Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial.

BACKGROUND: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. METHODS: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. INTERPRETATION: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. FUNDING: UK Research and Innovation and National Institute for Health and Care Research.

Changes in the medical admissions and mortality amongst children in four South African hospitals following the COVID-19 pandemic: A five-year review.

Vulnerable children from poor communities with high HIV and Tuberculosis(TB) burdens were impacted by COVID-19 lockdowns. Concern was raised about the extent of this impact and anticipated post-pandemic surges in mortality. Interrupted time series segmented regression analyses were done using routinely collected facility-level data of children admitted for medical conditions at four South African referral hospitals. Monthly admission and mortality data over 60 months from 01 April 2018 to 31 January 2023 was analysed using models which included dummy lockdown level variables, a dummy post-COVID period variable, Fourier terms to account for seasonality, and excess mortality as a proxy for healthcare burden. Of the 45 015 admissions analysed, 1237(2·75%) demised with significant decreases in admissions during all the lockdown levels, with the most significant mean monthly decrease of 450(95%, CI = 657·3, -244·3) p<0·001 in level 5 (the most severe) lockdown. There was evidence of loss of seasonality on a six-month scale during the COVID periods for all admissions (p = 0·002), including under-one-year-olds (p = 0·034) and under-five-year-olds (p = 0·004). No decreases in mortality accompanied decreased admissions. Post-pandemic surges in admissions or mortality were not identified in children with acute gastroenteritis, acute pneumonia and severe acute malnutrition.During the COVID-19 pandemic, paediatric admissions in 4 hospitals serving communities with high levels of HIV, TB and poverty decreased, similar to global experiences; however, there was no change in in-hospital mortality. No post-pandemic surge in admissions or mortality was documented. Differences in the impact of pandemic control measures on the transmission of childhood infections and access to health care may account for differing outcomes seen in our setting compared to the global experiences. Further studies are needed to understand the impact of pandemic control measures on healthcare provision and transmission dynamics and to better inform future responses amongst vulnerable child populations.

Healthcare worker perspectives on adaptations to differentiated anti-retroviral therapy delivery during COVID-19 in South Africa: A qualitative inquiry.

During the COVID-19 pandemic, the South African Centralized Chronic Medicines Dispensing and Distribution (CCMDD) programme, adapted to include extended 12-month antiretroviral therapy (ART) prescriptions, 3-months ART refills and earlier eligibility criteria at 6-months after ART initiation. We aimed to explore the experiences of healthcare workers (HCWs) in implementing these adaptations, and to understand the overall impact of COVID-19 on CCMDD. We conducted semi-structured in-depth interviews with HCWs in eThekwini District clinics, KwaZulu-Natal, South Africa. Interviews were audio-recorded, transcribed, translated, and analysed thematically. Between 18 February and 13 December 2022, we conducted 21 interviews with nurses, doctors, pharmacists, clinic managers and a community pick-up-point staff member. There were mixed perceptions about COVID-19 adaptations to CCMDD. HCWs reported that COVID-19 adaptations to CCMDD helped keep clients away from clinics, reducing exposure to COVID-19, minimizing queues, alleviating client frustration, and easing workload, which enabled more focused attention on clients with greater needs. Clients reportedly preferred 12-month prescriptions as it gave them independence. However, HCWs were concerned about clients' ART adherence, potential to miss out on clinical input, and difficulties aligning annual viral load results, during the 12 months without clinic attendance. The extended eligibility and multi-month dispensing were acceptable to HCWs, but concerns were expressed about non-adherence and stock shortages. Challenges, including staff shortages due to sickness, increased workload, inadequate training, HCWs' distrust in clients' ability to manage their health autonomously, and staff's limited involvement in decisions about the adaptations, impacted on their implementation. While HCWs reported benefits of 12-month prescribing, extended eligibility and multi-month dispensing in CCMDD, long-term implementation would require addressing concerns about impacts on adherence, alignment of annual viral loads and timely follow up. Prioritizing HCW input in decision-making processes and enhancing provider-client interactions will be pivotal in ensuring the effectiveness of CCMDD adaptations.

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. METHODS: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). INTERPRETATION: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Intimate Partner Violence and HIV Outcomes Among Women Living with HIV in Durban, South Africa.

We examined the impact of past-year intimate partner violence (IPV) on HIV outcomes among women living with HIV (WLHIV) in Durban, South Africa. We assessed past-year IPV using the WHO Violence Against Women Questionnaire. We conducted logistic regression to assess associations between demographic variables and IPV at baseline, and between IPV at baseline and longitudinal HIV outcomes. Among 235 WLHIV, 17% reported past-year emotional, physical, or sexual IPV. At baseline, HIV-disclosure to partner was associated with 4.35-fold odds of past-year IPV (95% CI 1.17-16.10) after controlling for children, education, and harmful alcohol use. In the prospective analysis, IPV was associated with not achieving the co-primary outcome of retention in care and viral suppression in univariate (OR = 2.32, 95% CI 1.04-5.18), but not in the multivariate model. In the context of rapid treatment scale-up, the high burden of IPV among WLHIV needs to be prioritized, with an emphasis on disclosure support.

Early HIV viral suppression associated with subsequent 12-month treatment success among people living with HIV in South Africa.

BACKGROUND: We analyzed the STREAM (Simplifying HIV TREAtment and Monitoring) study to determine risk factors associated with HIV viraemia and poor retention 18 months after initiation of antiretroviral therapy (ART). METHODS: The STREAM study was an open-label randomized controlled trial in Durban, South Africa, that enrolled 390 people living with HIV presenting for their first HIV viral load measurement ~6 months after ART initiation. We used modified Poisson regression with robust standard errors to describe associations between baseline characteristics and three HIV outcomes 18 months after ART initiation: HIV viraemia (>50 copies/mL), poor retention in HIV care, and a composite outcome of poor retention in care and/or HIV viraemia. RESULTS: Approximately 18 months after ART initiation, 45 (11.5%) participants were no longer retained in care and 43 (11.8%) had viraemia. People with CD4 counts <200 and those with viraemia 6 months after ART initiation were significantly more likely to have viraemia 18 months after ART initiation (adjusted relative risk [aRR] 4.0; 95% confidence interval [CI] 2.1-7.5 and aRR 5.5; 95% CI 3.3-9.0, respectively). People who did not disclose their HIV status and had viraemia after ART initiation were more likely to not be retained in care 12 months later (aRR 2.6; 95% CI 1.1-6.1 and aRR 2.2; 95% CI 1.0-4.8). People with a CD4 count <200 and those with viraemia were more likely to not achieve the composite outcome 18 months after ART initiation. CONCLUSIONS: Viraemia after ART initiation was the strongest predictor of subsequent viraemia and poor care retention. Understanding early indicators can help target our interventions to better engage people who may be more likely to experience persistent viraemia or disengage from HIV care.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients.

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031.

Cost-utility analysis of molnupiravir for high-risk, community-based adults with COVID-19: an economic evaluation of the PANORAMIC trial.

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.