Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

Switching from twice-daily raltegravir plus tenofovir disoproxil fumarate/emtricitabine to once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in virologically suppressed, HIV-1-infected subjects: 48 weeks data.

BACKGROUND: Pill burden, dosing frequency, and concerns about safety and tolerability are important obstacles to maintaining adequate medication adherence. Raltegravir (RAL) is indicated for twice-daily dosing and when taken with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), it becomes a twice-daily multiple-tablet regimen. Elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF, STB, is the first approved once-a-day integrase strand transfer inhibitor (INSTI) containing single-tablet regimen that combines EVG, an INSTI, and COBI, a novel pharmacoenhancer, with the preferred nucleos(t)ide backbone of FTC/TDF. METHODS: This was a 48-week prospective, single-arm open-label study of the switch to STB in virologically sup-pressed HIV-1-infected adult patients on FTC/TDF and twice-daily RAL for at least 6 months. Objectives were to evaluate the tolerability and safety of a regimen simplification to once-a-day STB, while maintaining viral suppression through 48 weeks. RESULTS: Forty-eight individuals in the United States were enrolled. The median age was 44 years, 96% were male, and 83% were White. The median time on RAL + FTC/TDF treatment prior to enrollment was 34 months. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At base-line, the median CD4 count was 714 cell/µL and estimated glomerular filtration rate (eGFR) was 105 mL/min. At week 48, all assessed study participants remained viro-logically suppressed to the lower limit of quantification (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min). STB was well tolerated with no discontinuations, no study drug-related serious adverse events, and no study drug-related grade 3/4 adverse events. CONCLUSIONS: All participants switching to 1 tablet once-a-day STB from a twice-daily RAL + FTC/TDF regimen remained virologically suppressed. STB was well tolerated. Switching to STB may be a viable option for virologically suppressed patients wanting to simplify from a twice-daily RAL-containing regimen.

Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency.

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.