HIV epidemiology, prevention, treatment, and implementation strategies for public health.

The global HIV response has made tremendous progress but is entering a new phase with additional challenges. Scientific innovations have led to multiple safe, effective, and durable options for treatment and prevention, and long-acting formulations for 2-monthly and 6-monthly dosing are becoming available with even longer dosing intervals possible on the horizon. The scientific agenda for HIV cure and remission strategies is moving forward but faces uncertain thresholds for success and acceptability. Nonetheless, innovations in prevention and treatment have often failed to reach large segments of the global population (eg, key and marginalised populations), and these major disparities in access and uptake at multiple levels have caused progress to fall short of their potential to affect public health. Moving forward, sharper epidemiologic tools based on longitudinal, person-centred data are needed to more accurately characterise remaining gaps and guide continued progress against the HIV epidemic. We should also increase prioritisation of strategies that address socio-behavioural challenges and can lead to effective and equitable implementation of existing interventions with high levels of quality that better match individual needs. We review HIV epidemiologic trends; advances in HIV prevention, treatment, and care delivery; and discuss emerging challenges for ending the HIV epidemic over the next decade that are relevant for general practitioners and others involved in HIV care.

Assessing the Response Results of an mHealth-Based Patient Experience Survey Among People Receiving HIV Care in Lusaka, Zambia: Cohort Study.

BACKGROUND: This pilot study evaluates the effectiveness of mobile talk-time incentives in maintaining participation in a longitudinal mobile health (mHealth) data collection program among people living with HIV in Lusaka, Zambia. While mHealth tools, such as mobile phone surveys, provide vital health feedback, optimal incentive strategies to ensure long-term engagement remain limited. This study explores how different incentive levels affect response rates in multiple survey rounds, providing insights into effective methods for encouraging ongoing participation, especially in the context of Zambia's prepaid mobile system and multi-SIM usage, a common practice in sub-Saharan Africa. OBJECTIVE: This study aimed to assess the response rate success across multiple invitations to participate in a care experience survey using a mobile phone short codes and unstructured supplementary service data (USSD) model among individuals in an HIV care setting in the Lusaka, Zambia. METHODS: Participants were recruited from 2 study clinics-1 in a periurban setting and 1 in an urban setting. A total of 2 rounds of survey invitations were sent to study participants on a 3-month interval between November 1, 2018, and September 23, 2019. Overall, 3 incentive levels were randomly assigned by participant and survey round: (1) no incentive, (2) 2 Zambian Kwacha (ZMW; US $0.16), and (3) 5 ZMW (US $0.42). Survey response rates were analyzed using mixed-effects Poisson regression, adjusting for individual- and facility-level factors. Probability plots for survey completion were generated based on language, incentive level, and survey round. We projected the cost per additional response for different incentive levels. RESULTS: A total of 1006 participants were enrolled, with 72.3% (727/1006) from the urban HIV care facility and 62.4% (628/1006) requesting the survey in English. We sent a total of 1992 survey invitations for both rounds. Overall, survey completion across both surveys was 32.1% (637/1992), with significantly different survey completion between the first (40.5%, 95% CI 37.4-43.6%) and second (23.7%, 95% CI 21.1-26.4) invitations. Implementing a 5 ZMW (US $0.42) incentive significantly increased the adjusted prevalence ratio (aPR) for survey completion compared with those that received no incentive (aPR 1.35, 95% CI 1.11-1.63). The cost per additional response was highest at 5 ZMW, equivalent to US $0.42 (72.8 ZMW [US $5.82] per 1% increase in response). CONCLUSIONS: We observed a sharp decline of almost 50% in survey completion success from the initial invitation to follow-up survey administered 3 months later. This substantial decrease suggests that longitudinal data collection potential for a care experience survey may be limited without additional sensitization and, potentially, added survey reminders. Implementing a moderate incentive increased response rates to our health care experience survey. Tailoring survey strategies to accommodate language preferences and providing moderate incentives can optimize response rates in Zambia. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202101847907585; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=14613.

Strengthening implementation guidelines for HIV service delivery: Considerations for future evidence generation and synthesis.

Ingrid Eshun-Wilson and colleagues summarize gaps in primary HIV implementation research methods and reporting, and propose areas for future methodological development.

On-the-Go Adaptation of Implementation Approaches and Strategies in Health: Emerging Perspectives and Research Opportunities.

In many cases, implementation approaches (composed of one or more strategies) may need to change over time to work optimally. We use a literature review to inform a mechanistic analysis of such on-the-go adaptations. We suggest that such adaptations of implementation strategies consist of three necessary steps. The first component is the initial effect of the implementation approach on intended implementation, service delivery, or clinical outcomes. Second, these initial effects must in turn be used to modify, alter, intensify, or otherwise change the implementation approach. Third, the modified approach itself has effects. Conceiving of adaptation as all three steps implies that a full understanding of adaptation involves (a) a sense of initial effects, (b) conceptualizing and documenting content and rationale for changes in approach (e.g., alteration, intensification), and (c) the effects of the changed approach (including how the latter effects depend on initial effects). Conceptualizing these steps can help researchers ask questions about adaptation (e.g., thresholds for change, dosing, potentiation, sequencing) to advance our understanding of implementation strategies.

Deliberation, Dissent, and Distrust: Understanding Distinct Drivers of Coronavirus Disease 2019 Vaccine Hesitancy in the United States.

BACKGROUND: Despite the availability of safe and efficacious coronavirus disease 2019 vaccines, a significant proportion of the American public remains unvaccinated and does not appear to be immediately interested in receiving the vaccine. METHODS: In this study, we analyzed data from the US Census Bureau's Household Pulse Survey, a biweekly cross-sectional survey of US households. We estimated the prevalence of vaccine hesitancy across states and nationally and assessed the predictors of vaccine hesitancy and vaccine rejection. In addition, we examined the underlying reasons for vaccine hesitancy, grouped into thematic categories. RESULTS: A total of 459 235 participants were surveyed from 6 January to 29 March 2021. While vaccine uptake increased from 7.7% to 47%, vaccine hesitancy rates remained relatively fixed: overall, 10.2% reported that they would probably not get a vaccine and 8.2% that they would definitely not get a vaccine. Income, education, and state political leaning strongly predicted vaccine hesitancy. However, while both female sex and black race were factors predicting hesitancy, among those who were hesitant, these same characteristics predicted vaccine reluctance rather than rejection. Those who expressed reluctance invoked mostly "deliberative" reasons, while those who rejected the vaccine were also likely to invoke reasons of "dissent" or "distrust." CONCLUSIONS: Vaccine hesitancy comprises a sizable proportion of the population and is large enough to threaten achieving herd immunity. Distinct subgroups of hesitancy have distinctive sociodemographic associations as well as cognitive and affective predilections. Segmented public health solutions are needed to target interventions and optimize vaccine uptake.

Evaluation of HIV treatment outcomes with reduced frequency of clinical encounters and antiretroviral treatment refills: A systematic review and meta-analysis.

BACKGROUND: Global HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART. METHODS AND FINDINGS: We searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97-1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75-1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98-1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63-3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa. CONCLUSIONS: Based on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings.

Quantifying inequities in COVID-19 vaccine distribution over time by social vulnerability, race and ethnicity, and location: A population-level analysis in St. Louis and Kansas City, Missouri.

BACKGROUND: Equity in vaccination coverage is a cornerstone for a successful public health response to COVID-19. To deepen understanding of the extent to which vaccination coverage compares with initial strategies for equitable vaccination, we explore primary vaccine series and booster rollout over time and by race/ethnicity, social vulnerability, and geography. METHODS AND FINDINGS: We analyzed data from the Missouri Department of Health and Senior Services on all COVID-19 vaccinations administered across 7 counties in the St. Louis region and 4 counties in the Kansas City region. We compared rates of receiving the primary COVID-19 vaccine series and boosters relative to time, race/ethnicity, zip-code-level Social Vulnerability Index (SVI), vaccine location type, and COVID-19 disease burden. We adapted a well-established tool for measuring inequity-the Lorenz curve-to quantify inequities in COVID-19 vaccination relative to these key metrics. Between 15 December 2020 and 15 February 2022, 1,763,036 individuals completed the primary series and 872,324 received a booster. During early phases of the primary series rollout, Black and Hispanic individuals from high SVI zip codes were vaccinated at less than half the rate of White individuals from low SVI zip codes, but rates increased over time until they were higher than rates in White individuals after June 2021; Asian individuals maintained high levels of vaccination throughout. Increasing vaccination rates in Black and Hispanic communities corresponded with periods when more vaccinations were offered at small community-based sites such as pharmacies rather than larger health systems and mass vaccination sites. Using Lorenz curves, zip codes in the quartile with the lowest rates of primary series completion accounted for 19.3%, 18.1%, 10.8%, and 8.8% of vaccinations while representing 25% of the total population, cases, deaths, or population-level SVI, respectively. When tracking Gini coefficients, these disparities were greatest earlier during rollout, but improvements were slow and modest and vaccine disparities remained across all metrics even after 1 year. Patterns of disparities for boosters were similar but often of much greater magnitude during rollout in fall 2021. Study limitations include inherent limitations in the vaccine registry dataset such as missing and misclassified race/ethnicity and zip code variables and potential changes in zip code population sizes since census enumeration. CONCLUSIONS: Inequities in the initial COVID-19 vaccination and booster rollout in 2 large US metropolitan areas were apparent across racial/ethnic communities, across levels of social vulnerability, over time, and across types of vaccination administration sites. Disparities in receipt of the primary vaccine series attenuated over time during a period in which sites of vaccination administration diversified, but were recapitulated during booster rollout. These findings highlight how public health strategies from the outset must directly target these deeply embedded structural and systemic determinants of disparities and track equity metrics over time to avoid perpetuating inequities in healthcare access.

Understanding Drivers of Coronavirus Disease 2019 (COVID-19) Racial Disparities: A Population-Level Analysis of COVID-19 Testing Among Black and White Populations.

BACKGROUND: Disparities in coronavirus disease 2019 (COVID-19) testing-the pandemic's most critical but limited resource-may be an important but modifiable driver of COVID-19 inequities. METHODS: We analyzed data from the Missouri State Department of Health and Senior Services on all COVID-19 tests conducted in the St Louis and Kansas City regions. We adapted a well-established tool for measuring inequity-the Lorenz curve-to compare COVID-19 testing rates per diagnosed case among Black and White populations. RESULTS: Between 14/3/2020 and 15/9/2020, 606 725 and 328 204 COVID-19 tests were conducted in the St Louis and Kansas City regions, respectively. Over time, Black individuals consistently had approximately half the rate of testing per case than White individuals. In the early period (14/3/2020 to 15/6/2020), zip codes in the lowest quartile of testing rates accounted for only 12.1% and 8.8% of all tests in the St Louis and Kansas City regions, respectively, even though they accounted for 25% of all cases in each region. These zip codes had higher proportions of residents who were Black, without insurance, and with lower median incomes. These disparities were reduced but still persisted during later phases of the pandemic (16/6/2020 to 15/9/2020). Last, even within the same zip code, Black residents had lower rates of tests per case than White residents. CONCLUSIONS: Black populations had consistently lower COVID-19 testing rates per diagnosed case than White populations in 2 Missouri regions. Public health strategies should proactively focus on addressing equity gaps in COVID-19 testing to improve equity of the overall response.

Patient-reported Reasons for Stopping Care or Switching Clinics in Zambia: A Multisite, Regionally Representative Estimate Using a Multistage Sampling-based Approach in Zambia.

BACKGROUND: Understanding patient-reported reasons for lapses of retention in human immunodeficiency virus (HIV) treatment can drive improvements in the care cascade. A systematic assessment of outcomes among a random sample of patients lost to follow-up (LTFU) from 32 clinics in Zambia to understand the reasons for silent transfers and disengagement from care was undertaken. METHODS: We traced a simple random sample of LTFU patients (>90 days from last scheduled visit) as determined from clinic-based electronic medical records from a probability sample of facilities. Among patients found in person, we solicited reasons for either stopping or switching care and predictors for re-engagement. We coded reasons into structural, psychosocial, and clinic-based barriers. RESULTS: Among 1751 LTFU patients traced and found alive, 31% of patients starting antiretroviral therapy (ART) between 1 July 2013 and 31 July 2015 silently transferred or were disengaged (40% male; median age, 35 years; median CD4 level, 239 cells/µL); median time on ART at LTFU was 480 days (interquartile range, 110-1295). Among the 544 patients not in care, median prevalences for patient-reported structural, psychosocial, and clinic-level barriers were 27.3%, 13.9%, and 13.4%, respectively, and were highly variable across facilities. Structural reasons, including, "relocated to a new place" were mostly cited among 289 patients who silently transferred (35.5%). We found that men were less likely to re-engage in care than women (odds ratio, .39; 95% confidence interval, .22-.67; P = .001). CONCLUSIONS: Efforts to improve retention of patients on ART may need to be tailored at the facility level to address patient-reported barriers.

The Clinical Course of Coronavirus Disease 2019 in a US Hospital System: A Multistate Analysis.

There are limited data on longitudinal outcomes for coronavirus disease 2019 (COVID-19) hospitalizations that account for transitions between clinical states over time. Using electronic health record data from a hospital network in the St. Louis, Missouri, region, we performed multistate analyses to examine longitudinal transitions and outcomes among hospitalized adults with laboratory-confirmed COVID-19 with respect to 15 mutually exclusive clinical states. Between March 15 and July 25, 2020, a total of 1,577 patients in the network were hospitalized with COVID-19 (49.9% male; median age, 63 years (interquartile range, 50-75); 58.8% Black). Overall, 34.1% (95% confidence interval (CI): 26.4, 41.8) had an intensive care unit admission and 12.3% (95% CI: 8.5, 16.1) received invasive mechanical ventilation (IMV). The risk of decompensation peaked immediately after admission; discharges peaked around days 3-5, and deaths plateaued between days 7 and 16. At 28 days, 12.6% (95% CI: 9.6, 15.6) of patients had died (4.2% (95% CI: 3.2, 5.2) had received IMV) and 80.8% (95% CI: 75.4, 86.1) had been discharged. Among those receiving IMV, 35.1% (95% CI: 28.2, 42.0) remained intubated after 14 days; after 28 days, 37.6% (95% CI: 30.4, 44.7) had died and only 37.7% (95% CI: 30.6, 44.7) had been discharged. Multistate methods offer granular characterizations of the clinical course of COVID-19 and provide essential information for guiding both clinical decision-making and public health planning.

Novel Longitudinal Methods for Assessing Retention in Care: a Synthetic Review.

PURPOSE OF REVIEW: Retention in care is both dynamic and longitudinal in nature, but current approaches to retention often reduce these complex histories into cross-sectional metrics that obscure the nuanced experiences of patients receiving HIV care. In this review, we discuss contemporary approaches to assessing retention in care that captures its dynamic nature and the methodological and data considerations to do so. RECENT FINDINGS: Enhancing retention measurements either through patient tracing or "big data" approaches (including probabilistic matching) to link databases from different sources can be used to assess longitudinal retention from the perspective of the patient when they transition in and out of care and access care at different facilities. Novel longitudinal analytic approaches such as multi-state and group-based trajectory analyses are designed specifically for assessing metrics that can change over time such as retention in care. Multi-state analyses capture the transitions individuals make in between different retention states over time and provide a comprehensive depiction of longitudinal population-level outcomes. Group-based trajectory analyses can identify patient subgroups that follow distinctive retention trajectories over time and highlight the heterogeneity of retention patterns across the population. Emerging approaches to longitudinally measure retention in care provide nuanced assessments that reveal unique insights into different care gaps at different time points over an individuals' treatment. These methods help meet the needs of the current scientific agenda for retention and reveal important opportunities for developing more tailored interventions that target the varied care challenges patients may face over the course of lifelong treatment.

Longitudinal Care Cascade Outcomes Among People Eligible for Antiretroviral Therapy Who Are Newly Linking to Care in Zambia: A Multistate Analysis.

BACKGROUND: Retention in human immunodeficiency virus (HIV) care is dynamic, with patients frequently transitioning in and out of care. Analytical approaches (eg, survival analyses) commonly used to assess HIV care cascade outcomes fail to capture such transitions and therefore incompletely represent care outcomes over time. METHODS: We analyzed antiretroviral therapy (ART)-eligible adults newly linking to care at 64 clinics in Zambia between 1 April 2014 and 31 July 2015. We used electronic medical record data and supplemented these with updated care outcomes ascertained by tracing a multistage random sample of patients lost to follow-up (LTFU, >90 days late for last appointment). We performed multistate analyses, incorporating weights from sampling, to estimate the prevalence of 9 care states over time since linkage with respect to ART initiation, retention in care, transfers, and mortality. RESULTS: In sum, 23 227 patients (58% female; median age 34 years [interquartile range 28-41]) were ART-eligible at enrollment. At 1 year, 75.2% had initiated ART and were in care: 61.8% were continuously retained, 6.1% had reengaged after LTFU, and 7.3% had transferred. Also, 10.1% were LTFU within 7 days of enrollment, and 15.2% were LTFU at 1 year (6.7% prior to ART). One year after LTFU, 51.6% of those LTFU prior to ART remained out of care compared to 30.2% of those LTFU after initiating ART. Overall, 6.9% of patients had died by 1 year with 3.0% dying prior to ART. CONCLUSION: Multistate analyses provide more complete assessments of longitudinal HIV cascade outcomes and reveal treatment gaps at distinct timepoints in care that will still need to be addressed even with universal treatment.

Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach.

BACKGROUND: Although the success of HIV treatment programs depends on retention and viral suppression, routine program monitoring of these outcomes may be incomplete. We used data from the national electronic medical record (EMR) system in Zambia to enumerate a large and regionally representative cohort of patients on treatment. We traced a random sample with unknown outcomes (lost to follow-up) to document true care status and HIV RNA levels. METHODS AND FINDINGS: On 31 July 2015, we selected facilities from 4 provinces in 12 joint strata defined by facility type and province with probability proportional to size. In each facility, we enumerated adults with at least 1 clinical encounter after treatment initiation in the previous 24 months. From this cohort, we identified lost-to-follow-up patients (defined as 90 or more days late for their last appointment), selected a random sample, and intensively reviewed their records and traced them via phone calls and in-person visits in the community. In 1 of 4 provinces, we also collected dried blood spots (DBSs) for plasma HIV RNA testing. We used inverse probability weights to incorporate sampling outcomes into Aalen-Johansen and Cox proportional hazards regression to estimate retention and viremia. We used a bias analysis approach to correct for the known inaccuracy of plasma HIV RNA levels obtained from DBSs. From a total of 64 facilities with 165,464 adults on ART, we selected 32 facilities with 104,966 patients, of whom 17,602 (17%) were lost to follow-up: Those lost to follow-up had median age 36 years, 60% were female (N = 11,241), they had median enrollment CD4 count of 220 cells/µl, and 38% had WHO stage 1 clinical disease (N = 10,690). We traced 2,892 (16%) and found updated outcomes for 2,163 (75%): 412 (19%) had died, 836 (39%) were alive and in care at their original clinic, 457 (21%) had transferred to a new clinic, 255 (12%) were alive and out of care, and 203 (9%) were alive but we were unable to determine care status. Estimates using data from the EMR only suggested that 42.7% (95% CI 38.0%-47.1%) of new ART starters and 72.3% (95% CI 71.8%-73.0%) of all ART users were retained at 2 years. After incorporating updated data through tracing, we found that 77.3% (95% CI 70.5%-84.0%) of new initiates and 91.2% (95% CI 90.5%-91.8%) of all ART users were retained (at original clinic or transferred), indicating that routine program data underestimated retention in care markedly. In Lusaka Province, HIV RNA levels greater than or equal to 1,000 copies/ml were present in 18.1% (95% CI 14.0%-22.3%) of patients in care, 71.3% (95% CI 58.2%-84.4%) of lost patients, and 24.7% (95% CI 21.0%-29.3%). The main study limitations were imperfect response rates and the use of self-reported care status. CONCLUSIONS: In this region of Zambia, routine program data underestimated retention, and the point prevalence of unsuppressed HIV RNA was high when lost patients were accounted for. Viremia was prevalent among patients who unofficially transferred: Sustained engagement remains a challenge among HIV patients in Zambia, and targeted sampling is an effective strategy to identify such gaps in the care cascade and monitor programmatic progress.

Correction: Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach.

[This corrects the article DOI: 10.1371/journal.pmed.1002811.].

Longitudinal engagement trajectories and risk of death among new ART starters in Zambia: A group-based multi-trajectory analysis.

BACKGROUND: Retention in HIV treatment must be improved to advance the HIV response, but research to characterize gaps in retention has focused on estimates from single time points and population-level averages. These approaches do not assess the engagement patterns of individual patients over time and fail to account for both their dynamic nature and the heterogeneity between patients. We apply group-based trajectory analysis-a special application of latent class analysis to longitudinal data-among new antiretroviral therapy (ART) starters in Zambia to identify groups defined by engagement patterns over time and to assess their association with mortality. METHODS AND FINDINGS: We analyzed a cohort of HIV-infected adults who newly started ART between August 1, 2013, and February 1, 2015, across 64 clinics in Zambia. We performed group-based multi-trajectory analysis to identify subgroups with distinct trajectories in medication possession ratio (MPR, a validated adherence metric based on pharmacy refill data) over the past 3 months and loss to follow-up (LTFU, >90 days late for last visit) among patients with at least 180 days of observation time. We used multinomial logistic regression to identify baseline factors associated with belonging to particular trajectory groups. We obtained Kaplan-Meier estimates with bootstrapped confidence intervals of the cumulative incidence of mortality stratified by trajectory group and performed adjusted Poisson regression to estimate adjusted incidence rate ratios (aIRRs) for mortality by trajectory group. Inverse probability weights were applied to all analyses to account for updated outcomes ascertained from tracing a random subset of patients lost to follow-up as of July 31, 2015. Overall, 38,879 patients (63.3% female, median age 35 years [IQR 29-41], median enrollment CD4 count 280 cells/µl [IQR 146-431]) were included in our cohort. Analyses revealed 6 trajectory groups among the new ART starters: (1) 28.5% of patients demonstrated consistently high adherence and retention; (2) 22.2% showed early nonadherence but consistent retention; (3) 21.6% showed gradually decreasing adherence and retention; (4) 8.6% showed early LTFU with later reengagement; (5) 8.7% had early LTFU without reengagement; and (6) 10.4% had late LTFU without reengagement. Identified groups exhibited large differences in survival: after adjustment, the "early LTFU with reengagement" group (aIRR 3.4 [95% CI 1.2-9.7], p = 0.019), the "early LTFU" group (aIRR 6.4 [95% CI 2.5-16.3], p < 0.001), and the "late LTFU" group (aIRR 4.7 [95% CI 2.0-11.3], p = 0.001) had higher rates of mortality as compared to the group with consistently high adherence/retention. Limitations of this study include using data observed after baseline to identify trajectory groups and to classify patients into these groups, excluding patients who died or transferred within the first 180 days, and the uncertain generalizability of the data to current care standards. CONCLUSIONS: Among new ART starters in Zambia, we observed 6 patient subgroups that demonstrated distinctive engagement trajectories over time and that were associated with marked differences in the subsequent risk of mortality. Further efforts to develop tailored intervention strategies for different types of engagement behaviors, monitor early engagement to identify higher-risk patients, and better understand the determinants of these heterogeneous behaviors can help improve care delivery and survival in this population.

Improved Retention With 6-Month Clinic Return Intervals for Stable Human Immunodeficiency Virus-Infected Patients in Zambia.

Background: Extending appointment intervals for stable HIV-infected patients in sub-Saharan Africa can reduce patient opportunity costs and decongest overcrowded facilities. Methods: We analyzed a cohort of stable HIV-infected adults (on treatment with CD4 >200 cells/µL for more than 6 months) who presented for clinic visits in Lusaka, Zambia. We used multilevel, mixed-effects logistic regression adjusting for patient characteristics, including prior retention, to assess the association between scheduled appointment intervals and subsequent missed visits (>14 days late to next visit), gaps in medication (>14 days late to next pharmacy refill), and loss to follow-up (LTFU; >90 days late to next visit). Results: A total of 62084 patients (66.6% female, median age 38, median CD4 438 cells/µL) made 501281 visits while stable on antiretroviral therapy. Most visits were scheduled around 1-month (25.0% clinical, 44.4% pharmacy) or 3-month intervals (49.8% clinical, 35.2% pharmacy), with fewer patients scheduled at 6-month intervals (10.3% clinical, 0.4% pharmacy). After adjustment and compared to patients scheduled to return in 1 month, patients with six-month clinic return intervals were the least likely to miss visits (adjusted odds ratio [aOR], 0.20; 95% confidence interval [CI], 0.17-0.24); miss medication pickups (aOR, 0.47; 95% CI 0.39-0.57), and become LTFU prior to the next visit (aOR, 0.41; 95% CI, 0.31-0.54). Conclusions: Six-month clinic return intervals were associated with decreased lateness, gaps in medication, and LTFU in stable HIV-infected patients and may represent a promising strategy to reduce patient burdens and decongest clinics.

Estimating the real-world effects of expanding antiretroviral treatment eligibility: Evidence from a regression discontinuity analysis in Zambia.

BACKGROUND: Although randomized trials have established the clinical efficacy of treating all persons living with HIV (PLWHs), expanding treatment eligibility in the real world may have additional behavioral effects (e.g., changes in retention) or lead to unintended consequences (e.g., crowding out sicker patients owing to increased patient volume). Using a regression discontinuity design, we sought to assess the effects of a previous change to Zambia's HIV treatment guidelines increasing the threshold for treatment eligibility from 350 to 500 cells/µL to anticipate effects of current global efforts to treat all PLWHs. METHODS AND FINDINGS: We analyzed antiretroviral therapy (ART)-naïve adults who newly enrolled in HIV care in a network of 64 clinics operated by the Zambian Ministry of Health and supported by the Centre for Infectious Disease Research in Zambia (CIDRZ). Patients were restricted to those enrolling in a narrow window around the April 1, 2014 change to Zambian HIV treatment guidelines that raised the CD4 threshold for treatment from 350 to 500 cells/µL (i.e., August 1, 2013, to November 1, 2014). Clinical and sociodemographic data were obtained from an electronic medical record system used in routine care. We used a regression discontinuity design to estimate the effects of this change in treatment eligibility on ART initiation within 3 months of enrollment, retention in care at 6 months (defined as clinic attendance between 3 and 9 months after enrollment), and a composite of both ART initiation by 3 months and retention in care at 6 months in all new enrollees. We also performed an instrumental variable (IV) analysis to quantify the effect of actually initiating ART because of this guideline change on retention. Overall, 34,857 ART-naïve patients (39.1% male, median age 34 years [IQR 28-41], median CD4 268 cells/µL [IQR 134-430]) newly enrolled in HIV care during this period; 23,036 were analyzed after excluding patients around the threshold to allow for clinic-to-clinic variations in actual guideline uptake. In all newly enrolling patients, expanding the CD4 threshold for treatment from 350 to 500 cells/µL was associated with a 13.6% absolute increase in ART initiation within 3 months of enrollment (95% CI, 11.1%-16.2%), a 4.1% absolute increase in retention at 6 months (95% CI, 1.6%-6.7%), and a 10.8% absolute increase in the percentage of patients who initiated ART by 3 months and were retained at six months (95% CI, 8.1%-13.5%). These effects were greatest in patients who would have become newly eligible for ART with the change in guidelines: a 43.7% increase in ART initiation by 3 months (95% CI, 37.5%-49.9%), 13.6% increase in retention at six months (95% CI, 7.3%-20.0%), and a 35.5% increase in the percentage of patients on ART at 3 months and still in care at 6 months [95% CI, 29.2%-41.9%). We did not observe decreases in ART initiation or retention in patients not directly targeted by the guideline change. An IV analysis found that initiating ART in response to the guideline change led to a 37.9% (95% CI, 28.8%-46.9%) absolute increase in retention in care. Limitations of this study include uncertain generalizability under newer models of care, lack of laboratory data (e.g., viral load), inability to account for earlier stages in the HIV care cascade (e.g., HIV testing and linkage), and potential for misclassification of eligibility status or outcome. CONCLUSIONS: In this study, guidelines raising the CD4 threshold for treatment from 350 to 500 cells/µL were associated with a rapid rise in ART initiation as well as enhanced retention among newly treatment-eligible patients, without negatively impacting patients with lower CD4 levels. These data suggest that health systems in Zambia and other high-prevalence settings could substantially enhance engagement even among those with high CD4 levels (i.e., above 500 cells/µL) by expanding treatment without undermining existing care standards.

Barriers and facilitators to patient retention in HIV care.

BACKGROUND: Retention in HIV care improves survival and reduces the risk of HIV transmission to others. Multiple quantitative studies have described demographic and clinical characteristics associated with retention in HIV care. However, qualitative studies are needed to better understand barriers and facilitators. METHODS: Semi-structured interviews were conducted with 51 HIV-infected individuals, 25 who were retained in care and 26 not retained in care, from 3 urban clinics. Interview data were analyzed for themes using a modified grounded theory approach. Identified themes were compared between the two groups of interest: patients retained in care and those not retained in care. RESULTS: Overall, participants identified 12 barriers and 5 facilitators to retention in HIV care. On average, retained individuals provided 3 barriers, while persons not retained in care provided 5 barriers. Both groups commonly discussed depression/mental illness, feeling sick, and competing life activities as barriers. In addition, individuals not retained in care commonly reported expensive and unreliable transportation, stigma, and insufficient insurance as barriers. On average, participants in both groups referenced 2 facilitators, including the presence of social support, patient-friendly clinic services (transportation, co-location of services, scheduling/reminders), and positive relationships with providers and clinic staff. CONCLUSIONS: In our study, patients not retained in care faced more barriers, particularly social and structural barriers, than those retained in care. Developing care models where social and financial barriers are addressed, mental health and substance abuse treatment is integrated, and patient-friendly services are offered is important to keeping HIV-infected individuals engaged in care.

Integrating hypertension detection and management in HIV care in South Africa: protocol for a stepped-wedged cluster randomized effectiveness-implementation hybrid trial.

BACKGROUND: HIV clinical guidelines recommend hypertension detection and management to lower cardiovascular disease risk, but these have not been effectively implemented for people living with HIV (PWH). Addressing this implementation gap requires community-engaged implementation studies focused on addressing implementation barriers specific to the HIV care context. METHODS: This protocol describes a type 2 effectiveness-implementation hybrid study conducted in nine primary care clinics in Johannesburg. The study will evaluate the effect of implementation strategies on guideline-recommended blood pressure assessment and management in HIV clinics and the effects of assessment/management on patient blood pressure. A stepped-wedge, cluster randomized study design was used to randomize clinics to the time at which they receive the implementation strategies and patient intervention. The implementation strategies tested include identifying and preparing care champions, changing record systems, conducting ongoing training, providing audit and feedback, and changing the physical structure/equipment. The patient intervention tested includes detection of elevated blood pressure, educational materials, lifestyle modification advice, and medication where needed. Implementation outcomes include adoption, fidelity (co-primary outcome), cost, and maintenance of the blood pressure assessment protocol in participating clinics, while patient outcomes include reach, effectiveness (co-primary outcome), and long-term effects of the intervention on patient blood pressure. These will be assessed via direct observation, study records, staff logs, medical chart reviews, and patient and healthcare worker surveys. To examine effects on the implementation (intervention fidelity) and effectiveness (patient blood pressure changes) co-primary outcomes, we will use the standard Hussey and Hughes model for analysis of stepped-wedge designs which includes fixed effects for both interventions and time periods, and a random effect for sites. Finally, we will examine the costs for the implementation strategies, healthcare worker time, and patient-facing intervention materials, as well as the cost-effectiveness and cost-utility of the intervention using study records, patient surveys, and a time and motion assessment. DISCUSSION: This study will address knowledge gaps around implementation of cardiovascular disease preventive practices in HIV care in South Africa. In doing so, it will provide a dual opportunity to promote evidence-based care in the South African HIV care context and help refine implementation research methods to better serve HIV populations globally. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05846503. Registered on May 6, 2023. https://classic. CLINICALTRIALS: gov/ct2/show/NCT05846503 .