Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.

Ending AIDS as a public health threat by 2030: Time to reset targets for 2025.

Paul De Lay and co-authors introduce a Collection on the design of targets for ending the AIDS epidemic.

Building from the HIV Response toward Universal Health Coverage.

Jonathan Jay and colleagues draw lessons from the the global HIV response that could help guide the universal health coverage movement.

Maximising the effect of combination HIV prevention through prioritisation of the people and places in greatest need: a modelling study.

BACKGROUND: Epidemiological data show substantial variation in the risk of HIV infection between communities within African countries. We hypothesised that focusing appropriate interventions on geographies and key populations at high risk of HIV infection could improve the effect of investments in the HIV response. METHODS: With use of Kenya as a case study, we developed a mathematical model that described the spatiotemporal evolution of the HIV epidemic and that incorporated the demographic, behavioural, and programmatic differences across subnational units. Modelled interventions (male circumcision, behaviour change communication, early antiretoviral therapy, and pre-exposure prophylaxis) could be provided to different population groups according to their risk behaviours or their location. For a given national budget, we compared the effect of a uniform intervention strategy, in which the same complement of interventions is provided across the country, with a focused strategy that tailors the set of interventions and amount of resources allocated to the local epidemiological conditions. FINDINGS: A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years-almost 100,000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150,000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention. INTERPRETATION: The focused approach achieves greater effect than the uniform approach despite exactly the same investment. Through prioritisation of the people and locations at greatest risk of infection, and adaption of the interventions to reflect the local epidemiological context, the focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention. FUNDING: The Bill & Melinda Gates Foundation and UNAIDS.

Transformation of HIV from pandemic to low-endemic levels: a public health approach to combination prevention.

Large declines in HIV incidence have been reported since 2001, and scientific advances in HIV prevention provide strong hope to reduce incidence further. Now is the time to replace the quest for so-called silver bullets with a public health approach to combination prevention that understands that risk is not evenly distributed and that effective interventions can vary by risk profile. Different countries have different microepidemics, with very different levels of transmission and risk groups, changing over time. Therefore, focus should be on high-transmission geographies, people at highest risk for HIV, and the package of interventions that are most likely to have the largest effect in each different microepidemic. Building on the backbone of behaviour change, condom use, and medical male circumcision, as well as expanded use of antiretroviral drugs for infected people and pre-exposure prophylaxis for uninfected people at high risk of infection, it is now possible to consider the prospect of what would be one of the most remarkable achievements in the history of public health: reduction of HIV transmission from a pandemic to low-level endemicity.

Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda.

BACKGROUND: Little is known about the effect of combination antiretroviral therapy (cART) on life expectancy in sub-Saharan Africa. OBJECTIVE: To estimate life expectancy of patients once they initiate cART in Uganda. DESIGN: Prospective cohort study. SETTING: Public sector HIV and AIDS disease-management program in Uganda. PATIENTS: 22 315 eligible patients initiated cART during the study period, of whom 1943 were considered to have died. MEASUREMENTS: All-cause mortality rates were calculated and abridged life tables were constructed and stratified by sex and baseline CD4 cell count status to estimate life expectancies for patients receiving cART. The average number of years remaining to be lived by patients who received cART at varying age categories was estimated. RESULTS: After adjustment for loss to follow-up, crude mortality rates (deaths per 1000 person-years) ranged from 26.9 (95% CI, 25.4 to 28.5) in women to 43.9 (CI, 40.7 to 47.0) in men. For patients with a baseline CD4 cell count less than 0.050 × 10(9) cells/L, the mortality rate was 67.3 (CI, 62.1 to 72.9) deaths per 1000 person-years, whereas among persons with a baseline CD4 cell count of 0.250 × 10(9) cells/L or more, the mortality rate was 19.1 (CI, 16.0 to 22.7) deaths per 1000 person-years. Life expectancy at age 20 years for the overall cohort was 26.7 (CI, 25.0 to 28.4) additional years and at age 35 years was 27.9 (CI, 26.7 to 29.1) additional years. Life expectancy increased substantially with increasing baseline CD4 cell count. Similar trends are observed for older age groups. LIMITATIONS: A small (6.4%) proportion of patients were lost to follow-up, and it was imputed that 30% of these patients had died. Few patients with a CD4 cell count greater than 0.250 × 10(9) cells/L initiated cART. CONCLUSION: Ugandan patients receiving cART can expect an almost normal life expectancy, although there is considerable variability among subgroups of patients. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Toward a New Paradigm of North-South and South-South Partnerships for Pandemic Preparedness: Lessons Learned from COVID-19 and Other Outbreaks.

COVID-19 underscores the need to reimagine North-South partnerships and redefine best practices for building public health and research capacity to address emergent health threats and pandemic preparedness in low- and-middle income countries (LMICs). Historically, outbreak and emergency responses have failed to ensure that the Global South has the autonomy and capacity to respond to public health threats in a timely and equitable manner. The COVID-19 response, however, has demonstrated that innovations and solutions in the Global South can not only fill resource and capacity gaps in LMICs but can also provide solutions to challenges globally. These innovations offer valuable lessons about strengthening local manufacturing capacity to produce essential diagnostic, treatment, and prevention tools; implementing high-quality research studies; expanding laboratory and research capacity; and promoting effective cooperation and governance. We discuss specific examples of capacity-building from Rwanda, South Africa, and Senegal. To fulfill promises made to the Global South during the COVID-19 pandemic, restore and resume health service delivery, and effectively prevent and respond to the next health threat, we need to prioritize equitable access to local manufacturing of basic health tools while building health systems capacities in the Global South.

The case for an HIV cure and how to get there.

In light of the increasing global burden of new HIV infections, growing financial requirements, and shifting funding landscape, the global health community must accelerate the development and delivery of an HIV cure to complement existing prevention modalities. An effective curative intervention could prevent new infections, overcome the limitations of antiretroviral treatment, combat stigma and discrimination, and provide a sustainable financial solution for pandemic control. We propose steps to plan for an HIV cure now, including defining a target product profile and establishing the HIV Cure Africa Acceleration Partnership (HCAAP), a multidisciplinary public-private partnership that will catalyse and promote HIV cure research through diverse stakeholder engagement. HCAAP will convene stakeholders, including people living with HIV, at an early stage to accelerate the design, social acceptability, and rapid adoption of HIV-cure products.

Multi-stakeholder consensus on a target product profile for an HIV cure.

Developing a cure for HIV is a global priority. Target product profiles are a tool commonly used throughout the drug development process to align interested parties around a clear set of goals or requirements for a potential product. Three distinct therapeutic modalities (combination therapies, ex-vivo gene therapy, and in-vivo gene therapy) for a target product profile for an HIV cure were identified. Using a process of expert face-to-face consultation and an online Delphi consultation, we found a high degree of agreement regarding the criteria for the optimum target product profile. Although the minimum attributes for a cure were debated, the broad consensus was that an acceptable cure need not be as safe and effective as optimally delivered antiretroviral therapy. An intervention that successfully cured a reasonable fraction of adults would be sufficient to advance to the clinic. These target product profiles will require further discussion and ongoing revisions as the field matures.