Impact of interrupting antiretroviral therapy started during primary HIV-1 infection on plasma neurofilament light chain protein, a marker of neuronal injury: The SPARTAC trial.

Objective: Antiretroviral therapy (ART)-conferred suppression of HIV replication limits neuronal injury and inflammation. ART interruption tests efficacy in HIV cure trials and viral rebound after ART interruption may induce neuronal injury. We investigated the impact of protocol-defined ART interruption, commenced during primary HIV-1 infection (PHI) on a biomarker of neuro-axonal injury (neurofilament light protein (NfL)), and its associations with inflammation (D-dimer and interleukin-6 (IL-6)) and HIV-1 reservoir size (total HIV-1 DNA). Design: Retrospective study measuring plasma NfL in 83 participants enrolled in SPARTAC randomised to receive 48-weeks ART initiated during PHI, followed by ART interruption. Methods: NfL (Simoa immunoassay, Quanterix™) was measured before ART, after 48 weeks on ART, and 12 weeks after stopping ART. Plasma D-dimer and IL-6, and total HIV-1 DNA in peripheral CD4+ T-cells results were available in a subset of participants. Longitudinal NfL changes were assessed using mixed models, and associations with clinical and laboratory parameters using linear regression. Results: NfL decreased following 48-weeks ART (geometric mean 6.9 to 5.8 pg/mL, p = 0.006) with no further significant change up to 12-weeks post-stopping ART despite viral rebound in the majority of participants (median 1.7 to 3.9 plasma HIV-1 RNA log10 copies/mL). Higher baseline NfL was independently associated with higher plasma HIV-1 RNA (p = 0.020) and older age (p = 0.002). While NfL was positively associated with D-dimer (n = 48; p = 0.002), there was no significant association with IL-6 (n = 48) or total HIV-1 DNA (n = 51). Conclusions: Using plasma NfL as a surrogate marker, a decrease in neuro-axonal injury was observed in a cohort of participants following ART initiation during PHI, with no evidence of neuro-axonal injury rebound following ART interruption for up to 12 weeks, despite viral rebound in the majority of participants.

Prevalence and risk of burnout among HIV service providers in South Africa and Zambia: findings from the HPTN 071 (PopART) trial.

BACKGROUND: In the high disease burden and resource-constrained contexts of sub-Saharan Africa (SSA), health workers experience a range of psychosocial stressors that leave them vulnerable to developing burnout, which can reduce service quality and negatively impact their own health and wellbeing. As universal testing and treatment (UTT) for HIV scales up across SSA, we sought to understand the implications of this human resource-intensive approach to HIV prevention to inform decision-making about health workforce staffing and support needs. METHODS: Using the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), we assessed the prevalence of three domains of burnout-emotional exhaustion, depersonalization, and personal accomplishment-among three cadres of health workers delivering health services in areas receiving a UTT intervention in Zambia and South Africa. These cadres included health facility workers (n = 478), community health workers (n = 159), and a study-specific cadre of community HIV care providers (n = 529). We used linear regression to assess risk factors associated with emotional exhaustion, the only domain with sufficient variation in our sample. RESULTS: The MBI-HSS was completed by 1499/2153 eligible participants (69.6% response rate). Less than 1% of health workers met Maslach's definition for burnout. All groups of health workers reported lower levels of emotional exhaustion than found in previous studies of this type (mean score scores ranged from 10.7 to 15.4 out of 54 across health cadres). Higher emotional exhaustion was associated with higher educational attainment (ßadj = 2.24, 95% CI 0.76 to 3.72), greater years providing HIV services (ßadj = 0.20, 95% CI 0.03 to 0.36), and testing negative for HIV at last HIV test (ßadj = - 3.88 - 95% CI 5.69 to - 2.07). Working as a CHW was significantly associated with lower emotional exhaustion (ßadj = - 2.52, 95% CI - 4.69 to - 0.35). Among all health workers, irrespective of HIV status, witnessing stigmatizing behaviors towards people living with HIV among their co-workers was associated with significantly increased emotional exhaustion (ßadj = 3.38, 95% CI 1.99 to 4.76). CONCLUSIONS: The low level of burnout detected among health workers is reassuring. However, it remains important to assess how UTT may affect levels of emotional exhaustion among health workers over time, particularly in the context of emerging global pandemics, as burnout may impact the quality of HIV services they provide and their own mental health and wellbeing. Interventions to reduce HIV stigma in health facilities may protect against emotional exhaustion among health workers, as well as interventions to increase mindfulness and resilience among health workers at risk of burnout. Trial registration ClinicalTrials.gov number: NCT01900977.

Associations between HIV stigma and health-related quality-of-life among people living with HIV: cross-sectional analysis of data from HPTN 071 (PopART).

People living with HIV (PLHIV) report lower health-related quality-of-life (HRQoL) than HIV-negative people. HIV stigma may contribute to this. We explored the association between HIV stigma and HRQoL among PLHIV. We used cross-sectional data from 3991 randomly selected PLHIV who were surveyed in 2017-2018 for HPTN 071 (PopART), a cluster randomised trial in Zambia and South Africa. Participants were 18-44 years, had laboratory-confirmed HIV infection, and knew their status. HRQoL was measured using the EuroQol-5-dimensions-5-levels (EQ-5D-5L) questionnaire. Stigma outcomes included: internalised stigma, stigma experienced in the community, and stigma experienced in healthcare settings. Associations were examined using logistic regression. Participants who had experienced community stigma (n = 693/3991) had higher odds of reporting problems in at least one HRQoL domain, compared to those who had not (adjusted odds ratio, aOR: 1.51, 95% confidence interval, 95% Cl: 1.16-1.98, p = 0.002). Having experienced internalised stigma was also associated with reporting problems in at least one HRQoL domain (n = 552/3991, aOR: 1.98, 95% CI: 1.54-2.54, p < 0.001). However, having experienced stigma in a healthcare setting was less common (n = 158/3991) and not associated with HRQoL (aOR: 1.04, 95% CI: 0.68-1.58, p = 0.850). A stronger focus on interventions for internalised stigma and stigma experienced in the community is required.

Comparing patterns of recent and remote Mycobacterium tuberculosis infection determined using the QuantiFERON-TB Gold Plus assay in a high TB burden setting.

One quarter of the world's population is estimated to be infected with Mycobacterium tuberculosis. Identifying recent TB infection (TBI) offers an avenue to targeted TB preventative therapy provision, and prevention to disease progression. However, detecting recent TBI remains challenging. The QuantiFERON-TB Gold Plus assay (QFT-Plus) claims to have improved sensitivity in detecting recent TBI, by the addition of the TB2 antigen tube to the TB1 tube used in previous tests. TB2 detects CD8-mediated interferon gamma response, a potential marker of recent infection. We compared QFT-Plus TB1 and TB2 responses in individuals with recent and remote infection in high-burden settings. The Tuberculosis Reduction through Expanded Antiretroviral Treatment and TB Screening (TREATS) Project followed a cohort of adolescents and young people (AYP) aged 15-24 years in Zambia and South Africa to determine TBI incidence measured by QFT-Plus over 24 months. We categorised individuals with QTF-Plus positive result into recent and remote infection. We compared their TB1 and TB2 responses and the antigen tube differential [TB2-TB1], an indicator of CD8-activity, using logistic regression. At baseline, 3876 AYP, 1852/3876 (47.8%) were QFT-Plus positive whilst 2024/3876 (52.2%) QFT-Plus negative. Of the QFT-Plus baseline positives, 1069/1852 (57.7%) tested positive at both 12 and 24 months-remote infection. Of the QFT-Plus baseline negatives, 274/2024(13.3%) converted within a 12-month period- recent infection. TB1 and TB2 responses were higher in remote than recent infection. In recent infection, TB2 responses were greater than TB1 responses. The mean differential was 0.01 IU/ml in recent and -0.22 IU/ml in remote infection, (p = 0.145). The quantitative QFT-Plus results did not appear to reflect a marked distinction between recent and remote infection. Further analysis of the responses of infected individuals who developed disease is required to determine whether any signal in QFT-Plus results may predict progression to disease.

The impact of an innovative community-based peer-led intervention on uptake and coverage of sexual and reproductive health services among adolescents and young people 15-24 years old: results from the Yathu Yathu cluster randomised trial.

BACKGROUND: The Yathu Yathu ("For Us, By Us") cluster-randomized trial (CRT) evaluated a peer-led community-based sexual and reproductive health(SRH) intervention implemented to address persistent barriers to SRH service use among adolescents and young people (AYP). We report the impact of the intervention on coverage of key SRH services among AYP. METHODS: The trial was conducted from Jul 2019-Oct 2021 in two urban communities in Lusaka, Zambia, divided into 20 zones (~ 2350 AYP/zone). Zones were randomly allocated to intervention (N = 10) or control (N = 10) arm. In all zones, a census was conducted and all AYP aged 15-24-years offered participation. The intervention consisted of peer-led community-based hubs providing SRH services; a prevention points card (PPC) system to incentivize and track SRH service use and community engagement. This paper reports on the outcome of coverage (accessing at least one key SRH service), comparing intervention and control arms using PPC data and standard methods of analysis for CRTs. RESULTS: Among enumerated AYP, 93.6% (14,872/15,894) consented to participate from intervention zones and 95.1% (14,500/15,255) from control zones. Among those who accepted a PPC, 63.8% (9,493/14,872) accessed at least one key SRH service during the study period in the intervention arm, compared to 5.4% (776/14,500) in the control arm (adjPR 12.3 95%CI 9.3-16.2, p < 0.001). CONCLUSIONS: The Yathu Yathu intervention increased coverage of key SRH services among AYP and reached two-thirds of AYP. These findings demonstrate the potential of providing peer-led community-based SRH services. TRIAL REGISTRATION: ISRCTN75609016 (11/10/2021), clinicaltrials.gov number NCT04060420 (19/08/2019); retrospectively registered.

Prevalence of resistance-associated viral variants to the HIV-specific broadly neutralising antibody 10-1074 in a UK bNAb-naïve population.

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.

Pregnancy Management in HIV Viral Controllers: Twenty Years of Experience.

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (<100 copies/mL 2 occasions before or after pregnancy off ART). (2) Methods: A multi-centre, retrospective case series (1999-2021) comparing pre- and post-2012 when guidelines departed from zidovudine-monotherapy (ZDVm) as a first-line option. Demographic, virologic, obstetric and neonatal information were anonymised, collated and analysed in SPSS. (3) Results: A total of 49 live births were recorded in 29 women, 35 pre-2012 and 14 post. HIV infection was more commonly diagnosed in first reported pregnancy pre-2012 (15/35) compared to post (2/14), p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51-6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

Adults with Perinatally Acquired HIV; Emerging Clinical Outcomes and Data Gaps.

In resourced settings, adults living with perinatally acquired HIV are approaching the 5th decade of life. Their clinical and psychological outcomes highlight potential future issues for the much larger number of adolescents growing up with HIV in sub-Saharan Africa, and will inform the development of appropriate healthcare services. Lifelong exposure to HIV, and increasingly to antiretroviral therapy throughout growth and development, contrasts with adults acquiring HIV in later life. This review describes the clinical outcomes for adults living with perinatally acquired HIV including post transition mortality, morbidity and retention in care. Rates of viral suppression, drug resistance and immunological function are explored. Co-morbidities focus on metabolic, cardiovascular, respiratory and bone health with quality-of-life data including neurocognitive functioning and mental health. Sexual and reproductive health including vaccine-preventable disease and the prevention of onward transmission to partners and infants are considered. The data gaps and future research questions to optimise outcomes for this emerging adult cohort are highlighted.

Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study.

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.

Self-reported uptake of STI testing services among adolescents and young people aged 15-24 years: Findings from the Yathu Yathu cluster randomized trial in Lusaka, Zambia.

There is little evidence regarding community-based delivery of STI testing and treatment for youth aged 15-24 (AYP) in Zambia. In a cluster-randomised trial, we evaluated whether offering syndromic STI screening through community-based, peer-led sexual and reproductive health services (Yathu Yathu) with referral to a local health facility for testing, increased self-reported testing for STIs (other than HIV) among AYP. Two communities in Lusaka were divided into 10 zones each (20 zones in total); by community, zones were randomly allocated (1:1) to Yathu Yathu or control. Monitoring data were used to describe syndromic STI screening through Yathu Yathu and an endline cross-sectional survey used to evaluate the impact of Yathu Yathu on self-reported ever and recent (last 12 months) STI testing. 10,974 AYP accessed Yathu Yathu; 66.6% (females-67.7%; males-64.7%) were screened for STIs, 6.2% reported any STI symptoms. In the endline survey, 23.3% (n = 350/1501) of AYP who ever had sex ever STI tested; 13.5% (n = 174/1498) who had sex in the last 12 months recently STI tested. By trial arm, there was no difference in self-reported ever or recent STI testing among all AYP. Among men aged 20-24, there was evidence that ever STI testing was higher in the Yathu Yathu compared to control arm (24.1% vs 16.1%; adjPR = 1.67 95%CI = 1.02, 2.74; p = 0.04). Among AYP who ever STI tested, 6.6% (n = 23) reported ever being diagnosed with an STI. Syndromic STI management through community-based, peer-led services showed no impact on self-reported STI testing among AYP. Research on community-based delivery of (near) point-of-care diagnostics is needed. Trial registration number(s): NCT04060420 https://clinicaltrials.gov/ct2/show/NCT04060420; and ISRCTN75609016; https://doi.org/10.1186/ISRCTN75609016.

Hospitalisation rates for youth living with perinatally acquired HIV in England.

INTRODUCTION: Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10-35 years) living with PaHIV in England. METHOD: Retrospective observational cohort study over a three-year period 2016-2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. RESULTS: 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16-22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9-11.6). The respective crude incidence rates were 1.5 PY (0.0-8.2) in those aged 10-14 years and 3.5 PY (1.5-7.0) in the 15-19-year-olds. In those aged 20-24 years it was 14.5 PY (10.1-20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9-18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8-8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6-5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. CONCLUSIONS: Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10-19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

The HIV Empowering Adults' Decisions to Share: UK/Uganda (HEADS-UP) Study-A Randomised Feasibility Trial of an HIV Disclosure Intervention for Young Adults with Perinatally Acquired HIV.

Young adults with perinatally acquired HIV (PAH) face numerous challenges, including antiretroviral therapy (ART) adherence, managing onward HIV transmission risks and maintaining wellbeing. Sharing one's HIV status with others (onward HIV disclosure) may assist with these challenges but this is difficult. We developed and tested the feasibility of an intervention to help HIV status sharing decision-making for young adults with PAH. The study used a randomised parallel group feasibility design with 18-25-year-olds in Uganda and 18-29 year-olds in the UK. Participants were randomly assigned to intervention or standard of care (SOC) condition. The intervention consisted of four sessions (3 group, 1 individual) with follow-up support, delivered in person in Uganda and remotely in the UK. Assessments were carried out at: Pre-intervention /baseline; Post-intervention (intervention group only); Six-month follow-up. 142 participants were recruited (94 Uganda, 48 UK; 89 female, 53 male). At six-month follow-up, 92/94 (98%) participants were retained in Uganda, 25/48 (52%) in the UK. Multivariate analysis of combined data from both countries, showed a non-significant effect of intervention condition on HIV disclosure cognitions and affect (p = 0.08) and HIV disclosure intention (p = 0.09). There was a significant intervention effect on well-being (p = 0.005). This study addressed important gaps in understanding acceptable and feasible ways of delivering HIV status sharing support for young people living with PAH across two very different settings. The intervention was acceptable in both countries and feasible in Uganda. In the UK, retention may have been affected by its remote delivery.Trial registration: ISRCTN Registry, ISRCTN31852047, Registered on 21 January 2019.

Assessment of a screening tool to aid home-based identification of adolescents (aged 10-14) living with HIV in Zambia and South Africa: HPTN 071 (PopART) study.

INTRODUCTION: The HPTN071 (PopART) for Youth (P-ART-Y) study evaluated the acceptability and uptake of a community-level combination HIV prevention package including universal testing and treatment (UTT) among young people in Zambia and South Africa. We determined whether a four-question primary care level screening tool, validated for use in clinical settings, could enhance community (door-to-door) identification of undiagnosed HIV-positive younger adolescents (aged 10-14) who are frequently left out of HIV interventions. METHOD: Community HIV-care Providers (CHiPs) contacted and consented adolescents in their homes and offered them participation in the PopART intervention. CHiPs used a four question-screening tool, which included: history of hospital admission; recurring skin problems; poor health in last 3 months; and death of at least one parent. A "yes" response to one or more questions was classified as being "at risk" of being HIV-positive. Rapid HIV tests were offered to all children. Data were captured through an electronic data capture device from August 2016 to December 2017. The sensitivity, specificity, positive predictive value and negative predictive value were estimated for the screening tool, using the rapid HIV test result as the gold standard. RESULTS: In our 14 study sites, 33,710 adolescents aged 10-14 in Zambia and 8,610 in South Africa participated in the study. About 1.3% (427/33,710) and 1.2% (106/8,610) self-reported to be HIV positive. Excluding the self-reported HIV-positive, we classified 11.3% (3,746/33,283) of adolescents in Zambia and 17.5% (1,491/8,504) in South Africa as "at risk". In Zambia the estimated sensitivity was 35.3% (95% CI 27.3%-44.2%) and estimated specificity was 88.9% (88.5%-89.2%). In South Africa the sensitivity was 72.3% (26.8%-94.9%) and specificity was 82.5% (81.6-83.4%). CONCLUSION: The sensitivity of the screening tool in a community setting in Zambia was low, so this tool should not be considered a substitute for universal testing where that is possible. In South Africa the sensitivity was higher, but with a wide confidence interval. Where universal testing is not possible the tool may help direct resources to adolescents more likely to be living with undiagnosed HIV. TRIAL REGISTRATION: Clinical Trial Number: NCT01900977.

Demographics of sources of HIV-1 transmission in Zambia: a molecular epidemiology analysis in the HPTN 071 PopART study.

BACKGROUND: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study. METHODS: Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We used these sequences to identify likely transmission pairs. After demographic weighting of the recipients in these pairs to match the overall HIV-positive population, we analysed the demographic characteristics of the sources to better understand transmission in the general population. FINDINGS: We identified a total of 300 likely transmission pairs. 178 (59·4%) were male to female, with 130 (95% CI 110-150; 43·3%) from males aged 25-40 years. Overall, men transmitted 2·09-fold (2·06-2·29) more infections per capita than women, a ratio peaking at 5·87 (2·78-15·8) in the 35-39 years source age group. 40 (26-57; 13·2%) transmissions linked individuals from different communities in the trial. Of 288 sources with recorded information on drug resistance mutations, 52 (38-69; 18·1%) carried viruses resistant to first-line ART. INTERPRETATION: HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and there is no outsized contribution to new infections from importation or drug resistance mutations. Men aged 25-39 years, underserved by current treatment and prevention services, should be prioritised for HIV testing and ART. FUNDING: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Cultural Adaption, Translation, Preliminary Reliability and Validity of Key Psychological and Behavioural Measures for 18 to 25 Year-Olds Living with HIV in Uganda: A Multi-Stage Approach.

HIV remains a significant public health issue among young adults living in Uganda. There is a need for reliable and valid measures of key psychological and behavioural constructs that are related to important outcomes for this population. We translated, adapted and tested the psychometric properties of questionnaires measuring HIV stigma, HIV disclosure cognitions and affect, antiretroviral therapy (ART) adherence, social support, personal values, and hope, using a multi-step process. This included: translation, back-translation, expert review, cognitive interviewing, readability and assessments of internal consistency with 93 young adults (18-25 years) living with perinatally acquired HIV in Uganda. Preliminary criterion validity was assessed by examining relationships between the adapted measures and wellbeing, HIV disclosure behaviour, HIV disclosure intention and viral load suppression. The measures all showed acceptable reliability and every questionnaire apart from the Agentic and Communal Value Scale was easy to read. Those scales measuring HIV disclosure affect and cognitions, social support, HIV stigma and hope showed relationships with other constructs suggestive of validity. There is preliminary evidence to support the use of these measures in research and clinical contexts for young adults living with perinatally acquired HIV in Uganda.

Rapid antiretroviral therapy in primary HIV-1 infection enhances immune recovery.

OBJECTIVE: We present findings from a large cohort of individuals treated during primary HIV infection (PHI) and examine the impact of time from HIV-1 acquisition to antiretroviral therapy (ART) initiation on clinical outcomes. We also examine the temporal changes in the demographics of individuals presenting with PHI to inform HIV-1 prevention strategies. METHODS: Individuals who fulfilled the criteria of PHI and started ART within 3 months of confirmed HIV-1 diagnosis were enrolled between 2009 and 2020. Baseline demographics of those diagnosed between 2009 and 2015 (before preexposure prophylaxis (PrEP) and universal ART availability) and 2015-2020 (post-PrEP and universal ART availability) were compared. We examined the factors associated with immune recovery and time to viral suppression. RESULTS: Two hundred four individuals enrolled, 144 from 2009 to 2015 and 90 from 2015 to 2020; median follow-up was 33 months. At PHI, the median age was 33 years; 4% were women, 39% were UK-born, and 84% were MSM. The proportion of UK-born individuals was 47% in 2009-2015, compared with 29% in 2015-2020. There was an association between earlier ART initiation after PHI diagnosis and increased immune recovery; each day that ART was delayed was associated with a lower likelihood of achieving a CD4 + cell count more than 900 cells/µl [hazard ratio 0.99 (95% confidence interval, 95% CI 0.98-0.99), P  = 0.02) and CD4/CD8 more than 1.0 (hazard ratio 0.98 (95% CI 0.97-0.99). CONCLUSION: Early initiation of ART at PHI diagnosis is associated with enhanced immune recovery, providing further evidence to support immediate ART in the context of PHI. Non-UK-born MSM accounts for an increasing proportion of those with primary infection; UK HIV-1 prevention strategies should better target this group.

Factors associated with use of community-based, peer-led sexual and reproductive health services by adolescent boys and young men aged 18-24 in Lusaka, Zambia: A case control study nested in the Yathu Yathu trial.

INTRODUCTION: Adolescents and young people (AYP) aged 15-24 years have the least access to facility-based sexual and reproductive health (SRH) services, including HIV services. The Yathu-Yathu cluster-randomized trial (CRT) in Zambia tested whether a novel peer-led community-based approach increased knowledge of HIV status amongst AYP. In this nested case-control study, we aimed to identify factors associated with non-attendance to the Yathu Yathu hubs by adolescent boys and young men (ABYM) aged 18-24-years. METHODS: Yathu Yathu was a CRT conducted in two communities in Lusaka, Zambia, with 10 intervention and 10 control zones. AYP in all zones were offered prevention points cards (PPC), which incentivized and tracked service use at the hubs and health facility. In intervention zones, services were provided to AYP through community-based spaces (hubs) led by peer support workers. In these zones, cases were defined as those not having accessed any service at a hub and controls as those that accessed at least one service. Data were collected from October 2020 to January 2021 and analysed using methods appropriate for unmatched case-control studies. RESULTS: 161 cases and 160 controls consented to participate in the study. Participants aged 20-24 years (adjOR 1.99, 95%CI 1.26-3.12, p = 0.003), who were educated up to college level (adjOR 8.47,95%CI 2.08-34.53, p = 0.001) or who reported being employed in the last 12 months (adjOR 2.15, 95%CI 1.31-3.53, p = 0.002) were more likely to not attend the hubs. ABYM who had a friend with a PPC were more likely to attend the hubs (adjOR 0.18 95%CI 0.09-0.35, p<0.001). Most cases reported having their last HIV test at the local government health facility (58%) while most controls reported HIV-testing at a Yathu Yathu hub (82%). Among the controls, 84% (134/160) rated the hub experience as excellent. Among cases, 65% (104/161) stated they didn't visit the hubs "due to employment". CONCLUSIONS: Despite Yathu Yathu services being community-based and more accessible compared to health facilities, we found age, education and employment were associated with not attending hubs. Strategies are needed to reach employed young men who may not have access to SRH/HIV services during conventional working hours and to better utilise peer networks to increase service use.

Population-level analysis of natural control of HIV infection in Zambia and South Africa: HPTN 071 (PopART).

INTRODUCTION: HIV controllers have low viral loads (VL) without antiretroviral treatment (ART). We evaluated viraemic control in a community-randomized trial conducted in Zambia and South Africa that evaluated the impact of a combination prevention intervention on HIV incidence (HPTN 071 [PopART]; 2013-2018). METHODS: VL and antiretroviral (ARV) drug testing were performed using plasma samples collected 2 years after enrolment for 4072 participants who were HIV positive at the start of the study intervention. ARV drug use was assessed using a qualitative laboratory assay that detects 22 ARV drugs in five drug classes. Participants were classified as non-controllers if they had a VL ≥2000 copies/ml with no ARV drugs detected at this visit. Additional VL and ARV drug testing was performed at a second annual study visit to confirm controller status. Participants were classified as controllers if they had VLs <2000 with no ARV drugs detected at both visits. Non-controllers who had ARV drugs detected at either visit were excluded from the analysis to minimize potential confounders associated with ARV drug access and uptake. RESULTS: The final cohort included 126 viraemic controllers and 766 non-controllers who had no ARV drugs detected. The prevalence of controllers among the 4072 persons assessed was 3.1% (95% confidence interval [CI]: 2.6%, 3.6%). This should be considered a minimum estimate, since high rates of ARV drug use in the parent study limited the ability to identify controllers. Among the 892 participants in the final cohort, controller status was associated with biological sex (female > male, p = 0.027). There was no significant association between controller status and age, study country or herpes simplex virus type 2 (HSV-2) status at study enrolment. CONCLUSIONS: To our knowledge, this report presents the first large-scale, population-level study evaluating the prevalence of viraemic control and associated factors in Africa. A key advantage of this study was that a biomedical assessment was used to assess ARV drug use (vs. self-reported data). This study identified a large cohort of HIV controllers and non-controllers not taking ARV drugs, providing a unique repository of longitudinal samples for additional research. This cohort may be useful for further studies investigating the mechanisms of virologic control.

Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions.

'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo.

Tuberculosis prevalence after 4 years of population-wide systematic TB symptom screening and universal testing and treatment for HIV in the HPTN 071 (PopART) community-randomised trial in Zambia and South Africa: A cross-sectional survey (TREATS).

BACKGROUND: Tuberculosis (TB) prevalence remains persistently high in many settings, with new or expanded interventions required to achieve substantial reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART) community-randomised trial randomised 14 communities to receive the "PopART" intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7 communities to receive standard-of-care (arm C). The intervention was delivered door-to-door by community HIV care providers (CHiPs) and included universal HIV testing, facilitated linkage to HIV care at government health clinics, and systematic TB symptom screening. The Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the impact of delivering the PopART intervention on TB outcomes, in communities with high HIV and TB prevalence. METHODS AND FINDINGS: The study population of the HPTN 071 (PopART) trial included individuals aged ≥15 years living in 21 urban and peri-urban communities in Zambia and South Africa, with a total population of approximately 1 million and an adult HIV prevalence of around 15% at the time of the trial. Two sputum samples for TB testing were provided to CHiPs by individuals who reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight loss ≥1.5 kg in the last month, or current night sweats) or that a household member was currently on TB treatment. Antiretroviral therapy (ART) was offered universally at clinics in arm A and according to local guidelines in arms B and C. The TREATS study was conducted in the same 21 communities as the HPTN 071 (PopART) trial between 2017 and 2022, and TB prevalence was a co-primary endpoint of the TREATS study. The primary comparison was between the PopART intervention (arms A and B combined) and the standard-of-care (arm C). During 2019 to 2021, a TB prevalence survey was conducted among randomly selected individuals aged ≥15 years (approximately 1,750 per community in arms A and B, approximately 3,500 in arm C). Participants were screened on TB symptoms and chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for individuals who screened positive. Sputum eligibility was determined by the presence of a cough for ≥2 weeks, or ≥2 of 5 "TB suggestive" symptoms (cough, weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was compared between trial arms using standard methods for cluster-randomised trials, with adjustment for age, sex, and HIV status, and multiple imputation was used for missing data on prevalent TB. Among 83,092 individuals who were eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing, and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence was 0.92% (457/49,556). The geometric means of 7 community-level prevalence estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with no evidence of a difference comparing arms A and B combined with arm C (adjusted prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB prevalence was higher among people living with HIV than HIV-negative individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54, 3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African communities. The primary limitations are that the study was powered to detect only large reductions in TB prevalence in the intervention arm compared with standard-of-care, and the between-community variation in TB prevalence was larger than anticipated. CONCLUSIONS: There was no evidence that the PopART intervention reduced TB prevalence. Systematic screening for TB that is based on symptom screening alone may not be sufficient to achieve a large reduction in TB prevalence over a period of several years. Including chest X-ray screening alongside TB symptom screening could substantially increase the sensitivity of systematic screening for TB. TRIAL REGISTRATION: The TREATS study was registered with ClinicalTrials.gov Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013.