NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials

BACKGROUND HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. METHODS Data from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. RESULTS Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. CONCLUSIONS A single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated. TRIAL REGISTRATION C107 = NCT00064623; C119 = NCT00321672

South African national household survey of HIV/AIDS prevalence, behavioural risks and mass media impact-detailed methodology and response rate results

Objectives. To describe the methodology used in a recent survey of HIV/AIDS in South Africa and to present the response rates.Methods. A cross-sectional, national household-based survey was conducted using second-generation surveillance procedures. A complex multistage sampling technique was used to create a master sample of 1 000 census enumerator areas out of a total of 86 000 nationally. Aerial photographs were taken and used to randomly select more than 10 197 households and ultimately 13 518 individuals from a sampling frame of 31 321 people. Phase 1 of the study involved notifying the household residents about the study and collecting key demographic information on respondents aged 2 years and older. This information was used to randomly select up to 3 respondents from each household: 1 adult (25 years and older), 1 youth (15- 24 years), and 1 child (2- 14 years). In phase 2 nurses interviewed respondents and collected oral fluid specimens for HIV testing. In the case of children aged 2 - 11 years, parents or guardians were interviewed, but HIV testing was performed on the selected children. Questionnaire data were anonymously linked with HIV test results.Results. A total of 9 963 persons agreed to be interviewed and 8 840 were tested for HIV, yielding a response rate of 73.7% and 65.4% respectively. However, only 8 428 (62.3%) HIV test results were correctly matched with behavioural data. The results showed that those tested for HIV did not differ from those not tested in terms of key determinants.Conclusion. It is possible to use community-based surveys to study the prevalence of HIV in the general population

Impacts of intimate partner violence and sexual abuse on antiretroviral adherence among adolescents living with HIV in South Africa.

OBJECTIVE: We are failing to reach 95-95-95 for adolescents living with HIV (ALHIV). Sexual abuse and intimate partner violence (IPV) may impact antiretroviral therapy (ART) adherence, with high rates of 17.4 and 29.7%, respectively, across the southern sub-Saharan African region. However, evidence on their associations with adolescent ART adherence remains limited, with only three cross-sectional studies globally. DESIGN: A prospective cohort of ALHIV (sample N = 980, 55% female individuals, baseline mean age 13.6 years) were recruited from 53 health facilities in South Africa's Eastern Cape Province and responded to a structured questionnaire at 18-month and 36-month follow-up (2015-2016, 2017-2018). METHODS: A repeated-measures random effects model assessed multivariable associations of self-reported sexual abuse and IPV with past-week ART adherence, controlling for individual, socioeconomic, and HIV-related factors. Past-week adherence was defined based on currently taking ART and not having missed any doses in the past 7 days (including weekends). We further fitted a moderation model by sex. RESULTS: Fifty-one percent of adolescents reported consistent ART adherence at both time points. Exposure to IPV was associated with lower odds of self-reported ART adherence (aOR 0.39, 95% CI 0.21-0.72, P = 0.003), as was sexual abuse (aOR 0.54, 95% CI 0.29-0.99, P = 0.048). The marginal predicted probability of ART adherence for adolescents with no exposure to either IPV or sexual abuse was 72% (95% CI 70-74%) compared with 38% (95% CI 20-56%) for adolescents with exposure to both IPV and sexual abuse. Moderation results showed similar associations between sexual violence and ART adherence by sex. CONCLUSION: Sexual violence prevention and postviolence care may be essential components of supporting adolescent ART adherence. Integration of HIV and violence prevention services will require accessible services and simple referral systems

Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial

BACKGROUND: Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. METHODS: In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074. FINDINGS: Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events. INTERPRETATION: Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection. FUNDING: National Institute for Health Research

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT).

BACKGROUND: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. METHODS: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. FINDINGS: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. INTERPRETATION: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Cross-sectional survey of sexual health professionals’ experiences and perceptions of the 2022 mpox outbreak in the UK

Objective: To understand the experiences and perceptions of sexual health professionals responding to the May 2022 mpox outbreak in the UK. Design: Cross-sectional, anonymous, online survey collecting quantitative and qualitative data. Convenience sample recruited via an international network of sexual health and HIV clinicians responding to mpox and promoted through clinical associations and social media. Survey domains included: clinical workload; preparedness, support, and training; safety at work; vaccination; and well-being. Qualitative descriptive analysis of open-text responses was conducted to support interpretation of the quantitative data. Participants: Participants who were employed as sexual health professionals in the UK and had direct clinical experience of mpox were included in the analysis. The survey was completed between 11 August and 31 October 2022 by 139 respondents, the majority of whom were doctors (72.7%), cis-female (70.5%) and White (78.4%). Results: 70.3% reported that they were required to respond to mpox in addition to their existing clinical responsibilities, with 46.8% working longer hours as a result. In the open-text data, respondents highlighted that workload pressures were exacerbated by a lack of additional funding for mpox, pre-existing pressures on sexual health services, and unrealistic expectations around capacity. 67.6% of respondents reported experiencing negative emotional impact due to their mpox work, with stress (59.0%), fatigue (43.2%) and anxiety (36.0%) being the most common symptoms. 35.8% stated that they were less likely to remain in their profession because of their experiences during the mpox outbreak. In the open-text data, these feelings were ascribed to post-COVID exhaustion, understaffing and frustration among some participants at the handling of the mpox response. Conclusions: These findings indicate that sexual health services require increased funding and resources, along with evidence-based well-being interventions, to support sexual health professionals’ outbreak preparedness and recovery

Power to participants: methodological and ethical reflections from a decade of adolescent advisory groups in South Africa

Whilst the HIV response has made significant progress in increasing representation of adults affected by HIV, the meaningful inclusion of children and adolescents has lagged. But this may be a pivotal moment of change. We report on a decade of conducting adolescent advisory groups in South Africa, to reflect on youth advisory processes. Data was collected from 2008 to 2018 from adolescent advisors (n = 60) and researchers (n = 25), and included feedback sessions, social media, anonymous “post-boxes” and interviews. Findings include the value of adolescent involvement in multiple stages of research co-creation and engagement in policy processes, the need for a safe environment and supporting adolescents living in extreme vulnerability. We also discuss the reconfiguring of power and personal relationships, and logistical and financial needs of adolescent advisory groups. Findings suggest that adolescent co-creation of research is feasible, even with very vulnerable adolescents, although ethical considerations need to be carefully addressed. Benefits include increased methodological rigour, enhanced adolescent acceptability of research and the recalibration of research dynamics for the empowerment of their target beneficiaries. Future studies could benefit from meaningfully involving adolescents through youth advisory groups

Comparative models of biological and social pathways to predict child growth through age 2 years from birth cohorts in Brazil, India, the Philippines, and South Africa

Background: Early growth faltering accounts for one-third of child deaths, and adversely impacts the health and human capital of surviving children. Social as well as biological factors contribute to growth faltering, but their relative strength and interrelations in different contexts have not been fully described. Objective: The aim of this study was to use structural equation modelling to explore social and biological multidetermination of child height at age 2 y in longitudinal data from 4 birth cohort studies in low- and middle-income countries. Methods: We analyzed data from 13,824 participants in birth cohort studies in Brazil, India, the Philippines, and South Africa. We used exploratory structural equation models, with height-for-age at 24 mo as the outcome to derive factors, and path analysis to estimate relations among a wide set of social and biological variables common to the 4 sites. Results: The prevalence of stunting at 24 mo ranged from 14.0% in Brazil to 67.7% in the Philippines. Maternal height and birthweight were strongly predictive of height-for-age at 24 mo in all 4 sites (all P values <0.001). Three social-environmental factors, which we characterized as “child circumstances,” “family socioeconomic status,” and “community facilities,” were identified in all sites. Each social-environmental factor was also strongly predictive of height-for-age at 24 mo (all P values <0.001), with some relations partly mediated through birthweight. The biological pathways accounted for 59% of the total explained variance and the social-environmental pathways accounted for 41%. The resulting path coefficients were broadly similar across the 4 sites. Conclusions: Early child growth faltering is determined by both biological and social factors. Maternal height, itself a marker of intergenerational deprivation, strongly influences child height at 2 y, including indirect effects through birthweight and social factors. However, concurrent social factors, many of which are modifiable, directly and indirectly contribute to child growth. This study highlights opportunities for interventions that address both biological and social determinants over the long and short term

The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E–binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.National Institutes of Health (U.S.) (P01 HL032262

Involvement of integrin-linked kinase in capillary/tube-like network formation of human vascular endothelial cells

Angiogenesis is a complex process involving an ECM and vascular endothelial cells (EC), and is regulated by various angiogenic factors including VEGF. The ability to form a capillary/tube-like network is a specialized function of EC. Therefore, in vitro angiogenesis was assessed by a capillary/tube-like network formation assay. There are three angiogenic parameters: capillary length, number of capillaries, and relative capillary area per field. We evaluated capillary length per field in the assay. VEGF promoted capillary/tube-like network formation of EC in a type I collagen gel matrix in vitro. Moreover, we demonstrated the involvement of ILK in a VEGF signaling pathway mediating capillary/tube-like network formation of EC using dominant-negative, kinase deficient ILK. This is a straightforward assay to monitor responses of human vascular endothelial cells