RESUMEN
INTRODUCTION: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart. METHODS: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re-suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI-only groups. Random-effects proportional meta-analysis and multivariable Cox proportional hazards analysis were performed using R. RESULTS: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI-only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow-up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40-0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46-0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89-0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59-0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16-2.59). DISCUSSION: When designing studies involving ATIs, information on time to viral re-suppression after restarting ART is important to share with participants, and should be regularly monitored and reported, to assess the impact and safety of specific trial interventions in ATI studies. CONCLUSIONS: The majority of participants achieved viral suppression after restarting ART in ATI studies. ART regimens containing integrase inhibitors and frequent VL monitoring should be offered for people restarting ART after ATI studies to ensure rapid re-suppression.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Carga Viral , Humanos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Factores de Tiempo , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Privación de TratamientoRESUMEN
BACKGROUND: Effectiveness of HIV postexposure prophylaxis (PEPSE) correlates with speed of uptake following HIV exposure. Time to first dose has not improved in the UK for over 10 years. On-demand pre-exposure prophylaxis (PrEP) has shown that people can self-start medication for HIV prevention.We hypothesised that advanced provision of PEPSE (HOME PEPSE) for men who have sex with men (MSM) to self- initiate would reduce time to first dose following HIV exposure. METHODS: Phase IV, randomised, prospective, 48-week, open-label study was carried out. MSM at medium risk of acquiring HIV were randomised (1:1) to immediate or deferred standard of care (SOC) HOME PEPSE. Every 12 weeks, participants self-completed mental health/risk behaviour surveys and had HIV/sexually transmitted infection (STI) testing.HOME PEPSE comprised a 5-day pack of emtricitabine/tenofovir disoproxil fumarate/maraviroc 600 mg once daily initiated following potential exposure to HIV. If taken, participants completed a risk survey; PEPSE continuation was physician directed. Primary outcome was time from potential exposure to HIV to first PEPSE dose. FINDINGS: 139 participants randomised 1:1; 69 to immediate HOME PEPSE and 70 to deferred HOME PEPSE. Median age 30 years (IQR 26-39), 75% white, 55% UK born and 72% university educated. 31 in HOME PEPSE and 15 in SOC arm initiated PEPSE. Uptake of HOME PEPSE was appropriate in 27/31 cases (87%, 95% CI: 71% to 95%). Median time from exposure to first dose was 7.3 hours (3.0, 20.9) for HOME PEPSE and 28.5 hours (17.3, 34.0) for SOC (p<0.01). HOME PEPSE was well tolerated with no discontinuations.No significant differences in missed opportunities for PEPSE uptake, sexual behaviour or bacterial STI infections between treatment arms. INTERPRETATION: HOME PEPSE reduced the time from exposure to first-dose PEPSE by 21+ hours, with no impact on safety. This significantly improves the efficacy of PEPSE and provides an option for people declining PrEP.
RESUMEN
BACKGROUND: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. METHODS: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. DISCUSSION: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. TRIAL REGISTRATION: The protocol is registered on Clinical. TRIALS: gov and EudraCT and has approval from UK Ethics and MHRA.
Asunto(s)
COVID-19 , Infecciones por VIH , VIH-1 , Anticuerpos ampliamente neutralizantes , Ensayos Clínicos Fase II como Asunto , Participación de la Comunidad , Anticuerpos Anti-VIH , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Humanos , Estudios Prospectivos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND: The contribution of HIV to COVID-19 outcomes in hospitalized inpatients remains unclear. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV status. METHODS: HIV-negative patients were matched to people living with HIV (PLWH) admitted from 1 February 2020 to 31 May 2020 up to a 3:1 ratio by the following: hospital site, SARS-CoV-2 test date ± 7 days, age ± 5 years, gender, and index of multiple deprivation decile ± 1. The primary objective was clinical improvement (two-point improvement or better on a seven-point ordinal scale) or hospital discharge by day 28, whichever was earlier. RESULTS: A total of 68 PLWH and 181 HIV-negative comparators were included. In unadjusted analyses, PLWH had a reduced hazard of achieving clinical improvement or discharge [adjusted hazard ratio (aHR) = 0.57, 95% confidence interval (CI): 0.39-0.85, p = 0.005], but this association was ameliorated (aHR = 0.70, 95% CI: 0.43-1.17, p = 0.18) after additional adjustment for ethnicity, frailty, baseline hypoxaemia, duration of symptoms prior to baseline, body mass index (BMI) categories and comorbidities. Baseline frailty (aHR = 0.79, 95% CI: 0.65-0.95, p = 0.011), malignancy (aHR = 0.37, 95% CI 0.17, 0.82, p = 0.014) remained associated with poorer outcomes. The PLWH were more likely to be of black, Asian and minority ethnic background (75.0% vs 48.6%, p = 0.0002), higher median clinical frailty score [3 × interquartile range (IQR): 2-5 vs, 2 × IQR: 1-4, p = 0.0069), and to have a non-significantly higher proportion of active malignancy (14.4% vs 9.9%, p = 0.29). CONCLUSIONS: Adjusting for confounding comorbidities and demographics in a matched cohort ameliorated differences in outcomes of PLWH hospitalized with COVID-19, highlighting the importance of an appropriate comparison group when assessing outcomes of PLWH hospitalized with COVID-19.
Asunto(s)
COVID-19 , Infecciones por VIH , COVID-19/epidemiología , COVID-19/terapia , Inglaterra/epidemiología , Femenino , Infecciones por VIH/epidemiología , Hospitalización , Humanos , Masculino , Pandemias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Late HIV diagnosis is associated with significant mortality in people living with HIV (PLWH) and high numbers of missed opportunities (MO) for earlier testing have been identified. A pilot of a national late diagnosis review process (LDRP) was undertaken in 15 HIV services evaluating the feasibility of LDRP implementation, as a patient safety initiative. All newly diagnosed PLWH with CD4 counts <200 cells/mm3 were included, and healthcare episodes within 5 years of presentation reviewed. Of 127 patients identified, 40 (31.5%) had MO and were more often white, UK-born and suffered more serious harm around diagnosis. Of these, four were designated serious incidents (undergoing root cause analysis) and eight were serious learning events. Engagement with services where MO occurred was challenging, however 75% of services found the LDRP sustainable. Widespread implementation of the LDRP should enable progress with training and policy changes within external services, enabling earlier HIV diagnosis and preventing deaths.
Asunto(s)
Diagnóstico Tardío , Infecciones por VIH , Inglaterra/epidemiología , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Gales/epidemiologíaAsunto(s)
Fármacos Anti-VIH/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Infecciones por VIH/tratamiento farmacológico , Rilpivirina/efectos adversos , Adulto , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Fármacos Anti-VIH/uso terapéutico , Bilirrubina/sangre , Bilirrubina/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Humanos , Masculino , Rilpivirina/uso terapéuticoRESUMEN
Hepatitis A is a self-limiting infection caused by the hepatitis A virus (HAV), transmitted predominantly by the faecal-oral route including some sexual practices. Outbreaks are commonly reported in the men who have sex with men (population. Previous exposure is thought to provide life-long immunity against subsequent infections with the development of an HAV IgG response. This paper reports a case of acute Hepatitis A infection, despite evidence of a previously positive Hepatitis A IgG results in an HIV-positive individual.