Risk Factors for HIV Acquisition in High Risk Women in a Generalised Epidemic Setting.

In South Africa young women bear a disproportionate burden of HIV infection however, risk factors for HIV acquisition are not fully understood in this setting. In a cohort of 245 women, we used proportional hazard regression analysis to examine the association of demographic, clinical and behavioural characteristics with HIV acquisition. The overall HIV incidence rate (IR) was 7.20 per 100 women years (wy), 95 % confidence interval (CI) 4.50-9.80. Women 18-24 years had the highest HIV incidence (IR 13.20 per 100 wy, 95 % CI 6.59-23.62) and were almost three times more likely to acquire HIV compared to women 25 years and older [adjusted Hazard Ratio (aHR) 2.61, 95 % CI 1.05-6.47]. Similarly, women in relationships with multiple sex partners had more than twice the risk of acquiring HIV when compared to women who had no partner or who had a husband or stable partner (aHR 2.47, 95 % CI 0.98-6.26). HIV prevention programmes must address young women's vulnerability and sex partner reduction in this setting.

Individualised motivational counselling to enhance adherence to antiretroviral therapy is not superior to didactic counselling in South African patients: findings of the CAPRISA 058 randomised controlled trial.

Concerns that standard didactic adherence counselling may be inadequate to maximise antiretroviral therapy (ART) adherence led us to evaluate more intensive individualised motivational adherence counselling. We randomised 297 HIV-positive ART-naïve patients in Durban, South Africa, to receive either didactic counselling, prior to ART initiation (n = 150), or an intensive motivational adherence intervention after initiating ART (n = 147). Study arms were similar for age (mean 35.8 years), sex (43.1 % male), CD4+ cell count (median 121.5 cells/µl) and viral load (median 119,000 copies/ml). Virologic suppression at 9 months was achieved in 89.8 % of didactic and 87.9 % of motivational counselling participants (risk ratio [RR] 0.98, 95 % confidence interval [CI] 0.90-1.07, p = 0.62). 82.9 % of didactic and 79.5 % of motivational counselling participants achieved >95 % adherence by pill count at 6 months (RR 0.96, 95 % CI 0.85-1.09, p = 0.51). Participants receiving intensive motivational counselling did not achieve higher treatment adherence or virological suppression than those receiving routinely provided didactic adherence counselling. These data are reassuring that less resource intensive didactic counselling was adequate for excellent treatment outcomes in this setting.

Rapid disease progression in HIV-1 subtype C-infected South African women.

BACKGROUND: Whereas human immunodeficiency virus (HIV) subtype B-infected individuals generally progress to AIDS within 8-10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C-infected South African women. METHODS: Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/µL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. RESULTS: Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34-59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/µL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/µL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31-3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51-9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31-15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non-rapid progression (HR, 0.19; 95% CI, .05-.74; P = .016). CONCLUSIONS: Nearly half of subtype C-infected women progressed to a CD4 count <350 cells/µL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/µL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection.

Assessing adherence in the CAPRISA 004 tenofovir gel HIV prevention trial: results of a nested case-control study.

Adherence undeniably impacts product effectiveness in microbicide trials, but the connection has proven challenging to quantify using routinely collected behavioral data. We explored this relationship using a nested case-control study in the CAPRISA 004 Tenofovir (TFV) gel HIV prevention trial. Detailed 3-month recall data on sex events, condom and gel use were collected from 72 incident cases and 205 uninfected controls. We then assessed how the relationship between self-reported adherence and HIV acquisition differed between the TFV and placebo gel groups, an interaction effect that should exist if effectiveness increases with adherence. The CAPRISA 004 trial determined that randomization to TFV gel was associated with a significant reduction in risk of HIV acquisition. In our nested case-control study, however, we did not observe a meaningful decrease in the relative odds of infection-TFV versus placebo-as self-reported adherence increased. To the contrary, exploratory sub-group analysis of the case-control data identified greater evidence for a protective effect of TFV gel among participants reporting less than 80 % adherence to the protocol-defined regimen (odds ratio (OR) 0.30; 95 % CI 0.11-0.78) than among those reporting ≥ 80 % adherence (Odds Ratio 0.81; 95 % CI 0.34-1.92). The small number of cases may have inhibited our ability to detect the hypothesized interaction between adherence and effectiveness. Nonetheless, our results re-emphasize the challenges faced by investigators when adherence may be miss-measured, miss-reported, or confounded with the risk of HIV.

Impact of antiretroviral therapy on health-related quality of life among South African women in the CAPRISA 002 acute infection study.

Concerns are often raised regarding potentially adverse effects of antiretroviral therapy (ART) on health-related quality of life (HRQoL), but there is limited longitudinal data to prove this. Building on our prior investigation, we examined the impact of ART on HRQoL among HIV-infected South African women with extensive follow-up in the CAPRISA 002 Acute Infection Cohort Study. Overall HRQoL and five sub-domains [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were assessed using the Functional Assessment of HIV Infection (FAHI) instrument. Our analyses comparing FAHI scores between pre-ART (established infection) and ART phases using paired Wilcoxon signed-rank tests and adjusted mixed-effects regression models revealed improvements on ART in overall HRQoL, and in PWB, EWB, and SWB, but not in FGWB and CF. No long-term adverse impact of ART on HRQoL was detected, providing additional non-biomedical support to early treatment strategies.

Health-related quality of life dynamics of HIV-positive South African women up to ART initiation: evidence from the CAPRISA 002 acute infection cohort study.

Few studies have investigated the long-term dynamics in health-related quality of life (HRQoL) among HIV-positive persons from acute infection. From 2004, 160 women were enrolled into the CAPRISA 002 Acute Infection study at two sites in the province of KwaZulu-Natal and underwent 3-6 monthly HRQoL assessments using the functional assessment of HIV infection (FAHI) instrument. Overall and 5 sub-scale FAHI scores [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were calculated up to antiretroviral therapy (ART) initiation and scores at enrollment were compared to the acute, early and established infection phases. Mixed-effects regression models adjusting for behavioral and clinical factors were applied to assess HRQoL trends and the proportion of women meeting minimally important differences was calculated. Our analyses revealed that overall/sub-scale scores improved over time, except from PWB and CF. A higher educational status, contraceptive use and a higher BMI were the strongest predictors of higher overall/sub-scale FAHI scores. CD4 count and HIV viral load were strongly associated with PWB and CF, but not overall FAHI and other sub-scales. Women newly diagnosed with acute HIV infection face profound HRQoL challenges. While early ART delivery may be important for PWB and CF, factors such as education, contraception provision and good nutritional status should be promoted to maximize HRQoL in HIV positive individuals.

HIV transmission risk behavior among HIV-positive patients receiving antiretroviral therapy in KwaZulu-Natal, South Africa.

The aim of this investigation was to identify factors associated with HIV transmission risk behavior among HIV-positive women and men receiving antiretroviral therapy (ART) in KwaZulu-Natal, South Africa. Across 16 clinics, 1,890 HIV+ patients on ART completed a risk-focused audio computer-assisted self-interview upon enrolling in a prevention-with-positives intervention trial. Results demonstrated that 62 % of HIV-positive patients' recent unprotected sexual acts involved HIV-negative or HIV status unknown partners. For HIV-positive women, multivariable correlates of unprotected sex with HIV-negative or HIV status unknown partners were indicative of poor HIV prevention-related information and of sexual partnership-associated behavioral skills barriers. For HIV-positive men, multivariable correlates represented motivational barriers, characterized by negative condom attitudes and the experience of depressive symptomatology, as well as possible underlying information deficits. Findings suggest that interventions addressing gender-specific and culturally-relevant information, motivation, and behavioral skills barriers could help reduce HIV transmission risk behavior among HIV-positive South Africans.

Trial participation disclosure and gel use behavior in the CAPRISA 004 tenofovir gel trial.

Disclosure, or open communication, by female microbicide trial participants of their trial participation and use of an investigational HIV prevention drug to a sexual partner may affect participants' trial product usage behavior and contribute to poor adherence. With mixed results from recent microbicide clinical trials being linked to differing participant adherence, insights into the communication dynamics between trial participants and their sexual partners are particularly important. We examined the quantitative association between (1) communication of trial participation to a partner and participant adherence to gel and (2) communication of trial participation to a partner and participant HIV status. An in-depth adherence and product acceptability assessment was administered to the women participating in the CAPRISA 004 trial. Additionally, we collected qualitative data related to communication of trial participation and gel use. Qualitatively, among 165 women who had reported that they had discussed trial participation with others, most (68%) stated that they communicated participation to their sexual partner. Most of the women who had communicated study participation with their partners had received a positive/neutral response from their partner. Some of these women stated that gel use was easy; only a small number said that gel use was difficult. Among women who did not communicate their study participation to their partners, difficulty with gel use was more common and some women stated that they feared communicating their participation. Quantitatively, there was no statistically significant difference in the proportions of women who had communicated study participation to a partner across different adherence levels or HIV status. A deeper knowledge of the dynamics surrounding trial participation communication to male partners will be critical to understanding the spectrum of trial product usage behavior, and ultimately to designing tailored strategies to assist trial participants with product adherence.

Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa.

BACKGROUND: Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. METHODS: HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. RESULTS: Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5-7.2)], clinical symptoms were not. CONCLUSIONS: Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.

One-year recovery rates for young people with depression and/or anxiety not receiving treatment: a systematic review and meta-analysis.

OBJECTIVES: To systematically review 1-year recovery rates for young people experiencing depression and/or anxiety who are not receiving any specific mental health treatment. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, PsycINFO, Web of Science and Global Health were searched for articles published from 1980 through to August 2022. ELIGIBILITY CRITERIA: Articles were peer-reviewed, published in English and had baseline and 1-year follow-up depression and/or anxiety outcomes for young people aged 10-24 years without specific treatment. DATA EXTRACTION AND SYNTHESIS: Three reviewers extracted relevant data. Meta-analysis was conducted to calculate the proportion of individuals classified as recovered after 1 year. The quality of evidence was assessed by the Newcastle-Ottawa Scale. RESULTS: Of the 17 250 references screened for inclusion, five articles with 1011 participants in total were included. Studies reported a 1-year recovery rate of between 47% and 64%. In the meta-analysis, the overall pooled proportion of recovered young people is 0.54 (0.45 to 0.63). CONCLUSIONS: The findings suggest that after 1 year about 54% of young people with symptoms of anxiety and/or depression recover without any specific mental health treatment. Future research should identify individual characteristics predicting recovery and explore resources and activities which may help young people recover from depression and/or anxiety. PROSPERO REGISTRATION NUMBER: CRD42021251556.

Mental health problems and resilience in adolescents during the COVID-19 pandemic in a post-armed conflict area in Colombia.

The impact of COVID-19 pandemic on mental health of adolescents are emerging and require particular attention in settings where challenges like armed conflict, poverty and internal displacement have previously affected their mental wellbeing. This study aimed to determine the prevalence of anxiety symptoms, depressive symptomatology, probable post-traumatic stress disorder and resilience in school-attending adolescents in a post-conflict area of Tolima, Colombia during the COVID-19. A cross-sectional study was carried out with 657 adolescents from 12 to 18 years old, recruited by convenience sampling in 8 public schools in the south of Tolima, Colombia, who completed a self-administered questionnaire. Mental health information was obtained through screening scales for anxiety symptoms (GAD-7), depressive symptomatology (PHQ-8), probable post-traumatic stress disorder (PCL-5) and resilience (CD-RISC-25). The prevalence observed for moderate to severe anxiety symptoms was 18.9% (95% CI 16.0-22.1) and for moderate to severe depressive symptomatology was 30.0% (95% CI 26.5-33.7). A prevalence of probable post-traumatic stress disorder (PTSD) of 22.3% (95% CI 18.1-27.2) was found. The CD-RISC-25 results for resilience had a median score of 54 [IQR 30]. These results suggest that approximately two-thirds of school-attending adolescents in this post-conflict area experienced at least one mental health problem such as anxiety symptoms, depressive symptomatology or probable PTSD during the COVID-19 pandemic. Future studies are of interest to establish the causal relationship between these findings and the impact of the pandemic. These findings highlight the challenge that schools have after pandemic to address the mental health of their students in order to promoting adequate coping strategies and implement prompt multidisciplinary interventions to reduce the burden of mental health problems in adolescents.

Feasibility and outcomes of using DIALOG+ in primary care to improve quality of life and mental distress of patients with long-term physical conditions: an exploratory non-controlled study in Bosnia and Herzegovina, Colombia and Uganda.

INTRODUCTION: The management of long-term physical conditions is a challenge worldwide, absorbing a majority resources despite the importance of acute care. The management of these conditions is done largely in primary care and so interventions to improve primary care could have an enormous impact. However, very little data exist on how to do this. Mental distress is frequently comorbid with long term physical conditions, and can impact on health behaviour and adherence, leading to poorer outcomes. DIALOG+ is a low-cost, patient-centred and solution-focused intervention, which is used in routine patient-clinician meetings and has been shown to improve outcomes in mental health care. The question arises as to whether it could also be used in primary care to improve the quality of life and mental health of patients with long-term physical conditions. This is particularly important for low- and middle-income countries with limited health care resources. METHODS: An exploratory non-controlled multi-site trial was conducted in Bosnia and Herzegovina, Colombia, and Uganda. Feasibility was determined by recruitment, retention, and session completion. Patient outcomes (quality of life, anxiety and depression symptoms, objective social situation) were assessed at baseline and after three approximately monthly DIALOG+ sessions. RESULTS: A total of 117 patients were enrolled in the study, 25 in Bosnia and Herzegovina, 32 in Colombia, and 60 in Uganda. In each country, more than 75% of anticipated participants were recruited, with retention rates over 90% and completion of the intervention exceeding 92%. Patients had significantly higher quality of life and fewer anxiety and depression symptoms at post-intervention follow-up, with moderate to large effect sizes. There were no significant improvements in objective social situation. CONCLUSION: The findings from this exploratory trial suggest that DIALOG+ is feasible in primary care settings for patients with long-term physical conditions and may substantially improve patient outcomes. Future research may test implementation and effectiveness of DIALOG+ in randomized controlled trials in wider primary care settings in low- and middle-income countries. TRIAL REGISTRATION: All studies were registered prospectively within the ISRCTN Registry. ISRCTN17003451, 02/12/2020 (Bosnia and Herzegovina), ISRCTN14018729, 01/12/2020 (Colombia) and ISRCTN50335796, 02/12/2020 (Uganda).

Development and Implementation of DIALOG+S in the School Setting as a Tool for Promoting Adolescent Mental Well-Being and Resilience in a Post-Armed Conflict Area in Colombia: Exploratory Cluster Randomized Controlled Trial.

BACKGROUND: Educational settings are ideal for promoting mental well-being and resilience in children. The challenges of the COVID-19 pandemic made evident the important role that teachers and school counselors play in the mental health of their students. Therefore, it is imperative to develop and implement cost-effective interventions that allow them to identify and address mental health problems early, especially in post-armed conflict areas, to reduce the burden of mental disorders in this population. OBJECTIVE: This study aimed to adapt an existing patient-focused digital intervention called DIALOG+ from an adult clinical setting to an adolescent educational setting and to assess the feasibility, acceptability, and estimated effect of implementing this intervention as a tool for promoting quality of life, mental well-being, and resilience. METHODS: We conducted an exploratory mixed methods study in 2 public schools in postconflict areas in Tolima, Colombia. This study was conducted in 3 phases. In the adaptation phase, focus groups were conducted with students and teachers to identify changes required in DIALOG+ for it to be used in the school setting. The exploration phase consisted of an exploratory cluster randomized controlled trial. A total of 14 clusters, each with 1 teacher and 5 students, were randomly allocated to either the experimental (DIALOG+S) group or to an active control group (counseling as usual). Teachers in both groups delivered the intervention once a month for 6 months. Through screening scales, information was collected on mental health symptoms, quality of life, self-esteem, resilience, and family functionality before and after the intervention. Finally, the consolidation phase explored the experiences of teachers and students with DIALOG+S using focus group discussions. RESULTS: The changes suggested by participants in the adaptation phase highlighted the central importance of the school setting in the mental health of adolescents. In the exploratory phase, 70 participants with a mean age of 14.69 (SD 2.13) years were included. Changes observed in the screening scale scores of the intervention group suggest that the DIALOG+S intervention has the potential to improve aspects of mental health, especially quality of life, resilience, and emotional symptoms. The consolidation phase showed that stakeholders felt that using this intervention in the school setting was feasible, acceptable, and an enriching experience that generated changes in the perceived mental health and behavior of participants. CONCLUSIONS: Our results are encouraging and show that the DIALOG+S intervention is feasible and acceptable as a promising opportunity to promote well-being and prevent and identify mental health problems in the school context in a postconflict area in Colombia. Larger, fully powered studies are warranted to properly assess the efficacy and potential impact of the intervention and to refine implementation plans. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) registry ISRCTN14396374; https://www.isrctn.com/ISRCTN14396374. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/40286.

What are the expectations and experiences of a GMH research programme delivered in Bosnia-Herzegovina, Colombia and Uganda? A prospective longitudinal qualitative study.

OBJECTIVES: Global health research collaborations between partners in high-income countries and low-income and middle-income countries (LMICs) aim to generate new evidence, strengthen research capacity, tackle health inequalities and improve outcomes. Previous evaluations of such programmes have identified areas for improvement but consisted only of retrospective experiences. We conducted the first prospective study to assess the initial expectations as well as the final experiences of participants of a global health research programme. DESIGN, SETTINGS AND PARTICIPANTS: This study adopted a prospective longitudinal qualitative study, 38 participants of a global mental health research programme with partners in Bosnia-Herzegovina, Colombia, Uganda and the (UK). The interviewees included senior investigators, coordinators and researchers. Framework analysis was used to analyse the data. OUTCOME MEASURES: Participants were interviewed about their initial expectations at the inception of the research programme and their final experiences at the end. RESULTS: Many of the original expectations were later reported as met or even exceeded. They included experiences of communication, relationships, developed research expertise, further research opportunities and extending networks. However, other expectations were not met or only partially met, mainly on developing local leadership, strengthening institutional research capacity and opportunities for innovation and for mutual learning. Around equity of partnership and ownership of research the views of participants in the UK tended to be more critical than those of partners in LMICs. CONCLUSIONS: The findings suggest that global health research programmes can achieve several of their aims, and that partners in LMICs feel equity has been established in the partnership despite the imbalance of the funding arrangement. Aims of global health research projects should have a realistic focus and be proportionate to the parameters of the funding arrangement. More resources and longer time scales may be required to address sustainable structural capacity and long-standing local leadership sufficiently.

Adapting DIALOG+ in a School Setting-A Tool to Support Well-being and Resilience in Adolescents Living in Postconflict Areas During the COVID-19 Pandemic: Protocol for a Cluster Randomized Exploratory Study.

BACKGROUND: Colombia has a long history of an armed conflict that has severely affected communities with forced internal displacement and violence. Victims of violence and armed conflicts have higher rates of mental health disorders, and children and adolescents are particularly affected. However, the mental health needs of this population are often overlooked, especially in low- and middle-Income countries, where scarcity of resources exacerbates the problem that has been further compounded by the global COVID-19 pandemic. Thus, special attention should be paid to the development of interventions that target this population. OBJECTIVE: Our research aims to adapt an existing patient-centered digital intervention called DIALOG+ from a clinical setting to an educational setting using stakeholders' (teachers' and students') perspectives. We aim to evaluate the feasibility, acceptability, and estimated effect of implementing this intervention as a tool for the identification and mobilization of personal and social resources to mitigate the impact of social difficulties and to promote mental well-being. METHODS: We will conduct an exploratory mixed methods study in public schools of postconflict areas in Tolima, Colombia. The study consists of 3 phases: adaptation, exploration, and consolidation of the DIALOG+ tool. The adaptation phase will identify possible changes that the intervention requires on the basis of data from focus groups with teachers and students. The exploration phase will be an exploratory cluster randomized trial with teachers and school counselors to assess the acceptability, feasibility, and estimated effect of DIALOG+ for adolescents in school settings. Adolescents' data about mental health symptoms and wellness will be collected before and after DIALOG+ implementation. During this phase, teachers or counselors who were part of the intervention group will share their opinions through the think-aloud method. Lastly, the consolidation phase will consist of 2 focus groups with teachers and students to discuss their experiences and to understand acceptability. RESULTS: Study recruitment was completed in March 2022, and follow-up is anticipated to last through November 2022. CONCLUSIONS: This exploratory study will evaluate the acceptability, feasibility, and estimated effect of DIALOG+ for adolescents in postconflict school settings in Colombia. The use of this technology-supported tool aims to support interactions between teachers or counselors and students and to provide an effective student-centered communication guide. This is an innovative approach in both the school and the postconflict contexts that could help improve the mental health and wellness of adolescents in vulnerable zones in Colombia. Subsequent studies will be needed to evaluate the effectiveness of DIALOG+ in an educational context as a viable option to reduce the gap and inequities of mental health care access. TRIAL REGISTRATION: ISRCTN Registry ISRCTN14396374; https://www.isrctn.com/ISRCTN14396374?q=ISRCTN14396374. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40286.

Fluidity of HIV-1-specific T-cell responses during acute and early subtype C HIV-1 infection and associations with early disease progression.

Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.

Feasibility, experiences and outcomes of using DIALOG+ in primary care to improve quality of life and mental distress of patients with chronic conditions: an exploratory non-controlled trial in Bosnia and Herzegovina, Colombia and Uganda.

BACKGROUND: DIALOG+ is a resource-oriented and evidence-based intervention to improve quality of life and reduce mental distress. While it has been extensively studied in mental health care, there is little evidence for how to use it in primary care settings for patients with chronic physical conditions. Considering that DIALOG+ is used in existing routine patient-clinician meetings and is very low cost, it may have the potential to help large numbers of patients with chronic physical conditions, mental distress and poor quality of life who are treated in primary care. This is particularly relevant in low- and middle-income countries (LMICs) where resources for specialised services for such patients are scarce or non-existent. METHODS: An exploratory non-controlled trial will be conducted to primarily assess the feasibility and acceptability and, secondarily, outcomes of delivering DIALOG+ to patients with chronic physical conditions and poor quality of life in primary care settings in Bosnia and Herzegovina, Colombia and Uganda. Thirty patients in each country will receive DIALOG+ up to three times in monthly meetings over a 3-month period. Feasibility will be assessed by determining the extent to which the intervention is implemented as planned. Experiences will be captured in interviews and focus groups with care providers and participants to understand acceptability. Quality of life, symptoms of anxiety and depression, objective social situation and health status will be assessed at baseline and again after the three-session intervention. DISCUSSION: This study will inform our understanding of the extent to which DIALOG+ may be used in the routine care of patients with chronic physical conditions in different primary care settings. The findings of this exploratory trial can inform the design of future full randomised controlled trials of DIALOG+ in primary care settings in LMICs. TRIAL REGISTRATION: All studies were registered prospectively (on 02/12/2020 for Uganda and Bosnia and Herzegovina, and 01/12/2020 for Colombia) within the ISRCTN Registry. ISRCTN17003451 (Bosnia and Herzegovina), ISRCTN14018729 (Colombia) and ISRCTN50335796 (Uganda). Protocol version and date: v2.0; 28/07/2020 (Bosnia and Herzegovina), v0.3 02/08/2020 (Colombia) and v1.0, 05/11/2020 (Uganda).

Human immunodeficiency virus-specific gamma interferon enzyme-linked immunospot assay responses targeting specific regions of the proteome during primary subtype C infection are poor predictors of the course of viremia and set point.

It is unknown whether patterns of human immunodeficiency virus (HIV)-specific T-cell responses during acute infection may influence the viral set point and the course of disease. We wished to establish whether the magnitude and breadth of HIV type 1 (HIV-1)-specific T-cell responses at 3 months postinfection were correlated with the viral-load set point at 12 months and hypothesized that the magnitude and breadth of HIV-specific T-cell responses during primary infection would predict the set point. Gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay responses across the complete proteome were measured in 47 subtype C HIV-1-infected participants at a median of 12 weeks postinfection. When corrected for amino acid length and individuals responding to each region, the order of recognition was as follows: Nef > Gag > Pol > Rev > Vpr > Env > Vpu > Vif > Tat. Nef responses were significantly (P < 0.05) dominant, targeted six epitopic regions, and were unrelated to the course of viremia. There was no significant difference in the magnitude and breadth of responses for each protein region with disease progression, although there was a trend of increased breadth (mean, four to seven pools) in rapid progressors. Correlation of the magnitude and breadth of IFN-gamma responses with the viral set point at 12 months revealed almost zero association for each protein region. Taken together, these data demonstrate that the magnitude and breadth of IFN-gamma ELISPOT assay responses at 3 months postinfection are unrelated to the course of disease in the first year of infection and are not associated with, and have low predictive power for, the viral set point at 12 months.

Developing a globally applicable evidence-informed competency framework to support capacity strengthening in clinical research.

Capacity development for clinical research is held back by a lack of recognition for the skills acquired through involvement in clinical trials and in other varied types of global health research studies. Although some competency frameworks and associated recognised career pathways exist for different clinical research roles, they mostly apply to a single role or study setting. Our experience supports the need for an integrated approach, looking at the many roles in parallel and at all types of clinical research beyond trials. Here, we propose a single, flexible framework which is applicable to the full global health research team, and can be used for recognising staff by highlighting acquired skills and possible progression between various roles. It can also illuminate where capacity needs strengthening and contribute to raising research engagement. Through systematic analysis of existing competency frameworks and current job descriptions covering 11 distinct, broad clinical research roles, we identified and defined 50 key competencies required by the team as a whole and throughout the study life cycle. The competencies are relevant and adaptable to studies that differ in design, geographical location or disease, and fall in five main areas-(1) Ethics, Quality and Risk Management; (2) Study and Site Management; (3) Research Operations; (4) Scientific Thinking; and (5) Professional Skills. A pilot framework and implementation tools are now available online and in paper format. They have the potential to be a new mechanism for enabling research skills development and career progression for all staff engaged in clinical research globally.