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1.
Viruses ; 15(5)2023 05 08.
Article in English | MEDLINE | ID: covidwho-20235357

ABSTRACT

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 (p > 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%, p = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, p = 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.


Subject(s)
Acquired Immunodeficiency Syndrome , Anti-HIV Agents , HIV Infections , Male , Humans , Adult , Female , Darunavir/therapeutic use , HIV Infections/drug therapy , Acquired Immunodeficiency Syndrome/drug therapy , Heterocyclic Compounds, 3-Ring/adverse effects , RNA , Anti-HIV Agents/adverse effects , Viral Load
2.
AIDS Res Hum Retroviruses ; 39(4): 204-210, 2023 04.
Article in English | MEDLINE | ID: covidwho-2212672

ABSTRACT

Menopause is a high-risk period for osteoporosis, which may be exacerbated by HIV and/or antiretroviral therapy (ART). Our goal was to study the impact of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on bone mineral density (BMD) in peri- and early postmenopausal women living with HIV. This is a randomized international multicenter study of an early versus delayed (48-week) switch. BMD was measured by dual energy X-ray absorptiometry scan. Thirty-four women were enrolled: 19 in the immediate and 15 in the delayed switch arm from September 2017 to April 2019; 30 completed the 96-week protocol. The study closed for futility during the COVID-19 pandemic. The median (intraquartile range [IQR]) age was 51 years (47, 53), with a median (IQR) of 16.5 years (14, 23) since HIV diagnosis, median (IQR) 14 years (11, 20) of ART, and mean 8.6 years TDF. At enrollment, TDF was used in combination with a boosted protease inhibitor (n = 7), a non-nucleoside reverse transcriptase inhibitor (n = 13), an integrase inhibitor (n = 11), or more than one ART class (n = 3). The median (95% confidence interval [CI]) percentage change in BMD at the lumbar spine from 0 to 48 weeks in the immediate switch group was 1.97% (-1.15 to 5.49) compared with a median (95% CI) decrease of 2.32% (-5.11 to 0.19) in the delayed arm. The median (95% CI) percentage change in BMD from 0 to 96 weeks was 2.33% (0-4.51) in the immediate arm compared with 0.70% (-3.19 to 2.47) in the delayed arm. We demonstrated a trend to increased BMD at the lumbar spine after a switch from TDF to TAF in peri- and early postmenopausal women living with HIV. Clinical Trials.gov: NCT02815566.


Subject(s)
Anti-HIV Agents , COVID-19 , HIV Infections , Humans , Female , Middle Aged , HIV Infections/complications , HIV Infections/drug therapy , Bone Density , Anti-HIV Agents/adverse effects , Tenofovir/adverse effects , Pandemics , Perimenopause , Adenine/pharmacology , Aging
4.
PLoS One ; 17(11): e0277606, 2022.
Article in English | MEDLINE | ID: covidwho-2140654

ABSTRACT

BACKGROUND: The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, information in real-life cohorts is relatively scarce for first-line use. METHODS: A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL. RESULTS: 135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure [M = F]) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic. CONCLUSIONS: In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness.


Subject(s)
Anti-HIV Agents , COVID-19 , HIV Infections , HIV-1 , Adult , Humans , Lamivudine/pharmacology , Anti-HIV Agents/adverse effects , Pandemics , HIV-1/genetics , Anti-Retroviral Agents/therapeutic use
5.
Nature ; 606(7913): 375-381, 2022 06.
Article in English | MEDLINE | ID: covidwho-1890198

ABSTRACT

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.


Subject(s)
Anti-HIV Agents , Antibodies, Neutralizing , HIV Antibodies , HIV Infections , HIV-1 , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Anti-HIV Agents/immunology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Broadly Neutralizing Antibodies/administration & dosage , Broadly Neutralizing Antibodies/adverse effects , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , Double-Blind Method , HIV Antibodies/administration & dosage , HIV Antibodies/adverse effects , HIV Antibodies/immunology , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/virology , HIV-1/drug effects , HIV-1/immunology , HIV-1/isolation & purification , Humans , Viral Load/drug effects , Viremia/drug therapy , Viremia/immunology , Viremia/virology
6.
Br J Clin Pharmacol ; 88(3): 942-964, 2022 03.
Article in English | MEDLINE | ID: covidwho-1701553

ABSTRACT

AIMS: In 2018, 1.07 million pregnant women received antiretroviral drugs, raising whether this affects pregnancy outcomes. We assessed the adverse pregnancy outcomes associated with prenatal antiretroviral drug exposure, notified to the French ANRS pharmacovigilance system. METHODS: An exhaustive case report series has been performed using the ANRS pharmacovigilance database. All ANRS-sponsored HIV clinical research studies using antiretroviral drugs either in pregnant women or women of childbearing age were eligible from 2004 to 2019. We analysed the following pregnancy outcomes: abortion, ectopic pregnancy, stillbirth, prematurity (<37 weeks of gestational age), low birth weight (<2500 g) and congenital abnormalities. A logistic regression was performed to assess the odds ratio (OR) for each outcome separately (if occurrence >50) compared to the outcome observed when exposed to non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based regimen as the reference. RESULTS: Among the 34 studies selected, 918 deliveries occurred, of whom 88% had pregnancy outcomes documented. Pregnant women were mainly exposed to PI (n = 387, 48.6%), NNRTI (n = 331, 41.5%) and INI-based combinations (n = 40, 5.0%, 18 on dolutegravir). Compared to NNRTI-based combinations, there was no significant association observed with exposure to other antiretroviral combination for spontaneous abortion, prematurity or low birth weight, except an increased risk of low birth weight in new-born exposed to exclusive nucleoside-reverse-transcriptase-inhibitor (NRTI) combinations (n = 4; OR 7.50 [1.49-37.83]). CONCLUSIONS: Our study, mainly based on protease inhibitor (PI) and NNRTI-based regimens, is overall reassuring on the risk of adverse pregnancy outcomes, except for NRTI which should be interpreted cautiously (small number, indication bias). In this study, the number of integrase inhibitor (INI)-based combinations was too low to draw any conclusions.


Subject(s)
Anti-HIV Agents , HIV Infections , HIV Integrase Inhibitors , Anti-HIV Agents/adverse effects , DNA-Directed RNA Polymerases/therapeutic use , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Pharmacovigilance , Pregnancy , Pregnancy Outcome/epidemiology , Reverse Transcriptase Inhibitors/adverse effects
8.
Lancet HIV ; 8(11): e723-e728, 2021 11.
Article in English | MEDLINE | ID: covidwho-1373322

ABSTRACT

Two multinational clinical trials have shown safety and efficacy of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis (PrEP). These results will alter the landscape of HIV prevention and related research. Nevertheless, designing and conducting this research involved several ethical issues. This Viewpoint describes how we managed ethical issues over the duration of one of these trials (HPTN 083). Specifically, we discuss the rationale for pursuing a long-acting injectable agent in the presence of effective oral PrEP, trial design choices, site selection and local standards of prevention, data monitoring and early stopping, effects of the COVID-19 pandemic, post-trial access, and assessment of long-term safety.


Subject(s)
Anti-HIV Agents/administration & dosage , COVID-19 , HIV Infections/prevention & control , Pre-Exposure Prophylaxis/ethics , Anti-HIV Agents/adverse effects , Health Services Accessibility , Humans , Pandemics , Pre-Exposure Prophylaxis/methods , SARS-CoV-2
9.
AIDS Res Hum Retroviruses ; 37(4): 283-291, 2021 04.
Article in English | MEDLINE | ID: covidwho-1207222

ABSTRACT

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.


Subject(s)
Anti-HIV Agents/therapeutic use , COVID-19 Drug Treatment , Cobicistat/therapeutic use , Darunavir/therapeutic use , Adult , Anti-HIV Agents/adverse effects , COVID-19/mortality , COVID-19/virology , Cobicistat/adverse effects , Darunavir/adverse effects , Drug Combinations , Female , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/isolation & purification
10.
Contemp Clin Trials ; 105: 106402, 2021 06.
Article in English | MEDLINE | ID: covidwho-1188374

ABSTRACT

Post-natal HIV infection through breastfeeding remains a challenge in many low and middle-income countries, particularly due to non-availability of alternative infant feeding options and the suboptimal Prevention of Mother to Child Transmission of HIV-1 (PMTCT) cascade implementation and monitoring. The PROMISE-EPI study aims to address the latter by identifying HIV infected mothers during an almost never-missed visit for their infant, the second extended program on immunization visit at 6-8 weeks of age (EPI-2). The study is divided into 3 components inclusive of an open-label randomized controlled trial aiming to assess the efficacy of a responsive preventive intervention compared to routine intervention based on the national PMTCT guidelines for HIV-1 uninfected exposed breastfeeding infants. The preventive intervention includes: a) Point of care testing for early infant HIV diagnosis and maternal viral load; b) infant, single-drug Pre-Exposure Prophylaxis (PrEP) (lamivudine) if mothers are virally unsuppressed. The primary outcome is HIV-transmission rate from EPI-2 to 12 months. The study targets to screen 37,000 mother/infant pairs in Zambia and Burkina Faso to identify 2000 mother/infant pairs for the clinical trial. The study design and challenges faced during study implementation are described, including the COVID-19 pandemic and the amended HIV guidelines in Zambia in 2020 (triple-drug PrEP in HIV exposed infants guided by quarterly maternal viral load). The changes in the Zambian guidelines raised several questions including the equipoise of PrEP options, the standard of care-triple-drug (control arm in Zambia) versus the study-single-drug (intervention arm). Trial registration number (www.clinicaltrials.gov): NCT03869944. Submission category: Study Design, Statistical Design, Study Protocols.


Subject(s)
Anti-HIV Agents/therapeutic use , Breast Feeding , HIV Infections/drug therapy , HIV Infections/transmission , Infectious Disease Transmission, Vertical/prevention & control , Lamivudine/therapeutic use , Adolescent , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Burkina Faso , COVID-19/epidemiology , Cross-Sectional Studies , Female , HIV Infections/diagnosis , Humans , Infant , Lamivudine/administration & dosage , Lamivudine/adverse effects , Pandemics , Pre-Exposure Prophylaxis/methods , Research Design , SARS-CoV-2 , Viral Load , Young Adult , Zambia
11.
Yonsei Med J ; 61(9): 826-830, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-745127

ABSTRACT

We retrospectively reviewed patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who were admitted to an intensive care unit in Daegu, South Korea. The outcomes of patients who did (cases) or did not (controls) receive darunavir-cobicistat (800-150 mg) therapy were compared. Fourteen patients received darunavir-cobicistat treatment, and 96 received other antiviral therapy (controls). Overall, the darunavir-cobicistat group comprised patients with milder illness, and the crude mortality rate of all patients in the darunavir-cobicistat group was lower than that in the controls [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.04-0.89, p=0.035]. After 1:2 propensity-score matching, there were 14 patients in the darunavir-cobicistat group, and 28 patients in the controls. In propensity score-matched analysis, the darunavir-cobicistat group had lower mortality than the controls (OR 0.07, 95% CI 0.01-0.52, p=0.009). In conclusion, darunavir-cobicistat therapy was found to be associated with a significant survival benefit in critically ill patients with SARS-CoV-2 infection.


Subject(s)
Anti-HIV Agents/therapeutic use , Cobicistat/therapeutic use , Coronavirus Infections/drug therapy , Darunavir/therapeutic use , HIV Protease Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Betacoronavirus , COVID-19 , Case-Control Studies , Cobicistat/administration & dosage , Cobicistat/adverse effects , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Critical Illness , Darunavir/administration & dosage , Darunavir/adverse effects , Female , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Republic of Korea/epidemiology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
12.
Transpl Infect Dis ; 22(5): e13351, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-539680

ABSTRACT

Coronavirus disease 2019 (COVID-19), mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with flu-like illness and severe pneumonia with acute respiratory distress syndrome (ARDS). Immunocompromised patients merit particular attention as altered host immunity may influence both disease severity and duration of viral shedding as is described with several other ribonucleic acid respiratory viruses. Yet immunocompromised status alone, in the absence of other comorbidities, may not necessarily predict severe illness presentations and poorer clinical outcomes as indicated by recent reports of COVID-19-infected solid organ transplant recipients and people living with human immunodeficiency virus (HIV). Such patients may even be spared the robust inflammatory response that precipitates ARDS associated with COVID-19, complicating the management of iatrogenic immunosuppression in this setting. We present a case of an orthotopic liver transplant recipient with well-controlled HIV who successfully recovered from a mild, flu-like illness attributed to SARS-CoV-2.


Subject(s)
Anti-HIV Agents/adverse effects , COVID-19/diagnosis , HIV Infections/drug therapy , Liver Transplantation/adverse effects , SARS-CoV-2/immunology , Adult , Anti-HIV Agents/administration & dosage , COVID-19/immunology , COVID-19/virology , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/surgery , Dose-Response Relationship, Drug , Drug Therapy, Combination/methods , Graft Rejection/immunology , Graft Rejection/prevention & control , HIV Infections/immunology , Humans , Hydroxychloroquine/administration & dosage , Immunocompromised Host , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Prednisone/administration & dosage , SARS-CoV-2/isolation & purification , Treatment Outcome , COVID-19 Drug Treatment
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