Characterizing participants who respond to text, email, phone calls, or postcards in a SARS-CoV-2 prevalence study.

INTRODUCTION: Multiple modalities and frequencies of contact are needed to maximize recruitment in many public health surveys. The purpose of this analysis is to characterize respondents to a statewide SARS-CoV-2 testing study whose participation followed either postcard, phone outreach or electronic means of invitation. In addition, we examine how participant characteristics differ based upon the number of contacts needed to elicit participation. METHODS: This is a cross-sectional analysis of survey data collected from participants who were randomly selected to represent Indiana residents and were invited to be tested for Covid-19 in April 2020. Participants received invitations via postcard, text/emails, and/or robocalls/texts based upon available contact information. The modality, and frequency of contacts, that prompted participation was determined by when the notification was sent and when the participant responded and subsequently registered to participate in the study. Chi square analyses were used to determine differences between groups and significant findings were analyzed using multinomial logistic regression. RESULTS: Respondents included 3,658 individuals and were stratified by postcards (7.9%), text/emails (26.5%), and robocalls/text (65.7%) with 19.7% registering after 1 contact, 47.9% after 2 contacts, and 32.4% after 3 contacts encouraging participation. Females made up 54.6% of the sample and responded at a higher rate for postcards (8.2% vs. 7.5%) and text/emails (28.1 vs. 24.6%) as compared to males (χ2 = 7.43, p = 0.025). Compared to males, females responded at a higher percentage after 1 contact (21.4 vs. 17.9%, χ2 = 7.6, p = 0.023). Those over 60 years responded most often after 2 contacts (χ2 = 27.5, p < 0.001) when compared to others at younger age groups. In regression analysis, participant sex (p = 0.036) age (p = 0.005), educational attainment (p = < 0.0001), and being motivated by "free testing" (p = 0.036) were correlated with participation in the prevalence study. DISCUSSION: Researchers should be aware that the modality of contact as well as the number of prompts used could influence differential participation in public health studies. Our findings can inform researchers developing studies that rely on selective participation by study subjects. We explore how to increase participation within targeted demographic groups using specific modalities and examining frequency of contact.

Adaptation of the Client Diagnostic Questionnaire for East Africa.

Research increasingly involves cross-cultural work with non-English-speaking populations, necessitating translation and cultural validation of research tools. This paper describes the process of translating and criterion validation of the Client Diagnostic Questionnaire (CDQ) for use in a multisite study in Kenya and Uganda. The English CDQ was translated into Swahili, Dholuo (Kenya) and Runyankole/Rukiga (Uganda) by expert translators. The translated documents underwent face validation by a bilingual committee, who resolved unclear statements, agreed on final translations and reviewed back translations to English. A diagnostic interview by a mental health specialist was used for criterion validation, and Kappa statistics assessed the strength of agreement between non-specialist scores and mental health professionals' diagnoses. Achieving semantic equivalence between translations was a challenge. Validation analysis was done with 30 participants at each site (median age 32.3 years (IQR = (26.5, 36.3)); 58 (64.4%) female). The sensitivity was 86.7%, specificity 64.4%, positive predictive value 70.9% and negative predictive value 82.9%. Diagnostic accuracy by the non-specialist was 75.6%. Agreement was substantial for major depressive episode and positive alcohol (past 6 months) and alcohol abuse (past 30 days). Agreement was moderate for other depressive disorders, panic disorder and psychosis screen; fair for generalized anxiety, drug abuse (past 6 months) and Post Traumatic Stress Disorder (PTSD); and poor for drug abuse (past 30 days). Variability of agreement between sites was seen for drug use (past 6 months) and PTSD. Our study successfully adapted the CDQ for use among people living with HIV in East Africa. We established that trained non-specialists can use the CDQ to screen for common mental health and substance use disorders with reasonable accuracy. Its use has the potential to increase case identification, improve linkage to mental healthcare, and improve outcomes. We recommend further studies to establish the psychometric properties of the translated tool.

Self-transfers, Hospital Admissions and Mortality Among Children and Adolescents Lost to Follow-up From Antiretroviral Therapy Programs in the Western Cape, South Africa Between 2004 and 2019: Linkage to Provincial Records.

BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy <15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

Mortality Among HIV-Infected Adults on Antiretroviral Therapy in Southern Uganda.

BACKGROUND: Monitoring and evaluation of clinical programs requires assessing patient outcomes. Numerous challenges complicate these efforts, the most insidious of which is loss to follow-up (LTFU). LTFU is a composite outcome, including individuals out of care, undocumented transfers, and unreported deaths. Incorporation of vital status information from routine patient outreach may improve the mortality estimates for those LTFU. SETTINGS: We analyzed routinely collected clinical and patient tracing data for individuals (15 years or older) initiating antiretroviral treatment between January 2014 and December 2018 at 2 public HIV care clinics in greater Rakai, Uganda. METHODS: We derived unadjusted mortality estimates using Kaplan-Meier methods. Estimates, adjusted for unreported deaths, applied weighting through the Frangakis and Rubin method to represent outcomes among LTFU patients who were successfully traced and for whom vital status was ascertained. Confidence intervals were determined through bootstrap methods. RESULTS: Of 1969 patients with median age at antiretroviral treatment initiation of 31 years (interquartile range: 25-38), 1126 (57.2%) were female patients and 808 (41%) were lost. Of the lost patients, 640 patient files (79.2%) were found and reviewed, of which 204 (31.8%) had a tracing attempt. Within the electronic health records of the program, 28 deaths were identified with an estimated unadjusted mortality 1 year after antiretroviral treatment initiation of 2.5% (95% CI: 1.8% to 3.3%). Using chart review and patient tracing data, an additional 24 deaths (total 52) were discovered with an adjusted 1-year mortality of 3.8% (95% CI: 2.6% to 5.0%). CONCLUSIONS: Data from routine outreach efforts by HIV care and treatment programs can be used to support plausible adjustments to estimates of client mortality. Mortality estimates without active ascertainment of vital status of LTFU patients may significantly underestimate program mortality.

Preswitch Regimens Influence the Rate of Weight Gain After Switch to Tenofovir Disoproxil Fumarate, Lamivudine, and Dolutegravir (TLD): Study From an East African Cohort.

Background: Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to dolutegravir (DTG) has been associated with greater weight gain. Methods: We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate. Results: A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens. Conclusions: Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch.

Assessing HIV-infected patient retention in a program of differentiated care in sub-Saharan Africa: a G-estimation approach.

Differentiated care delivery aims to simplify care of people living with HIV, reflect their preferences, reduce burdens on the healthcare system, maintain care quality and preserve resources. However, assessing program effectiveness using observational data is difficult due to confounding by indication and randomized trials may be infeasible. Also, benefits can reach patients directly, through enrollment in the program, and indirectly, by increasing quality of and accessibility to care. Low-risk express care (LREC), the program under evaluation, is a nurse-centered model which assigns patients stable on ART to a nurse every two months and a clinician every third visit, reducing annual clinician visits by two thirds. Study population is comprised of 16,832 subjects from 15 clinics in Kenya. We focus on patient retention in care based on whether the LREC program is available at a clinic and whether the patient is enrolled in LREC. We use G-estimation to assess the effect on retention of two "strategies": (i) program availability but no enrollment; (ii) enrollment at an available program; versus no program availability. Compared to no availability, LREC results in a non-significant increase in patient retention, among patients not enrolled in the program (indirect effect), while enrollment in LREC is associated with a significant extension of the time retained in care (direct effect). G-estimation provides an analytical framework useful to the assessment of similar programs using observational data.

The Effect of HIV Treatment Interruption on Subsequent Immunological Response.

Recovery of CD4-positive T lymphocyte count after initiation of antiretroviral therapy (ART) has been thoroughly examined among people with human immunodeficiency virus infection. However, immunological response after restart of ART following care interruption is less well studied. We compared CD4 cell-count trends before disengagement from care and after ART reinitiation. Data were obtained from the East Africa International Epidemiology Databases to Evaluate AIDS (IeDEA) Collaboration (2001-2011; n = 62,534). CD4 cell-count trends before disengagement, during disengagement, and after ART reinitiation were simultaneously estimated through a linear mixed model with 2 subject-specific knots placed at the times of disengagement and treatment reinitiation. We also estimated CD4 trends conditional on the baseline CD4 value. A total of 10,961 patients returned to care after disengagement from care, with the median gap in care being 2.7 (interquartile range, 2.1-5.4) months. Our model showed that CD4 cell-count increases after ART reinitiation were much slower than those before disengagement. Assuming that disengagement from care occurred 12 months after ART initiation and a 3-month treatment gap, CD4 counts measured at 3 years since ART initiation would be lower by 36.5 cells/µL than those obtained under no disengagement. Given that poorer CD4 restoration is associated with increased mortality/morbidity, specific interventions targeted at better retention in care are urgently required.

Global HIV prevention, care and treatment services for children: a cross-sectional survey from the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium.

OBJECTIVES: To assess access children with HIV have to comprehensive HIV care services, to longitudinally evaluate the implementation and scale-up of services, and to use site services and clinical cohort data to explore whether access to these services influences retention in care. METHODS: A cross-sectional standardised survey was completed in 2014-2015 by sites providing paediatric HIV care across regions of the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. We developed a comprehensiveness score based on the WHO's nine categories of essential services to categorise sites as 'low' (0-5), 'medium', (6-7) or 'high' (8-9). When available, comprehensiveness scores were compared with scores from a 2009 survey. We used patient-level data with site services to investigate the relationship between the comprehensiveness of services and retention. RESULTS: Survey data from 174 IeDEA sites in 32 countries were analysed. Of the WHO essential services, sites were most likely to offer antiretroviral therapy (ART) provision and counselling (n=173; 99%), co-trimoxazole prophylaxis (168; 97%), prevention of perinatal transmission services (167; 96%), outreach for patient engagement and follow-up (166; 95%), CD4 cell count testing (126; 88%), tuberculosis screening (151; 87%) and select immunisation services (126; 72%). Sites were less likely to offer nutrition/food support (97; 56%), viral load testing (99; 69%) and HIV counselling and testing (69; 40%). 10% of sites rated 'low', 59% 'medium' and 31% 'high' in the comprehensiveness score. The mean comprehensiveness of services score increased significantly from 5.6 in 2009 to 7.3 in 2014 (p<0.001; n=30). Patient-level analysis of lost to follow-up after ART initiation estimated the hazard was highest in sites rated 'low' and lowest in sites rated 'high'. CONCLUSION: This global assessment suggests the potential care impact of scaling-up and sustaining comprehensive paediatric HIV services. Meeting recommendations for comprehensive HIV services should remain a global priority.

Semiparametric marginal regression for clustered competing risks data with missing cause of failure.

Clustered competing risks data are commonly encountered in multicenter studies. The analysis of such data is often complicated due to informative cluster size (ICS), a situation where the outcomes under study are associated with the size of the cluster. In addition, the cause of failure is frequently incompletely observed in real-world settings. To the best of our knowledge, there is no methodology for population-averaged analysis with clustered competing risks data with an ICS and missing causes of failure. To address this problem, we consider the semiparametric marginal proportional cause-specific hazards model and propose a maximum partial pseudolikelihood estimator under a missing at random assumption. To make the latter assumption more plausible in practice, we allow for auxiliary variables that may be related to the probability of missingness. The proposed method does not impose assumptions regarding the within-cluster dependence and allows for ICS. The asymptotic properties of the proposed estimators for both regression coefficients and infinite-dimensional parameters, such as the marginal cumulative incidence functions, are rigorously established. Simulation studies show that the proposed method performs well and that methods that ignore the within-cluster dependence and the ICS lead to invalid inferences. The proposed method is applied to competing risks data from a large multicenter HIV study in sub-Saharan Africa where a significant portion of causes of failure is missing.

Same-Day Antiretroviral Therapy Initiation as a Predictor of Loss to Follow-up and Viral Suppression Among People With Human Immunodeficiency Virus in Sub-Saharan Africa.

BACKGROUND: Treat-All guidelines recommend initiation of antiretroviral therapy (ART) for all people with HIV (PWH) on the day of diagnosis when possible, yet uncertainty exists about the impact of same-day ART initiation on subsequent care engagement. We examined the association of same-day ART initiation with loss to follow-up and viral suppression among patients in 11 sub-Saharan African countries. METHODS: We included ART-naive adult PWH from sites participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium who enrolled in care after Treat-All implementation and prior to January 2019. We used multivariable Cox regression to estimate the association between same-day ART initiation and loss to follow-up and Poisson regression to estimate the association between same-day ART initiation and 6-month viral suppression. RESULTS: Among 29 017 patients from 63 sites, 18 584 (64.0%) initiated ART on the day of enrollment. Same-day ART initiation was less likely among those with advanced HIV disease versus early-stage disease. Loss to follow-up was significantly lower among those initiating ART ≥1 day of enrollment, compared with same-day ART initiators (20.6% vs 27.7%; adjusted hazard ratio: .66; 95% CI .57-.76). No difference in viral suppression was observed by time to ART initiation (adjusted rate ratio: 1.00; 95% CI: .98-1.02). CONCLUSIONS: Patients initiating ART on the day of enrollment were more frequently lost to follow-up than those initiating later but were equally likely to be virally suppressed. Our findings support recent World Health Organization recommendations for providing tailored counseling and support to patients who accept an offer of same-day ART.

Joint modeling of longitudinal and competing-risk data using cumulative incidence functions for the failure submodels accounting for potential failure cause misclassification through double sampling.

Most of the literature on joint modeling of longitudinal and competing-risk data is based on cause-specific hazards, although modeling of the cumulative incidence function (CIF) is an easier and more direct approach to evaluate the prognosis of an event. We propose a flexible class of shared parameter models to jointly model a normally distributed marker over time and multiple causes of failure using CIFs for the survival submodels, with CIFs depending on the "true" marker value over time (i.e., removing the measurement error). The generalized odds rate transformation is applied, thus a proportional subdistribution hazards model is a special case. The requirement that the all-cause CIF should be bounded by 1 is formally considered. The proposed models are extended to account for potential failure cause misclassification, where the true failure causes are available in a small random sample of individuals. We also provide a multistate representation of the whole population by defining mutually exclusive states based on the marker values and the competing risks. Based solely on the assumed joint model, we derive fully Bayesian posterior samples for state occupation and transition probabilities. The proposed approach is evaluated in a simulation study and, as an illustration, it is fitted to real data from people with HIV.

Contraceptive implant use duration is not associated with breakthrough pregnancy among women living with HIV and using efavirenz: a retrospective, longitudinal analysis.

INTRODUCTION: Contraceptive implants containing etonogestrel and levonorgestrel have emerged as popular contraceptive options among women in areas of high HIV burden in sub-Saharan Africa. However, recent pharmacokinetic data have shown drug-drug interactions between implants and efavirenz-containing antiretroviral therapy (ART), reducing the effectiveness of the implants. Here, we evaluated pregnancy incidence in 6-month intervals following implant initiation among women using efavirenz and contraceptive implants to assess whether the risk of breakthrough pregnancy is higher after specific periods of implant use. METHODS: We used data from a retrospective longitudinal analysis of women living with HIV ages 18-45 years in western Kenya who attended HIV-care facilities between 2011 and 2015. We used Cox proportional hazard models to compute hazard ratios (HRs) for breakthrough pregnancy by implant type and ART regimen. Depending on the model, we adjusted for socio-demographic and clinical factors, programme, site and interaction between calendar time and ART regimen. We utilized inverse probability weights (IPWs) to account for three sampling phases (electronic medical record [EMR], chart review and phone interview) and calculated overall parameter estimates. RESULTS: Women contributed 14,768 woman-years from the largest sampling phase (EMR). The median age was 31 years. Women used etonogestrel implants for 26-69% of the time and levonorgestrel implants for 7-31% of the time, depending on the sampling phase. Women used efavirenz, nevirapine or no ART for 27-33%, 40-46% and 15-26% of follow-ups, respectively. When combining sampling phases, there was little evidence to suggest that the relative hazard of pregnancy among efavirenz-containing ART users relative to nevirapine-containing ART changed with length of time on implants: IPW-adjusted HR of 3.1 (CI: [1.5; 6.4]) at 12 months, 3.4 (CI: [1.8; 6.3]) at 24 months, 3.8 (CI: [1.9; 7.7]) at 36 months and 4.2 (CI: [1.6; 11.1]) at 48 months (interaction p-value = 0.88). Similarly, no significant change in HRs over time was found when comparing women not using ART to nevirapine-containing ART users (interaction p-value = 0.49). CONCLUSIONS: We did not find evidence to suggest implants being more fallible from drug-drug interactions with efavirenz at later time intervals of implant use. Thus, we would not recommend shortening the duration of implant use or replacing implants sooner when concomitantly used with efavirenz.

High Unreported Mortality in Children and Youth (<25 Years) Living With HIV Who Were Lost to Care From Antiretroviral Therapy Programs in Southern Africa: Results From a Multicountry Tracing Study.

BACKGROUND: Antiretroviral therapy program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS: We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS: Among 680 children and youth aged <25 years on antiretroviral therapy who were lost and traced in Southern Africa between October 2017 and November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared with infants aged <2 years [adjusted hazard ratio: 0.40 (95% confidence interval: 0.31 to 0.51)]. CONCLUSIONS: Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.

Weight Gain Among Treatment-Naïve Persons With HIV Receiving Dolutegravir in Kenya.

BACKGROUND: Several recent studies have linked integrase strand transfer inhibitors (INSTI) with increased weight gain. SETTING: The effects of sex on weight gain with dolutegravir (DTG)-based antiretroviral therapy (ART) among treatment-naïve participants in a lower-income, sub-Saharan population with high rates of pre-ART underweight and tuberculosis (TB) coinfection are unknown. METHODS: Our analysis included treatment-naïve participants in Kenya and starting their first treatment regimen between January 1, 2015, and September 30, 2018. Participants were grouped into 2 cohorts based on the initial treatment regimen [DTG vs. nonnucleoside reverse transcriptase inhibitors (NNRTI)]. We modelled weight changes over time using a multivariable nonlinear mixed-effect model, with participant as a random effect. Logistic regression models were constructed to evaluate the association between different variables with extreme increase in body mass index (≥10% increase). RESULTS: Seventeen thousand forty-four participants met our inclusion criteria. Sixty-two percent of participants were women, 6% were receiving active TB therapy, and 97% were on NNRTI-based regimens. Participants starting DTG-based regimens were more likely to gain weight when compared with participants starting NNRTI-based regimens. Female participants starting DTG-based regimens experienced the highest weight gain compared with other participants (mean gain of 6.1 kgs at 18 months). Female participants receiving DTG-based regimens, along with participants with lower CD4 cell counts, underweight at baseline, and those receiving active TB therapy were also at higher risk for extreme body mass index increase. CONCLUSIONS: Our study in a lower-income sub-Saharan African population confirms higher weight gain with DTG-based regimens compared with traditional ART for treatment-naïve patients.

Site-Level Comprehensiveness of Care Is Associated with Individual Clinical Retention Among Adults Living with HIV in International Epidemiology Databases to Evaluate AIDS, a Global HIV Cohort Collaboration, 2000-2016.

Retention in care (RIC) reduces HIV transmission and associated morbidity and mortality. We examined whether delivery of comprehensive services influenced individual RIC within the International epidemiology Databases to Evaluate AIDS (IeDEA) network. We collected site data through IeDEA assessments 1.0 (2000-2009) and 2.0 (2010-2016). Each site received a comprehensiveness score for service availability (1 = present, 0 = absent), with tallies ranging from 0 to 7. We obtained individual-level cohort data for adults with at least one visit from 2000 to 2016 at sites responding to either assessment. Person-time was recorded annually, with RIC defined as completing two visits at least 90 days apart in each calendar year. Multivariable modified Poisson regression clustered by site yielded risk ratios and predicted probabilities for individual RIC by comprehensiveness. Among 347,060 individuals in care at 122 sites with 1,619,558 person-years of follow-up, 69.8% of person-time was retained in care, varying by region from 53.8% (Asia-Pacific) to 82.7% (East Africa); RIC improved by about 2% per year from 2000 to 2016 (p = 0.012). Every site provided CD4+ count testing, and >90% of individuals received care at sites that provided combination antiretroviral therapy adherence measures, prevention of mother-to-child transmission, tuberculosis screening, HIV-related prevention, and community tracing services. In adjusted models, individuals at sites with more comprehensive services had higher probabilities of RIC (0.71, 0.74, and 0.83 for scores 5, 6, and 7, respectively; p = 0.019). Within IeDEA, greater site-level comprehensiveness of services was associated with improved individual RIC. Much work remains in exploring this relationship, which may inform HIV clinical practice and health systems planning.

Factors that differentiate COVID-19 vaccine intentions among Indiana parents: Implications for targeted vaccine promotion.

Given low rates of uptake of the COVID-19 vaccine for children 12-17 and 5-11 years old, research is needed to understand parental behaviors and behavioral intentions related to COVID-19 vaccination for their children. In the state of Indiana, we conducted a non-random, online survey of parents or caregivers (N = 10,266) about their COVID-19 vaccine intentions or behaviors, demographic characteristics, and potential motivating reasons for getting the vaccine. In terms of behaviors/intentions, 44.8% of participants indicated they were vaccine acceptors (i.e., had already had their children vaccinated or would as soon as it was possible), 13.0% indicated they were vaccine hesitators (i.e., wanted to wait and see), and 42.2% indicated they were vaccine rejecters (i.e., would not vaccinate or only would if mandated). Compared to vaccine rejecters, vaccine hesitators were more likely to be motivated by perceptions of vaccine safety and efficacy, normative influences such as close friends/family who had been vaccinated and a recommendation from a provider, as well as if they were vaccinated themselves. These findings have implications for the development of targeted vaccine promotion strategies, such as social norms messaging and a focus on vaccine safety, in order to increase COVID-19 vaccination for eligible children.

Virologic non-suppression and early loss to follow up among pregnant and non-pregnant adolescents aged 15-19 years initiating antiretroviral therapy in South Africa: a retrospective cohort study.

INTRODUCTION: Older adolescents aged 15-19 years continue to have high rates of loss to follow up (LTFU), and high rates of virologic non-suppression (VNS) compared to younger adolescents and adults. Adolescent females are at risk of pregnancy, which puts those living with HIV at a dual vulnerability. Our study assessed the factors associated with VNS and LTFU in older adolescents (including pregnant females) who initiated antiretroviral therapy (ART) in South Africa. METHODS: We included adolescents aged 15-19 years initiating ART between 2004 and 2019, with ≥ one viral load (VL) measurement between 4 and 24.5 months, and ≥ 6 months follow-up, from six South African cohorts of the International epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA). We defined VNS as VL ≥400 copies/ml and LTFU as not being in care for ≥180 days from ART start and not known as transferred out of the clinic or dead in the first 24 months on ART. We examined factors associated with VNS and LTFU using Fine&Gray competing risk models. RESULTS: We included a total of 2733 adolescents, 415 (15.2%) males, median (IQR) age at ART start of 18.6 (17.3, 19.4) years. Among females, 585/2318 (25.2%) were pregnant. Over the 24-month follow-up, 424 (15.5%) of all adolescents experienced VNS: range (11.1% pregnant females and 20.5% males). Over half of all adolescents were LTFU before any other event could occur. The hazard of VNS reduced with increasing age and CD4 count above 200 cells/µl at ART initiation among all adolescents having adjusted for all measured patient characteristics [adjusted sub-distribution hazard ratio (aSHR) 19 vs. 15 years: 0.50 (95% CI: 0.36, 0.68), aSHR: >500 vs. ≤200 cells/µl: 0.22 (95% CI: 0.16, 0.31)]. The effect of CD4 count persisted in pregnant females. Increasing age and CD4 count >200 cells/µl were risk factors for LTFU among all adolescents. CONCLUSIONS: Older adolescents had a high risk of LTFU shortly after ART start and a low risk of VNS, especially those initiating treatment during pregnancy. Interventions addressing adherence and retention should be incorporated into adolescent-friendly services to prevent VNS and LTFU and endeavour to trace lost adolescents as soon as they are identified.

Semiparametric regression on cumulative incidence function with interval-censored competing risks data and missing event types.

Competing risk data are frequently interval-censored, that is, the exact event time is not observed but only known to lie between two examination time points such as clinic visits. In addition to interval censoring, another common complication is that the event type is missing for some study participants. In this article, we propose an augmented inverse probability weighted sieve maximum likelihood estimator for the analysis of interval-censored competing risk data in the presence of missing event types. The estimator imposes weaker than usual missing at random assumptions by allowing for the inclusion of auxiliary variables that are potentially associated with the probability of missingness. The proposed estimator is shown to be doubly robust, in the sense that it is consistent even if either the model for the probability of missingness or the model for the probability of the event type is misspecified. Extensive Monte Carlo simulation studies show good performance of the proposed method even under a large amount of missing event types. The method is illustrated using data from an HIV cohort study in sub-Saharan Africa, where a significant portion of events types is missing. The proposed method can be readily implemented using the new function ciregic_aipw in the R package intccr.

Achieving consistency in measures of HIV-1 viral suppression across countries: derivation of an adjustment based on international antiretroviral treatment cohort data.

INTRODUCTION: The third of the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets is to achieve a 90% rate of viral suppression (HIV viral load <1000 HIV-1 RNA copies/ml) in patients on antiretroviral treatment (ART) by 2020. However, some countries use different thresholds when reporting viral suppression, and there is thus a need for an adjustment to standardize estimates to the <1000 threshold. We aim to propose such an adjustment, to support consistent monitoring of progress towards the "third 90" target. METHODS: We considered three possible distributions for viral loads in ART patients: Weibull, Pareto and reverse Weibull (imposing an upper limit but no lower limit on the log scale). The models were fitted to data on viral load distributions in ART patients in the International epidemiology Databases to Evaluate AIDS (IeDEA) collaboration (representing seven global regions) and the ART Cohort Collaboration (representing Europe), using separate random effects models for adults and children. The models were validated using data from the World Health Organization (WHO) HIV drug resistance report and the Brazilian national ART programme. RESULTS: Models were calibrated using 921,157 adult and 37,431 paediatric viral load measurements, over 2010-2019. The Pareto and reverse Weibull models provided the best fits to the data, but for all models, the "shape" parameters for the viral load distributions differed significantly between regions. The Weibull model performed best in the validation against the WHO drug resistance survey data, while the Pareto model produced uncertainty ranges that were too narrow, relative to the validation data. Based on these analyses, we recommend using the reverse Weibull model. For example, if a country reports an 80% rate of viral suppression at <200 copies/ml, this model estimates the proportion virally suppressed at <1000 copies/ml is 88.3% (0.800.56 ), with uncertainty range 85.5-90.6% (0.800.70 -0.800.44 ). CONCLUSIONS: Estimates of viral suppression can change substantially depending on the threshold used in defining viral suppression. It is, therefore, important that viral suppression rates are standardized to the same threshold for the purpose of assessing progress towards UNAIDS targets. We have proposed a simple adjustment that allows this, and this has been incorporated into UNAIDS modelling software.

Global HIV mortality trends among children on antiretroviral treatment corrected for under-reported deaths: an updated analysis of the International epidemiology Databases to Evaluate AIDS collaboration.

INTRODUCTION: The Joint United Nations Programme on HIV/AIDS (UNAIDS) projections of paediatric HIV prevalence and deaths rely on the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium for mortality estimates among children living with HIV (CHIV) receiving antiretroviral therapy (ART). Previous estimates, based on data through 2014, may no longer be accurate due to expanded paediatric HIV care and treatment eligibility, and the possibility of unreported deaths in CHIV considered lost to follow-up (LTFU). We therefore estimated all-cause mortality and its trends in CHIV (<15 years old) on ART using extended and new IeDEA data. METHODS: We analysed (i) IeDEA observational data from CHIV in routine care globally, and (ii) novel data from an IeDEA tracing study that determined outcomes in a sample of CHIV after being LTFU in southern Africa. We included 45,711 CHIV on ART during 2004 to 2017 at 72 programmes in Africa, Asia-Pacific and Latin America. We used mixed effects Poisson regression to estimate mortality by age, sex, CD4 at ART start, time on ART, region and calendar year. For Africa, in an adjusted analysis that accounts for unreported deaths among those LTFU, we first modified the routine data by simulating mortality outcomes within six months after LTFU, based on a Gompertz survival model fitted to the tracing data (n = 221). RESULTS: Observed mortality rates were 1.8 (95% CI: 1.7 to 1.9) and 9.4 (6.3 to 13.4) deaths per 100 person-years in the routine and tracing data, respectively. We found strong evidence of higher mortality at shorter ART durations, lower CD4 values, and in infancy. Averaging over covariate patterns, the adjusted mortality rate was 54% higher than the unadjusted rate. In unadjusted analyses, mortality reduced by an average 60% and 73% from 2005 to 2017, within and outside of Africa, respectively. In the adjusted analysis for Africa, this temporal reduction was 42%. CONCLUSIONS: Mortality rates among CHIV have decreased substantially over time. However, when accounting for worse outcomes among those LTFU, mortality estimates increased and temporal improvements were slightly reduced, suggesting caution in interpreting analyses based only on programme data. The improved and updated IeDEA estimates on mortality among CHIV on ART support UNAIDS efforts to accurately model global HIV statistics.