Darunavir 800mg / Cobicistat 150mg tablets

INTRODUCTION: Darunavir and lopinavir solid formulations are recommended protease inhibitors for treating HIV. An evidence review of their effectiveness/efficacy and safety in young populations was needed to inform the 2025 World Health Organization guidelines. METHODS: We conducted a systematic review of publications reporting efficacy/effectiveness and/or safety of darunavir and/or lopinavir solid formulations in children and/or adolescents with HIV aged 0–19 years, with at least 6 months follow-up. Sources included MEDLINE, Embase, Cochrane Library, recent HIV conferences and trial registries. Data were synthesized narratively. RESULTS: We screened 4,196 abstracts and 421 papers. Thirteen studies (including two randomized controlled trials (RCTs)) on darunavir were identified in 1,895 children/adolescents (2% treatment-naïve). Among treatment-experienced participants on ritonavir-boosted darunavir, 86% (198/229) and 95% (143/150) had viral suppression (< 50 or < 400 copies/mL) at 48 weeks in the RCTs and 29% (4/14)-100% (12/12) across seven other studies (N = 736), respectively. Participants in the four studies (N = 184) with < 70% suppression were heavily treatment-experienced and unsuppressed at darunavir start. Grade 3/4 adverse events (clinical/laboratory) occurred in 0%-30% of participants on ritonavir-boosted darunavir (seven studies, N = 515; 8–9% in two large RCTs), and adverse events leading to discontinuation or treatment modification in 0%-10% (10 studies, N = 974; 2–3% in two RCTs). Three grade 3/4 adverse events in one study were drug related. Twenty-nine studies (including four randomized trials) on ritonavir-boosted lopinavir solid formulations were identified in 3,605 children/adolescents (17% treatment-naïve). Among treatment-experienced children/adolescents at 48–52 weeks, viral suppression was 80% (179/223) in one RCT and 53% (448/852)-100% (12/12) across five other studies (N = 1305). Across all populations, grade 3/4 adverse events were reported in 8%-60% of participants (four studies, N = 1405; 8–13% in two large RCTs), and events leading to discontinuation or treatment modification in 0%-9% (seven studies, N = 905; 2–3% in two RCTs). Five participants experienced drug-related grade 3/4 adverse events (five studies, N = 1107). Lipid levels were significantly greater with lopinavir versus other regimens (five studies). CONCLUSIONS: Darunavir was safe in treatment-experienced children and adolescents, and viral suppression was high in RCTs; data were limited in treatment-naïve populations. Viral suppression with lopinavir solid formulations was variable. Lopinavir was generally well-tolerated but compared unfavourably with other drugs in terms of lipid outcomes. PROSPERO NUMBER: CRD42020204432.

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BackgroundTo date, clinical trials have been underpowered to assess which antiretrovirals perform best in people with advanced HIV disease. We aimed to investigate the efficacy and safety of an integrase inhibitor-containing versus a boosted protease inhibitor-containing regimen for this population.MethodsIn this open-label, multicentre, non-inferiority trial in seven European countries (Spain, France, Italy, Germany, Belgium, Ireland, and the UK), therapy-naive adults with advanced HIV disease were randomly allocated (1:1) to receive either bictegravir, emtricitabine, and tenofovir alafenamide (integrase inhibitor group) or darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (boosted protease inhibitor group) for 48 weeks. Randomisation was computer generated in permuted blocks within strata with block sizes of four and stratified by country and baseline CD4 cell count. The primary composite outcome (time to first occurrence of specified virological or clinical events) and its components were evaluated by Kaplan-Meier and Cox regression analyses in both modified intention-to-treat (mITT) and per-protocol populations. The mITT population included all randomly allocated participants who received at least one dose of the study drug, whereas the per-protocol population excluded those who received incorrect treatment. Non-inferiority of the integrase inhibitor-based regimen versus the boosted protease inhibitor-containing regimen was declared if the upper limit of the 95% CI of the hazard ratio (HR) for the primary composite endpoint was less than 1·606, corresponding to a 12% difference in the cumulative probability of the composite primary endpoint. Adverse events, a secondary endpoint, were recorded at eight visits in all participants. This trial is registered with ClinicalTrials.gov, NCT03696160, and is completed.FindingsBetween May 13, 2019, and June 26, 2023, 222 people were randomly assigned to the integrase inhibitor group and 225 to the boosted protease inhibitor group. Of these 447 recruited participants, 442 (99%) participants with a median CD4 count of 41 cells per μL (IQR 17-79) received at least one dose. 358 (81%) of the 442 treated participants self-reported as male and 84 (19%) female, and 276 (62%) were of White ethnicity, 83 (19%) Black, and 83 (19%) other. In the mITT analysis, the 48-week composite primary outcome event occurred in 49 (22%) of 220 participants in the integrase inhibitor group versus 70 (32%) of 222 participants in the boosted protease inhibitor group (adjusted HR 0·70 [95% CI 0·48-1·00]; non-inferiority shown). The per-protocol analysis gave a similar estimated adjusted HR of 0·69 (0·48-1·00; non-inferiority shown). By mITT, drug-related adverse events (grade ≥2) occurred in 16 (7%) of 220 participants in the integrase inhibitor group versus 32 (14%) of 222 in the boosted protease inhibitor group (p=0·043). The rates of serious adverse events or adverse events leading to study discontinuation did not differ between groups. 12 deaths occurred during the study (nine in the integrase inhibitor group and three in the boosted protease inhibitor group), not related to the study drugs.InterpretationIn people with advanced HIV disease, bictegravir, emtricitabine, and tenofovir alafenamide was shown to be non-inferior to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide and resulted in fewer adverse events, supporting its use as a preferred first-line antiretroviral regimen in this vulnerable population.FundingGilead Sciences and Janssen Pharmaceuticals.

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A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2′,3′-dideoxy-5-fluoro-3′-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naïve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05–0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naïve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.

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