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The New England Journal of Medicine Oct 2023Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy.
METHODS
We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization.
RESULTS
A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52).
CONCLUSIONS
Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).
Topics: Adult; Humans; Dexamethasone; Double-Blind Method; Glucocorticoids; HIV; HIV Infections; HIV Seropositivity; Tuberculosis, Meningeal; Antitubercular Agents; Drug Therapy, Combination; Anti-Retroviral Agents
PubMed: 37819954
DOI: 10.1056/NEJMoa2216218 -
Safety and Efficacy of Long-Acting Injectable Agents for HIV-1: Systematic Review and Meta-Analysis.JMIR Public Health and Surveillance Jul 2023HIV-1 infection continues to affect global health. Although antiretrovirals can reduce the viral load or prevent HIV-1 infection, current drugs require daily oral use... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
HIV-1 infection continues to affect global health. Although antiretrovirals can reduce the viral load or prevent HIV-1 infection, current drugs require daily oral use with a high adherence level. Long-acting antiretrovirals (LA-ARVs) significantly improve medication adherence and are essential for HIV-1 prophylaxis and therapy.
OBJECTIVE
This study aimed to investigate the safety and efficacy of long-acting cabotegravir (CAB-LA) and long-acting rilpivirine (RPV-LA) in the prevention and treatment of HIV-1 infection.
METHODS
PubMed, Embase, and the Cochrane Library were searched for studies from database inception to November 12, 2022. We included studies that reported efficacy and safety data on LA-ARV intervention in people living with HIV and excluded reviews, animal studies, and articles with missing or duplicate data. Virological suppression was defined as plasma viral load <50 copies/mL 6 months after antiviral therapy initiation. We extracted outcomes for analysis and expressed dichotomous data as risk ratios (RRs) and continuous data as mean differences. Depending on the heterogeneity assessment, a fixed- or random-effects model was used for data synthesis. We performed subgroup analyses of the partial safety and efficacy outcomes of CAB-LA+RPV-LA. The protocol was registered with the Open Science Framework.
RESULTS
We included 12 trials comprising 10,957 individuals, of which 7 were prevention trials and 5 were treatment trials. CAB-LA and RPV-LA demonstrated safety profiles comparable with those of the placebo in terms of adverse event-related withdrawal. Moreover, the efficacy data showed that CAB-LA had a better effect on HIV-1 prevention than tenofovir disoproxil fumarate-emtricitabine (17/5161, 0.33% vs 75/5129, 1.46%; RR 0.21, 95% CI 0.07-0.61; I=70%). Although CAB-LA+RPV-LA had more drug-related adverse events (556/681, 81.6% vs 37/598, 6.2%; RR 12.50, 95% CI 3.98-39.23; I=85%), a mild or moderate injection site reaction was the most common reaction, and its frequency decreased over time. The efficacy of CAB-LA+RPV-LA was comparable with that of daily oral drugs at 48 and 96 weeks (1302/1424, 91.43% vs 915/993, 92.2%; RR 0.99, 95% CI 0.97-1.02; I=0%), and a high level of virological suppression of 80.9% (186/230) was maintained even after 5 years of LA-ARV use. Similar efficacy outcomes were observed in both treatment-naive and treatment-experienced patients (849/911, 93.2% vs 615/654, 94%; RR 0.99, 95% CI 0.96-1.02; I=0%). According to the questionnaires, more than 85% of people living with HIV favored LA-ARVs.
CONCLUSIONS
LA-ARVs showed favorable safety profiles for both the prevention and treatment of HIV-1 infection and were well tolerated. CAB-LA has more satisfactory efficacy than tenofovir disoproxil fumarate-emtricitabine, significantly reducing the rate of HIV-1 infection. CAB-LA+RPV-LA maintains virological suppression for a long time and may be a viable switching strategy with enhanced public health benefits by reducing transmission. However, further trials are required to confirm the efficacy of these drugs.
Topics: Humans; Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Tenofovir
PubMed: 37498645
DOI: 10.2196/46767 -
Annals of Internal Medicine Jul 2023Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting... (Observational Study)
Observational Study
BACKGROUND
Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables.
OBJECTIVE
To examine LA-ART in a population of PWH that includes those with viremia.
DESIGN
Observational cohort study.
SETTING
Urban academic safety-net HIV clinic.
PATIENTS
Publicly insured adults living with HIV with and without viral suppression, high rates of unstable housing, mental illness, and substance use.
INTERVENTION
Demonstration project of long-acting injectable CAB-RPV.
MEASUREMENTS
Descriptive statistics summarizing cohort outcomes to date, based on pharmacy team logs and electronic medical record data.
RESULTS
Between June 2021 and November 2022, 133 PWH at the Ward 86 HIV Clinic were started on LA-ART, 76 of whom had virologic suppression while using oral ART and 57 of whom had viremia. The median age was 46 years (IQR, 25 to 68 years); 117 (88%) were cisgender men, 83 (62%) had non-White race, 56 (42%) were experiencing unstable housing or homelessness, and 45 (34%) had substance use. Among those with virologic suppression, 100% (95% CI, 94% to 100%) maintained suppression. Among PWH with viremia, at a median of 33 days, 54 of 57 had viral suppression, 1 showed the expected 2-log reduction in HIV RNA level, and 2 experienced early virologic failure. Overall, 97.5% (CI, 89.1% to 99.8%) were projected to achieve virologic suppression by a median of 33 weeks. The current virologic failure rate of 1.5% in the cohort is similar to that across registrational clinical trials at 48 weeks.
LIMITATION
Single-site study.
CONCLUSION
This project demonstrates the ability of LA-ART to achieve virologic suppression among PWH, including those with viremia and challenges to adherence. Further data on the ability of LA-ART to achieve viral suppression in people with barriers to adherence are needed.
PRIMARY FUNDING SOURCE
National Institutes of Health, City and County of San Francisco, and Health Resources and Services Administration.
Topics: Adult; Male; Humans; Middle Aged; Anti-HIV Agents; Viremia; HIV Infections; Rilpivirine; Cohort Studies; Viral Load
PubMed: 37399555
DOI: 10.7326/M23-0788 -
Lancet (London, England) Aug 2023The risk of sexual transmission of HIV from individuals with low-level HIV viraemia receiving antiretroviral therapy (ART) has important public health implications,...
BACKGROUND
The risk of sexual transmission of HIV from individuals with low-level HIV viraemia receiving antiretroviral therapy (ART) has important public health implications, especially in resource-limited settings that use alternatives to plasma-based viral load testing. This Article summarises the evidence related to sexual transmission of HIV at varying HIV viral load levels to inform messaging for people living with HIV, their partners, their health-care providers, and the wider public.
METHODS
We conducted a systematic review and searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus, for work published from Jan 1, 2010 to Nov 17, 2022. Studies were included if they pertained to sexual transmission between serodiscordant couples at various levels of viraemia, the science behind undetectable=untransmittable, or the public health impact of low-level viraemia. Studies were excluded if they did not specify viral load thresholds or a definition for low-level viraemia or did not provide quantitative viral load information for transmission outcomes. Reviews, non-research letters, commentaries, and editorials were excluded. Risk of bias was evaluated using the ROBINS-I framework. Data were extracted and summarised with a focus on HIV sexual transmission at varying HIV viral loads.
FINDINGS
244 studies were identified and eight were included in the analysis, comprising 7762 serodiscordant couples across 25 countries. The certainty of evidence was moderate; the risk of bias was low. Three studies showed no HIV transmission when the partner living with HIV had a viral load less than 200 copies per mL. Across the remaining four prospective studies, there were 323 transmission events; none were in patients considered stably suppressed on ART. Among all studies there were two cases of transmission when the index patient's (ie, patient with previously diagnosed HIV infection) most recent viral load was less than 1000 copies per mL. However, interpretation of both cases was complicated by long intervals (ie, 50 days and 53 days) between the transmission date and the most recent index viral load result.
INTERPRETATION
There is almost zero risk of sexual transmission of HIV with viral loads of less than 1000 copies per mL. These data provide a powerful opportunity to destigmatise HIV and promote adherence to ART through dissemination of this positive public health message. These findings can also promote access to viral load testing in resource-limited settings for all people living with HIV by facilitating uptake of alternative sample types and technologies.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Humans; HIV Infections; Anti-HIV Agents; Prospective Studies; Viremia; Viral Load
PubMed: 37490935
DOI: 10.1016/S0140-6736(23)00877-2 -
Clinical Infectious Diseases : An... Sep 2023Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting... (Clinical Trial)
Clinical Trial
BACKGROUND
Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with human immunodeficiency virus using a target trial framework, which reduces the potential for confounding and selection bias.
METHODS
We included Swiss HIV Cohort Study participants who were ART-naïve after May 2008, when INSTIs became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights.
RESULTS
Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (interquartile range, 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increased risk for CVD events (adjusted hazard ratio, 0.80; 95% confidence interval [CI], .46-1.39). Adjusted risk differences between individuals who started INSTIs and those who started other ART were -0.17% (95% CI, -.37 to .19) after 1 year, -0.61% (-1.54 to 0.22) after 5 years, and -0.71% (-2.16 to 0.94) after 8 years.
CONCLUSIONS
In this target trial emulation, we found no difference in short- or long-term risk for CVD events between treatment-naïve people with human immunodeficiency virus who started INSTI-based ART and those on other ART.
Topics: Adult; Female; Humans; Male; Anti-HIV Agents; Cardiovascular Diseases; Cohort Studies; HIV; HIV Infections; HIV Integrase Inhibitors
PubMed: 37157869
DOI: 10.1093/cid/ciad286 -
Clinical Infectious Diseases : An... Sep 2023Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system.
METHODS
A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48.
RESULTS
Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10).
CONCLUSIONS
This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
Topics: Humans; Male; Middle Aged; Female; Antiretroviral Therapy, Highly Active; HIV-1; HIV Infections; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Viral Load
PubMed: 37183889
DOI: 10.1093/cid/ciad265 -
Einstein (Sao Paulo, Brazil) 2023The human immunodeficiency virus (HIV) pandemic remains an important issue. In 2020, approximately 37.7 million people were living with the disease and there were more... (Review)
Review Meta-Analysis
INTRODUCTION
The human immunodeficiency virus (HIV) pandemic remains an important issue. In 2020, approximately 37.7 million people were living with the disease and there were more than 680 thousand deaths due to complications linked to the disease. Despite these exorbitant numbers, the introduction of highly active antiretroviral therapy has marked a new era, changing the epidemiological profile of the infection and related pathologies, including neoplasms.
OBJECTIVE
We performed a literature review to assess the role of neoplasms in patients with HIV after the introduction of antiretroviral therapy.
METHODS
A literature review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, searching the MEDLINE, LILACS, and COCHRANE databases for articles published from 2010 onwards.
RESULTS
Using specific key terms, 1,341 articles were identified; two were duplicates, 107 were selected for full-text evaluation, and 20 were included in the meta-analysis. The selected studies included 2,605,869 patients. Fifteen of the 20 articles indicated a reduction in the global incidence of AIDS-defining neoplasms and 12 indicated an overall increase in non-AIDS-defining cancers after the introduction of antiretrovirals. This growth trend could be explained by a range of factors including the aging population with HIV, risky behaviors, and coinfection with oncogenic viruses.
CONCLUSIONS
There was a decreasing trend in the incidence of AIDS-defining neoplasms and increasing trend in non-AIDS-defining neoplasms. However, the carcinogenic effect of antiretrovirals could not be confirmed. In addition, studies focusing on the oncogenic role of HIV and screening for neoplasms in individuals with HIV are required.
Topics: Humans; Aged; HIV; Neoplasms; Aging; Anti-Retroviral Agents; HIV Infections
PubMed: 37341221
DOI: 10.31744/einstein_journal/2023RW0231 -
Clinical Infectious Diseases : An... Nov 2023Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA)...
Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure.
BACKGROUND
Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants.
METHODS
Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination).
RESULTS
Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses.
CONCLUSIONS
The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.
Topics: Humans; Rilpivirine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV Infections; Patient Selection; HIV-1; Anti-Retroviral Agents
PubMed: 37340869
DOI: 10.1093/cid/ciad370 -
The Journal of Clinical Investigation Sep 2023HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44...
HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.
Topics: Humans; HIV-1; Anti-Retroviral Agents; HIV Infections; Virus Replication; Proviruses; CD4-Positive T-Lymphocytes; Viral Load; Virus Latency
PubMed: 37463049
DOI: 10.1172/JCI171554 -
Current HIV/AIDS Reports Feb 2024Selection of antiretroviral therapy during pregnancy must consider maternal physiology and resulting pharmacokinetic changes in pregnancy, resistance and efficacy... (Review)
Review
PURPOSE OF REVIEW
Selection of antiretroviral therapy during pregnancy must consider maternal physiology and resulting pharmacokinetic changes in pregnancy, resistance and efficacy profiles, tolerability and frequency of adverse effects, teratogenicity, and maternal, neonatal, and pregnancy outcomes. The objective of this review is to summarize the underlying data that informs the current clinical perinatal guidelines in the USA.
RECENT FINDINGS
Data now supports the use of dolutegravir at all stages of pregnancy with no significant increase in neural tube defects. Safety and pharmacokinetic data on newer antiretroviral medications in pregnancy continue to lag behind the general population. While there are multiple safety and tolerability concerns with older regimens, there are now multiple options of regimens that are highly efficacious and have good safety data in pregnancy. Most pregnant patients who are virally suppressed on a well-tolerated regimen are able to safely continue those medications during pregnancy.
Topics: Pregnancy; Female; Infant, Newborn; Humans; HIV Infections; Pregnancy Complications, Infectious; Anti-Retroviral Agents; Anti-HIV Agents
PubMed: 38277098
DOI: 10.1007/s11904-024-00688-y