-
The Lancet. HIV Jun 2022WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial.
BACKGROUND
WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.
METHODS
In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
FINDINGS
Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.
INTERPRETATION
Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.
FUNDING
Janssen.
Topics: Anti-HIV Agents; Darunavir; Drug Therapy, Combination; HIV Infections; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Oxazines; Piperazines; Prospective Studies; Pyridones; RNA; Ritonavir; Tenofovir; Viral Load; Zidovudine
PubMed: 35460601
DOI: 10.1016/S2352-3018(22)00092-3 -
AIDS (London, England) Jul 2021To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.
OBJECTIVE
To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.
DESIGN
Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States.
METHODS
Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons.
RESULTS
A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited.
CONCLUSION
Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.
Topics: Anti-HIV Agents; Child; Cobicistat; Darunavir; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Placenta; Postpartum Period; Pregnancy; Prospective Studies
PubMed: 34076612
DOI: 10.1097/QAD.0000000000002857 -
The Journal of Infectious Diseases Feb 2020
Topics: Atazanavir Sulfate; Cardiovascular Diseases; Case-Control Studies; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Myocardial Infarction; Risk Factors
PubMed: 31828327
DOI: 10.1093/infdis/jiz482 -
The Journal of Antimicrobial... Jan 2021Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with... (Observational Study)
Observational Study
BACKGROUND
Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection.
OBJECTIVES
To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir.
METHODS
This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines.
RESULTS
Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration.
CONCLUSIONS
Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.
Topics: Antiviral Agents; COVID-19; Cohort Studies; Darunavir; Drug Therapy, Combination; Electrocardiography; France; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; SARS-CoV-2; Severity of Illness Index; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33221868
DOI: 10.1093/jac/dkaa441 -
Viruses May 2023Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients.
BACKGROUND
Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients.
METHODS
Retrospective multicenter study including AIDS- or late-presenting (def. CD4 ≤ 200/µL) HIV-infected patients starting dolutegravir or ritonavir/cobicistat-boosted darunavir+2NRTIs. Patients were followed from the date of first-line therapy initiation (baseline, BL) to the discontinuation of darunavir or dolutegravir, or for a maximum of 36 months of follow-up.
RESULTS
Overall 308 patients (79.2% males, median age 43 years, 40.3% AIDS-presenters, median CD4 66 cells/µL) were enrolled; 181 (58.8%) and 127 (41.2%) were treated with dolutegravir and darunavir, respectively. Incidence of treatment discontinuation (TD), virological failure (VF, defined as a single HIV-RNA > 1000 cp/mL or two consecutive HIV-RNA > 50 cp/mL after 6 months of therapy or after virological suppression had been achieved), treatment failure (the first of TD or VF), and optimal immunological recovery (defined as CD4 ≥ 500/µL + CD4 ≥ 30% + CD4/CD8 ≥ 1) were 21.9, 5.2, 25.6 and 1.4 per 100 person-years of follow-up, respectively, without significant differences between dolutegravir and darunavir ( > 0.05 for all outcomes). However, a higher estimated probability of TD for central nervous system (CNS) toxicity (at 36 months: 11.7% vs. 0%, = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, = 0.046).
CONCLUSIONS
Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir.
Topics: Male; Humans; Adult; Female; Darunavir; HIV Infections; Acquired Immunodeficiency Syndrome; Heterocyclic Compounds, 3-Ring; RNA; Anti-HIV Agents; Viral Load
PubMed: 37243208
DOI: 10.3390/v15051123 -
Antimicrobial Agents and Chemotherapy May 2017Treatment of HIV-infected patients coinfected with is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB)...
Treatment of HIV-infected patients coinfected with is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL in a concentration-dependent manner. Linear regression analysis showed that log RTV and log COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL, where β was equal to -234 (95% confidence interval [CI] = -275 to -193; < 0.0001) and -73 (95% CI = -89 to -57; < 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CL (half-maximal [50%] inhibitory concentration [IC] = 0.025 μM) than COBI (IC = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL, with RTV being more potent than COBI. These data provide the first experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and .
Topics: Antirheumatic Agents; Antitubercular Agents; Cells, Cultured; Cobicistat; Darunavir; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV-1; Hepatocytes; Humans; Metabolic Clearance Rate; Mycobacterium tuberculosis; Rifampin; Ritonavir; Tuberculosis, Pulmonary
PubMed: 28193650
DOI: 10.1128/AAC.01776-16 -
HIV/AIDS (Auckland, N.Z.) 2016Atazanavir/cobicistat (ATV/c) and darunavir/cobicistat (DRV/c) are newly approved once daily fixed-dose protease inhibitor combinations for the treatment of HIV-1... (Review)
Review
Atazanavir/cobicistat (ATV/c) and darunavir/cobicistat (DRV/c) are newly approved once daily fixed-dose protease inhibitor combinations for the treatment of HIV-1 infection. Studies in healthy volunteers have established bioequivalence between cobicistat and ritonavir as pharmacoenhancers of both atazanavir (ATV) and darunavir (DRV). In addition, two randomized clinical trials (one Phase II and one Phase III noninferiority trial with a 144-week followup period) demonstrated that cobicistat had sustainable and comparable efficacy and safety to ritonavir as a pharmacoenhancer of ATV through 144 weeks of treatment in HIV-1-infected patients. Furthermore, one Phase III, open-label, single-arm, clinical trial reflected virologic and immunologic responses and safety outcomes consistent with prior published data for DRV/ritonavir 800/100 mg once daily, supporting the use of DRV/c 800/150 mg once daily for future treatment of treatment-naïve and -experienced HIV-1-infected patients with no DRV resistance-associated mutations. Low rates of virologic failure secondary to resistance to antiretroviral regimens were present in these clinical studies. Most notable adverse events in the ATV studies were hyperbilirubinemia and in the DRV study rash. Small increases in serum creatinine and minimally reduced estimated glomerular filtration rate Cockcroft-Gault calculation (eGFRCG) were observed in ATV/c and DRV/c clinical studies consistent with other studies evaluating elvitegravir/cobicistat/tenofovir/emtricitabine for the treatment of HIV-1 infection. These renal parameter changes occurred acutely in the first few weeks and plateaued off for the remaining study periods and are not necessarily clinically relevant. Cobicistat has numerous advantages compared to ritonavir such as fewer drug-drug interactions, being devoid of anti-HIV-1 activity, as well as it has better solubility affording coformulation with other antiretrovirals as simplified fixed-dose combinations. Overall, the recent approval of ATV/c and DRV/c offers HIV patients opportunities for improved adherence to lifelong treatment. Future studies are warranted to determine the efficacy and safety of ATV/c and DRV/c in treatment-experienced patients.
PubMed: 27022304
DOI: 10.2147/HIV.S99063