test results at virologic failure, 5 had integrase resistance mutations; all of these had baseline HIV-1 RNA > 100,000 copies/mL. This combination was also compared with darunavir plus ritonavir plus emtricitabine/tenofovir DF in the randomized, open-label, noninferiority phase III ANRS 143/NEAT 100 trial that enrolled 805 treatment-naive patients. Darunavir plus ritonavir plus raltegravir was found to be noninferior to darunavir plus ritonavir plus emtricitabine/tenofovir DF for the primary endpoint of time to treatment failure by virologic or clinical endpoints. The Kaplan-Meier estimated proportion of patients with virologic or clinical failure at Week 96 was 17.8% in the raltegravir arm vs 13.8% in the emtricitabine/tenofovir DF arm (95% CI: -0.8% to 8.8%). However, a planned subgroup analysis demonstrated that, among patients with baseline CD4+ cell counts < 200 cells/mm3, the raltegravir regimen was statistically inferior to the emtricitabine/tenofovir DF regimen for the primary endpoint (P = .01). There was also a trend toward a higher rate of virologic or clinical failure at Week 96 with the raltegravir regimen vs the emtricitabine/tenofovir regimen among patients with baseline HIV-1 RNA levels ≥ 100,000 copies/mL (interaction test: P = .01). Adverse event rates were similar in both treatment arms, but drug resistance occurred more frequently with the raltegravir regimen: 6 of 29 patients in the raltegravir arm vs 0 of 13 patients in the emtricitabine/tenofovir DF arm who had genotypic data available at virologic failure developed treatment-emergent resistance. A recent substudy showed no difference in cognitive function at Week 96 between these 2 regimens. The DHHS, IAS-USA, and EACS guidelines recommend this regimen as an option for patients who cannot receive abacavir, tenofovir AF, or tenofovir DF but only if baseline HIV-1 RNA is < 100,000 copies/mL and CD4+ cell count is > 200 cells/mm3.[1,2,8]
Darunavir plus ritonavir plus lamivudine was studied in the ANDES trial. This trial investigated a generic fixed-dose combination of these drugs (n = 75) vs generic darunavir plus ritonavir plus generic tenofovir DF/lamivudine (n = 70) in previously untreated patients in Argentina. At Week 24, 95% of patients in the dual-therapy group and 97% in the triple-therapy group had HIV-1 RNA < 400 copies/mL, establishing noninferiority of dual therapy to triple therapy. Median increases in CD4+ cell counts were similar: 206 cells/mm³ with dual therapy and 204 cells/mm³ with triple therapy. One person in the triple-therapy arm and 0 in the dual-therapy arm experienced protocol-defined virologic failure. All patients in the high baseline viral load stratum (HIV-1 RNA > 100,000 copies/mL) had HIV-1 RNA < 400 copies/mL at Week 24. The rate of grade 2/3 drug-related adverse events was higher with triple therapy (22.9% vs 13.3%). Gastrointestinal and neurologic adverse events were more frequent in the triple-therapy arm, but similar proportions in the double-therapy and triple-therapy arms had rashes (8.0% and 7.1%). The ANDES trial will continue to Week 48.
The parallel, double-blind, randomized phase III GEMINI-1 and GEMINI-2 trials compared initial ART with dolutegravir plus lamivudine vs dolutegravir plus emtricitabine/tenofovir DF and demonstrated noninferiority of the 2-drug regimen after 48 weeks by a snapshot analysis of the intent-to-treat–exposed population. In a pooled analysis of both trials, 91% of patients treated with the 2-drug regimen vs 93% of patients treated with the 3-drug regimen had HIV-1 RNA < 50 copies/mL (primary endpoint) at Week 48 (adjusted difference -1.7%; 95% CI: -4.4% to 1.1%), meeting the prespecified -10% noninferiority margin. Virologic efficacy was generally consistent across patient subgroups stratified by baseline HIV-1 RNA level and CD4+ cell count. However, among patients in the dolutegravir plus lamivudine arm, the rate of virologic suppression at Week 48 by Snapshot analysis was numerically lower, at 79% (50/63), for the subgroup of patients with baseline CD4+ cell counts ≤ 200 cells/mm3 vs 93% (605/653) among those with baseline CD4+ cell counts > 200 cells/mm3. The rates of confirmed virologic withdrawal through Week 48 were low (≤ 1%) in both treatment arms, and no treatment-emergent INSTI or NRTI resistance-associated mutations were detected among patients with confirmed virologic withdrawal in either arm. Although the overall adverse event profiles were similar between treatment arms, there were significant differences in the magnitude of change from baseline to Week 48 for renal and bone biomarkers (P < .001 for all renal and bone markers assessed), with the differences indicating a more favorable renal and bone profile for dolutegravir plus lamivudine vs dolutegravir plus emtricitabine/tenofovir DF. The results of the 96-week analysis were reported at the 2019 IAS Conference and showed that the 2-drug dolutegravir/lamivudine regimen had high efficacy rates compared to the 3-drug regimen of dolutegravir plus emtricitabine/tenofovir DF with no treatment-emergent resistance detected. In a pooled analysis, 86% (616/716) of patients receiving dolutegravir/lamivudine had HIV-1 RNA < 50 copies/mL vs 90% (642/717) of patients receiving dolutegravir plus emtricitabine/tenofovir DF (adjusted difference: -3.4; 95% CI: -6.7% to 0%). In addition, 11 patients (1.5%) receiving dolutegravir/lamivudine and 7 patients (1.0%) receiving the 3-drug regimen met protocol-defined virologic withdrawal criteria. Treatment with dolutegravir/lamivudine was associated with significantly lower drug-related adverse events and more favorable changes in renal and bone biomarkers vs the 3-drug regimen.
This combination was also studied in the single-arm pilot ACTG A5353 trial in 120 patients with HIV-1 RNA < 500,000 copies/mL. Virologic efficacy by FDA snapshot analysis at Week 24 was 90% (95% CI: 83% to 95%). Comparable results were observed among those with baseline HIV-1 RNA > 100,000 copies/mL (89%; 95% CI: 75% to 97%) and those with baseline HIV-1 RNA ≤ 100,000 copies/mL (90%; 95% CI: 82% to 96%). Three patients experienced virologic failure; all had undetectable plasma dolutegravir at ≥ 1 time points. One patient developed M184V in reverse transcriptase and R263R/K in integrase. Grade 3 treatment-related adverse events were reported in 2 patients; none discontinued treatment due to adverse events.
In April 2019, the FDA approved dolutegravir/lamivudine as the first complete 2-drug regimen indicated for first-line ART. The approval notes that it is not indicated for patients with hepatitis B virus (HBV) coinfection, those with HIV-1 RNA > 500,000 copies/mL, or those who will start ART before the results of HBV testing or HIV genotypic resistance testing are known.[1,149]