Incidence of cardiometabolic diseases in a Lesotho HIV cohort : evidence for policy decision-making

BACKGROUND: Antiretroviral treatment (ART) has been associated with the development of certain cardiometabolic diseases (CMDs). The burden of CMDs amongst ART-experienced patients in sub-Saharan Africa was unknown. OBJECTIVE: We quantified the burden of CMDs and identified the associated risk factors in a large treatment cohort on ART at a high-volume facility in Lesotho. METHODS: In this retrospective cohort study, we extracted data from the daily dispensing electronic system and routine clinical records of 785 adults on ART between 2011 and 2015 in Maseru, Lesotho. CMD was defined as a diagnosis of hypertension, diabetes mellitus or dyslipidaemia (singly or collectively). Descriptive statistics were used to describe the disease burden; Kaplan–Meier curves and cause-specific Cox proportional hazards models were fitted to examine the impact of the ART regimen and identify the risk factors associated with the occurrence of CMD. RESULTS: Of the 785 participants, 473 (60%) were women. The median age of the group was 42 years, interquartile range (IQR), 36–51 years. The overall incidence of CMD was 5.6 (95% confidence interval [CI] = 4.4–7.1) per 100 person-months of follow-up. The median time to onset of CMD was 16.6 months (IQR = 7.4–23.4). ART was not associated with the occurrence of CMD (cause-specific hazard ratio [CHR] = 1.55; 95% CI = 0.14–16.85; P = 0.72). Higher body mass index (BMI) was associated with the occurrence of diabetes mellitus (CHR = 1.19; 95% CI = 1.14–1.38; P = 0.026). CONLCUSION: The incidence of CMD in this relatively young patient population is low yet noteworthy. We recommend that patients living with HIV and AIDS should be routinely screened for CMD. Higher BMI is generally associated with the occurrence of CMD.http://www.sajhivmed.org.za/index.php/hivmeddm2022School of Health Systems and Public Health (SHSPH

Clinical correlations to distinguish severe from milder forms of obstructive sleep apnoea syndrome using overnight oximetry for prioritising adenotonsillectomy in a limited-resource setting

BACKGROUND : In resource-poor settings with limited surgical services, it is essential to identify and prioritise children with severe and very severe obstructive sleep apnoea syndrome (OSAS) to expedite surgery. McGill's Oximetry Score (MOS) has been validated against polysomnography for OSAS and is affordable and easy to use. AIMS : The aim of this study was to assess the correlation of tonsillar size and clinical symptoms with MOS grade 3 or 4, to identify who requires overnight oximetry and who to prioritise for adenotonsillectomy. METHODS : Children with suspected OSAS were recruited from the otolaryngology clinic at the Red Cross War Memorial Children's Hospital. Demographics, symptom screening scores (SSS), patient characteristics, overnight oximetry (OO), echocardiography and MOS scores (graded 1–4) were recorded. Multivariate modified-Poisson regression models were used to examine correlations of patient characteristics ‘with grade 3 or 4 MOS. RESULTS : One-hundred-and-three children were analysed, 38% were female, and median (IQR) age was 3.8 (2.5–5.3) years. Increased tonsil size was associated with a 60% increased risk of grade 3 or 4 MOS, risk ratio (RR) 1.59, 95% CI 1.10–2.29 (p = 0.014). Children with witnessed apnoeic events during sleep had 1.3 times increased risk of MOS Grade 3 or 4, RR 1.31, 95% CI (p = 0.033). A significant correlation was shown with grade 3 or 4 MOS, RR 1.15, 95% CI 1.03–1.27 (p = 0.010) by combining tonsillar size with the following symptoms: apnoeic events; struggling to breathe during sleep and needing to stimulate the child to breathe. CONCLUSION : Identifying children with suspected OSAS who require overnight oximetry can be performed using a simple 3-question screening tool: witnessed apnoeic events, struggling to breathe and the need to shake them awake to breathe. This is more precise with an additional clinical finding of grade 3 or 4 tonsils. These children should have surgery expedited. Any child with a MOS 3 or 4 score on OO needs to have expedited surgery.https://www.elsevier.com/locate/ijporlhj2023School of Health Systems and Public Health (SHSPH

Allergic reactions to the Ad26.COV2.S vaccine in South Africa

BACKGROUND : The Janssen-Ad26.COV2.S vaccine is authorized for use in several countries, with more than 30 million doses administered. Mild and severe allergic adverse events following immunization (AEFI) have been reported. OBJECTIVE : We sought to detail allergic reactions reported during the Sisonke phase 3B study in South Africa. METHODS : A single dose of the Ad26.COV2.S vaccine was administered to 4,77,234 South African health care workers between February 17 and May 17, 2021. Monitoring of adverse events used a combination of passive reporting and active case finding. Telephonic contact was attempted for all adverse events reported as “allergy.” Anaphylaxis adjudication was performed using the Brighton Collaboration and National Institute of Allergy and Infectious Disease case definitions. RESULTS : Only 251 (0.052%) patients reported any allergic-type reaction (<1 in 2000), with 4 cases of adjudicated anaphylaxis (Brighton Collaboration level 1, n = 3) (prevalence of 8.4 per million doses). All anaphylaxis cases had a previous history of drug or vaccine-associated anaphylaxis. Cutaneous allergic reactions were the commonest nonanaphylatic reactions and included self-limiting, transient/localized rashes requiring no health care contact (n = 92) or isolated urticaria and/or angioedema (n = 70; median onset, 48 [interquartile range, 11.5-120] hours postvaccination) that necessitated health care contact (81%), antihistamine (63%), and/or systemic/topical corticosteroid (16%). All immediate (including adjudicated anaphylaxis) and most delayed AEFI (65 of 69) cases resolved completely. CONCLUSIONS : Allergic AEFI are rare following a single dose of Ad26.COV, with complete resolution in all cases of anaphylaxis. Although rare, isolated, delayed-onset urticaria and/or angioedema was the commonest allergic AEFI requiring treatment, with nearly half occurring in participants without known atopic disease.The Sinsonke Study is funded by the South African Medical Research Council. J.P.’s research is supported by a career development award and financial support from the National Institutes of Health; the European Developing Clinical Trials Partnership (EDCTP2 Program supported by the European Union; and the SA Medical Research Council and National Research Foundation.https://www.sciencedirect.com/journal/journal-of-allergy-and-clinical-immunology-globalhj2023Paediatrics and Child HealthSchool of Health Systems and Public Health (SHSPH

Infusion reactions after receiving the broadly neutralizing antibody VRC01 or placebo to reduce HIV-1 acquisition : results from the Phase 2b antibody-mediated prevention randomized trials

Presented at Conference for Retroviruses and Opportunistic Infections; March 06–10, 2021.BACKGROUND : The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS : From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS : Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and “other.” Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae. CONCLUSIONS : IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.Clinical trial funding from Janssen Vaccines.http://www.jaids.comhj2023School of Health Systems and Public Health (SHSPH

Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition

BACKGROUND : Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS : We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS : Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/ HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], −11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, −45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS : VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective.Supported by Public Health Service Grants (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Research Center [FHCRC]; UM1 AI068618, to HVTN Laboratory Center, FHCRC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, University of Washington) from the National Institute of Allergy and Infectious Diseases (NIAID) and by the Intramural Research Program of the NIAID.http://www.nejm.orgam2022School of Health Systems and Public Health (SHSPH

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study) : results from a single-arm, open-label, phase 3B, implementation study

DATA SHARING : Individual participant data will not be made available. Study protocol, statistical analysis plan, and analytical code will be available from the time of publication in response to any reasonable request to the corresponding author.BACKGROUND : We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS : In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 x 10¹⁰ viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS : Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0–51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75–89) to prevent COVID-19-related deaths, 75% (69–82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62–71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42–76] and during delta wave was 67% [62–71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57–100] and during delta wave was 82% [74–89]). INTERPRETATION : The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally.National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.http;//thelancet.comam2023Paediatrics and Child HealthSchool of Health Systems and Public Health (SHSPH

Vaccine efficacy of ALVAC-HIV and bivalent subtype C gp120–MF59 in adults

BACKGROUND : A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox–protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1–2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS : In this phase 2b–3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120–MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS : In January 2020, prespecified criteria for non-efficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month followup, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS : The ALVAC–gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity.Supported by grants (HHSN272201300033C and HHSN272201600012C) to Novartis Vaccines and Diagnostics (now part of the GlaxoSmithKline [GSK] Biologicals) by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) for the selection and process development of the two gp120 envelope proteins TV1.C and 1086.C; by the Bill and Melinda Gates Foundation Global Health Grant (OPP1017604) and NIAID for the manufacture and release of the gp120 clinical grade material; and by U.S. Public Health Service Grants — UM1 AI068614 to the HIV Vaccine Trials Network (HVTN), UM1 AI068635 to the HVTN Statistical and Data Management Center, and UM1 AI068618 to the HVTN Laboratory Center — from the NIAID. GSK Biologicals contributed financially to the provision of preexposure prophylaxis to trial participants. The South African Medical Research Council supported its affiliated research sites.http://www.nejm.orgam2022School of Health Systems and Public Health (SHSPH

A retrospective cohort analysis of antiretroviral treatment modifications at the referral HIV clinic in Mbabane, Swaziland

Background: Optimizing initial antiretroviral therapy (ART) regimens is of paramount importance in improving the durability of treatment efficacy and patient prognosis. We evaluated the reasons for and risk factors relating to ART modifications in an outpatient cohort in Mbabane, Swaziland. Methods: Retrospective cohort analysis of data for 782 patients who started first-line ART between 1 March 2006 and 31 March 2008. Multivariate piecewise Cox regression models were used to identify potential predictors of treatment modification. Results: Over a median follow-up period of 21 months, 17.5% of patients modified their regimen. Drug toxicity was the commonest reason (77 %) while drug contra-indications, namely tuberculosis (13.1%) and pregnancy (6.6%) accounted for 20% of the modifications. In the adjusted multivariate Cox piecewise regression model; after 11 months on ART, baseline CD4 cell count < 200cells/mm3 (HR = 4.42; 95% CI: 1.62 – 12.1), having Stavudine (d4T) in the initial regimen (HR = 2.64; 95% CI: 1.56 – 4.46) and baseline weight > 60kg (HR = 2.40; 95% CI: 1.43 – 4.04) significantly increased the hazards for modification. Conclusions: Initiating HAART at higher CD4 counts, avoiding drugs with poor safety profiles, such as Stavudine (d4T), and identifying individuals who may require therapy for tuberculosis or who may become pregnant could reduce modification rates.Dissertation (MSc)--University of Pretoria, 2010.Clinical EpidemiologyUnrestricte

Durability of first line antiretroviral therapy : reasons and predictive factors for modifications in a Swaziland cohort

BACKGROUND: Optimizing initial antiretroviral therapy (ART) regimens is critical in improving the durability of treatment efficacy and patient prognosis. Reasons for and risk factors relating to the need for ART modifications were evaluated in an outpatient cohort in Mbabane, Swaziland. METHODS: We examined routine clinical data for 782 patients initiating first-line ART between 1 March 2006 and 31 March 2008. Treatment modification was defined as either a first time single drug substitution or first time regimen switch. Multivariate piecewise Cox regression models were used to identify risk factors for ART modification. RESULTS: Over a median follow-up period of 21 months, 17.5% of patients modified their regimen. Drug toxicity (incidence rate of 6.3 per 100 person years (95% CI 5.2-7.7)) accounted for 76.6% of the reasons for modification. Drug contra-indications (incidence rate 9.5 per 100 person years (95% CI 6.5-13.9)), namely tuberculosis (13.1%) and pregnancy (6.6%), accounted for 19.7% of modifications. In the adjusted multivariate Cox piecewise regression model, beyond 11 months on ART, a baseline CD4 cell count 60kg (HR 2.40; 95% CI: 1.43 – 4.04) and increase in age (HR 1.03; 95% CI: 1.00 – 1.05) increased the risk of modification. CONCLUSIONS: Initiating ART earlier, at higher CD4 counts, avoiding drugs with poor safety profiles, such as d4T, and identifying individuals who may require tuberculosis treatment or may become pregnant could reduce modification rates. This would improve regimen tolerability, while preserving future treatment options.The Swaziland government and the Global Fund to Fight Tuberculosis, HIV and Malaria.http://omicsonline.org/jaahome.ph

Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

BACKGROUND: Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. METHODS: A decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables. RESULTS: The highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay. CONCLUSIONS: The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.United States Agency for International Development (USAID) through The USAID funded Global Health Supply Chain - Technical Assistance program.http://www.biomedcentral.com/bmchealthservrespm2021School of Health Systems and Public Health (SHSPH