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Background: Treatment as prevention and pre-exposure prophylaxis (PrEP) are key strategies in the control of HIV/AIDS. We aimed to characterise the longitudinal effects of antiretroviral therapy (ART), followed by treatment as prevention and the addition of PrEP, on the HIV effective reproduction number (R e ) in British Columbia, Canada., Methods: This population-level programme evaluation used data from the Drug Treatment Program of the British Columbia Centre for Excellence in HIV/AIDS (Vancouver, British Columbia, Canada). We also used estimates of HIV incidence and prevalence from the Public Health Agency of Canada, data on the number of new HIV diagnoses per year from the British Columbia Centre for Disease Control, and mortality data from the British Columbia Vital Statistics Agency. Data were obtained from 1985 until 2022, depending on the database source. Outcomes were the annual HIV prevalence, HIV incidence, number of new HIV diagnoses, number of people living with HIV on ART, HIV/AIDS-related and all-cause mortality rates, the HIV incidence-to-all-cause-mortality ratio, and R e . We calculated the modified effective reproduction number (R me ) using two thresholds of viral suppression and compared these values with R e ., Findings: We found a 95% decline in HIV/AIDS-related mortality and a 91% decrease in HIV incidence over the study period. The R e progressively declined from 1996 to 2022; however, from 1996 to 2017, R me remained stable (>1) when calculated for people living with HIV with unsuppressed viraemia, suggesting that treatment as prevention reduces HIV incidence by decreasing the pool of individuals who are potentially able to transmit the virus. From 2018 to 2022, a decline in the estimated R e and R me (<1) was observed regardless of whether we considered all people living with HIV or only those who were virologically unsuppressed. This finding suggests that PrEP decreases HIV incidence by reducing the number of susceptible individuals in the community, independently of viral suppression., Interpretation: Our results show the synergy between generalised treatment as prevention and targeted PrEP in terms of decreasing HIV incidence. These findings support the incorporation of longitudinal monitoring of R e at a programmatic level to identify opportunities for the optimisation of treatment-as-prevention and PrEP programmes., Funding: British Columbia Ministry of Health, Health Canada, Public Health Agency of Canada, Vancouver Coastal Health, Vancouver General Hospital Foundation, Genome British Columbia, and the Canadian Institutes of Health Research., Competing Interests: Declaration of interests JSGM received institutional grants from Gilead Sciences, Merck, and ViiV Healthcare. VDL received honoraria to present at the 2023 Conference on Retroviruses and Opportunistic Infections ViiV Healthcare Ambassador Program. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Hope for the future has been found protective against suicidal ideation (SI) in adolescents and young adults (AYA) yet has not been examined in AYA with perinatal HIV-infection (PHIV) or AYA who were perinatally HIV-exposed but uninfected (PHEU), who are at higher risk for SI than general populations. Using data from a New York City-based longitudinal study of AYAPHIV and AYAPHEU enrolled when 9-16 years old, we examined associations between hope for the future, psychiatric disorders, and SI over time using validated measures. Generalized estimating equations were used to estimate differences in mean hope for the future scores by PHIV-status and to estimate adjusted odds ratios for associations between hope for the future and SI. AYA reported high hope for the future scores and low SI across visits, irrespective of PHIV-status. Higher hope for the future scores were associated with lower odds of SI (AOR = 0.48, 95% CI: 0.23, 0.996). Mood disorder was associated with increased odds of SI (AOR = 13.57, 95% CI: 5.11, 36.05) in a model including age, sex, follow-up, PHIV-status, mood disorder, and hope for the future. Understanding how hope can be cultivated and how it protects against SI can help to inform preventive interventions for HIV-affected AYA.

Background: Street-connected individuals (SCI) in Kenya experience barriers to accessing HIV care. This pilot study provides proof-of-concept for Enabling Adherence to Treatment (EAT), a combination intervention providing modified directly observed therapy (mDOT), daily meals, and peer navigation services to SCI living with HIV or requiring therapy for other conditions (e.g. tuberculosis). The goal of the EAT intervention was to improve engagement in HIV care and viral suppression among SCI living with HIV in an urban setting in Kenya., Methods: This pilot study used a single group, pre/post-test design, and enrolled a convenience sample of self-identified SCI of any age. Participants were able to access free hot meals, peer navigation services, and mDOT 6 days per week. We carried out descriptive statistics to characterize participants' engagement in EAT and HIV treatment outcomes. We used McNemar's chi-square test to calculate unadjusted differences in HIV outcomes pre- and post-intervention among participants enrolled in HIV care prior to EAT. We compared unadjusted time to initiation of antiretroviral therapy (ART) and first episode of viral load (VL) suppression among participants enrolled in HIV care prior to EAT vs. concurrently with EAT using the Wilcoxon rank sum test. Statistical significance was defined as p < 0.05. We calculated total, fixed, and variable costs of the intervention., Results: Between July 2018 and February 2020, EAT enrolled 87 participants: 46 (53%) female and 75 (86%) living with HIV. At baseline, 60 out of 75 participants living with HIV (80%) had previously enrolled in HIV care. Out of 60, 56 (93%) had initiated ART, 44 (73%) were active in care, and 25 (42%) were virally suppressed (VL < 1000 copies/mL) at their last VL measure in the 19 months before EAT. After 19 months of follow-up, all 75 participants living with HIV had enrolled in HIV care and initiated ART, 65 (87%) were active in care, and 44 (59%) were virally suppressed at their last VL measure. Among the participants who were enrolled in HIV care before EAT, there was a significant increase in the proportion who were active in HIV care and virally suppressed at their last VL measure during EAT enrollment compared to before EAT enrollment. Participants who enrolled in HIV care concurrently with EAT had a significantly shorter time to initiation of ART and first episode of viral suppression compared to participants who enrolled in HIV care prior to EAT. The total cost of the intervention over 19 months was USD $57,448.64. Fixed costs were USD $3623.04 and variable costs were USD $63.75/month/participant., Conclusions: This pilot study provided proof of concept that EAT, a combination intervention providing mDOT, food, and peer navigation services, was feasible to implement and may support engagement in HIV care and achievement of viral suppression among SCI living with HIV in an urban setting in Kenya. Future work should focus on controlled trials of EAT, assessments of feasibility in other contexts, and cost-effectiveness studies., (© 2023. The Author(s).)

Background: The leading causes of street involvement worldwide are poverty, family conflict, and abuse. A common misconception is that street involvement is due to delinquency, a belief leading to social exclusion and social inequality for children in street situations (CSS). Exploring community perceptions of CSS and the reproduction of social difference and inequalities can help reduce stigma and discrimination., Objective: To explore how stigma and discrimination of CSS was produced and reproduced in specific contexts of culture and power., Participants and Setting: Social actors including CSS, healthcare providers, children's officers, and police officers in western Kenya., Methods: Using a sociological conceptualization of stigma, this qualitative study explored the stigmatization processes that take shape in specific contexts of culture and power. We conducted 41 in-depth interviews and 7 focus group discussions with a total of 100 participants., Results: CSS were often labeled "chokoraa" or garbage picker, a label linked to undesirable characteristics constituting "evils" in society and stereotyped beliefs that they were "delinquents," reinforcing their "otherness" and devalued social status. CSS experienced individual and structural discrimination leading to exclusion from social and economic life., Conclusion: CSS were stigmatized when labeled, set apart, and linked to negative characteristics leading to their experience of status loss and discrimination. CSS's differentness and devalued status served to limit their access to societal resources and deemed them unworthy of equal rights. Interventions involving various social actors are needed to challenge negative stereotypes, reduce stigma, and uphold CSS's human rights., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Theatre testing (TT) method demonstrates whole or portions of an evidence-based intervention to stakeholders to elicit feedback on context-specific adaptations and future implementation. The Peer Navigator Project (PNP) studied the adaptation and implementation of Peer Navigators in five urban sites to increase street-connected youth (SCY) access to HIV prevention, testing, and treatment in Canada and Kenya. TT was used with SCY, healthcare providers, and community stakeholders to collect feedback on the optimal characteristics of the PNs (e.g., social identities) and their professional activities and responsibilities in each site. Sites scripted unique scenarios of PNs supporting SCY and interacting with social service providers. Local actors were employed, and the scenarios were filmed and edited into videos alongside audience discussion questions. Videos were screened to separate audiences of SCY ( n = 40), healthcare providers ( n = 12), and community stakeholders ( n = 59). Facilitated discussion about the scenarios were recorded as data, and transcripts were analyzed thematically by the research team. The scenario videos are presented as a unique adaptation to the TT method. The adaptations were time-consuming and limited the ability to present responsive changes while presenting the method to different audiences. They were also effective at maintaining presentation fidelity and eliciting diverse and meaningful responses from different stakeholder groups. One site successfully adapted the method for use in a physically distanced manner that complied with COVID-19 public health regulations. TT using video scenarios is an engaging approach that garners rich responses from diverse stakeholder groups about the adaptation of evidence-based interventions preparing for implementation in international settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 MacEntee, Lee, Oudshoorn, Abramovich, Kiptui, Ayuku, Van Berkum, Saarela, Tang, Apondi, Wachira, MacDonald and Braitstein.)

Purpose of Review: After over 40 years, the HIV pandemic is amongst the deadliest in history - 100% fatal without treatment, HIV has infected over 84 million people, and has caused over 40 million deaths. Global HIV spending between 2000 and 2015 totaled over a half trillion dollars. Delays in harnessing scientific advances, including 'test and treat' and treatment as prevention of illness, death, and transmission (TasP) provide a cautionary tale applicable to other pandemics. Resource allocation has also been problematic with many highest burden countries spending less than 50% on care and treatment., Recent Findings: Between 2002 and 2021, over $94 billion was budgeted for HIV in 40 sub-Saharan African countries, with 19 countries over $1 billion. In 2021, 8.1 million (32%) People Living with HIV (PLHIV) are still not on treatment; viral suppression data, the most important programme success indicator, is unavailable for 50% of countries. Of 19 countries with at least one billion dollars budgeted, seven have below 80% ART coverage, leaving 3.5 million (29%) of PLHIV off treatment and vulnerable to illness, death, and transmitting the virus to partners and children., Summary: With additional funding and improved efficiency, achieving the 95-95-95 target to diagnose 95% of all HIV-positive individuals, provide antiretroviral therapy (ART) for 95% of those diagnosed and achieve viral suppression for 95% of those treated by 2030 is feasible and the humane pathway towards ending the HIV pandemic., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: UNICEF estimates that there are as many as 100 million street-involved youth (SIY) globally. Marginalized conditions put SIY at higher risk of HIV and adverse outcomes once HIV-positive. The objective of this analysis was to describe barriers and facilitators of accessing HIV prevention, testing, and treatment services as Phase I of an implementation study evaluating the use of peer navigators to increase access to HIV services., Methods: Semi-structured interviews, focus group discussions (FGD), and theatre testing were conducted with individuals who identify as SIY, health care providers, and community stakeholders living in Canada (Toronto, Montreal, London) and Kenya (Eldoret, Huruma, Kitale). Data were analyzed using a directed content approach, guided by the socio-ecological model (SEM)., Results: Across the six sites were 195 participants: 64 SIY, 42 healthcare providers, and 97 community-based stakeholders. Barriers were identified at the societal (e.g. intersectional stigma and discrimination), public policy (e.g., inadequate access to basic needs, legal documentation, lack of health insurance, and limited community-based funding), institutional (e.g. lack of inclusive education and training, inadequate HIV educational outreach, and restrictive service provision), interpersonal (e.g., ineffective communication from healthcare providers), and intrapersonal levels (e.g. lack of trust and associated fear, low perception for healthcare, and lack of self-esteem). These contributed to limited HIV services utilization among SIY. Conversely, numerous facilitators were also identified at the public policy (e.g. affordable HIV services and treatment), institutional (e.g. available and accessible HIV prevention tools, HIV education and awareness programs, and holistic models of care), interpersonal level (e.g., systems navigation support, peer support, and personal relationships), and intrapersonal levels (e.g. self-efficacy) as positively supporting SIY access to HIV services., Conclusion: Intersectional stigma was a critical barrier in all sites, and policies and programs that foster welcoming environments for youth from diverse backgrounds and living circumstances may be better able to respond to the HIV service needs of this high risk population. Social support and navigation services were reported to facilitate access to HIV services in all sites., (© 2022. The Author(s).)

T and natural killer (NK) cells are effector cells with key roles in anti-HIV immunity, including in lymphoid tissues, the major site of HIV persistence. However, little is known about the features of these effector cells from people living with HIV (PLWH), particularly from those who initiated antiretroviral therapy (ART) during acute infection. Our study design was to use 42-parameter CyTOF to conduct deep phenotyping of paired blood- and lymph node (LN)-derived T and NK cells from three groups of HIV+ aviremic individuals: elite controllers (N = 5), and ART-suppressed individuals who had started therapy during chronic (N = 6) vs. acute infection (N = 8), the latter of which is associated with better outcomes. We found that acute-treated individuals are enriched for specific subsets of T and NK cells, including blood-derived CD56-CD16+ NK cells previously associated with HIV control, and LN-derived CD4+ T follicular helper cells with heightened expansion potential. An in-depth comparison of the features of the cells from blood vs. LNs of individuals from our cohort revealed that T cells from blood were more activated than those from LNs. By contrast, LNs were enriched for follicle-homing CXCR5+ CD8+ T cells, which expressed increased levels of inhibitory receptors and markers of survival and proliferation as compared to their CXCR5- counterparts. In addition, a subset of memory-like CD56 bright TCF1+ NK cells was enriched in LNs relative to blood. These results together suggest unique T and NK cell features in acute-treated individuals, and highlight the importance of examining effector cells not only in blood but also the lymphoid tissue compartment, where the reservoir mostly persists, and where these cells take on distinct phenotypic features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 George, Luo, Neidleman, Hoh, Vohra, Thomas, Shin, Lee, Blish, Deeks, Greene, Lee and Roan.)

Background: Major depressive disorder (MDD) is common among young adults with perinatally acquired HIV (YAPHIV), however it is often underdiagnosed and untreated. The PHQ-9 and PHQ-2 are widely used screening instruments for MDD. This study evaluates the accuracy of recommended PHQ-9 and PHQ-2 cut-scores of 10 and 3 for YAPHIV and YA who were perinatally HIV exposed but uninfected (YAPHEU)., Methods: The PHQ-9 was administered to participants (n = 203) in a longitudinal cohort study using the DISC-IV as the gold standard for diagnosing depression. PHQ-9 and PHQ-2 sensitivity and specificity were calculated. ROC curves were constructed for the overall sample and YAPHIV and YAPHEU subsamples., Results: Almost all participants were Black and Latinx, ages 18-29. Overall, the recommended PHQ-9 cut-score of ≥10 yielded a sensitivity of 0.47 (95%CI [0.23,0.72]) and specificity of 0.86 (95%CI [0.80, 0.91]). Results indicate that PHQ-9 cut-scores of 7 and PHQ-2 cut-scores of 2 increased sensitivity to 0.76 (95%CI [0.50, 0.93]) and 0.71(95%CI [0.44,0.90]), and decreased specificity to 0.72 (95%CI [0.65, 0.79]) and 0.73 (95%CI [0.66, 0.79]) respectively. Among subsamples, existing PHQ-9 cut-scores were more accurate for MDD diagnoses in YAPHEU (N = 11) than YAPHIV(N = 6). No race/ethnicity or age differences were found., Limitations: Participants were recruited from clinics in NYC and may not reflect all YAPHIV and YAPHEU. Without a white HIV comparison group, no conclusions could be made on the impact of race/ethnicity on optimized PHQ-9 cut-scores., Conclusions: Using tailored cut scores for HIV-affected populations may increase identification of those experiencing or at risk for MDD. Given the need for increased depression screening in HIV care, use of optimized cut-scores could benefit at-risk populations in the US and globally., (Copyright © 2021. Published by Elsevier B.V.)

Human immunodeficiency virus (HIV) treatment prevents illness, death, and transmission. The 90-90-90 disease control target is only 73% of people living with HIV virally suppressed. For 2010 to 2019, we abstracted HIV funding data for 40 countries in sub-Saharan Africa (70% of global HIV burden and >99% of HIV burden in the region in 2018). During 2010-2019, there was ∼$52 billion funding for 40 countries (99% Africa HIV burden). Domestic funding ranged from $0 to $3.2 billion. PEPFAR funding was $32 billion (average $1.4 billion; range $0.089-4.3 billion) among 22 countries. Global Fund averaged $306 million ($1.9 million to $1.1 billion) for 40 countries. Among PLHIV, known HIV status averaged 80% (11% to 94%). ART coverage averaged 64% (9% to 90%). Viral suppression among PLHIV ranged from 8% to 87%. Of the 40 countries, 21 reported under 60% of PLHIV to be on treatment and 13 did not report viral suppression for 2018. Achieving 90-90-90 is feasible in challenging settings if resources are used efficiently. Despite the significant investment in the HIV response, many countries have not reached the 90-90-90 target. Greater attention to efficiency and prioritizing important targets will be required to end AIDS in Africa.

Background: In people living with HIV (PLWH), statins may be disproportionately effective but remain underutilized. A large prospective trial in patients with low to moderate cardiovascular (ASCVD) risk will reveal whether they should be considered in all PLWH. But its effect size may not apply to real-world PLWH with higher ASCVD and mortality risk. Also, the clinical role of non-statin lipid-lowering therapy (LLT) and LLT adherence in this population is unknown., Methods: Comparative multi-level marginal structural model for all-cause mortality examining four time-updated exposure levels to LLT, antihypertensives, and aspirin in a virtual cohort of older PLWH. Incident coronary, cerebrovascular, and overall ASCVD events, serious infections, and new cancer diagnoses served as explanatory outcomes., Results: In 23,276 HIV-infected US-veterans who were followed for a median of 5.2 years after virologic suppression overall mortality was 33/1000 patient years: > 3 times higher than in the US population. Use of antihypertensives or aspirin was associated with increased mortality. Past LLT use (> 1 year ago) had no effect on mortality. LLT exposure in the past year was associated with a reduced hazard ratio (HR) of death: 0.59, 95% confidence interval (CI) 0.51-0.69, p < 0.0001 for statin containing LLT and 0.71 (CI: 0.54-0.93), p = 0.03 for statin-free LLT. For consistent LLT use (> 11/12 past months) the HR of death was 0.48 (CI: 0.35-0.66) for statin-only LLT, 0.34 (CI: 0.23-0.52) for combination LLT, and 0.27 (CI: 0.15-0.48) for statin-free LLT (p < 0.0001 for all). The ASCVD risk in these patients was reduced in similar fashion. Use of statin containing LLT was also associated with reduced infection and cancer risk. Multiple contrasting subgroup analyses yielded comparable results. Confounding is unlikely to be a major contributor to our findings., Conclusions: In PLWH, ongoing LLT use may lead to substantially lower mortality, but consistent long-term adherence may be required to reduce ASCVD risk. Consistent non-statin LLT may be highly effective and should be studied prospectively.

Objective: We monitored a large-scale implementation of the Simple Amplification-Based Assay semi-quantitative viral load test for HIV-1 version I (SAMBA I Viral Load = SAMBA I VL) within Médecins Sans Frontières' HIV programmes in Malawi and Uganda, to assess its performance and operational feasibility., Methods: Descriptive analysis of routine programme data between August 2013 and December 2016. The dataset included samples collected for VL monitoring and tested using SAMBA I VL in five HIV clinics in Malawi (four peripheral health centres and one district hospital), and one HIV clinic in a regional referral hospital in Uganda. SAMBA I VL was used for VL testing in patients who had been receiving ART for between 6 months and ten years, to determine whether plasma VL was above or below 1000 copies/mL of HIV-1, reflecting ART failure or efficacy. Randomly selected samples were quantified with commercial VL assays. SAMBA I instruments and test performance, site throughput, and delays in communicating results to clinicians and patients were monitored., Results: Between August 2013 and December 2016 a total of 60 889 patient samples were analysed with SAMBA I VL. Overall, 0.23% of initial SAMBA I VL results were invalid; this was reduced to 0.04% after repeating the test once. Global test failure, including instrument failure, was 1.34%. Concordance with reference quantitative testing of VL was 2620/2727, 96.0% (1338/1382, 96.8% in Malawi; 1282/1345, 95.3% in Uganda). For Chiradzulu peripheral health centres and Arua Hospital HIV clinic, where testing was performed on-site, same-day results were communicated to clinicians for between 91% and 97% of samples. Same-day clinical review was obtained for 84.7% across the whole set of samples tested., Conclusions: SAMBA I VL testing is feasible for monitoring cohorts of 1000 to 5000 ART-experienced patients. Same-day results can be used to inform rapid clinical decision-making at rural and remote health facilities, potentially reducing time available for development of resistance and conceivably helping to reduce morbidity and mortality., (© 2020 John Wiley & Sons Ltd.)

Background: With combination antiretroviral therapy (cART), infants with perinatally acquired HIV (pHIV) are living into adolescence and adulthood. Worldwide, many have not received cART in the first years of life, and challenges of adolescence complicate transition to adulthood. Neurobehavioral outcomes in pHIV young adults (pHIVAd) are infrequently reported., Objectives: To examine neurobehavioral characteristics of pHIVAd ages 21-30 years, and to compare them with age-matched young adults infected in the second or third decade of life (HIVagematch), and older adults with similar duration HIV disease (HIVOA)., Methods: A comprehensive neuropsychological test battery and questionnaires to determine cognitive function and mood, and reviews of neuromedical and behavioral records were undertaken in three groups of 13 individuals each. Descriptive analysis and bivariate techniques were used for comparisons., Results: Rates of cognitive impairment were highest in pHIVAd (85%) compared with HIVagematch (38%) and HIVOA (62%). pHIVAd had the worst scores in global cognition, speed of information processing, working memory, and verbal fluency (0.5--1.0 SD below other groups). There was a trend for higher rates of psychiatric dysfunction (predominantly mood disorders) in pHIVAd (85%) compared with HIV-agematch (46%) and HIVOA (54%). Only four pHIVAd reported employment or enrollment in school. Four had autoimmune disorders., Conclusion: These pHIVAd displayed high rates of cognitive, psychiatric, and autoimmune dysfunction, greater than age-matched or HIV duration-matched comparators. Although this small study is largely descriptive in nature, it suggests that a lack of cART in early life may result in long-term neurobehavioral and immune abnormalities manifesting into adulthood.

Background: Achievement of the elimination target for mother-to-child transmission (MTCT) of HIV in selected countries has increased hope to end the HIV epidemic in children across the world. However, MTCT rates remain well above the 5% elimination target in most sub-Saharan Africa countries. These countries require innovative strategies to scale-up their interventions to end paediatric HIV. We describe how the Elizabeth Glaser Paediatric AIDS Foundation (EGPAF) consortium and the Children's Investment Fund Foundation (CIFF) used the critical path method to facilitate rapid expansion and optimization of 2010 and 2013 WHO PMTCT guidelines to reduce Zimbabwe's MTCT rate from 22% in 2010 to 6.4% in 2015., Methods: We analysed activities implemented and PMTCT programme data for the period before and during the EGPAF-CIFF project. The critical path method involved a cycle of collecting and analysing quarterly PMTCT indicator data and planning and implementing targeted activities to improve the PMTCT indicators. We performed a graphical trend analysis of data that measured availability of PMTCT services. Using Pearson's Chi2 test, we compared results of PMTCT uptake indicators at the start and end of the EGPAF-CIFF project and used regression discontinuity analysis to assess effectiveness of activities implemented to improve the PMTCT service uptake indicators., Results: Zimbabwe rolled out WHO 2010 and 2013 PMTCT guidelines in less than 1 year during the EGPAF-CIFF project, yet it took more than 4 years to roll-out previous guidelines. All PMTCT indicators increased significantly (p < 0.001) comparing the five-year periods before and during the EGPAF-CIFF project. Critical path activities implemented increased five of the seven PMTCT uptake indicators., Conclusion: Zimbabwe rapidly rolled-out and optimised new WHO PMTCT guidelines and drastically reduced its MTCT rate using the critical path method. We recommend wider use of the critical path method in public health programmes.

The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8-10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence., Competing Interests: JN, XL, JF, GX, FH, TM, VM, AL, ST, RT, WT, BW, RH, MS, PV, JM, KJ, NA, PH, SD, SY, SP, WG, NR No competing interests declared, (© 2020, Neidleman et al.)

Objective: Identify factors associated with trajectories of psychiatric disorder among 340 adolescents and young adults (AYA) living with perinatal HIV infection (PHIV) and perinatal HIV-exposure but not infection (PHEU)., Design: Longitudinal cohort study of AYA in New York City, 9-16 years at enrollment., Methods: We used multivariate longitudinal latent class analysis to identify trajectories of psychiatric disorder, and logistic regression to examine predictors of trajectories (e.g. PHIV status) and associations between trajectories and viremia in young adulthood (AYA with PHIV only)., Results: Among all AYA, we identified three psychiatric trajectories: relatively 'low disorder' (63%), 'consistent anxiety' (26%), and 'escalating comorbidity' (11%). Compared with AYA with 'low disorder', AYA with 'escalating comorbidity' were significantly older, reported more neighborhood stress, and lived with a caregiver with alcohol use disorder, whereas AYA with 'consistent anxiety' were more likely female individuals. Although we found no statistically significant HIV status differences, among AYA with PHIV, nearly half (48%) were viremic in young adulthood, with higher odds of viremia among AYA with 'escalating comorbidity' (OR: 3.88, 95% CI: 0.93-16.26) and 'consistent anxiety' (OR: 2.41, 95% CI: 1.011-5.75) compared with 'low disorder'., Conclusion: Despite significant adversity, AYA with PHIV and PHEU had relatively low prevalence of psychiatric disorder over time, although one-third had consistent or escalating psychiatric disorders. Among AYA with PHIV, psychiatric trajectories were associated with viremia in young adulthood. Given the growing population of AYA living with PHIV and PHEU worldwide, addressing the substantial and evolving mental health needs of both groups as they reach young adulthood is critical., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In 2017, Zimbabwe adopted a modified version of the World Health Organization 2016 recommendation on HIV birth testing by offering HIV testing at birth only to infants at "high risk" of HIV transmission. There is limited evidence on the effectiveness of this approach. Our study assessed the sensitivity and specificity of birth testing "high risk" infants only., Methods: We conducted a cross-sectional study at 10 health facilities from November 2018 to July 2019. A nucleic acid test for HIV was performed on all HIV-exposed infants identified within 48 hours of life, irrespective of risk status. Univariate and bivariate analyses were used to estimate the performance of the risk screening tool., Results: HIV nucleic acid test was successfully performed on 1970 infants (95%), of whom 266 (13.5%) were classified as high-risk infants. HIV prevalence for all infants tested was 1.5% (95% CI: 1% to 2%), whereas prevalence among high-risk infants and low-risk infants was 6.8% (95% CI: 3.7% to 9.8%) and 0.6% (95% CI: 0.3% to 1%) respectively. Sensitivity and specificity of the maternal risk screening tool was at 62.1% (95% CI: 44.4% to 79.7%) and 87.2% (95% CI: 85.7% to 88.7%), respectively; positive and negative predictive values were 6.8% (95% CI: 3.7% to 9.8%) and 99.4% (95% CI: 99.0% to 99.7%) respectively., Conclusions: Despite high negative predictive value, sensitivity was relatively low, with potential of missing 2 in every 5 HIV infected infants. Given the potential benefits of early ART initiation for all exposed infants, where feasible, universal testing for HIV-exposed infants at birth may be preferred to reduce missing infected infants.

Background: Large numbers of perinatally HIV-infected (PHIV) children are aging into adolescence. We examined cognitive and behavioral outcomes in a longitudinal cohort of Asian youth., Methods: We followed up 231 PHIV, 125 perinatally HIV-exposed, uninfected (HEU), and 138 HIV-unexposed, uninfected (HUU) adolescents (aged 10 years and older), matched by age/sex, in Thailand and Cambodia for 3 years. Executive function was assessed with Children's Color Trails Tests 1 and 2 (CCTT-1 and -2), the design fluency test, and the verbal fluency test. Working memory (Freedom from Distractibility Index) and processing speed index were assessed using WISC-III. Visual memory was assessed by design memory and design recognition subtests of the Wide Range Assessment of Memory and Learning (WRAML-2) and behavioral problems using the Child Behavior Checklist (CBCL). Generalized estimating equations examined adjusted odds ratios of cognitive impairment (Z-scores ≥2 SD below age-adjusted means of the HUU group) and CBCL T-scores in the borderline-clinical range (T-Scores ≥60) in PHIV and HEU versus HUU youth, adjusting for ethnicity, household income, and caregiver characteristics., Results: The median age at enrollment was 13.8 years, with 58% women and 63% Thai participants. PHIV youth had >86% virological suppression and significantly higher impairment rates on CCTT-1 and -2 tests, design fluency test, verbal fluency tests, design memory, and CBCL internalizing and externalizing problems. Results were mostly similar between HEU and HUU groups, apart from higher impairment rates on CCTT-1 and internalizing problems in HEU., Conclusion: Asian adolescents with PHIV remain at risk of cognitive and mental health problems despite HIV treatment. Selective risks are observed among HEU youth.

Born out of a necessity for fiscal sustainability, simulation modeling is playing an increasingly prominent role in setting priorities for combination implementation strategies for HIV treatment and prevention globally. The design of a model and the data inputted into it are central factors in ensuring credible inferences. We executed a narrative review of a set of dynamic HIV transmission models to comprehensively synthesize and compare the structural design and the quality of evidence used to support each model. We included 19 models representing both generalized and concentrated epidemics, classified as compartmental, agent-based, individual-based microsimulation or hybrid in our review. We focused on four structural components (population construction; model entry, exit and HIV care engagement; HIV disease progression; and the force of HIV infection), and two analytical components (model calibration/validation; and health economic evaluation, including uncertainty analysis). While the models we reviewed focused on a variety of individual interventions and their combinations, their structural designs were relatively homogenous across three of the four focal components, with key structural elements influenced by model type and epidemiological context. In contrast, model entry, exit and HIV care engagement tended to differ most across models, with some health system interactions-particularly HIV testing-not modeled explicitly in many contexts. The quality of data used in the models and the transparency with which the data was presented differed substantially across model components. Representative and high-quality data on health service delivery were most commonly not accessed or were unavailable. The structure of an HIV model should ideally fit its epidemiological context and be able to capture all efficacious treatment and prevention services relevant to a robust combination implementation strategy. Developing standardized guidelines on evidence syntheses for health economic evaluation would improve transparency and help prioritize data collection to reduce decision uncertainty.

Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo., Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385., Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log 10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log 10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity., Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations., Funding: National Institutes of Health and Medical Research Council, Wellcome Trust., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Dynamic HIV transmission models can provide evidence-based guidance on optimal combination implementation strategies to treat and prevent HIV/AIDS. However, these models can be extremely data intensive, and the availability of good-quality data characterizing regional microepidemics varies substantially within and across countries. We aim to provide a comprehensive and transparent description of an evidence synthesis process and reporting framework employed to populate and calibrate a dynamic, compartmental HIV transmission model for six US cities., Methods: We executed a mixed-method evidence synthesis strategy to populate model parameters in six categories: (i) initial HIV-negative and HIV-infected populations; (ii) parameters used to calculate the probability of HIV transmission; (iii) screening, diagnosis, treatment and HIV disease progression; (iv) HIV prevention programs; (v) the costs of medical care; and (vi) health utility weights for each stage of HIV disease progression. We identified parameters that required city-specific data and stratification by gender, risk group and race/ethnicity a priori and sought out databases for primary analysis to augment our evidence synthesis. We ranked the quality of each parameter using context- and domain-specific criteria and verified sources and assumptions with our scientific advisory committee., Findings: To inform the 1,667 parameters needed to populate our model, we synthesized evidence from 59 peer-reviewed publications and 24 public health and surveillance reports and executed primary analyses using 11 data sets. Of these 1,667 parameters, 1,517 (91%) were city-specific and 150 (9%) were common for all cities. Notably, 1,074 (64%), 201 (12%) and 312 (19%) parameters corresponded to categories (i), (ii) and (iii), respectively. Parameters ranked as best- to moderate-quality evidence comprised 39% of the common parameters and ranged from 56%-60% across cities for the city-specific parameters. We identified variation in parameter values across cities as well as within cities across risk and race/ethnic groups., Conclusions: Better integration of modelling in decision making can be achieved by systematically reporting on the evidence synthesis process that is used to populate models, and by explicitly assessing the quality of data entered into the model. The effective communication of this process can help prioritize data collection of the most informative components of local HIV prevention and care services in order to reduce decision uncertainty and strengthen model conclusions., Competing Interests: The authors have declared that no competing interests exist.

Background: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts., Methods: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival., Results: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/μL (P = .04)., Conclusion: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework., Clinical Trial Registration: NCT01075152 and NCT01802385., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Voluntary medical male circumcision (VMMC) reduces the risk of HIV infection in heterosexual men and has long-term indirect protection for women, yet VMMC uptake in South Africa remains low (49.8%) in men (25-49 years). We explored the attitude and willingness of women to start conversations on VMMC with their sexual partners in a South African peri-urban setting to increase VMMC uptake., Methods: Thirty women with median age of 30 years (inter-quartile range 26-33 years) were interviewed in a language of their choice. Key questions included: types of approach to use, gender roles, benefits and barriers to introducing the topic of VMMC, and perceptions of VMMC. Interviews were digitally-recorded, transcribed, and translated. Through a standard iterative process, a codebook was developed (QSR NVIVO 10 software) and inductive thematic analysis applied., Results: Most women were willing talk to their sexual partners about circumcision, but indicated that the decision to circumcise remained that of their sexual partner. Women felt that they should encourage their partners, show more interest in circumcision, be patient, speak in a caring and respectful tone, choose a correct time when their partner was relaxed and talk in a private space about VMMC. Using magazine/newspaper articles, pamphlets or advertisements were identified as tools that could aid their discussion. Substantial barriers to initiating conversations on VMMC included accusations by partner on infidelity, fear of gender-based violence, cultural restrictions and hesitation to speak to a mature partner about circumcision., Conclusions: Women need to ensure that before talking to their partner about circumcision, the environment and approach that they use are conducive. Female social network forums could be used to educate women on conversation techniques, skills to use when talking to their partners and how to address communication challenges about circumcision. Involvement of women in VMMC awareness campaigns could encourage circumcision uptake among men., Competing Interests: The authors have declared that no competing interests exist.

With efficacious behavioral, biomedical, and structural interventions available, combination implementation strategies are being implemented to combat HIV/AIDS across settings internationally. However, priority statements from national and international bodies make it unclear whether the objective should be the reduction in HIV incidence or the maximization of health, most commonly measured with quality-adjusted life years (QALYs). Building off a model-based evaluation of HIV care interventions in British Columbia, Canada, we compare the optimal sets of interventions that would be identified using HIV infections averted, and QALYs as the primary outcome in a cost-effectiveness analysis. We found an explicit focus on averting new infections undervalues the health benefits derived from antiretroviral therapy, resulting in suboptimal and potentially harmful funding recommendations.

Purpose of Review: The HIV and Mycobacterium tuberculosis syndemic remains a major global public health threat. HIV and tuberculosis (TB) global targets have been set. Success will depend on achieving combined disease control. We explore current policy, economic investment, and disease control strategies for HIV, TB, and HIV-associated TB. We review published HIV, TB, and HIV-associated TB data for 30 WHO priority countries and propose a comprehensive HIV and TB care continua., Recent Findings: In 2016, people living with HIV (PLHIV) on antiretroviral treatment (ART) ranged from 13 to 84%; viral suppression ranged from 21 to 79%. Only 5% of PLHIV without TB reported a course of isoniazid preventive therapy (IPT). TB treatment success (2015) ranged from 34 to 94%. Data for the combined indicators: TB treatment success and viral suppression and IPT and ART for PLHIV are not collected. Reported 2003-2017 global international and domestic resources for TB and HIV-associated TB averaged $2.9 billion per year; cumulative total was $43 billion., Summary: Integrating HIV and TB control efforts including monitoring and evaluation systems will be necessary to end both TB and HIV. A comprehensive HIV and TB continuum supports integrated, comprehensive HIV and TB disease control efforts focused on improving both individual and public health.

Background: In Malawi in 2014, <20% of human immunodeficiency virus (HIV)-exposed infants received an early infant diagnosis (EID) test in the first 2 months of life and only 30% of HIV-infected children were on antiretroviral therapy (ART). We sought to understand the potential patient impact of improving timely infant diagnosis and treatment initiation through implementation of point-of-care (POC) EID technologies in Malawi., Methods: In this observational study, POC EID technologies were introduced into routine services at 7 health facilities across Malawi in September 2015. The primary outcome was the proportion of HIV-infected infants initiating ART within 60 days of sample collection in the POC arm compared to the baseline arm with conventional laboratory-based EID testing., Results: The time from sample collection to result received by the patient decreased significantly from 56 days (interquartile range [IQR], 30-81 days) in the baseline arm to <1 day in the POC arm (P < .001). Of the HIV-infected infants, the time between sample collection and ART initiation was reduced from 38 days (IQR, 30-54 days) in the baseline arm to <1 day (IQR, 0-1 day) in the POC arm (P = .019). Furthermore, the proportion of HIV-infected infants initiated on ART within 60 days of sample collection increased significantly from 41.9% to 91.1% after the introduction of POC (adjusted risk ratio, 2.28; P < .001)., Conclusions: ART initiation rates were significantly improved with the implementation of same-day POC EID testing compared with referred, longer-turnaround laboratory-based testing.

The human immunodeficiency virus (HIV) and Mycobacterium tuberculosis syndemic remains a global public health threat. Separate HIV and tuberculosis (TB) global targets have been set; however, success will depend on achieving combined disease control objectives and care continua. The objective of this study was to review available policy, budgets, and data to reconceptualize TB and HIV disease control objectives by combining HIV and TB care continua. For 22 World Health Organization (WHO) TB and TB/HIV priority countries, we used 2015 data from the HIV90-90-90watch website, UNAIDS AIDSinfo, and WHO 2016 and 2017 Global TB Reports. Global resources available in TB and HIV/TB activities for 2003-2017 were collected from publicly available sources. In 22 high-burden countries, people living with HIV on antiretroviral therapy ranged from 9 to 70%; viral suppression was 38-63%. TB treatment success ranged from 71 to 94% with 14 (81% HIV/TB burden) countries above 80% TB treatment success. From 2003 to 2017, reported global international and domestic resources for HIV-associated TB and TB averaged $2.85 billion per year; the total for 2003-2017 was 43 billion dollars. Reviewing combined HIV and TB targets demonstrate disease control progress and challenges. Using an integrated HIV and TB continuum supports HIV and TB disease control efforts focused on improving both individual and public health.

Background: Practical ways are needed to scale-up pediatric HIV testing in sub-Saharan Africa, where testing is usually limited to HIV-exposed children in maternal and child health clinics., Methods: We implemented an enhanced pediatric HIV testing program in 33 health facilities in Zimbabwe by integrating HIV testing into all pediatric health services. We collected individual data on children tested by having health care workers complete a program-specific child health booklet. We compared numbers of children tested before and during the program using routinely collected aggregate program data reported by health facilities., Results: A total of 12,556 children aged 0-5 years were recorded in child health booklets; 9431 (75.1%) had information on HIV testing, of whom 7326 (77.7%) were tested; 7167 had test results of whom 122 (1.7%) were HIV-infected. Among children seen in outpatient clinics, 82.1% were tested compared with 66.5% tested among children seen in maternal/child health clinics. Of the 122 HIV-infected children identified, 77 (63.1%) could be missed under existing pediatric testing guidelines. The number of HIV-infected children identified during the 6-month program increased by 55% compared with the prior 6-month period (RR = 1.55, 95% CI: 1.22 to 1.96). Factors independently associated with HIV infection included being malnourished (adjusted odds ratio [AOR] = 7.7, 95% CI: 2.1 to 28.6), being exposed to TB (AOR = 8.1, 95% CI: 2.0 to 32.2), and having an HIV-infected mother (AOR = 41.6, 95% CI: 15.9 to 108.8)., Conclusions: Integrating HIV testing into all pediatric health services is feasible and can assist in identifying HIV-infected children who could be missed in current testing guidelines.

Background: With the introduction of 2016 World Health Organization guidelines recommending universal antiretroviral therapy (ART), there has been increased recognition of the lack of men engaging in HIV testing and treatment. Studies in sub-Saharan Africa indicate there have been challenges engaging men in HIV testing and HIV-positive men into treatment., Methods: This qualitative study explored women's perspective of their male partner's attitudes towards HIV and ART and how it shapes woman's experience with ART. Data were collected through in-depth interviews and focus group discussions with HIV-positive pregnant and postpartum women on Option B+ and health care workers in Malawi and Zimbabwe. In Malawi, 19 in-depth interviews and 12 focus group discussions were conducted from September-December 2013. In Zimbabwe, 15 in-depth interviews and 21 focus-group discussions were conducted from July 2014-March 2014., Results: The findings highlighted that many men discourage their partners from initiating or adhering to ART. One of the main findings indicated that despite the many advancements in HIV care and ART regimens, there are still many lingering negative beliefs about HIV and ART from the earlier days of the epidemic. In addition to existing theories explaining men's resistance to/absence in HIV testing and treatment as a threat to their masculinity or because of female-focused health facilities, this paper argues that men's aversion to HIV may be a result of old beliefs about HIV and ART which have not been addressed., Conclusions: Due to lack of accurate and up to date information about HIV and ART, many men discourage their female partners from initiating and adhering to ART. The effect of lingering and outdated beliefs about HIV and ART needs to be addressed through strengthened communication about developments in HIV care and treatment. Universal ART offers a unique opportunity to curb the epidemic, but successful implementation of these new guidelines is dependent on ART initiation and adherence by both women and men. Strengthening men's understanding about HIV and ART will greatly enhance women's ability to initiate and adhere to ART and improve men's health.

Background: Zimbabwe's Ministry of Health and Child Care (MOHCC) adopted 2013 World Health Organization (WHO) prevention of mother-to-child HIV transmission (PMTCT) guidelines recommending initiation of HIV-positive pregnant and breastfeeding women (PPBW) on lifelong antiretroviral treatment (ART) irrespective of clinical stage (Option B+). Option B+ was officially launched in Zimbabwe in November 2013; however the acceptability of life-long ART and its potential uptake among women was not known., Methods: A qualitative study was conducted at selected sites in Harare (urban) and Zvimba (rural) to explore Option B+ acceptability; barriers, and facilitators to ART adherence and service uptake. In-depth interviews (IDIs), focus group discussions (FGDs) and key informant interviews (KIIs) were conducted with PPBW, healthcare providers, and community members. All interviews were audio-recorded, transcribed, and translated; data were coded and analyzed in MaxQDA v10., Results: Forty-three IDIs, 22 FGDs, and five KIIs were conducted. The majority of women accepted lifelong ART. There was however, a fear of commitment to taking lifelong medication because they were afraid of defaulting, especially after cessation of breastfeeding. There was confusion around dosage; and fear of side effects, not having enough food to take drugs, and the lack of opportunities to ask questions in counseling. Participants reported the need for strengthening community sensitization for Option B+. Facilitators included receiving a simplified pill regimen; ability to continue breastfeeding beyond 6 months like HIV-negative women; and partner, community and health worker support. Barriers included distance of health facility, non-disclosure of HIV status, poor male partner support and knowing someone who had negative experience on ART., Conclusions: This study found that Option B+ is generally accepted among PPBW as a means to strengthen their health and protect their babies. Consistent with previous literature, this study demonstrated the importance of male partner and community support in satisfactory adherence to ART and enhancing counseling techniques. Strengthening community sensitization and male knowledge is critical to encourage women to disclose their HIV status and ensure successful adherence to ART. Targeting and engaging partners of women will remain key determinants to women's acceptance and adherence on ART under Option B+.

Background: Age-disaggregated analyses of prevention of mother-to-child transmission (PMTCT) program data to assess the uptake of HIV services by pregnant adolescent women are limited but are critical to understanding the unique needs of this vulnerable high-risk population., Methods: We conducted a retrospective analysis of patient-level PMTCT data collected from 2011 to 2013 in 36 health facilities in 5 districts of Zimbabwe using an electronic database. We compared uptake proportions for PMTCT services between adolescent (≤19 years) and adult (>19 years) women. Multivariable binomial regression analysis was used to estimate the association of the women's age group with each PMTCT service indicator., Results: The study analyzed data from 22,215 women aged 12-50 years (22.5% adolescents). Adolescents were more likely to present to antenatal care (ANC) before 14 weeks of gestational age compared with older women [adjusted relative risk (aRR) = 1.34; 95% confidence interval: 1.22 to 1.47] with equally low rates of completion of 4 ANC visits. Adolescents were less likely to present with known HIV status (aRR = 0.34; 95% confidence interval: 0.29 to 0.41) but equally likely to be HIV tested in ANC. HIV prevalence was 5.5% in adolescents vs 20.1% in adults. While >84% of both HIV-positive groups received antiretroviral drugs for PMTCT, 44% of eligible adolescents were initiated on antiretroviral therapy vs 51.3% of eligible adults, though not statistically significant., Conclusions: Pregnant adolescents must be a priority for primary HIV prevention services and expanded HIV treatment services among pregnant women to achieve an AIDS-free generation in Zimbabwe and similar high HIV burden countries.

Background: In September, 2016, South Africa adopted a policy of providing antiretroviral treatment to everyone infected with HIV irrespective of their CD4 cell count. Studies of universal treatment and expanded prevention of HIV differ widely in their projections of effects and the associated costs, so we did this analysis to attempt to find a consensus., Methods: We used data on HIV from the Joint UN Programme on HIV and AIDS (UNAIDS) from 1988 to 2013 and from data from WHO on tuberculosis from 1980 to to 2013 to fit a dynamical model to time trends in HIV prevalence, antiretroviral therapy (ART) coverage, and tuberculosis notification rates in South Africa. We then used the model to estimate current trends and project future patterns in HIV prevalence and incidence, AIDS-related mortality, and tuberculosis notification rates, and we used data from the South African National AIDS Council to assess current and future costs under different combinations of treatment and prevention approaches. We considered two treatment strategies: the Constant Effort strategy, in which people infected with HIV continue to start treatment at the rate in 2016, and the Expanded Treatment and Prevention (ETP) strategy, in which testing rates are increased, treatment is started immediately after HIV is detected, and prevention programmes are expanded., Findings: Our estimates show that HIV incidence among adults aged 15 years or older fell from 2·3% per year in 1996 to 0·65% per year in 2016, AIDS-related mortality decreased from 1·4% per year in 2006 to 0·37% per year in 2016, and both continue to fall at a relative rate of 17% per year. Our model shows that maintenance of Constant Effort will have a substantial effect on HIV but will not end AIDS, whereas ETP could end AIDS by 2030, with incidence of HIV and AIDs-related mortality rates both at less than one event per 1000 adults per year. Under ETP the annual cost of health care and prevention will increase from US$2·3 billion in 2016 to $2·9 billion in 2018, then decrease to $1·7 billion in 2030 and $0·9 billion in 2050. Over the next 35 years, the expansion of treatment will avert an additional 3·8 million new infections, save 1·1 million lives, and save $3·2 billion compared with continuing Constant Effort up to 2050. Expansion of prevention, including provision of pre-exposure prophylaxis, condom distribution, and male circumcision, could avert a further 150 000 new infections, save 5000 lives, and cost an additional $5·7 billion compared with Constant Effort., Interpretation: Our results suggest that South Africa is on track to reduce HIV incidence and AIDS-related mortality substantially by 2030, saving both lives and money. Success will depend on high rates of HIV testing, ART delivery and adherence, good patient monitoring and support, and data to monitor progress., Funding: None., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2014, the Joint United Nations Program on HIV/AIDS (UNAIDS) issued treatment goals for human immunodeficiency virus (HIV). The 90-90-90 target specifies that by 2020, 90% of individuals living with HIV will know their HIV status, 90% of people with diagnosed HIV infection will receive antiretroviral treatment (ART), and 90% of those taking ART will be virally suppressed. Consistent methods and routine reporting in the public domain will be necessary for tracking progress towards the 90-90-90 target., Methods and Findings: For the period 2010-2016, we searched PubMed, UNAIDS country progress reports, World Health Organization (WHO), UNAIDS reports, national surveillance and program reports, United States President's Emergency Plan for AIDS Relief (PEPFAR) Country Operational Plans, and conference presentations and/or abstracts for the latest available national HIV care continuum in the public domain. Continua of care included the number and proportion of people living with HIV (PLHIV) who are diagnosed, on ART, and virally suppressed out of the estimated number of PLHIV. We ranked the described methods for indicators to derive high-, medium-, and low-quality continuum. For 2010-2016, we identified 53 national care continua with viral suppression estimates representing 19.7 million (54%) of the 2015 global estimate of PLHIV. Of the 53, 6 (with 2% of global burden) were high quality, using standard surveillance methods to derive an overall denominator and program data from national cohorts for estimating steps in the continuum. Only nine countries in sub-Saharan Africa had care continua with viral suppression estimates. Of the 53 countries, the average proportion of the aggregate of PLHIV from all countries on ART was 48%, and the proportion of PLHIV who were virally suppressed was 40%. Seven countries (Sweden, Cambodia, United Kingdom, Switzerland, Denmark, Rwanda, and Namibia) were within 12% and 10% of achieving the 90-90-90 target for "on ART" and for "viral suppression," respectively. The limitations to consider when interpreting the results include significant variation in methods used to determine national continua and the possibility that complete continua were not available through our comprehensive search of the public domain., Conclusions: Relatively few complete national continua of care are available in the public domain, and there is considerable variation in the methods for determining progress towards the 90-90-90 target. Despite bearing the highest HIV burden, national care continua from sub-Saharan Africa were less likely to be in the public domain. A standardized monitoring and evaluation approach could improve the use of scarce resources to achieve 90-90-90 through improved transparency, accountability, and efficiency.

We reviewed published national HIV care continua for men who have sex with men (MSM), people who inject drugs (PWID), and female sex workers (FSWs) to track progress toward the 90-90-90 target. We searched the Internet, PubMed, surveillance reports, United Nations Programme on HIV/AIDS country reports, US President's Emergency Plan for AIDS Relief country/regional operational plans, and conference abstracts for the continua and graded them on quality. We found 12 continua for MSM, 7 for PWID, and 5 for FSW from 12 countries. HIV diagnosis, antiretroviral therapy coverage, and viral suppression varied between (1) 5% and 85%, 2% and 73%, and 1% and 72%, respectively for MSM; (2) 54% and 96%, 14% and 80%, and 8% and 68%, respectively for PWID; and (3) 27% and 63%, 8% and 16%, and 2% and 14%, respectively for FSW. Two countries, using data from national cohorts, were high quality. There are limited key population continua in the public domain. Of the few available, none have achieved 90-90-90. Improved monitoring and evaluation of key population continua is necessary to achieve the 90-90-90 target.

Background: Efforts to reach UNAIDS' treatment and viral suppression targets have increased demand for viral load (VL) testing and strained existing laboratory networks, affecting turnaround time. Longer VL turnaround times delay both initiation of formal adherence counseling and switches to second-line therapy for persons failing treatment and contribute to poorer health outcomes., Methods: We utilized descriptive statistics and logistic regression to analyze VL testing data collected in Malawi between January 2013 and March 2016. The primary outcomes assessed were greater-than-median pretest phase turnaround time (days elapsed from specimen collection to receipt at the laboratory) and greater-than-median test phase turnaround time (days from receipt to testing)., Results: The median number of days between specimen collection and testing increased 3-fold between 2013 (8 days, interquartile range (IQR) = 6-16) and 2015 (24, IQR = 13-39) (p<0.001). Multivariable analysis indicated that the odds of longer pretest phase turnaround time were significantly higher for specimen collection districts without laboratories capable of conducting viral load tests (adjusted odds ratio (aOR) = 5.16; 95% confidence interval (CI) = 5.04-5.27) as well as for Malawi's Northern and Southern regions. Longer test phase turnaround time was significantly associated with use of dried blood spots instead of plasma (aOR = 2.30; 95% CI = 2.23-2.37) and for certain testing months and testing laboratories., Conclusion: Increased turnaround time for VL testing appeared to be driven in part by categorical factors specific to the phase of turnaround time assessed. Given the implications of longer turnaround time and the global effort to scale up VL testing, addressing these factors via increasing efficiencies, improving quality management systems and generally strengthening the VL spectrum should be considered essential components of controlling the HIV epidemic.

Pediatric human immunodeficiency virus (HIV) infection remains an important public health issue in resource-limited settings. In 2015, 1.4 million children aged <15 years were estimated to be living with HIV (including 170,000 infants born in 2015), with the vast majority living in sub-Saharan Africa (1). In 2014, 150,000 children died from HIV-related causes worldwide (2). Access to timely HIV diagnosis and treatment for HIV-infected infants reduces HIV-associated mortality, which is approximately 50% by age 2 years without treatment (3). Since 2011, the annual number of HIV-infected children has declined by 50%. Despite this gain, in 2014, only 42% of HIV-exposed infants received a diagnostic test for HIV (2), and in 2015, only 51% of children living with HIV received antiretroviral therapy (1). Access to services for early infant diagnosis of HIV (which includes access to testing for HIV-exposed infants and clinical diagnosis of HIV-infected infants) is critical for reducing HIV-associated mortality in children aged <15 years. Using data collected from seven countries supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), progress in the provision of HIV testing services for early infant diagnosis was assessed. During 2011-2015, the total number of HIV diagnostic tests performed among HIV-exposed infants within 6 weeks after birth (tests for early infant diagnosis of HIV), as recommended by the World Health Organization (WHO) increased in all seven countries (Cote d'Ivoire, the Democratic Republic of the Congo, Haiti, Malawi, South Africa, Uganda, and Zambia); however, in 2015, the rate of testing for early infant diagnosis among HIV-exposed infants was <50% in five countries. HIV positivity among those tested declined in all seven countries, with three countries (Cote d'Ivoire, the Democratic Republic of the Congo, and Uganda) reporting >50% decline. The most common challenges for access to testing for early infant diagnosis included difficulties in specimen transport, long turnaround time between specimen collection and receipt of results, and limitations in supply chain management. Further reductions in HIV mortality in children can be achieved through continued expansion and improvement of services for early infant diagnosis in PEPFAR-supported countries, including initiatives targeted to reach HIV-exposed infants, ensure access to programs for early infant diagnosis of HIV, and facilitate prompt linkage to treatment for children diagnosed with HIV infection.

Unlabelled: : Achieving the 90-90-90 targets by 2020 requires increased focus, resources, and efficiency to provide earlier access to antiretroviral therapy (ART)., Methods: We used 2009 to 2013 National AIDS Spending Assessment data to assess HIV care and treatment spending in 38 high-burden, low- and middle-income countries (LMICs)., Results: In 2013, 23 of the 38 high-burden countries spent less than 50% of total HIV spending on care and treatment. HIV spending on ART per people living with HIV (PLHIV; adjusted) averaged US$299 (US$32-US$2463). During 2009 to 2013, a 10% increase in average spending on care and treatment per PLHIV was associated with an increase in ART coverage of 2.4% and a decrease in estimated AIDS-related death rate of 2.4 per 1000 PLHIV., Discussion: HIV spending in high-burden LMICs does not consistently reflect the new science around the preventative and clinical benefits of earlier HIV diagnosis and ART initiation., (© The Author(s) 2016.)

Background: Despite sparse efficacy data, tenofovir-emtricitabine or tenofovir-lamivudine plus nevirapine is used in many resource-constrained settings., Methods: This retrospective cohort study included patients initiating nevirapine-based antiretroviral therapy (ART) with either tenofovir-emtricitabine or lamivudine (tenofovir group) or zidovudine-lamivudine (zidovudine group). Clinical, virologic, and immunologic evaluations were performed at baseline and every 6 months. Virologic failure was defined as 2 consecutive human immunodeficiency virus (HIV)-RNA values >1000 copies/mL. Patients were included from ART initiation until time of failure, regimen switch, discontinuation, or last HIV-RNA measurement. Cox proportional hazards regression was used to model factors influencing time to failure. Bias due to dependent censoring was investigated via inverse probability weighted pooled logistic regression., Results: A total of 5547 patients were evaluated; 1484 (26.8%) were in the tenofovir group and 4063 (73.2%) were in the zidovudine group. In the adjusted model, tenofovir regimen (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.21-1.79) and higher baseline log10 HIV-RNA (HR, 1.15; 95% CI, 1.03-1.28) were associated with virologic failure. Higher baseline log10 CD4+ cell count (HR, 0.50; 95% CI, .40-.63) and increasing age (HR, 0.98; 95% CI, .97-.99) decreased the risk of virologic failure. Inverse probability weighting results were consistent with the primary analysis., Conclusions: Compared with zidovudine-lamivudine, the use of tenofovir-lamivudine or emtricitabine in combination with nevirapine was a strong predictor of virologic failure in our cohort, which was not explained by other risk factors or criteria for regimen selection., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction.

Antiretroviral therapy (ART) is the main intervention needed to reduce morbidity and mortality and to prevent tuberculosis in adults living with HIV. However, in most resource-limited countries, especially in sub-Saharan Africa, ART is started too late to have an effect with substantial early morbidity and mortality, and in high tuberculosis burden settings ART does not reduce the tuberculosis risk to that reported in individuals not infected with HIV. Co-trimoxazole preventive therapy started before or with ART, irrespective of CD4 cell count, reduces morbidity and mortality with benefits that continue indefinitely. Isoniazid preventive therapy as an adjunct to ART prevents tuberculosis in high-exposure settings, with long-term treatment likely to be needed to sustain this benefit. Unfortunately, both preventive therapies are underused in low-income and high-burden settings. ART development has benefited from patient-centred simplification with several effective regimens now available as a one per day pill. We argue that co-trimoxazole and isoniazid should also be combined into a single fixed-dose pill, along with pyridoxine (vitamin B6), that would be taken once per day to help with individual uptake and national scale-up of therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: We estimated HIV-free infant survival and mother-to-child HIV transmission (MTCT) rates in Zimbabwe, some of the first community-based estimates from a UNAIDS priority country., Methods: In 2012 we surveyed mother-infant pairs residing in the catchment areas of 157 health facilities randomly selected from 5 of 10 provinces in Zimbabwe. Enrolled infants were born 9-18 months before the survey. We collected questionnaires, blood samples for HIV testing, and verbal autopsies for deceased mothers/infants. Estimates were assessed among i) all HIV-exposed infants, as part of an impact evaluation of Option A of the 2010 WHO guidelines (rolled out in Zimbabwe in 2011), and ii) the subgroup of infants unexposed to Option A. We compared province-level MTCT rates measured among women in the community with MTCT rates measured using program monitoring data from facilities serving those communities., Findings: Among 8568 women with known HIV serostatus, 1107 (12.9%) were HIV-infected. Among all HIV-exposed infants, HIV-free infant survival was 90.9% (95% confidence interval (CI): 88.7-92.7) and MTCT was 8.8% (95% CI: 6.9-11.1). Sixty-six percent of HIV-exposed infants were still breastfeeding. Among the 762 infants born before Option A was implemented, 90.5% (95% CI: 88.1-92.5) were alive and HIV-uninfected at 9-18 months of age, and 9.1% (95%CI: 7.1-11.7) were HIV-infected. In four provinces, the community-based MTCT rate was higher than the facility-based MTCT rate. In Harare, the community and facility-based rates were 6.0% and 9.1%, respectively., Conclusion: By 2012 Zimbabwe had made substantial progress towards the elimination of MTCT. Our HIV-free infant survival and MTCT estimates capture HIV transmissions during pregnancy, delivery and breastfeeding regardless of whether or not mothers accessed health services. These estimates also provide a baseline against which to measure the impact of Option A guidelines (and subsequently Option B+).

Background: Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV) disease progression, mortality and transmission. We assess the impact of expanded HIV treatment for the prevention of Acquired Immunodeficiency Syndrome (AIDS)-related deaths and simulate four treatment scenarios for Nigeria and South Africa., Methods: For 1990-2013, we used the Joint United Nations Programme on HIV/AIDS (UNAIDS) database to examine trends in AIDS deaths, HIV incidence and prevalence, ART coverage, annual AIDS death rate, AIDS death-to-treatment and HIV infections to treatment ratios for the top 30 countries with the highest AIDS mortality burden and compare them with data from high-income countries. We projected the 1990-2020 AIDS deaths for Nigeria and South Africa using four treatment scenarios: 1) no ART; 2) maintaining current ART coverage; 3) 90% ART coverage based on 2013 World Health Organization (WHO) ART guidelines by 2020; and 4) reaching the United Nations 90-90-90 Target by 2020., Findings: In 2013, there were 1.3 million (1.1 million-1.6 million) AIDS deaths in the top 30 countries representing 87% of global AIDS deaths. Eight countries accounted for 58% of the global AIDS deaths; Nigeria and South Africa accounted for 27% of global AIDS deaths. The highest death rates per 1000 people living with HIV were in Central African Republic (91), South Sudan (82), Côte d'Ivoire (75), Cameroon (72) and Chad (71), nearly 8-10 times higher than the high-income countries. ART access in 2013 has averted as estimated 1,051,354 and 422,448 deaths in South Africa and Nigeria, respectively. Increasing ART coverage in these two countries to meet the proposed UN 90-90-90 Target by 2020 could avert 2.2 and 1.2 million deaths, respectively., Interpretation: Over the past decade the expansion of access to ART averted millions of deaths. Reaching the proposed UN 90-90-90 Target by 2020 will prevent additional morbidity, mortality and HIV transmission. Despite progress, high-burden countries will need to accelerate access to ART treatment to avert millions of premature AIDS deaths and new HIV infections.

Objective: To examine the uptake of services and behaviors in the prevention of mother-to-child HIV transmission (PMTCT) cascade in Zimbabwe and to determine factors associated with MTCT and maternal antiretroviral therapy (ART) or antiretroviral (ARV) prophylaxis., Design: Analysis of cross-sectional data from mother-infant pairs., Methods: We analyzed baseline data collected in 2012 as part of the impact evaluation of Zimbabwe's Accelerated National PMTCT Program. Using multistage cluster sampling, eligible mother-infant pairs were randomly sampled from the catchment areas of 157 facilities in 5 provinces, tested for HIV infection, and interviewed about PMTCT service utilization., Results: Of 8800 women, 94% attended ≥ 1 antenatal care visit, 92% knew their HIV serostatus during pregnancy, 77% delivered in a health facility, and 92% attended the 6-8 week postnatal visit. Among 1075 (12%) HIV-infected women, 59% reported ART/ARV prophylaxis and 63% of their HIV-exposed infants received ARV prophylaxis. Among HIV-exposed infants, maternal receipt of ART/ARV prophylaxis was protective against MTCT [adjusted prevalence ratio (PR(a)): 0.41, 95% confidence interval (CI): 0.23 to 0.74]. Factors associated with receipt of maternal ART/ARV prophylaxis included ≥ 4 antenatal care visits (PR(a): 1.18, 95% CI: 1.01 to 1.38), institutional delivery (PR(a): 1.31, 95% CI: 1.13 to 1.52), and disclosure of serostatus (PRa: 1.30, 95% CI: 1.12 to 1.49)., Conclusions: These data from women in the community indicate gaps in the PMTCT cascade before the accelerated program, which may have been missed by examination of health facility data alone. These gaps were especially noteworthy for services targeted specifically to HIV-infected women and their infants, such as maternal and infant ART/ARV prophylaxis.

Objectives: To evaluate the feasibility and effectiveness of dried blood spots (DBS) use for viral load (VL) monitoring, describing patient outcomes and programmatic challenges that are relevant for DBS implementation in sub-Saharan Africa., Methods: We recruited adult antiretroviral therapy (ART) patients from five district hospitals in Malawi. Eligibility reflected anticipated Ministry of Health VL monitoring criteria. Testing was conducted at a central laboratory. Virological failure was defined as >5000 copies/ml. Primary outcomes were program feasibility (timely result availability and patient receipt) and effectiveness (second-line therapy initiation)., Results: We enrolled 1,498 participants; 5.9% were failing at baseline. Median time from enrollment to receipt of results was 42 days; 79.6% of participants received results within 3 months. Among participants with confirmed elevated VL, 92.6% initiated second-line therapy; 90.7% were switched within 365 days of VL testing. Nearly one-third (30.8%) of participants with elevated baseline VL had suppressed (<5,000 copies/ml) on confirmatory testing. Median period between enrollment and specimen testing was 23 days. Adjusting for relevant covariates, participants on ART >4 years were more likely to be failing than participants on therapy 1-4 years (RR 1.7, 95% CI 1.0-2.8); older participants were less likely to be failing (RR 0.95, 95% CI 0.92-0.98). There was no difference in likelihood of failure based on clinical symptoms (RR 1.17, 95% CI 0.65-2.11)., Conclusions: DBS for VL monitoring is feasible and effective in real-world clinical settings. Centralized DBS testing may increase access to VL monitoring in remote settings. Programmatic outcomes are encouraging, especially proportion of eligible participants switched to second-line therapy.

Objectives: Although CD8+ T cells play a critical role in the control of HIV-1 infection,their antiviral efficacy can be limited by antigenic variation and immune exhaustion.The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells., Design and Methods: Here, we used an array of different human leukocyte antigen(HLA)-B*15:03 and HLA-B*42:01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8+ T-cell populations(n = 128) spanning 11 different epitope targets., Results: Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8+ T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8+ T cells., Conclusion: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) Treatment 2015 calls for expanded access to HIV care and treatment, including cotrimoxazole preventive therapy (CPT), for prevention of HIV-related morbidity and mortality. We review 115 national guidelines from 92 countries for recommendations on CPT for adults and adolescents and determine the level of consistency with the World Health Organization (WHO) guidelines. Of the 66 countries with recommendations, 5 (8%) countries recommend lifelong CPT for people living with HIV; 19 (29%) countries recommend a CD4 count threshold of ≤350 cells/mm(3) or WHO clinical stages III and IV or II, III, and IV; and 19 (29%) countries recommend a CD4 count threshold of ≤200 cells/mm(3). Of the 48 countries with recommendations on discontinuing CPT, 25 (52%) countries recommend discontinuation of cotrimoxazole when the CD4 count is >200 cells/mm(3). World Health Organization guidelines offer countries flexibility on the use of CPT, and countries are recommending a wide range of CD4 counts and WHO clinical stage criteria for prophylaxis initiation and discontinuation., (© The Author(s) 2014.)