Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial (original) (raw)
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AIDS (London, England), 2016
The PIVOT trial found that protease inhibitor (PI) monotherapy as a simplification strategy is safe in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load (VL).We sought to identifyfactors associated with the risk of VL rebound in this trial. PIVOT was a randomized controlled trial in HIV-positive adults with suppressed VL for ≥24 weeks on combination therapycomparing a strategy of physician-selected ritonavir-boosted PI monotherapy versus ongoing triple therapy.In participants receiving monotherapy, we analysed time to confirmed VL rebound and its predictors using flexible parametric survival models. Of 290 participants initiatingPI monotherapy(80%darunavir, 14%lopinavir, 6% other),93 developed VL rebound on monotherapy. The risk of VL rebound peaked at 9 monthsafter starting monotherapy, and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of VL rebound were duration of VL suppressio...
Health technology assessment (Winchester, England), 2016
Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. Open-label, parallel-group, randomised controlled trial. Forty-three HIV clinical centres in the UK NHS. HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months. Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-m...
PloS one, 2017
The primary objective of this study was to estimate the incidence of treatment failure (TF) to protease inhibitor monotherapies (PI/r-MT) with lopinavir/ritonavir (LPV/r) or darunavir/ritonavir (DRV/r). A multicenter cohort of HIV-infected patients with viral load (VL) ≤50 copies/mL, who underwent a switch from any triple combination therapy to PI/r-MT with either LPV/r or DRV/r. VL was assessed in each center according to local procedures. Residual viremia was defined by any HIV-RNA value detectable below 50 copies/mL by a Real-Time PCR method. Standard survival analysis was used to estimate the rate of TF (defined by virological failure or interruption of monotherapy or reintroduction of combination therapy). A multivariable Cox regression analysis with automatic stepwise procedures was used to identify factors independently associated with TF among nadir and baseline CD4+ counts, residual viremia, time spent with <50 HIV-RNA copies/mL before switch, history of virological fail...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2016
In individuals with viral load (VL) suppression on a boosted protease inhibitor (PI) regimen, a switch to raltegravir (RAL) can be an option in case of comorbidities, but the SWITCHMRK trials challenged this strategy. Here, among individuals with VL suppression on a boosted PI, we compared outcomes between those who continued on the same regimen and those who switched to RAL. In this cohort study from the French Hospital Database on HIV, each individual who switched to RAL was matched with up to 3 individuals who continued PI, were being followed up during the calendar period of the switch, and had the same duration of VL suppression (both ±6 months). The primary endpoint was a composite endpoint of hospitalization, or AIDS event or death, and secondary endpoints the immunovirologic responses. To control for measured confounders, the inverse probability treatment weighting (IPTW) method was applied to estimate hazards ratios between the 2 groups. We matched 282 RAL switchers with...
Journal of Medical Virology, 2010
Table 1a. Multivariable Cox regression analysis: predictors of virological failure beginning from month 6 after treatment initiation (n=548). HIV-RNA measured at or after 6 months >50 copies/ml >500 copies/ml factor RH 95% CI p-value RH 95% CI p-value year of birth (per 1-year increase) 0.994 (0.958-1.03) 0.725 1.024 (0.983-1.066) 0.264 male vs. female 0.649 (0.298-1.415) 0.277 0.575 (0.248-1.336) 0.198 gender unknown vs. female 1.041 (0.128-8.463) 0.970 1.374 (0.17-11.079) 0.765 homo/bisexual vs. heterosexual 1.264 (0.524-3.046) 0.602 1.368 (0.53-3.534) 0.517 intravenous drug user vs. heterosexual 0.512 (0.105-2.498) 0.408 1.519 (0.432-5.346) 0.515 mode of HIV transmission other/unknown vs. heterosexual 1.236 (0.558-2.737) 0.602 1.156 (0.477-2.802) 0.748 calendar year of HAART initiation (per more recent) 0.919 (0.719-1.174) 0.497 0.978 (0.733-1.304) 0.878 abacavir+lamivudine vs. tenofovir+emtricitabine 0.362 (0.079-1.65) 0.189 0.197 (0.025-1.533) 0.121 zidovudine+lamivudine vs. tenofovir+emtricitabine 1.142 (0.47-2.773) 0.769 0.991 (0.375-2.619) 0.986 other backbone vs. tenofovir+emtricitabine 1.592 (0.403-6.299) 0.507 1.936 (0.402-9.323) 0.410 backbone HAART tenofovir+lamivudine vs. tenofovir+emtricitabine 0.275 (0.056-1.361) 0.114 0.754 (0.206-2.767) 0.671 baseline CD4+ cell count cells/mm3 (per log higher) 0.844 (0.656-1.087) 0.190 0.892 (0.679-1.173) 0.414 baseline HIV-RNA load cp/ml (per log10 higher) 0.844 (0.529-1.348) 0.479 1.790 (1.097-2.921) 0.020 lopinavir GRS (per 10 points higher) 0.975 (0.912-1.042) 0.450 0.945 (0.89-1.003) 0.064 backbone GRS (per 10 points higher) 1.002 (0.979-1.026) 0.849 1.038 (1.017-1.06) 0.0003 Table 1b. Multivariable Cox regression analysis: predictors of virological failure beginning from month 3 after treatment initiation (n=548). HIV-RNA measured at or after 3 months >50 copies/ml >500 copies/ml Factor RH 95% CI p-value RH 95% CI p-value year of birth (per 1 year increase) 1.018 (0.991-1.045) 0.2012 1.032 (1.002-1.063) 0.0365 male vs. female 1.233 (0.679-2.239) 0.4915 0.918 (0.504-1.67) 0.7784 gender unknown vs. female 1.497 (0.339-6.605) 0.5941 0.468 (0.06-3.63) 0.4677 homo/bisexual vs. heterosexual 0.875 (0.468-1.634) 0.6751 0.827 (0.407-1.678) 0.5984 intravenous drug user vs. heterosexual 0.202 (0.046-0.892) 0.0348 1.065 (0.433-2.621) 0.8909 mode of HIV transmission other/unknown vs. heterosexual 0.935 (0.517-1.69) 0.8228 1.223 (0.673-2.225) 0.5091 calendar year of HAART initiation (per more recent) 0.974 (0.805-1.178) 0.7859 1.101 (0.903-1.343) 0.3402 abacavir+lamivudine vs. tenofovir+emtricitabine 0.255 (0.077-0.849) 0.0259 0.111 (0.015-0.824) 0.0316 zidovudine+lamivudine vs. tenofovir+emtricitabine 0.895 (0.467-1.716) 0.7386 1.138 (0.585-2.212) 0.7041 other backbone vs. tenofovir+emtricitabine 1.546 (0.505-4.737) 0.4457 2.015 (0.646-6.291) 0.2275 backbone HAART tenofovir+lamivudine vs. tenofovir+emtricitabine 0.897 (0.397-2.029) 0.7948 1.199 (0.485-2.967) 0.6938 baseline CD4+ cell count cells/mm3 (per log higher) 0.875 (0.732-1.047) 0.145 0.967 (0.795-1.176) 0.7382 baseline HIV-RNA load cp/ml (per log10 higher) 1.127 (0.799-1.589) 0.4968 1.901 (1.312-2.754) 0.0007 lopinavir GRS (per 10 points higher) 0.997 (0.958-1.039) 0.9007 0.999 (0.966-1.032) 0.9361 backbone GRS (per 10 points higher) 1.001 (0.983-1.02) 0.8793 1.021 (1.005-1.037) 0.0101 RH = relative hazard; HAART = highly active antiretroviral therapy; GRS = Stanford's 6.0.1 genotypic resistance score
PLoS ONE, 2011
Background: The unparalleled success of combination antiretroviral therapy (cART) is based on the combination of three drugs from two classes. There is insufficient evidence whether simplification to ritonavir boosted protease inhibitor (PI/r) monotherapy in virologically suppressed HIV-infected patients is effective and safe to reduce cART side effects and costs. Methods: We systematically searched Medline, Embase, the Cochrane Library, conference proceedings and trial registries to identify all randomised controlled trials comparing PI/r monotherapy to cART in suppressed patients. We calculated in an intention to treat (loss-of follow-up, discontinuation of assigned drugs equals failure) and per-protocol analysis (exclusion of protocol violators following randomisation) and based on three different definitions for virological failure pooled risk ratios for remaining virologically suppressed. Findings: We identified 10 trials comparing 3 different PIs with cART based on a PI/r plus 2 reverse transcriptase inhibitors in 1189 patients. With the most conservative approach (viral load ,50 copies/ml on two consecutive measurements), the risk ratios for viral suppression at 48 weeks of PI/r monotherapy compared to cART were in the ITT analysis 0.94 8 (95% CI 0.89 to 1.00) p = 0.06; risk difference 20.06 (95%CI-0.11 to 0) p = 0.05, p for heterogeneity = 0.08, I 2 = 43.1%) and in the PP analysis 0.93 ((95%CI 0.90 to 0.97) p,0.001; risk difference 20.07 (95%CI 20.10 to 20.03) p,0.001, p for heterogeneity = 0.44, I 2 = 0%). Reintroduction of cART in 44 patients with virological failure led in 93% to de-novo viral suppression. Interpretation: Virologically well suppressed HIV-infected patients have a lower chance to maintain viral suppression when switching from cART to PI/r monotherapy. Failing patients achieve high rates of de-novo viral suppression following reintroduction of reverse transcriptase inhibitors.
Antiviral therapy, 2005
To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r). Design: Open-label, prospective, randomized (1:1), international multi-centre trial. Methods: Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks. Results: Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P=0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation=failure), 40/161 (25%) LPV/rtreated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment (P=0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (30%) in the SAQ/r-treated group (ITT/e; P=0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients' choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms (P=0.27, log rank test). Conclusion: LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients' preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.
HIV Medicine, 2018
ObjectivesThe aim of the study was to evaluate the long‐term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)‐, darunavir/ritonavir (DRV/r)‐, and lopinavir/ritonavir (LPV/r)‐containing regimens.MethodsData were analysed for 5678 EuroSIDA‐enrolled patients starting a DRV/r‐, ATZ/r‐ or LPV/r‐containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART‐naïve subjects (8%) at ritonavir‐boosted protease inhibitor (PI/r) initiation; (2) ART‐experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV‐1 RNA copies/mL; and (3) ART‐experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r‐based regimen. The main analysis was pe...