Diminishing Availability of Publicly Funded Slots for Antiretroviral Initiation among HIV-Infected ART-Eligible Patients in Uganda

Background: The impact of flat-line funding in the global scale up of antiretroviral therapy (ART) for HIV-infected patients in Africa has not yet been well described. Methods: We evaluated ART-eligible patients and patients starting ART at a prototypical scale up ART clinic in Mbarara, Uganda between April 1, 2009 and May 14, 2010 where four stakeholders sponsor treatment – two PEPFAR implementing organizations, the Ugandan Ministry of Health – Global Fund (MOH-GF) and a private foundation named the Family Treatment Fund (FTF). We assessed temporal trends in the number of eligible patients, the number starting ART and tabulated the distribution of the stakeholders supporting ART initiation by month and quartile of time during this interval. We used survival analyses to assess changes in the rate of ART initiation over calendar time. Findings: A total of 1309 patients who were eligible for ART made visits over the 14 month period of the study and of these 819 started ART. The median number of ART eligible patients each month was 88 (IQR: 74 to 115). By quartile of calendar time, PEPFAR and MOH sponsored 290, 192, 180, and 49 ART initiations whereas the FTF started 1, 2, 1 and 104 patients respectively. By May of 2010 (the last calendar month of observation) FTF sponsored 88% of all ART initiations. Becoming eligible for ART in the 3rd (HR = 0.58, 95% 0.45–0.74) and 4th quartiles (HR = 0.49, 95% CI: 0.36–0.65) was associated with delay in ART initiation compared to the first quartile in multivariable analyses. Interpretation: During a period of flat line funding from multinational donors for ART programs, reductions in the number of ART initiations by public programs (i.e., PEPFAR and MOH-GF) and delays in ART initiation became apparent at the a large prototypical scale-up ART clinic in Uganda

Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression

BACKGROUND: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (<50 copies/mL) persons with human immunodeficiency virus (PWH). The impact of improving adherence in the risk of severe non-AIDS events (SNAEs) and death in this population is unknown. METHODS: We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to <100% would need to be observed for an additional SNAE or death event to occur during 3- and 5-year follow-up. RESULTS: Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%-37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to <100% for an additional event to occur over 3- and 5-year follow-up, respectively. CONCLUSIONS: Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated

Implementation of Electronic Adherence Monitors and Associated Interventions for Routine HIV Antiretroviral Therapy in Uganda: Promising Findings

BackgroundHigh, sustained adherence is critical for achieving the individual and public health benefits of HIV antiretroviral therapy (ART). Electronic monitors provide detailed adherence information and can enable real-time interventions; however, their use to date has largely been confined to research. This pilot study (NCT03825952) sought to understand feasibility and acceptability a relatively low-cost version of this technology and associated interventions for routine ART delivery in sub-Saharan Africa.MethodsWe provided two ART clinics in rural, southwestern Uganda with electronic adherence monitors for data-informed counseling as well as optional SMS messages to clients and/or social supporters (daily or triggered by missed or delayed doses) and/or an alarm. Clinic and ART client experiences were observed for 3 months per client, including time and motion studies. Qualitative interviews among clients, clinicians, and healthcare administrators were informed by the Consolidated Framework for Implementation Research.ResultsFifty-one ART clients were enrolled; 57% were male and the median age was 34 years. Choice of associated intervention varied among participants. The median number of visits during follow-up was two per client. Counselors reviewed the adherence data with 90% of clients at least once; 67% reviewed data at all visits. Average adherence was 94%; four clients had adherence gaps &gt;1 week. Acceptability was high; all but one client found the monitor "very useful” and all found SMS “very useful.” Clinic visits among clients with the intervention lasted 4 min longer on average than those in standard care. The monitors and daily SMS generally functioned well, although excess SMS were triggered, primarily due to cellular network delays. Overall, participants felt the technology improved adherence, clinic experiences, and clinician-client relationships. Few worried about stigma and privacy. Cost was a concern for implementation, particularly at scale.ConclusionWe successfully implemented a relatively low-cost electronic ART adherence monitor and associated interventions for routine care in rural Uganda. Feasibility and acceptability were generally high, and individuals were identified who could benefit from adherence support. Future work should involve longitudinal follow-up of diverse populations, clinical outcomes, and detailed cost-effectiveness analysis to help drive policy decisions around the uptake of this technology for routine clinical care.Clinical Trial Registrationidentifier: NCT03825952

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Transition from pediatric to adult care for adolescents living with HIV in South Africa: A natural experiment and survival analysis.

ObjectiveTo determine rates of retention and viral suppression among adolescents living with perinatally-acquired HIV who remained in pediatric care compared to those who transitioned to adult care.MethodsWe evaluated a natural experiment involving adolescents living with perinatally-acquired HIV who were attending a government-supported antiretroviral clinic in KwaZulu-Natal, South Africa. Prior to 2011, all adolescents transitioned to adult care at 12 years of age. Due to a policy change, all adolescents were retained in pediatric care after 2011. We analyzed adolescents two years before and two years after this policy change. Outcomes were retention in care and HIV viral suppression one year after transition to adult care or the 13th birthday if remaining in pediatric care.ResultsIn the natural experiment, 180 adolescents who turned 12 years old between 2011 and 2014 were evaluated; 35 (20%) transitioned to adult care under the old policy and 145 (80%) remained in pediatric care under the new policy. Adolescents who transitioned to the adult clinic had lower rates of retention in care (49%; 17/35) compared to adolescents remaining in the pediatric clinic (92%; 134/145; pConclusionAdolescents living with perinatally-acquired HIV appear to have higher retention in care when cared for in pediatric clinics compared to adult clinics. Longer-term follow-up is needed to fully assess viral suppression

Super Learner Analysis of Real-Time Electronically Monitored Adherence to Antiretroviral Therapy under Constrained Optimization and Comparison to Non-Differentiated Care Approaches for Persons Living with HIV in Rural Uganda

Introduction Real‐time electronic adherence monitoring (EAM) systems could inform on‐going risk assessment for HIV viraemia and be used to personalize viral load testing schedules. We evaluated the potential of real‐time EAM (transferred via cellular signal) and standard EAM (downloaded via USB cable) in rural Uganda to inform individually differentiated viral load testing strategies by applying machine learning approaches. Methods We evaluated an observational cohort of persons living with HIV and treated with antiretroviral therapy (ART) who were monitored longitudinally with standard EAM from 2005 to 2011 and real‐time EAM from 2011 to 2015. Super learner, an ensemble machine learning method, was used to develop a tool for targeting viral load testing to detect viraemia (\u3e1000 copies/ml) based on clinical (CD4 count, ART regimen), viral load and demographic data, together with EAM‐based adherence. Using sample‐splitting (cross‐validation), we evaluated area under the receiver operating characteristic curve (cvAUC), potential for EAM data to selectively defer viral load tests while minimizing delays in viraemia detection, and performance compared to WHO‐recommended testing schedules. Results In total, 443 persons (1801 person‐years) and 485 persons (930 person‐years) contributed to standard and real‐time EAM analyses respectively. In the 2011 to 2015 dataset, addition of real‐time EAM (cvAUC: 0.88; 95% CI: 0.83, 0.93) significantly improved prediction compared to clinical/demographic data alone (cvAUC: 0.78; 95% CI: 0.72, 0.86; p = 0.03). In the 2005 to 2011 dataset, addition of standard EAM (cvAUC: 0.77; 95% CI: 0.72, 0.81) did not significantly improve prediction compared to clinical/demographic data alone (cvAUC: 0.70; 95% CI: 0.64, 0.76; p = 0.08). A hypothetical testing strategy using real‐time EAM to guide deferral of viral load tests would have reduced the number of tests by 32% while detecting 87% of viraemia cases without delay. By comparison, the WHO‐recommended testing schedule would have reduced the number of tests by 69%, but resulted in delayed detection of viraemia a mean of 74 days for 84% of individuals with viraemia. Similar rules derived from standard EAM also resulted in potential testing frequency reductions. Conclusions Our machine learning approach demonstrates potential for combining EAM data with other clinical measures to develop a selective testing rule that reduces number of viral load tests ordered, while still identifying those at highest risk for viraemia

Prevalence and Correlates of Physical and Sexual Intimate Partner Violence among Women Living with HIV in Uganda

Background: Intimate partner violence (IPV) is a significant global health problem. Women who experience IPV have increased HIV incidence, reduced antiretroviral adherence, and a lower likelihood of viral load suppression. There is a lack of evidence regarding how to effectively identify and support women living with HIV (WLWH) experiencing IPV, including uncertainty whether universal or targeted screening is most appropriate for lower-resourced settings. We examined physical and sexual IPV prevalence and correlates among WLWH in Uganda to understand the burden of IPV and factors that could help identify women at risk. Methods: We utilized data from women receiving ART and enrolled in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort study between 2011 and 2015. Bloodwork and interviewer-administered questionnaires were completed every 4 months. IPV was assessed annually or with any new pregnancy. Multivariate models assessed independent socio-demographic and clinical factors correlated with IPV, at baseline and follow-up visits. Results: 455 WLWH were included. Median age was 36 years, 43% were married, and median follow-up was 2.8 years. At baseline 131 women (29%) reported any experience of past or current IPV. In the adjusted models, being married was associated with a higher risk of baseline IPV (ARR 2.33, 95% CI 1.13–4.81) and follow-up IPV (ARR 2.43, 95% CI 1.33–4.45). Older age (ARR 0.96, 95% CI 0.94–0.99) and higher household asset index score (ARR 0.81, 95% CI 0.68–0.96) were associated with lower risk of IPV during follow-up. Conclusion: There was a high prevalence of physical and sexual IPV amongst WLWH, and many women experienced both types of violence. These findings suggest the need for clinic-based screening for IPV. If universal screening is not feasible, correlates of having experienced IPV can inform targeted approaches

Timing of Antiretroviral Therapy and Systemic Inflammation in Sub-Saharan Africa: Results From the META Longitudinal Cohort Study

Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count \u3e350/μL) or late-stage disease (CD4 T-cell count \u3c200/ μL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P \u3c .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P \u3e .05), owing to loss from observation and greater declines in biomarkers in latestage initiators (P \u3c .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months