Participants on Dolutegravir Resuppress Human Immunodeficiency Virus RNA After Virologic Failure: Updated Data from the ADVANCE Trial.

Following evidence of HIV RNA re-suppression on DTG-based regimens, we assess the re-suppressive capacity of ADVANCE participants on TAF/FTC+DTG, TDF/FTC+DTG, and TDF/FTC/EFV. Viraemic participants were able to re-suppress within 3 follow-up visits of protocol-defined virological failure (PDVF) in 77/121 (64%), 85/126 (67%), and 44/138 (32%) cases respectively (DTG regimens vs. TDF/FTC/EFV; P < 0.001).

Cabotegravir-Global Access to Long-Acting Pre-exposure Prophylaxis for HIV.

A novel injectable pre-exposure prophylaxis, cabotegravir, has greater efficacy and acceptability than oral tenofovir/emtricitabine for prevention of HIV infection. Cabotegravir is currently priced at $22 200 per year, >185 times higher than the $60-$119 estimated cost-effectiveness threshold for middle-income countries (MICs). Following civil society pressure, ViiV provided access to generic versions in 90 countries with the Medicines Patent Pool (MPP), including all African nations. However, several MICs outside Africa have rapidly growing HIV epidemics. We analyzed the ViiV-MPP deal to assess population covered and gross domestic product (GDP) per capita. There were 38 countries excluded from the ViiV-MPP deal despite having a GDP per capita lower than the highest-earning African country. These countries include 2.4 billion people (30% global population), with an incidence of 122 000 (8%). For cabotegravir to have a significant impact on HIV infections, millions will need to be treated at affordable prices in a wide range of countries.

Risks of metabolic syndrome in the ADVANCE and NAMSAL trials.

Introduction: The ADVANCE and NAMSAL trials evaluating antiretroviral drugs have both reported substantial levels of clinical obesity in participants. As one of the main risk factors for metabolic syndrome, growing rates of obesity may drive metabolic syndrome development. This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials. Methods: The number of participants with metabolic syndrome was calculated at baseline and week 192 as central obesity and any of the following two factors: raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting glucose. Differences between the treatment arms were calculated using the χ2 test. Results: Across all visits to week 192, treatment-emergent metabolic syndrome was 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) in ADVANCE. The results were significantly higher in the TAF/FTC + DTG arm compared to the TDF/FTC/EFV arm (p < 0.001), and the TDF/FTC + DTG vs. the TDF/FTC/EFV arms (p < 0.05) in all patients, and in females. In NAMSAL, the incidence of treatment-emergent metabolic syndrome at any time point was 14% (TDF/3TC + DTG) and 5% (TDF/3TC + EFV) (p < 0.001). This incidence was significantly greater in the TDF/3TC/DTG arm compared to the TDF/3TC/EFV arm in all patients (p < 0.001), and in males (p < 0.001). Conclusion: In this analysis, we highlight treatment-emergent metabolic syndrome associated with dolutegravir, likely driven by obesity. Clinicians initiating or monitoring patients on INSTI-based ART must counsel for lifestyle optimisation to prevent these effects.

Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19.

Pfizer and the Medicines Patent Pool (MPP) have reached a voluntary licensing agreement for Paxlovid (nirmatrelvir+ritonavir), a novel antiviral for coronavirus disease 2019 (COVID-19) taken orally in the first 5 days from symptom onset. The Pfizer-MPP deal enables 95 low- and middle-income countries (L/MICs) to access affordable biosimilars. Generics are delayed awaiting bioequivalence testing and may be ineffective in L/MICs with reduced testing capacity, which comprise only 10% of global diagnoses. Thirty-nine percent of diagnoses originate in MICs forced to pay high prices due to exclusion from the Pfizer-MPP deal. The cost-effectiveness of Paxlovid could be limited compared with the creation of sustainable vaccine infrastructure in these nations, delaying socioeconomic pandemic recovery. Furthermore, Paxlovid may not be cost-effective in vaccinated populations, and concerns remain over ritonavir drug interactions with COVID-19 comorbidity medications. We call for expanded coverage by the Paxlovid-MPP deal and greater access to testing.

Efficacy of Approved Versus Unapproved Vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Randomized Blinded Clinical Trials.

Background: Five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca, and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Zifivax, Medicago, Clover, and Cansino, but they are not approved in high-income countries. This meta-analysis compared the efficacy of US Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved and -unapproved vaccines in randomized clinical trials (RCTs). Methods: A systematic review of trial registries identified RCTs of SARS-CoV-2 vaccines. Risk of bias was assessed using the Cochrane tool (RoB 2). In the meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method). Results: Twenty-two RCTs were identified and 1 was excluded for high-risk of bias. Ten RCTs evaluated 5 approved vaccines and 11 RCTs evaluated 9 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% confidence interval [CI], 68%-92%) for approved vaccines versus 72% (95% CI, 66%-77%) for unapproved vaccines, with no significant difference between vaccine types (P = .12). Prevention of severe SARS-CoV-2 infection was 94% (95% CI, 75%-98%) for approved vaccines versus 86% (95% CI, 76%-92%) for unapproved vaccines (P = .33). The risk of serious adverse events was similar between vaccine types (P = .12). Conclusions: This meta-analysis of 21 RCTs in 390 459 participants showed no significant difference in efficacy between the FDA/EMA-approved and -unapproved vaccines for symptomatic or severe infection. Differences in study design, endpoint definitions, variants, and infection prevalence may have influenced results. New patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly.

Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Missing clinical trial data: the evidence gap in primary data for potential COVID-19 drugs.

BACKGROUND: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of overall clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in this data by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications to quantify the number of trials missing results for drugs potentially being repurposed for COVID-19. METHODS: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. RESULTS: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. Tabular results were available on ClinicalTrials.gov for 1172 (31.2%) completed trials. A further 1066 (28.4%) had published results in the academic literature, but did not report results on ClinicalTrials.gov . Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). CONCLUSIONS: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause unnecessary additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

Making a COVID-19 vaccine that works for everyone: ensuring equity and inclusivity in clinical trials.

Coronavirus disease 2019 (COVID-19) mortality and morbidity have been shown to increase with deprivation and impact non-White ethnicities more severely. Despite the extra risk Black, Asian and Minority Ethnicity (BAME) groups face in the pandemic, our current medical research system seems to prioritise innovation aimed at people of European descent. We found significant difficulties in assessing baseline demographics in clinical trials for COVID-19 vaccines, displaying a lack of transparency in reporting. Further, we found that most of these trials take place in high-income countries, with only 25 of 219 trials (11.4%) taking place in lower middle- or low-income countries. Trials for the current best vaccine candidates (BNT162b2, ChadOx1, mRNA-173) recruited 80.0% White participants. Underrepresentation of BAME groups in medical research will perpetuate historical distrust in healthcare processes, and poses a risk of unknown differences in efficacy and safety of these vaccines by phenotype. Limiting trial demographics and settings will mean a lack of global applicability of the results of COVID-19 vaccine trials, which will slow progress towards ending the pandemic.

Who funded the research behind the Oxford-AstraZeneca COVID-19 vaccine?

OBJECTIVES: The Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1 nCoV-19, Vaxzevira or Covishield) builds on two decades of research and development (R&D) into chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford. This study aimed to approximate the funding for the R&D of ChAdOx and the Oxford-AstraZeneca vaccine and to assess the transparency of funding reporting mechanisms. METHODS: We conducted a scoping review and publication history analysis of the principal investigators to reconstruct R&D funding the ChAdOx technology. We matched award numbers with publicly accessible grant databases. We filed freedom of information (FOI) requests to the University of Oxford for the disclosure of all grants for ChAdOx R&D. RESULTS: We identified 100 peer-reviewed articles relevant to ChAdOx technology published between January 2002 and October 2020, extracting 577 mentions of funding bodies from acknowledgements. Government funders from overseas (including the European Union) were mentioned 158 times (27.4%), the UK government 147 (25.5%) and charitable funders 138 (23.9%). Grant award numbers were identified for 215 (37.3%) mentions; amounts were publicly available for 121 (21.0%). Based on the FOIs, until December 2019, the biggest funders of ChAdOx R&D were the European Commission (34.0%), Wellcome Trust (20.4%) and Coalition for Epidemic Preparedness Innovations (17.5%). Since January 2020, the UK government contributed 95.5% of funding identified. The total identified R&D funding was £104 226 076 reported in the FOIs and £228 466 771 reconstructed from the literature search. CONCLUSION: Our study approximates that public and charitable financing accounted for 97%-99% of identifiable funding for the ChAdOx vaccine technology research at the University of Oxford underlying the Oxford-AstraZeneca vaccine until autumn 2020. We encountered a lack of transparency in research funding reporting.

Adherence, resistance, and viral suppression on dolutegravir in sub-Saharan Africa: implications for the TLD era.

Dolutegravir (DTG) is now a component of preferred first-line antiretroviral therapy (ART) worldwide. ADVANCE and NAMSAL were two landmark clinical trials conducted exclusively in sub-Saharan Africa, which studied the effectiveness of DTG-based first-line regimens for ART-naive individuals. In this review, we examine the data from these studies to consider the contributions of adherence and HIV drug resistance to treatment failure on DTG-based ART, as compared with efavirenz (EFV)-based ART, which has a lower genetic barrier to resistance. We also discuss the implications of virologic failure on DTG and consolidate currently available data to conclude with recommendations for virologic monitoring on DTG-based ART.

What we have learned from antiretroviral treatment optimization efforts over the last 5 years?

Progression in the development of antiretroviral therapy has been remarkable, with new agents continuing to appear as options for modern regimens, including in low-and-middle income countries where the HIV epidemic is concentrated. Here, we reflect on progress made in guiding regimen changes to public health programmes, and the challenges facing selection of newer agents.

A review of the safety of favipiravir - a potential treatment in the COVID-19 pandemic?

BACKGROUND: Repurposing broad-spectrum antivirals is an immediate treatment opportunity for 2019 coronavirus disease (COVID-19). Favipiravir is an antiviral previously indicated for influenza and Ebola, which has shown some promise in early trials for treatment of COVID-19. We aim to review existing favipiravir safety evidence, which is vital to informing the potential future use of favipiravir in COVID-19. METHODS: A search was conducted across EMBASE and MEDLINE databases, supplemented by relevant grey-literature and ClinicalTrials.gov. All studies assessing the use of favipiravir in humans by 27 March 2020 were considered for inclusion. Further analysis of available safety data from phase 2 and 3 studies was undertaken. Data extracted were adverse events (AEs) grade 1-4, serious AEs and discontinuation for AEs. Specific AEs of interest highlighted in early-phase studies, including gastrointestinal AEs and hyperuricaemia, were also examined. RESULTS: Twenty-nine studies were identified as potential sources of evidence of the clinical safety of favipiravir. Six were phase 2 and 3 studies reporting relevant safety data for statistical comparison, representing a total of 4299 participants, an estimated 175 person-years-of-follow-up (PYFU). Comparator drugs were oseltamivir, umifenovir, lopinavir/ritonavir or placebo. Study follow-up was between 5 and 21 days. The proportions of grade 1-4 AEs on favipiravir was 28.2% vs 28.4% (P = n.s.) in the comparison arms. The proportion of discontinuations due to AEs on favipiravir was 1.1% vs 1.2% (P = n.s.) in the comparison arms. For serious AEs the proportion was 0.4% in both arms (P = n.s.). There were significantly fewer gastrointestinal AEs occurring on favipiravir vs comparators [8.7% vs 11.5%; P = 0.003]. Favipiravir showed significantly more uric acid elevations than comparators [5.8% vs 1.3%; P<0.0001]. CONCLUSIONS: Favipiravir demonstrates a favourable safety profile regarding total and serious AEs. However, safety concerns remain: hyperuricaemia, teratogenicity and QTc prolongation have not yet been adequately studied. Favipiravir may be safe and tolerable in short-term use, but more evidence is needed to assess the longer-term effects of treatment. Given the limitations of the evidence and unresolved safety concerns, caution is warranted in the widespread use of favipiravir against pandemic COVID-19.

The same lesson over and over: drugs alone will not get us to 90--90--90.

: Addressing social determinants of health (SDH) has far greater potential to improve the real-world effectiveness of HIV treatment than expensive, incremental changes in antiretroviral therapy. The ADVANCE study demonstrates that SDH is more impactful than medication regimen on health outcomes. Younger patients and unemployed patients experience heightened precarity, which can have pervasive effects on adherence and suppression. Enhanced adherence counselling can help socioeconomically precarious patients maintain suppression, but in order to improve treatment effectiveness and population health, we should move beyond the short-term solution of helping patients 'cope' with insecurity toward tackling the underlying factors that lead to precarity. Data on intention-to-treat populations are critical to this effort, yet medical researchers and publications continue to obscure the influence of SDH by focusing on per-protocol populations.

Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19.

BACKGROUND: Many treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVID-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500 mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax : EC50 roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVID-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production. METHODS: A review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5-14 days in participants experiencing acute infections of any kind. Data extracted were grade 1-4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects.Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500 mg BD and a higher dose of 1100 mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries. RESULTS: Nine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited.Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500 mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100 mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day. CONCLUSION: Nitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500 mg BD, up to $4.08 at 1100 mg TDS. Further trials in COVID-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.

Phase 3 trials of new antiretrovirals are not representative of the global HIV epidemic.

INTRODUCTION: People living with HIV (PLWH) are mainly African or Asian, the majority female. In contrast, pharmaceutical companies typically conduct phase 3 regulatory randomised controlled trials (RCTs) in high-income countries (HICs), where PLWH are mainly white males. Regulatory authorities can be conservative about including pregnant women in trials, discouraging female participation. Some adverse events occur more frequently by sex or by race because of differing pharmacokinetics. Most drugs have insufficient safety data in pregnancy and non-white people even after regulatory approval. The present study compared race and sex demographics of phase 3 RCTs of dolutegravir (DTG), bictegravir (BIC) and tenofovir alafenamide (TAF) with global HIV epidemic demography. METHODS: National epidemic sizes by sex were extracted from UNAIDS 2018 data. National demographics were used to estimate prevalence by race. PLWH by national socio-economic status were calculated from World Bank data. Summary race and sex demographic data for 10 phase 3 trials of DTG (n = 7714), four of BIC (n = 2307), eight of TAF (n = 7573) and two of doravirine (DOR) (n = 1407) were extracted from ClinicalTrials.gov. RESULTS: Black females (42%) and black males (30%) have highest prevalence globally. White males comprise 6% of PLWH. Over 60% of PLWH live in low or low-middle-income countries, 68% of whom are black and 23% Asian. Seventy-six per cent of DTG trial centres were in high-income countries (HICs) (5% global burden) and 23% in upper-middle-income countries (UMICs). DTG trials were not representative of PLWH even within the UMIC and HIC setting (49% white male vs 31% income band). White males were overrecruited by 44% to DTG, BIC, TAF and DOR trials in comparison with prevalence. Black females were underrepresented by 35%. CONCLUSION: Phase 3 RCT populations for new antiretrovirals comprised 51% white males, vastly disproportionate to the global HIV epidemic (6%). Females and non-white people are underrepresented. Female safety data are insufficient despite drug approval in Europe and USA. HIV trials should be located in regions representing the global epidemic with no sex-based selection. Trials should aim for at least 50% female and 50% non-white recruitment to properly provide safety information.

Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14 894 patients across 14 trials.

BACKGROUND: Both tenofovir disoproxil fumarate (TDF)/emtricitabine and tenofovir alafenamide (TAF)/emtricitabine demonstrate excellent efficacy and safety overall, but concerns remain over specific changes in markers of bone and renal function. Lower plasma tenofovir concentrations are seen with TAF and in unboosted regimens. We assess TAF vs. TDF safety with and without booster coformulation. METHODS: A previous systematic review was updated with recent clinical trials. TAF vs. TDF efficacy and safety were compared in boosted and unboosted subgroups. Efficacy was measured by viral suppression. Key safety endpoints included all adverse events, serious adverse events, Grades 3-4 adverse events and adverse event discontinuation. Further specific renal and bone markers were also assessed. RESULTS: A total of 14 clinical trials comparing TDF and TAF regimens were identified. A significant difference (P = 0.0004) in efficacy was shown in the boosted subgroup in favour of TAF, but no difference was seen in the unboosted subgroup. There were no significant differences between TAF and TDF for any of the key safety endpoints analysed. No differences were seen for the bone markers analysed. No difference was found for renal tubular events. There was a difference in risk for discontinuation due to renal adverse events when boosted (P = 0.03), but none when unboosted. CONCLUSION: Across all main safety endpoints, no differences between TAF and TDF are seen. Boosted TDF regimens were associated with lesser comparative efficacy than boosted TAF and a higher risk of renal event discontinuation. However, modern antiretroviral regimens are more commonly unboosted. This study finds no difference in efficacy or safety in unboosted TAF vs. TDF.

Time to rethink endpoints for new clinical trials of antiretrovirals? Long-term re-suppression of HIV RNA with integrase inhibitors.

: In the ADVANCE study of first-line treatment, there were 48 participants with HIV RNA at least 50 copies/ml in the week 48 window who had subsequent follow-up data available with no change in randomized treatment. More participants achieved virological re-suppression in the TAF/FTC+DTG and TDF/FTC+DTG arms (26/34, 76%) than on TDF/FTC/EFV (6/14 = 43%; P = 0.0421). It is unclear whether participants with HIV RNA at least 50 copies/ml at week 48 should be termed 'virological failures' on integrase inhibitor-based treatment.