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Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug–drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50–199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of −12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference −0·6%, 95·002% CI −4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. Gilead Sciences.

Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. NCT02159599.

In this randomized pilot clinical trial, dolutegravir plus lamivudine was noninferior to continuation of standard 3-drug maintenance antiretroviral therapy. There was no emergence of drug resistance in the participant who experienced virologic failure while receiving dolutegravir plus lamivudine.

The timing of initiation of antiretroviral therapy in HIV-infected infants has been debated, in part because of the potential long-term toxicity of the medication, the risk of resistance, adherence challenges, and cost. In this randomized trial involving 377 HIV-infected infants in South Africa, early initiation of antiretroviral therapy reduced infant mortality by 76% and the rate of HIV progression by 75%. In this randomized trial involving 377 HIV-infected infants in South Africa, early initiation of antiretroviral therapy reduced infant mortality by 76 percent and the rate of HIV progression by 75 percent. Infants with human immunodeficiency virus type 1 (HIV-1) infection have higher rates of disease progression and mortality than older children, 1 – 3 even with a high percentage of CD4 lymphocytes (CD4 percentage). 4 Whereas early initiation of antiretroviral therapy may be appropriate for infants, continuing treatment for life is problematic, given the limitations of the available drugs, the long-term toxicity of antiretroviral therapy, adherence issues, the risk of resistance to antiretroviral therapy, and limited resources. This trial addresses the optimal time of initiation and duration of antiretroviral therapy in infants with in utero or intrapartum HIV-1 infection. We hypothesized that early initiation . . .

In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov, NCT01227824. Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. ViiV Healthcare.

Background. Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. Methods. In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. Results. A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, −1.9%; tenofovir-emtricitabine group, −3.6%; P <; .001) and lumbar spine (abacavir-lamivudine group, −1.6%; tenofoviremtricitabine group, −2.4%; P = .036). BMD loss of ⩾6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of ⩾6% in the hip; 15% vs 5% had a loss of ⩾6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofoviremtricitabine group, +11.92 mg/L; P < .001). Conclusions. This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Background Antiretroviral therapy (ART) in people with HIV (PWH) can lead to weight gain, but the effects of nucleoside reverse transcriptase inhibitors such as abacavir (ABC) are not well understood. In this study, we investigated whether discontinuing ABC would mitigate weight changes and metabolic complications in PWH. Methods In a randomized controlled trial including PWH on dolutegravir, ABC, and lamivudine (DTG/ABC/3TC), participants were randomized 2:1 to either switch to DTG/3TC or continue DTG/ABC/3TC. Data was collected at baseline, week 24, and week 48. This study was powered to detect a difference of 2 kg in weight between groups. Secondary outcomes included body composition, fat and muscle distribution, and metabolic parameters. Weight and metabolic changes were analyzed by linear mixed modeling. Results Eighty-one participants were randomized. Switching from DTG/ABC/3TC to DTG/3TC was not associated with a significant change in weight at 48 weeks in the intention to treat (ITT) analysis (mean difference − 0.5 kg, 95% confidence interval (CI): -2.5 to 1.5, p  = 0.599) or the modified ITT, (-0.1 kg, 95% CI: -1.7 to 1.5, p  = 0.914). In the ITT analysis, the DTG/3TC group gained 0.4 kg ± 5.1 SD ( p  = 0.589) compared to 0.9 kg ± 2.3 SD ( p  = 0.054) in the DTG/ABC/3TC group, while in the modified ITT, the changes were 0.9 ± 3.2 kg ( p  = 0.054) and 0.9 ± 3.6 kg ( p  = 0.071), respectively. The were no differences between groups in secondary outcomes. Conclusion Continuing or discontinuing abacavir for 48 weeks was associated with modest gains in weight that did not differ between groups. Similarly, fat distribution, or metabolic parameters were comparable between groups.

Background. There are 2 once-daily, fixed-dose-combination, dual-nucleoside analogue tablets: tenofovir 300 mg-emtricitabine 200 mg (TDF-FTC) and abacavir 600 mg-lamivudine 300 mg (ABC-3TC). Which fixed-dose-combination tablet is more effective and safe is uncertain. Methods. We compared TDF-FTC and ABC-3TC in a randomized, open-label, 96-week trial in which either fixed-dose-combination was substituted for current nucleoside treatments in human leukocyte antigen-B*5701-negative adults with human immunodeficiency virus loads <50 copies/mL. The primary end point was virological failure (consecutive viral load measurements >400 copies/mL, by intention-to-treat). Secondary end points included death, AIDS, adverse events, serious non-AIDS events, metabolic parameters, and body composition. We used exact statistics for differences in proportions, T tests to compare means, and Cox regression for hazard ratios. Results. Of 441 patients who were screened, 357 were treated; 98% were men, the mean age was 45 years, 30% were receiving TDF, 20% were receiving ABC, and 24% were receiving a protease inhibitor. Virological failure was uncommon (5.6% for ABC-3TC and 3.9% for TDF-FTC; difference, 1.7%; 95% confidence interval [CI], −2.8% to 6.1%; P=.62). No participant developed AIDS, whereas 18 (5%) participants developed a serious non-AIDS event (rate, 2.79 events per 100 person-years; 95% CI, 1.76–4.43), of which 4 were fatal. TDF-FTC was associated with significantly fewer serious non-AIDS events than ABC-3TC (1.2 vs 4.8 events per 100 patient-years; hazard ratio [HR], 0.24; 95% CI, 0.08–0.73; P=.012), influenced mostly by a lower rate of cardiovascular events (0.3 vs 2.2 events per 100 patient-years; HR, 0.12; 95% CI, 0.02–0.98; P=.048). TDF-FTC resulted in significantly lower bone mineral density (mean difference in hip t score, 0.16; 95% CI, 0.08–0.23; P<.001) but not in more fractures. Conclusions. In this population, TDF-FTC and ABC-3TC had similar virological efficacy, but ABC-3TC was associated with more serious non-AIDS events, particularly cardiovascular events. Clinical trials registration. NCT00192634.

Background. The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)—associated tuberculous meningitis is unknown. Methods. We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, perprotocol, and prespecified subgroup analyses. Results. A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI],.81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI,.87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). Conclusions. Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis.

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference −4·84 to 7·05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2–4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.