Antiretroviral Treatment Scale-up Research Articles

Applying Next-Generation Sequencing to Track HIV-1 Drug Resistance Mutations Circulating in Portugal.

The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV transmission. We investigated the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) among HIV-1 patients in Portugal. Data were obtained from 1050 HIV-1 patient samples submitted for HIV drug resistance (HIVDR) testing from January 2022 to June 2023. Evaluation of DRM affecting viral susceptibility to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was performed using an NGS technology, the Vela Diagnostics Sentosa SQ HIV-1 Genotyping Assay. About 71% of patients were ART naïve and 29% were experienced. Overall, 20% presented with any DRM. The prevalence of TDR and ADR was 12.6% and 41.1%, respectively. M184V, T215S, and M41L mutations for NRTI, K103N for NNRTI, and M46I/L for PIs were frequent in naïve and treated patients. E138K and R263K mutations against INSTIs were more frequent in naïve than treated patients. TDR and ADR to INSTIs were 0.3% and 7%, respectively. Patients aged 50 or over (OR: 1.81, p = 0.015), originating from Portuguese-speaking African countries (PALOPs) (OR: 1.55, p = 0.050), HIV-1 subtype G (OR: 1.78, p = 0.010), and with CD4 < 200 cells/mm3 (OR: 1.70, p = 0.043) were more likely to present with DRMs, while the males (OR: 0.63, p = 0.003) with a viral load between 4.1 to 5.0 Log10 (OR: 0.55, p = 0.003) or greater than 5.0 Log10 (OR: 0.52, p < 0.001), had lower chances of presenting with DRMs. We present the first evidence on TDR and ADR to INSTI regimens in followed up patients presenting for healthcare in Portugal. We observed low levels of TDR to INSTIs among ART-naïve and moderate levels in ART-exposed patients. Regimens containing PIs could be an alternative second line in patients with intermediate or high-level drug resistance, especially against second-generation INSTIs (dolutegravir, bictegravir, and cabotegravir).

The impact of antiretroviral treatment on the relationship between HIV/AIDS and economic growth

Although there is sufficient evidence to suggest that HIV/AIDS impedes economic growth, there is limited evidence on the nature of the relationship in a setting characterised by scale-up of antiretroviral treatment (ART). Using data from nine provinces over the period 1995 to 2019, we examine the impact of ART on the HIV/AIDS-real GDP per capita relationship in South Africa. We employ both linear and non-linear econometric approaches. Our results show that ART mitigates the negative effects of HIV/AIDS on real GDP per capita by increasing worker productivity. Furthermore, we find a U-shaped nonlinear relationship between HIV/AIDS and real GDP per capita that is conditional to the level of ART coverage. We also find that the impact of HIV/AIDS on real GDP per capita is higher in men compared to women. Our findings suggest that HIV testing and treatment should be expanded to enhance productivity, and men should be prioritised.

Impact of interventions for tuberculosis prevention and care in South Africa – a systematic review of mathematical modelling studies

Substantial additional efforts are needed to prevent, find and successfully treat tuberculosis (TB) in South Africa (SA). In thepast decade, an increasing body of mathematical modelling research has investigated the population-level impact of TB prevention and careinterventions. To date, this evidence has not been assessed in the SA context. To systematically review mathematical modelling studies that estimated the impact of interventions towards the World HealthOrganization's End TB Strategy targets for TB incidence, TB deaths and catastrophic costs due to TB in SA. We searched the PubMed, Web of Science and Scopus databases for studies that used transmission-dynamic models of TB in SAand reported on at least one of the End TB Strategy targets at population level. We described study populations, type of interventions andtheir target groups, and estimates of impact and other key findings. For studies of country-level interventions, we estimated average annualpercentage declines (AAPDs) in TB incidence and mortality attributable to the intervention. We identified 29 studies that met our inclusion criteria, of which 7 modelled TB preventive interventions (vaccination,antiretroviral treatment (ART) for HIV, TB preventive treatment (TPT)), 12 considered interventions along the care cascade for TB(screening/case finding, reducing initial loss to follow-up, diagnostic and treatment interventions), and 10 modelled combinationsof preventive and care-cascade interventions. Only one study focused on reducing catastrophic costs due to TB. The highest impactof a single intervention was estimated in studies of TB vaccination, TPT among people living with HIV, and scale-up of ART. Forpreventive interventions, AAPDs for TB incidence varied between 0.06% and 7.07%, and for care-cascade interventions between 0.05%and 3.27%. We describe a body of mathematical modelling research with a focus on TB prevention and care in SA. We found higherestimates of impact reported in studies of preventive interventions, highlighting the need to invest in TB prevention in SA. However, studyheterogeneity and inconsistent baseline scenarios limit the ability to compare impact estimates between studies. Combinations, rather thansingle interventions, are likely needed to reach the End TB Strategy targets in SA.

The urgent need to scale-up fungal diagnostics in Africa

Africa is home to two-thirds of the global population of people living with HIV infection.1 Despite a steady scale-up of antiretroviral treatment (ART), efforts to curtail HIV-related mortality are consistently thwarted by the high burden of advanced HIV disease, defined by WHO as a CD4 count of less than 200 cells/mL or WHO stage 3 or 4.2 In 2020, approximately 20–25% of people who commenced HIV care in Uganda and Botswana had advanced HIV disease.3 Besides denoting a failure in the HIV cascade of care, advanced HIV disease is increasingly documented in patients on ART who disengage from care and return with virological non-suppression.

Care during ART scale-up: surviving the HIV epidemic in Ethiopia

Over the last decades, there has been a worldwide rise of new technologies for controlling the HIV epidemic by expanding antiretroviral medicines. This article examines how the pharmaceutical-driven model of public health, which emerged as a byproduct of antiretroviral treatment (ART) scale-up in Ethiopia, interplayed with local forms of actions, engagements, and voices through which suffering inflicted by the epidemic was cared for. Through the eyes of an Ethiopian woman with HIV, this article illustrates how the increasing emphasis on ART facilitated the defunding of some community-based care practices. Moreover, it rendered the realities of precarious life with HIV invisible in the landscape of therapeutic citizenship. However, for Ethiopians, ART scale-up unfolded amid multiple forms of HIV care practices and relationships that endured stigma, alienation, and uncertainty before and after ART. The experience of surviving the HIV epidemic in Ethiopia provides a vital premise upon which claims of meaningful care are made, and ways to otherwise develop healthcare actions and engagements are sought.

English

Despite the achievements of Anti-retroviral Treatment (ART) scale-up programmes for HIV/AIDS, retention remains a challenge. Achievements of the &ldquo;90-90-90&rdquo; HIV targets for the sustainable development goals hinges on adherence. Despite the importance of indefinite retention of patients in care, 33% of HIV patients in Cameroon are still lost-to-follow-up, thereby compromising scale-up initiatives. This study analyses data of patients on ART in Treatment Centres (TCs) and the associated loss-to-follow-up factors and proposes measures to address them. This research was a retrospective analysis of data from selected HIV/AIDS TCs. After obtaining consent, questionnaires were filled by participating TCs. Collected data were analysed using SPSS and figures were expressed as bar charts, and histograms. Five out of seven TCs participated, giving a participation rate of 71.4%. Of the 12,165 patients, 11,852 (97.4%) were adults (28.0% males and 69.4% females) while 313 (2.6%) were children. A total of 232 (1.9%) were lost-to-follow-up and 38 died within six to twelve months. Possible causes of loss-to-follow-up included poor treatment and adherence counselling, ignorance, stigmatisation, financial hardship and traditional and religious beliefs. All TCs reported transfer into and out of their centre, caused by distance, nature of job, and overcrowding. Concerns of attrition rates throughout the continuum of care from diagnosis to long-term retention are corroborated by other studies. Such attrition compromises gains from ART scale-up, leading to poorer health outcomes and wastage of limited resources. Therefore, instituting sustained counselling and education services, addressing social determinants and building on social support factors provide measures to improve retention Key words: Retention, anti-retroviral therapy, treatment, loss-to-follow-up.

Did sexual behaviour differences between HIV infection and treatment groups offset the preventative biological effects of ART roll-out in Zimbabwe?

Declines in HIV incidence have been slower than expected during the roll-out of antiretroviral treatment (ART) services in sub-Saharan African populations suffering generalized epidemics. Using data from a population-based, open cohort HIV sero-survey (2004–13), we found evidence for initial reductions in sexual activity and multiple sexual partnerships, followed by increases during the period of ART scale-up in areas of high HIV prevalence in Manicaland, east Zimbabwe. Recent population-level increases in condom use were also recorded, but largely reflected high use by the rapidly growing proportion of HIV-infected individuals on treatment. Sexual risk behaviour increased in susceptible uninfected individuals and in untreated (and therefore more infectious) HIV-infected men, which may have slowed the decline in HIV incidence in this area. Intensified primary HIV prevention programmes, together with strengthened risk screening, referral, and support services following HIV testing, could help to maximize the impact of ‘test-and-treat’ programmes in reducing new infections.

Cognitive Reserve and Its Determinants in Newly HIV Diagnosed Antiretroviral-Naive Adults From Periurban and Informal Settlements: Evidence From an HIV Hyperendemic South African Setting.

Cognitive reserve (CR), the brain's capacity to resist pathology, plays an essential role in preserving the cognitive health of people living with HIV. Cognitive health differs by the HIV clinical stage, but there are few studies on CR in newly diagnosed antiretroviral treatment (ART)-naive HIV-positive adults to inform early intervention in sub-Saharan Africa. We investigated the CR profile and its determinants among 211 newly diagnosed ART-naive HIV-positive participants from 2 clinics that serve periurban and informal settlement communities in KwaZulu-Natal, South Africa. CR domains in education, work, and leisure were assessed using the Cognitive Reserve Index questionnaire (CRIq). The CR determinants included major depression, substance use, CD4 count, history of head injury/medical comorbidity, in addition to sociodemographic status. Regression models were fitted to investigate relationships between the total/domain scores and their determinants. CRIq-Total scores were concentrated in the low-medium/medium functioning range with no individual in the extreme low or high CR functioning group. The determinants of CRIq-Total and CRIq-Education were older age, higher education attainment, and being employed. For the CRIq-Work domain, we found older age associated with lower CR. Major depression was only associated with lower CRIq-Leisure. ART scale-up will undoubtedly improve the longevity of individuals living with HIV, but we found high degree of suboptimal CR in a relatively young group of newly diagnosed ART-naive HIV-positive individuals from periurban and informal settlement communities. Early intervention focusing on increasing CR especially in socioeconomically vulnerable populations is needed to mitigate HIV-associated neurocognitive impairment and promote long-term healthy independent living.

Impact of male circumcision on risk of HIV infection in men in a changing epidemic context - systematic review and meta-analysis.

IntroductionWHO/UNAIDS recommended Voluntary Medical Male Circumcision in 2007 based on systematic review of observational studies prior to 1999 and three randomized controlled trials (RCTs). To inform updated WHO guidance, we conducted a systematic review and meta‐analysis of impact of circumcision on the risk of HIV infection among heterosexual men.MethodsStudies in PubMed of HIV incidence and changes in prevalence in heterosexual men by circumcision status were identified. Pooled incidence rate ratios were computed using fixed‐ and random‐effects meta‐analysis and risk of bias was assessed using the ROBINS‐I tool.Results and DiscussionIn three RCTs, the pooled incidence ratio was 0.41 (95% CI 0.30 to 0.56), with risk difference 10 (8 to 12) fewer infections per 1000 person‐years (py). Pooled incidence ratios were 0.34 (0.24 to 0.49) in two post‐RCT follow‐up studies, 0.29 (0.19 to 0.43) in men at high HIV risk (five cohorts), 0.48 (0.33 to 0.70) in four community‐based cohorts before circumcision scale‐up, and 0.56 (0.49 to 0.64) (7 [6 to 8] fewer per 1000 py) in six community‐based cohorts during circumcision and antiretroviral treatment scale‐up. Heterogeneity between studies was low except in men at high HIV risk. We estimated 520,000 (425,000 to 605,000) fewer infections occurred in men by end of 2018 from 22.7 million circumcisions performed since 2008 and increasing by 155,000 (125,000 to 180,000) annually if epidemic conditions remain similar. After exclusion of studies with high risk of bias and those conducted outside Africa, pooled incidence ratios were similar. There was no evidence of confounding nor changes in risk behaviour following circumcision. In post‐hoc exploratory analyses we observed a trend of decreasing effectiveness of circumcision in cohorts with lower HIV incidence. ConclusionsEfficacy of medical male circumcision on HIV incidence from randomized controlled trials was supported by effectiveness from observational studies in populations with diverse HIV risk and changing epidemic contexts. Voluntary Medical Male Circumcision remains an important evidence‐based intervention for control of generalized HIV epidemics.

Which delivery model innovations can support sustainable HIV treatment?

The rapid scale-up of antiretroviral treatment (ART) for HIV since the mid-2000s, mostly through disease-specific or “vertical” programmes, has been a highly successful undertaking, which averted millions of deaths and prevented many new infections. However, the dynamics of the HIV epidemic and changing political and financial commitment to fight the disease will likely require new models for the delivery of ART over the coming decades if the promises of universal treatment are to be met. Delivery model innovations for ART are intended to improve both the effectiveness and efficiency of the HIV treatment cascade, reaching new people who require ART and providing ART to more people without an increase in resources. We describe twelve models for ART delivery, which could be achieved through five categories of delivery innovations: integrating ART (“vertical ART plus”, “partially-integrated ART” and “fully-integrated ART”); modifying steps in the ART value chain (“professional task-shifted ART”, “people task-shifted ART” and “technology-supported ART”); eliminating steps in the ART value chain (“immediate ART” and “less frequent ART pick-up”); changing ART locations (“private-sector ART”, “traditional-sector ART” and “ART outside the health sector”); and keeping the status quo (“vertical ART”). The different delivery model innovations are not mutually exclusive and several could be combined, such as “vertical ART plus” with “task-shifted ART”. Suitability of the models will highly depend on local and national contexts, including existing health systems resources, available funding, and type of HIV epidemic. Future implementation research needs to identify which models are the best fit for different contexts.

HIV and the growing health burden from noncommunicable diseases in Botswana: modelling study.

BackgroundThe “greying of AIDS” – the aging of the population living with HIV who benefit from antiretroviral treatment (ART) and the emergence of age-related non-communicable diseases (NCDs) – has been well documented. The emerging health systems challenges – eg, the implications of HIV on the disease burden from NCDs on the population level, and the evolving role of HIV as a co-morbidity or co-existing disease of various NCDs – are less well understood. The paper elucidates these challenges by providing a quantitative analysis of HIV-NCD interactions for Botswana.MethodsWe projected the prevalence of HIV and of selected NCDs in Botswana using demographic and HIV-specific estimates building on data on the state and the dynamics of the HIV epidemic, using the Spectrum modelling software, and extrapolating on estimates of the prevalence of NCDs from the 2015 global burden of disease (GBD).ResultsHIV has slowed down overall population aging and thus has attenuated the growing burden of many NCDs so far, because cohorts reaching old age have been decimated by AIDS-related mortality in the 1990s and early 2000s. Aging and the rise in the prevalence of NCDs, however, will accelerate rapidly from about 2030 because of reduced attrition of cohorts living with HIV since the start of the ART scale-up in Botswana. While HIV prevalence will decline over time, the health needs of people living with HIV will become more complex. HIV prevalence among the growing populations affected by various important NCDs will not decline for decades, because of the aging of the population living with HIV and interactions between HIV, ART and NCDs.ConclusionsEven though HIV prevalence is projected to decline steeply to 2030 because of reduced HIV incidence, the prevalence of HIV among people affected by many of the most important NCDs will increase or barely change. While the health care needs of people living with HIV will increase and become more complex, HIV will also emerge as a key factor complicating the management of the growing burden of NCDs. Health systems will need to prepare for the challenge of large numbers of patients living with both HIV and NCDs.

Can Changes in Service Delivery Models Improve Program Quality and Efficiency? A Closer Look at HIV Programs in Kenya and Uganda.

With the scale-up of antiretroviral treatment, many health facilities in low- and middle-income countries have implemented innovative practices targeted at overcoming operational challenges and delivering efficient quality HIV services. However, many of these practices remain largely unexplored as a means to better reach the global 90-90-90 targets. A study was conducted on selected facilities in districts of country programs supported by The Global Fund to Fight AIDS, Tuberculosis, and Malaria. The aims of the study were to understand how facilities seek to improve the delivery and uptake of HIV services and to examine what innovative practices might be contributing to their success. The study used a qualitative approach through observations, document reviews, and semistructured interviews with site management and clinical staff to identify service delivery innovations in 30 health facilities in Kenya and Uganda. Eleven innovative practices were observed along the HIV care cascade. These practices led to improvements in the quality of testing, treatment, and retention across the facilities. Effective human resource and data management processes also enabled the implementation of these innovative practices. Many facilities use innovative practices along the HIV care cascade to address bottlenecks and challenges. These have the potential to improve the quality and efficiency of service delivery and support the attainment of the 90-90-90 treatment targets. Replicating these practices would require further implementation research and a mind shift of donors, governments, and implementers from a metric of coverage to a stronger focus on efficiency and impact.

‘Management of a spoiled identity’: systematic review of interventions to address self-stigma among people living with and affected by HIV

BackgroundSelf-stigma, also known as internalised stigma, is a global public health threat because it keeps people from accessing HIV and other health services. By hampering HIV testing, treatment and prevention,...

Does per‐act HIV‐1 transmission risk through anal sex vary by gender? An updated systematic review and meta‐analysis

Quantifying HIV-1 transmission risk per-act of anal intercourse (AI) is important for HIV-1 prevention. We updated previous reviews by searching Medline and Embase to 02/2018. We derived pooled estimates of receptive AI (URAI) and insertive AI (UIAI) risk unprotected by condoms using random-effects models. Subgroup analyses were conducted by gender, study design, and whether antiretroviral treatment (ART) had been introduced by the time of the study. Two new relevant studies were identified, one of which met inclusion criteria, adding three new cohorts and increasing number of individuals/partnerships included from 1869 to 14277. Four studies, all from high-income countries, were included. Pooled HIV-1 risk was higher for URAI (1.25%, 95% CI 0.55%-2.23%, N=5, I2 =87%) than UIAI (0.17%, 95 % CI 0.09%-0.26%, N=3, I2 =0%). The sole heterosexual URAI estimate (3.38%, 95% CI 1.85%-4.91%), from a study of 72 women published in a peer-reviewed journal, was significantly higher than the men-who-have-sex-with-men (MSM) pooled estimate (0.75%, 95% CI 0.56%-0.98%, N=4, P<0.0001) and higher than the only other heterosexual estimate identified (0.4%, 95% CI 0.08%-2.0%, based on 59 women, excluded for being a pre-2013 abstract). Pooled per-act URAI risk varied by study design (retrospective-partner studies: 2.56%, 95% CI 1.20%-4.42%, N=2 (one MSM, one heterosexual); prospective studies: 0.71%, 95% CI 0.51%-0.93%, N=3 MSM, P<0.0001). URAI risk was lower for studies conducted in the ART era (0.75%, 95% CI 0.52%-1.03%) than pre-ART (1.67%, 95% CI 0.44%-3.67%) but not significantly so (P=0.537). Prevention messages must emphasize that HIV-1 infectiousness through AI remains high, even in the ART era. Further studies, particularly among heterosexual populations and in resource-limited settings, are required to elucidate whether AI risk differs by gender, region and following population-level ART scale-up.

Projected effectiveness and added value of HIV vaccination campaigns in South Africa: A modeling study

Promising multi-dose HIV vaccine regimens are being tested in trials in South Africa. We estimated the potential epidemiological and economic impact of HIV vaccine campaigns compared to continuous vaccination, assuming that vaccine efficacy is transient and dependent on immune response. We used a dynamic economic mathematical model of HIV transmission calibrated to 2012 epidemiological data to simulate vaccination with anticipated antiretroviral treatment scale-up in South Africa. We estimate that biennial vaccination with a 70% efficacious vaccine reaching 20% of the sexually active population could prevent 480,000–650,000 HIV infections (13.8–15.3% of all infections) over 10 years. Assuming a launch price of $15 per dose, vaccination was found to be cost-effective, with an incremental cost-effectiveness ratio of $13,746 per quality-adjusted life-year as compared to no vaccination. Increasing vaccination coverage to 50% will prevent more infections but is less likely to achieve cost-effectiveness. Campaign vaccination is consistently more effective and costs less than continuous vaccination across scenarios. Results suggest that a partially effective HIV vaccine will have substantial impact on the HIV epidemic in South Africa and offer good value if priced less than $105 for a five-dose series. Vaccination campaigns every two years may offer greater value for money than continuous vaccination reaching the same coverage level.

Collaborative care for the detection and management of depression among adults receiving antiretroviral therapy in South Africa: study protocol for the CobALT randomised controlled trial

BackgroundThe scale-up of antiretroviral treatment (ART) programmes has seen HIV/AIDS transition to a chronic condition characterised by high rates of comorbidity with tuberculosis, non-communicable diseases (NCDs) and mental health disorders. Depression is one such disorder that is associated with higher rates of non-adherence, progression to AIDS and greater mortality. Detection and treatment of comorbid depression is critical to achieve viral load suppression in more than 90% of those on ART and is in line with the recent 90-90-90 Joint United Nations Programme on HIV/AIDS (UNAIDS) targets. The CobALT trial aims to provide evidence on the effectiveness and cost-effectiveness of scalable interventions to reduce the treatment gap posed by the growing burden of depression among adults on lifelong ART.MethodsThe study design is a pragmatic, parallel group, stratified, cluster randomised trial in 40 clinics across two rural districts of the North West Province of South Africa. The unit of randomisation is the clinic, with outcomes measured among 2000 patients on ART who screen positive for depression using the Patient Health Questionnaire (PHQ-9). Control group clinics are implementing the South African Department of Health’s Integrated Clinical Services Management model, which aims to reduce fragmentation of care in the context of rising multimorbidity, and which includes training in the Primary Care 101 (PC101) guide covering communicable diseases, NCDs, women’s health and mental disorders. In intervention clinics, we supplemented this with training specifically in the mental health components of PC101 and clinical communications skills training to support nurse-led chronic care. We strengthened the referral pathways through the introduction of a clinic-based behavioural health counsellor equipped to provide manualised depression counselling (eight sessions, individual or group), as well as adherence counselling sessions (one session, individual). The co-primary patient outcomes are a reduction in PHQ-9 scores of at least 50% from baseline and viral load suppression rates measured at 6 and 12 months, respectively.DiscussionThe trial will provide real-world effectiveness of case detection and collaborative care for depression including facility-based counselling on the mental and physical outcomes for people on lifelong ART in resource-constrained settings.Trial registrationClinicalTrials.gov (NCT02407691) registered on 19 March 2015; Pan African Clinical Trials Registry (201504001078347) registered on 19/03/2015; South African National Clinical Trials Register (SANCTR) (DOH-27-0515-5048) NHREC number 4048 issued on 21/04/2015.

Incidence of Tuberculosis Among HIV-Positive Individuals Initiating Antiretroviral Treatment at Higher CD4 Counts in the HPTN 071 (PopART) Trial in South Africa.

Antiretroviral treatment (ART) guidelines recommend life-long ART for all HIV-positive individuals. This study evaluated tuberculosis (TB) incidence on ART in a cohort of HIV-positive individuals starting ART regardless of CD4 count in a programmatic setting at 3 clinics included in the HPTN 071 (PopART) trial in South Africa. A retrospective cohort analysis of HIV-positive individuals aged ≥18 years starting ART, between January 2014 and November 2015, was conducted. Follow-up was continued until 30 May 2016 or censored on the date of (1) incident TB, (2) loss to follow-up from HIV care or death, or (3) elective transfer out; whichever occurred first. The study included 2423 individuals. Median baseline CD4 count was 328 cells/μL (interquartile range 195-468); TB incidence rate was 4.41/100 person-years (95% confidence interval [CI]: 3.62 to 5.39). The adjusted hazard ratio of incident TB was 0.27 (95% CI: 0.12 to 0.62) when comparing individuals with baseline CD4 >500 and ≤500 cells/μL. Among individuals with baseline CD4 count >500 cells/μL, there were no incident TB cases in the first 3 months of follow-up. Adjusted hazard of incident TB was also higher among men (adjusted hazard ratio 2.16; 95% CI: 1.41 to 3.30). TB incidence after ART initiation was significantly lower among individuals starting ART at CD4 counts above 500 cells/μL. Scale-up of ART, regardless of CD4 count, has the potential to significantly reduce TB incidence among HIV-positive individuals. However, this needs to be combined with strengthening of other TB prevention strategies that target both HIV-positive and HIV-negative individuals.

Assessing the utility of the tipping point ratio to monitor HIV treatment programmes in the era of universal access to ART.

BackgroundThe epidemiological tipping point ratio (TPR) has been suggested as a useful indicator to monitor the scale-up of antiretroviral treatment (ART) programmes and determine when scale-up is sufficient to control the epidemic. TPR has been defined as the ratio of yearly number of new HIV infections to the yearly number of new ART initiations or to the yearly net increase in the number of people on ART. It has been used to rank the progress of treatment programmes across countries, with the objective of reaching a TPR value under 1. Our study aims to assess if TPR alone can be used as an indicator of ART success across settings by comparing the expected changes in HIV incidence and ART coverage when TPR is maintained constant over time. In particular, we focus on the effect of ART initiation timing (emphasis on ART being initiated early or late during HIV progression) on the interpretation of the TPR.MethodsWe used a dynamic model of HIV transmission in South Africa representing ART rollout leading to universal treatment in 2017. The model is calibrated to HIV incidence, HIV prevalence and ART coverage in 2012 in South Africa, and 1000 simulations are selected for the base-case scenario. To measure the effect of TPR, we simulate TPR-preserving interventions, maintaining TPR (yearly number of new ART initiations denominator) at the value observed in 2019 (between 0.65 and 1.25) for 15 years. We compare ART coverage and HIV incidence across TPR values and across strategies in which ART access is prioritized differently. In a secondary analysis, we illustrate the sensitivity of new ART initiations to ART retention, and we compare both definitions of the TPR.ResultsOur analysis shows that HIV incidence reduction is weakly correlated to TPR: the same reduction in HIV incidence (15%) can be achieved by implementing the same strategy with a wide range of TPR maintained (0.65–1.12). Assuming high retention in ART, TPR-preserving strategies prioritizing early ART initiation yield greater reduction in HIV incidence than strategies where most individuals initiate ART late. High ART coverage is associated with low HIV incidence and it can be reached with a TPR below or equal to one with strategies favoring early ART initiation. Low ART retention over time results in higher HIV incidence even if TPR is maintained low. If ART retention is low, strategies prioritizing late ART initiation are associated with lower HIV incidence than strategies where ART is initiated early. Maintaining a fixed TPR value based on the net increase in people on ART gives higher HIV incidence reduction and requires fast ART scale-up.ConclusionOur analysis suggests that the TPR is not an adequate indicator of ART programme impact, without information on ART coverage and retention. Achieving early initiation and adherence to treatment to improve ART coverage might be as important as attaining a specific TPR target. Comparisons of TPR in different settings should account for differences in epidemic conditions.

Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study.

BackgroundSubstantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART.Methods and findingsModel estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997–2013) and mortality data from the South African vital registration system (1997–2014), using a Bayesian approach. In the 1985–2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%–76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%–97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000–2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million–1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million–6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million–9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004–2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness.ConclusionsART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population-level recorded death data in Africa; models that are not calibrated to population-level death data may overestimate HIV-related mortality.

The Role of Immune Responses in HIV Mother-to-Child Transmission.

HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still occurs and better understanding of the basic biology and immunology of transmission will aid in future prevention and treatment efforts. MTCT is a unique setting given that the transmission pair is known and the infant receives passively transferred HIV-specific antibodies from the mother while in utero. Thus, infant exposure to HIV occurs in the face of HIV-specific antibodies, especially during delivery and breastfeeding. This review highlights the immune correlates of protection in HIV MTCT including humoral (neutralizing antibodies, antibody-dependent cellular cytotoxicity, and binding epitopes), cellular, and innate immune factors. We further discuss the future implications of this research as it pertains to opportunities for passive and active vaccination with the ultimate goal of eliminating HIV MTCT.