Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Background: Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. Methods: We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Results: Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Conclusions: Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

Specific quantification of inducible HIV-1 reservoir by RT-LAMP.

BACKGROUND: Strategies toward HIV-1 cure aim to clear, inactivate, reduce, or immunologically control the virus from a pool of latently infected cells such that combination antiretroviral therapy (cART) can be safely interrupted. In order to assess the impact of any putative curative interventions on the size and inducibility of the latent HIV-1 reservoir, robust and scalable assays are needed to precisely quantify the frequency of infected cells containing inducible HIV-1. METHODS: We developed Specific Quantification of Inducible HIV-1 by RT-LAMP (SQuHIVLa), leveraging the high sensitivity and specificity of RT-LAMP, performed in a single reaction, to detect and quantify cells expressing tat/rev HIV-1 multiply spliced RNA (msRNA) upon activation. The LAMP primer/probe used in SQuHIVLa was designed to exclusively detect HIV-1 tat/rev msRNA and adapted for different HIV-1 subtypes. RESULTS: Using SQuHIVLa, we successfully quantify the inducible viral reservoir in CD4+ T cells from people living with HIV-1 subtypes B and C on cART. The assay demonstrates high sensitivity, specificity, and reproducibility. CONCLUSIONS: SQuHIVLa offers a high throughput, scalable, and specific HIV-1 reservoir quantification tool that is amenable to resource-limited settings. This assay poses remarkable potential in facilitating the evaluation of potential interventional strategies toward achieving HIV-1 cure.

HIV infection remains challenging because the virus hides in certain cells, making it invisible to the immune system. This hidden virus forms what is called a latent HIV reservoir. If someone with HIV stops their antiviral therapy, the virus quickly re-emerges. Because of this, researchers are exploring various strategies to eliminate this reservoir and cure HIV. To evaluate these strategies, we need a method to measure the reservoir's size before and after trials. Our study introduces SQuHIVLa, a highly sensitive and specific method for quantifying the latent reservoir. SQuHIVLa could become a vital tool for monitoring HIV patients and assessing treatment effectiveness, bringing us closer to finding a cure.

Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission.

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

No detectable differences in Nef-mediated downregulation of HLA-I and CD4 molecules among HIV-1 group M lineages circulating in Cameroon, where the pandemic originated.

HIV-1 group M (HIV-1M) lineages downregulate HLA-I and CD4 expression via their Nef proteins. We hypothesized that these Nef functions may be partially responsible for the differences in prevalence of viruses from different lineages that co-circulate within an epidemic. Here, we characterized these two Nef activities in HIV-1M isolates from Cameroon, where multiple variants have been circulating since the pandemic's origin. Single HIV-1 Nef clones from 234 HIV-1-ART naïve individuals living in remote villages and two cosmopolitan cities of Cameroon, sampled between 2000 and 2013, were isolated from plasma HIV RNA and analyzed for their capacity to downregulate HLA-I and CD4 molecules. We found that, despite a large degree of within- and inter- lineage variation, the ability of Nef to downregulate HLA-I was similar across these different viruses. Moreover, Nef-mediated CD4 downregulation activity was also well conserved across the different lineages found in Cameroon. In addition, we observed a trend towards higher HLA-I downregulation activity of viruses circulating in the cosmopolitan cities versus the remote villages, whereas the CD4 downregulation activities were similar across the two settings. Furthermore, we noted a significant decline of HLA-I downregulation activity from 2000 to 2013, providing additional evidence supporting the attenuation of the global HIV-1M population over time. Finally, we identified 18 amino acids associated with differential HLA-I downregulation and 13 amino acids associated with differential CD4 downregulation within the dominant CRF02_AG lineage. Our lack of observation of HIV lineage-related differences in Nef-mediated HLA-I and CD4 downregulation function suggests that these activities do not substantively influence the prevalence of different HIV-1M lineages in Cameroon.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.

Advancing HIV cure research in low- and middle-income countries requires empowerment of the next generation of scientists.

While low- and middle-income countries (LMICs), especially in Southern and Eastern Africa, bear the largest burden of the HIV globally, investigators working on the front lines in these regions are leading a limited number of research efforts, particularly related to HIV cure. Conducting HIV cure research in high-burden HIV LIMCs provides an unparalleled opportunity to formulate innovative research strategies, design trials tailored to the local context, evaluate clinical outcomes within key and vulnerable populations, meaningful involvement of stakeholders, and to shape policies in areas where HIV prevention and cure interventions can yield the most significant impact. Further, the high prevalence of infection, with varied HIV strains affecting large diverse populations, creates a unique environment for studies that would not be feasible in any other part of the world. This underscores the critical importance of addressing obstacles to unlock the full potential of research efforts in these regions. In this viewpoint, we identify significant challenges facing early career investigators in LMICs, particularly in Africa, that hinder their full engagement in HIV cure research. Drawing examples from the International AIDS Society's Research-for-Cure Academy, we provide practical recommendations to overcome barriers that include limited access to funding, effective mentors, educational and career development opportunities, coupled with inadequate investment in infrastructure that contribute towards the limited number of investigators from high-burden HIV LIMCs who are spearheading cutting-edge cure research. Addressing these challenges is crucial to empower investigators who possess unique insights and expertise, and who are well positioned to lead HIV cure-related research efforts. We acknowledge and welcome initiatives that promote capacity building and knowledge exchange between early-career investigators in LMICs and their peers and scientific leaders from high-income countries (HICs). Prioritizing investment in global collaboration and partnership will play a pivotal role in empowering the next generation of African scientists and clinicians. To expedite advancements of cure-related strategies that will be effective in high-burden HIV LMICs, we endorse the sustainable expansion of these pivotal initiatives in these regions, to enhance their effectiveness and hasten progress in the pursuit of a global HIV cure.

Under-representation of the WHO African region in clinical trials of interventions against hepatitis B virus infection.

The WHO African region bears a disproportionate burden of morbidity and mortality related to chronic hepatitis B virus (HBV) infection and accounts for an estimated 70% of new HBV infections worldwide. We investigated the extent to which HBV clinical trials represented populations in this region by searching the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for interventional clinical trials published in English between database inception and May 29, 2023, using the search term "Hepatitis B". We identified 1804 unique clinical trials, of which 18 (1·0%) recorded involvement of the WHO African region. There is no evidence that the number of HBV clinical trials in this region has improved over time. The diversity of new interventions and industry sponsorship in the WHO African region were low, with trials of HBV comparing poorly with those of other endemic infectious diseases (eg, malaria, HIV, and SARS-CoV-2). HBV research and clinical trial investigations have neglected the WHO African region, leading to profound health inequities. HBV clinical trials are urgently needed to evaluate the efficacy of newly discovered therapeutics and to ensure that interventions can be equitably distributed and deployed as they become available.

HIV, multimorbidity, and health-related quality of life in rural KwaZulu-Natal, South Africa: A population-based study.

Health-related quality of life (HRQoL) assesses the perceived impact of health status across life domains. Although research has explored the relationship between specific conditions, including HIV, and HRQoL in low-resource settings, less attention has been paid to the association between multimorbidity and HRQoL. In a secondary analysis of cross-sectional data from the Vukuzazi ("Wake up and know ourselves" in isiZulu) study, which identified the prevalence and overlap of non-communicable and infectious diseases in the uMkhanyakunde district of KwaZulu-Natal, we (1) evaluated the impact of multimorbidity on HRQoL; (2) determined the relative associations among infectious diseases, non-communicable diseases (NCDs), and HRQoL; and (3) examined the effects of controlled versus non-controlled disease on HRQoL. HRQoL was measured using the EQ-5D-3L, which assesses overall perceived health, five specific domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and three levels of problems (no problems, some problems, and extreme problems). Six diseases and disease states were included in this analysis: HIV, diabetes, stroke, heart attack, high blood pressure, and TB. After examining the degree to which number of conditions affects HRQoL, we estimated the effect of joint associations among combinations of diseases, each HRQoL domain, and overall health. Then, in one set of ridge regression models, we assessed the relative impact of HIV, diabetes, stroke, heart attack, high blood pressure, and tuberculosis on the HRQoL domains; in a second set of models, the contribution of treatment (controlled vs. uncontrolled disease) was added. A total of 14,008 individuals were included in this analysis. Having more conditions adversely affected perceived health (r = -0.060, p<0.001, 95% CI: -0.073 to -0.046) and all HRQoL domains. Infectious conditions were related to better perceived health (r = 0.051, p<0.001, 95% CI: 0.037 to 0.064) and better HRQoL, whereas non-communicable diseases (NCDs) were associated with worse perceived health (r = -0.124, p<0.001, -95% CI: 0.137 to -0.110) and lower HRQoL. Particular combinations of NCDs were detrimental to perceived health, whereas HIV, which was characterized by access to care and suppressed viral load in the large majority of those affected, was counterintuitively associated with better perceived health. With respect to disease control, unique combinations of uncontrolled NCDs were significantly related to worse perceived health, and controlled HIV was associated with better perceived health. The presence of controlled and uncontrolled NCDs was associated with poor perceived health and worse HRQoL, whereas the presence of controlled HIV was associated with improved HRQoL. HIV disease control may be critical for HRQoL among people with HIV, and incorporating NCD prevention and attention to multimorbidity into healthcare strategies may improve HRQoL.

SARS-CoV-2 infection in immunosuppression evolves sub-lineages which independently accumulate neutralization escape mutations.

One mechanism of variant formation may be evolution during long-term infection in immunosuppressed people. To understand the viral phenotypes evolved during such infection, we tested SARS-CoV-2 viruses evolved from an ancestral B.1 lineage infection lasting over 190 days post-diagnosis in an advanced HIV disease immunosuppressed individual. Sequence and phylogenetic analysis showed two evolving sub-lineages, with the second sub-lineage replacing the first sub-lineage in a seeming evolutionary sweep. Each sub-lineage independently evolved escape from neutralizing antibodies. The most evolved virus for the first sub-lineage (isolated day 34) and the second sub-lineage (isolated day 190) showed similar escape from ancestral SARS-CoV-2 and Delta-variant infection elicited neutralizing immunity despite having no spike mutations in common relative to the B.1 lineage. The day 190 isolate also evolved higher cell-cell fusion and faster viral replication and caused more cell death relative to virus isolated soon after diagnosis, though cell death was similar to day 34 first sub-lineage virus. These data show that SARS-CoV-2 strains in prolonged infection in a single individual can follow independent evolutionary trajectories which lead to neutralization escape and other changes in viral properties.

Early Initiation of Antiretroviral Therapy Preserves the Metabolic Function of CD4+ T Cells in Subtype C Human Immunodeficiency Virus 1 Infection.

BACKGROUND: Immune dysfunction often persists in people living with human immunodeficiency virus (HIV) who are on antiretroviral therapy (ART), clinically manifesting as HIV-1-associated comorbid conditions. Early ART initiation may reduce incidence of HIV-1-associated immune dysfunction and comorbid conditions. Immunometabolism is a critical determinant of functional immunity. We investigated the effect of HIV-1 infection and timing of ART initiation on CD4+ T cell metabolism and function. METHODS: Longitudinal blood samples from people living with HIV who initiated ART during hyperacute HIV-1 infection (HHI; before peak viremia) or chronic HIV-1 infection (CHI) were assessed for the metabolic and immune functions of CD4+ T cells. Metabolite uptake and mitochondrial mass were measured using fluorescent analogues and MitoTracker Green accumulation, respectively, and were correlated with CD4+ T cell effector functions. RESULTS: Initiation of ART during HHI prevented dysregulation of glucose uptake by CD4+ T cells, but glucose uptake was reduced before and after ART initiation in CHI. Glucose uptake positively correlated with interleukin-2 and tumor necrosis factor-α production by CD4+ T cells. CHI was associated with elevated mitochondrial mass in effector memory CD4+ T cells that persisted after ART and correlated with PD-1 expression. CONCLUSIONS: ART initiation in HHI largely prevented metabolic impairment of CD4+ T cells. ART initiation in CHI was associated with persistently dysregulated immunometabolism of CD4+ T cells, which was associated with impaired cellular functions and exhaustion.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Despite the scale-up of antiretroviral therapy (ART) in South Africa, HIV-1 incidence remains high. The anticipated use of potent integrase strand transfer inhibitors and long-acting injectables aims to enhance viral suppression at the population level and diminish transmission. Nevertheless, pre-existing drug resistance could impede the efficacy of long-acting injectable ART combinations, such as rilpivirine (an NNRTI) and cabotegravir (an INSTI). Consequently, a thorough understanding of transmission networks and geospatial distributions is vital for tailored interventions, including pre-exposure prophylaxis with long-acting injectables. However, empirical data on background resistance and transmission networks remain limited. In a community-based study in rural KwaZulu-Natal (2018-2019), prior to the widespread use of integrase inhibitor-based first-line ART, we performed HIV testing with reflex HIV-1 RNA viral load quantification on 18,025 participants. From this cohort, 6,096 (33.9%) tested positive for HIV via ELISA, with 1,323 (21.7%) exhibiting detectable viral loads (> 40 copies/mL). Of those with detectable viral loads, 62.1% were ART-naïve, and the majority of the treated were on an efavirenz + cytosine analogue + tenofovir regimen. Deep sequencing analysis, with a variant abundance threshold of 20%, revealed NRTI resistance mutations such as M184V in 2% of ART-naïve and 32% of treated individuals. Tenofovir resistance mutations K65R and K70E were found in 12% and 5% of ART-experienced individuals, respectively, and in less than 1% of ART-naïve individuals. Integrase inhibitor resistance mutations were notably infrequent (< 1%). Prevalence of pre-treatment drug resistance to NNRTIs was 10%, predominantly consisting of the K103N mutation. Among those with viraemic ART, NNRTI resistance was 50%, with rilpivirine-associated mutations observed in 9% of treated and 6% of untreated individuals. Cluster analysis revealed that 20% (205/1,050) of those sequenced were part of a cluster. We identified 171 groups with at least two linked participants; three quarters of clusters had only two individuals, and a quarter had 3-6 individuals. Integrating phylogenetic with geospatial analyses, we revealed a complex transmission network with significant clustering in specific regions, notably peripheral and rural areas. These findings derived from population scale genomic analyses are encouraging in terms of the limited resistance to DTG, but indicate that transitioning to long-acting cabotegravir + rilpivirine for transmission reduction should be accompanied by prior screening for rilpivirine resistance. Whole HIV-1 genome sequencing allowed identification of significant proportions of clusters with multiple individuals, and geospatial analyses suggesting decentralised networks can inform targeting public health interventions to effectively curb HIV-1 transmission.

Developing a diversity, equity and inclusion compass to guide scientific capacity strengthening efforts in Africa.

Diversity, equity and inclusion (DEI) in science is vital to improve the scientific process and ensure societal uptake and application of scientific results. DEI challenges include a full spectrum of issues from the lack of, and promotion of, women in science, to the numerous barriers in place that limit representation of African scientists in global scientific efforts. DEI principles in African science remain relatively underdeveloped, with limited engagement and discussion among all stakeholders to ensure that initiatives are relevant to local environments. The Sub-Saharan African Network for TB/HIV research Excellence (SANTHE) is a network of African-led research in HIV, tuberculosis (TB), associated co-morbidities, and emerging pathogens, now based in eight African countries. Our aim, as a scientific capacity strengthening network, was to collaboratively produce a set of DEI guidelines and to represent them visually as a DEI compass. We implemented a consortium-wide survey, focus group discussions and a workshop where we were able to identify the key DEI challenges as viewed by scientists and support staff within the SANTHE network. Three thematic areas were identified: 1. Conquering Biases, 2. Respecting the Needs of a Diverse Workforce (including mental health challenges, physical disability, career stability issues, demands of parenthood, and female-specific challenges), and 3. Promotion of African Science. From this we constructed a compass that included proposed steps to start addressing these issues. The use of the compass metaphor allows 're-adjustment/re-positioning' making this a dynamic output. The compass can become a tool to establish an institution's DEI priorities and then to progress towards them.

How to improve research capacity strengthening efforts: learning from the monitoring and evaluation of four research consortia in Africa.

Recent efforts to shift the control and leadership of health research on African issues to Africa have led to increased investments for scientific research capacity strengthening (RCS) on the continent and a greater demand for accountability, value for money and demonstration of return on investment. There is limited literature on monitoring and evaluation (M&E) of RCS systems and there is a clear need to further explore whether the M&E frameworks and approaches that are currently used are fit for purpose. The M&E approaches taken by four African RCS consortia funded under the Developing Excellence in Leadership, Training and Science in Africa (DELTAS) I initiative were assessed using several methods, including a framework comparison of the M&E approaches, semi-structured interviews and facilitated discussion sessions. The findings revealed a wide range in the number of indicators used in the M&E plans of individual consortium, which were uniformly quantitative and at the output and outcome levels. Consortia revealed that additional information could have been captured to better evaluate the success of activities and measure the ripple effects of their efforts. While it is beneficial for RCS consortia to develop and implement their own M&E plans, this could be strengthened by routine engagement with funders/programme managers to further align efforts. It is also important for M&E plans to consider qualitative data capture for assessment of RCS efforts. Efforts could be further enhanced by supporting platforms for cross-consortia sharing, particularly when trying to assess more complex effects. Consortia should make sure that processes for developmental evaluation, and capturing and using the associated learning, are in place. Sharing the learning associated with M&E of RCS efforts is vital to improve future efforts. Investing and improving this aspect of RCS will help ensure tracking of progress and impact of future efforts, and ensure accountability and the return on investment. The findings are also likely applicable well beyond health research.

Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy.

BACKGROUND: For optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial phenotypes. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve anti-viral immune responses. METHODS: After consent and voluntary participation was confirmed, whole blood was drawn from HIV uninfected women and women with chronic HIV infection on long-term combination antiretroviral therapy (HIV/cART). Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescently tagged metabolites and markers of mitochondrial activity: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. RESULTS: During chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. CONCLUSIONS: Significant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells be dysfunctional or may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

Hen egg white bovine colostrum supplement reduces symptoms of mild/moderate COVID-19: a randomized control trial.

Aim: The ability of a hen egg white bovine colostrum supplement to prevent severe COVID-19 was tested in a double-blind randomized control study. Methods: Adults with mild/moderate COVID-19, risk factors for severe disease, and within 5 days of symptom onset were assigned to the intervention (n = 77) or placebo (n = 79) arms. Symptoms were documented until day 42 post-enrollment and viral clearance was assessed at 11-13 days post-symptom onset. Results: One participant developed severe COVID-19. The severe-type symptom score was lower in the active arm at 11-13 days post-symptom onset (p = 0.049). Chest pain, fever/chills, joint pain/malaise, and sore throat were significantly less frequent in the active arm. No differences in viral clearance were observed. Conclusion: The intervention reduced symptoms of mild/moderate COVID-19. Clinical Trial Registration: DOH-27-062021-9191 (South African National Clinical Trials Register).

Natural proteins found in milk (lactoferrin) and egg white (ovotransferrin and lysozyme) could have therapeutic value in COVID-19 through their effects on the immune system. We identified bovine colostrum and hen egg white powders containing adequate quantities of these proteins. We investigated whether short-term daily consumption of a hen egg white and bovine colostrum mixture (reconstituted with glycerin and water) could reduce the risk of progression to severe disease and assist in the recovery of patients with mild or moderate COVID-19. Adults with mild or moderate COVID-19 who were within 5 days of symptom onset and had risk factors for severe disease were enrolled, and randomly assigned to take a hen egg white and bovine colostrum mixture or placebo mixture twice daily for 5 days, and then followed up telephonically for 6 weeks. The main findings were that consumption of the hen egg white and bovine colostrum mixture was associated with fewer protocol-defined severe-type symptoms overall, and in particular lower frequencies of joint pain/malaise, chest pain, fever/chills, and sore throat. Only one individual developed severe COVID-19 and therefore the effect of the intervention on reducing the risk of progression to severe disease could not be assessed. The results of this study suggest that consumption of the hen egg white bovine colostrum mixture within a few days of symptom onset lessens symptoms in people with mild or moderate COVID-19.

Hepatitis B Virus Prevalence and Mother-to-Child Transmission Risk in an HIV Early Intervention Cohort in KwaZulu-Natal, South Africa.

Background: HIV and hepatitis B virus (HBV) prevalence are both high in KwaZulu-Natal, South Africa. HIV coinfection negatively affects HBV prognosis and can increase the likelihood of HBV mother-to-child transmission (MTCT). In an early HIV infant treatment intervention cohort of HIV-transmitting mother-child pairs in KwaZulu-Natal, we characterized maternal HBV prevalence and screened infants at risk. Methods: Infants were treated for HIV MTCT at birth, and combination regimens incidentally active against HBV were initiated within 21 days. Maternal samples (N = 175) were screened at birth for HBV infection (HBV surface antigen [HBsAg]), exposure to HBV (HBV anti-core IgG), and vaccination responses (HBV anti-S positive without other HBV markers). Infants of mothers who were HBV positive were screened for HBsAg at 1 and 12 months. Results: Evidence of HBV infection was present in 8.6% (n = 15) of maternal samples. Biomarkers for HBV exposure were present in 31.4% (n = 55). Evidence of HBV vaccination was uncommon in mothers (8.0%; n = 14). Despite prescription of antiretroviral therapy (ART) active against HBV, HBV DNA was detectable in 46.7% (7/15) of mothers who were HBsAg positive. Three mothers had HBV viral loads >5.3 log10 IU/mL, making them high risk for HBV MTCT. Screening of available infant samples at 1 month (n = 14) revealed no cases of HBV MTCT. At 12 months, we identified 1 HBV infection (1/13), and serologic evidence of vaccination was present in 53.8% (7/13) of infants. Discussion: This vulnerable cohort of HIV-transmitting mothers had a high prevalence of undiagnosed HBV. Early infant ART may have reduced the risk of MTCT in high-risk cases. Current HBV guidelines recommend ART prophylaxis, but these data underline the pressing need to increase availability of birth dose vaccines.

The met and unmet health needs for HIV, hypertension, and diabetes in rural KwaZulu-Natal, South Africa: analysis of a cross-sectional multimorbidity survey.

BACKGROUND: The convergence of infectious diseases and non-communicable diseases in South Africa is challenging to health systems. In this analysis, we assessed the multimorbidity health needs of individuals and communities in rural KwaZulu-Natal and established a framework to quantify met and unmet health needs for individuals living with infectious and non-communicable diseases. METHODS: We analysed data collected between May 25, 2018, and March 13, 2020, from participants of a large, community-based, cross-sectional multimorbidity survey (Vukuzazi) that offered community-based HIV, hypertension, and diabetes screening to all residents aged 15 years or older in a surveillance area in the uMkhanyakude district in KwaZulu-Natal, South Africa. Data from the Vukuzazi survey were linked with data from demographic and health surveillance surveys with a unique identifier common to both studies. Questionnaires were used to assess the diagnosed health conditions, treatment history, general health, and sociodemographic characteristics of an individual. For each condition (ie, HIV, hypertension, and diabetes), individuals were defined as having no health needs (absence of condition), met health needs (condition that is well controlled), or one or more unmet health needs (including diagnosis, engagement in care, or treatment optimisation). We analysed met and unmet health needs for individual and combined conditions and investigated their geospatial distribution. FINDINGS: Of 18 041 participants who completed the survey (12 229 [67·8%] were female and 5812 [32·2%] were male), 9898 (54·9%) had at least one of the three chronic diseases measured. 4942 (49·9%) of these 9898 individuals had at least one unmet health need (1802 [18·2%] of 9898 needed treatment optimisation, 1282 [13·0%] needed engagement in care, and 1858 [18·8%] needed a diagnosis). Unmet health needs varied by disease; 1617 (93·1%) of 1737 people who screened positive for diabetes, 2681 (58·2%) of 4603 people who screened positive for hypertension, and 1321 (21·7%) of 6096 people who screened positive for HIV had unmet health needs. Geospatially, met health needs for HIV were widely distributed and unmet health needs for all three conditions had specific sites of concentration; all three conditions had an overlapping geographical pattern for the need for diagnosis. INTERPRETATION: Although people living with HIV predominantly have a well controlled condition, there is a high burden of unmet health needs for people living with hypertension and diabetes. In South Africa, adapting current, widely available HIV care services to integrate non-communicable disease care is of high priority. FUNDING: Fogarty International Center and the National Institutes of Health, the Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, the South African Medical Research Council, the South African Population Research Infrastructure Network, and the Wellcome Trust. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.

'With this study, we have hope that something is coming': community members' perceptions of HIV cure-related research in Durban, South Africa - a qualitative focus group study.

BACKGROUND: Developing a cure for HIV remains a global scientific priority. In 2022, the Females Rising through Education, Support and Health (FRESH) cohort launched an HIV cure-related trial involving an analytical treatment interruption (ATI) in Durban, South Africa. OBJECTIVES: To explore community perspectives about HIV cure-related research. METHODS: Between July-August 2022, we conducted three focus groups with community members. We transcribed audio recordings verbatim and used content analysis to analyze the data. RESULTS: Twenty community members (13 women and 7 men) participated in three focus groups (HIV status not included). Participants viewed HIV cure-related research as a way to address the issue of defaulting on (not taking) HIV treatment. Participants expressed hesitancy around ATIs, since these contradict longstanding treatment adherence messages. Participants shared concerns around the risk of side effects from experimental interventions balanced against potential efficacy. They advocated for trial participants to have the right to decide whether to inform their sex partners about their HIV status and ATI participation, rather than research teams making disclosure mandatory. Focus group participants also emphasized the importance of using simple language to explain HIV cure-related research. CONCLUSIONS: With HIV cure trials set to launch across Africa in the future, there is a critical need to better understand and respond to local community needs and preferences and to adopt this as standard practice prior to regional trial implementation.