Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy - naive adults with HIV-1 infection.

OBJECTIVE: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2. DESIGN: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks). METHODS: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC. RESULTS: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC. CONCLUSIONS: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials.

BACKGROUND: The 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses. SETTING: One hundred eighty-seven centers in 21 countries. METHODS: GEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine. RESULTS: At week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ≥50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine. CONCLUSIONS: Consistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

Uptake and effectiveness of two-drug compared with three-drug antiretroviral regimens among HIV-positive individuals in Europe.

OBJECTIVE: To assess the use of two-drug antiretroviral regimens (2DR) and virologic and immunologic outcomes compared with three-drug regimens (3DR) in the EuroSIDA cohort. DESIGN: Multicentre, prospective cohort study. METHODS: Logistic regression was used to analyse the uptake and outcomes among HIV-positive individuals who started or switched to a 2DR compared with those on a 3DR. Virologic outcomes were assessed on-treatment as the proportion of individuals with controlled viral load (<400 copies/ml), or with a composite modified FDA snapshot endpoint (mFDA), with mFDA success defined as controlled viral load at 6 months or 12 months for individuals with a known viral load, no regimen changes, AIDS or death. Immunologic response was defined as a 100 cells/µl or a 25% increase in CD4 cell counts from baseline. RESULTS: Between 1 July 2010 and 31 December 2016, 423 individuals started or switched to a 2DR (eight antiretroviral-naive) and 4347 started a 3DR (566 naive). Individuals on 2DR tended to have suppressed viral load, higher CD4 cell counts and more comorbidities at baseline compared with those on 3DR. There were no differences in the proportions of individuals who obtained on-treatment or mFDA success, and no significant differences in the adjusted odds ratios for mFDA success or immunologic responses between the 2DR and 3DR groups at 6 months or 12 months. CONCLUSION: In routine clinical practice, 2DR were largely used for virologically suppressed individuals with higher cumulative exposure to antiretrovirals and comorbidities. Virologic and immunologic outcomes were similar among those on 2DR or 3DR, although confounding by indication cannot be fully excluded due to the observational nature of the study.

Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial.

Objectives: To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults. Methods: In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400-900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015. Results: We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30-43) years. Baseline CD4 count was 592 (491-694) cells/mm3 and VL was 4.04 (3.5-4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (-1.2%/year versus -1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events. Conclusions: Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.

BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING: ViiV Healthcare.