Adaptive Strategies for Retention in Care among Persons Living with HIV.

BACKGROUND: Optimizing retention in human immunodeficiency virus (HIV) treatment may require sequential behavioral interventions based on patients' response. METHODS: In a sequential multiple assignment randomized trial in Kenya, we randomly assigned adults initiating HIV treatment to standard of care (SOC), Short Message Service (SMS) messages, or conditional cash transfers (CCT). Those with retention lapse (missed a clinic visit by ≥14 days) were randomly assigned again to standard-of-care outreach (SOC-Outreach), SMS+CCT, or peer navigation. Those randomly assigned to SMS or CCT who did not lapse after 1 year were randomly assigned again to either stop or continue the initial intervention. Primary outcomes were retention in care without an initial lapse, return to the clinic among those who lapsed, and time in care; secondary outcomes included adjudicated viral suppression. Average treatment effect (ATE) was calculated using targeted maximum likelihood estimation with adjustment for baseline characteristics at randomization and certain time-varying characteristics at rerandomization. RESULTS: Among 1809 participants, 79.7% of those randomly assigned to CCT (n=523/656), 71.7% to SMS (n=393/548), and 70.7% to SOC (n=428/605) were retained in care in the first year (ATE: 9.9%; 95% confidence interval [CI]: 5.4%, 14.4% and ATE: 4.2%; 95% CI: -0.7%, 9.2% for CCT and SMS compared with SOC, respectively). Among 312 participants with an initial lapse who were randomly assigned again, 69.1% who were randomly assigned to a navigator (n=76/110) returned, 69.5% randomly assigned to CCT+SMS (n=73/105) returned, and 55.7% randomly assigned to SOC-Outreach (n=54/97) returned (ATE: 14.1%; 95% CI: 0.6%, 27.6% and ATE: 11.4%; 95% CI: -2.2%, 24.9% for navigator and CCT+SMS compared with SOC-Outreach, respectively). Among participants without lapse on SMS, continuing SMS did not affect retention (n=122/180; 67.8% retained) versus stopping (n=151/209; 72.2% retained; ATE: -4.4%; 95% CI: -16.6%, 7.9%). Among participants without lapse on CCT, those continuing CCT had higher retention (n=192/230; 83.5% retained) than those stopping (n=173/287; 60.3% retained; ATE: 28.6%; 95% CI: 19.9%, 37.3%). Among 15 sequenced strategies, initial CCT, escalated to navigator if lapse occurred and continued if no lapse occurred, increased time in care (ATE: 7.2%, 95% CI: 3.7%, 10.7%) and viral suppression (ATE: 8.2%, 95% CI: 2.2%, 14.2%), the most compared with SOC throughout. Initial SMS escalated to navigator if lapse occurred, and otherwise continued, showed similar effect sizes compared with SOC throughout. CONCLUSIONS: Active interventions to prevent retention lapses followed by navigation for those who lapse and maintenance of initial intervention for those without lapse resulted in best overall retention and viral suppression among the strategies studied. Among those who remained in care, discontinuation of CCT, but not SMS, compromised retention and suppression. (Funded by National Institutes of Health grants R01 MH104123, K24 AI134413, and R01 AI074345; ClinicalTrials.gov number, NCT02338739.).

Randomized controlled trial of a theory-informed mHealth intervention to support ART adherence and viral suppression among women with HIV in Mombasa, Kenya: preliminary efficacy and participant-level feasibility and acceptability.

BACKGROUND: Mobile Health ("mHealth") interventions have shown promise in improving HIV treatment outcomes for stigmatized populations. This paper presents the findings from a randomized controlled trial to assess the efficacy, participant-level feasibility and acceptability of a theory-informed mHealth intervention, Motivation Matters!, designed to improve viral suppression and ART adherence among HIV-seropositive women who engage in sex work in Mombasa, Kenya. METHODS: A total of 119 women were randomized between the intervention and standard of care control. The primary outcome examined viral suppression (≤ 30 copies/mL) six months following ART initiation. ART adherence was assessed monthly using a visual analogue scale. Participant-level feasibility was measured through response rates to study text messages. Acceptability was assessed through qualitative exit interviews. RESULTS: Six months following treatment initiation, 69% of intervention and 63% of control participants were virally suppressed (Risk Ratio [RR] = 1.09, 95% Confidence Interval [95% CI] (0.83, 1.44). Among women who were viremic at baseline and endorsed engagement in sex work, 74% of women in the intervention arm compared with 46% of women in the control arm achieved viral suppression at month six RR = 1.61, 95% CI (1.02, 2.55). Adherence was higher in intervention versus control participants every month. All participants responded to at least one message, and there was a 55% overall response rate to intervention text messages. Qualitative exit interviews suggested high acceptability and perceived impact of the intervention. CONCLUSION: The improvements in ART adherence and viral suppression, combined with encouraging data on feasibility and acceptability, provides preliminary evidence that Motivation Matters! could support ART adherence and viral suppression in women who engage in sex work. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02627365, 10/12/2015; http://clinicaltrials.gov ).

Adapt for Adolescents: Protocol for a sequential multiple assignment randomized trial to improve retention and viral suppression among adolescents and young adults living with HIV in Kenya.

BACKGROUND: Adolescents and young adults living with HIV (AYAH) aged 14-24 years in Africa experience substantially higher rates of virological failure and HIV-related mortality than adults. We propose to utilize developmentally appropriate interventions with high potential for effectiveness, tailored by AYAH pre-implementation, in a sequential multiple assignment randomized trial (SMART) aimed at improving viral suppression for AYAH in Kenya. METHODS: Using a SMART design, we will randomize 880 AYAH in Kisumu, Kenya to either youth-centered education and counseling (standard of care) or electronic peer navigation in which a peer provides support, information, and counseling via phone and automated monthly text messages. Those with a lapse in engagement (defined as either a missed clinic visit by ≥14 days or HIV viral load ≥1000 copies/ml) will be randomized a second time to one of three higher-intensity re-engagement interventions: This study will evaluate which interventions and which dynamic sequence of interventions improve sustained viral suppression and HIV care engagement in AYAH at 24 months post-enrollment and assess the cost-effectiveness of successful strategies. DISCUSSION: The study utilizes promising interventions tailored to AYAH while optimizing resources by intensifying services only for those AYAH who need more support. Findings from this innovative study will offer evidence for public health programming to end the HIV epidemic as a public health threat for AYAH in Africa. TRIAL REGISTRATION: Clinicaltrials.govNCT04432571, registered June 16, 2020.

Efficient and robust approaches for analysis of sequential multiple assignment randomized trials: Illustration using the ADAPT-R trial.

Personalized intervention strategies, in particular those that modify treatment based on a participant's own response, are a core component of precision medicine approaches. Sequential multiple assignment randomized trials (SMARTs) are growing in popularity and are specifically designed to facilitate the evaluation of sequential adaptive strategies, in particular those embedded within the SMART. Advances in efficient estimation approaches that are able to incorporate machine learning while retaining valid inference can allow for more precise estimates of the effectiveness of these embedded regimes. However, to the best of our knowledge, such approaches have not yet been applied as the primary analysis in SMART trials. In this paper, we present a robust and efficient approach using targeted maximum likelihood estimation (TMLE) for estimating and contrasting expected outcomes under the dynamic regimes embedded in a SMART, together with generating simultaneous confidence intervals for the resulting estimates. We contrast this method with two alternatives (G-computation and inverse probability weighting estimators). The precision gains and robust inference achievable through the use of TMLE to evaluate the effects of embedded regimes are illustrated using both outcome-blind simulations and a real-data analysis from the Adaptive Strategies for Preventing and Treating Lapses of Retention in Human Immunodeficiency Virus (HIV) Care (ADAPT-R) trial (NCT02338739), a SMART with a primary aim of identifying strategies to improve retention in HIV care among people living with HIV in sub-Saharan Africa.

Effects of behavioural interventions on postpartum retention and adherence among women with HIV on lifelong ART: the results of a cluster randomized trial in Kenya (the MOTIVATE trial).

INTRODUCTION: Retention in HIV care and adherence to antiretroviral therapy (ART) during pregnancy and postpartum for women living with HIV (WLWH) are necessary to optimize health outcomes for women and infants. The objective of this study was to evaluate the impact of two evidenced-based behavioural interventions on postpartum adherence and retention in WLWH in Kenya. METHODS: The Mother-Infant Visit Adherence and Treatment Engagement (MOTIVATE) study was a cluster-randomized trial enrolling pregnant WLWH from December 2015 to August 2017. Twenty-four health facilities in southwestern Kenya were randomized to: (1) standard care (control), (2) text-messaging, (3) community-based mentor mothers (cMM) or (4) text-messaging and cMM. Primary outcomes included retention in care and ART adherence at 12 months postpartum. Analyses utilized generalized estimating equations and competing risks regression. Per-protocol analyses examined differences in postpartum retention for women with high versus low levels of exposure to the interventions. RESULTS: We enrolled 1331 pregnant WLWH (mean age 28 years). At 12 months postpartum, 1140 (85.6%) women were retained in care, 96 women (7.2%) were lost-to-follow-up (LTFU) and 95 (7.1%) were discontinued from the study. In intention-to-treat analyses, the relative risk of being retained at 12-months postpartum was not significantly higher in the intervention arms versus the control arm. In time-to-event analysis, the cMM and text arm had significantly lower rates of LTFU (hazard ratio 0.44, p = 0.019). In per-protocol analysis, the relative risk of 12-month postpartum retention was 24-29% higher for women receiving at least 80% of the expected intervention compared to the control arm; text message only risk ratio (RR) 1.24 (95% confidence interval [CI] 1.16-1.32, p<0.001), cMM only RR 1.29 (95% CI 1.21-1.37, p<0.001) and cMM plus text RR 1.29 (1.21-1.37, p<0.001). Women LTFU were younger (p<0.001), less likely to be married (p<0.001) and more likely to be newly diagnosed with HIV during pregnancy (p<0.001). Self-reported ART adherence did not vary by study arm. CONCLUSIONS: Behavioural interventions using peer support and text messages did not appear to improve 12-month postpartum retention and adherence in intention-to-treat analyses. Higher levels of exposure to the interventions may be necessary to achieve the desired effects.

Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer.

BACKGROUND: The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients. METHODS: We conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model. RESULTS: Of 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210-495) among PWH and 356 cells/µL (IQR 260-470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1). CONCLUSIONS: There was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer.

Preferences of people living with HIV for differentiated care models in Kenya: A discrete choice experiment.

INTRODUCTION: To improve retention on HIV treatment in Africa, public health programs are promoting a family of innovations to service delivery-referred to as "differentiated service delivery" (DSD) models-which seek to better meet the needs of both systems and patients by reducing unnecessary encounters, expanding access, and incorporating peers and patients in patient care. Data on the relative desirability of different models to target populations, which is currently sparse, can help guide prioritization of specific models during scale-up. METHODS: We conducted a discrete choice experiment to assess patient preferences for various characteristics of treatment services. Clinically stable people living with HIV were recruited from an HIV clinic in Kisumu, Kenya. We selected seven attributes of DSD models drawn from literature review and previous qualitative work. We created a balanced and orthogonal design to identify main term effects. A total of ten choice tasks were solicited per respondent. We calculated relative utility (RU) for each attribute level, a numerical representation of the strength of patient preference. Data were analyzed using a Hierarchical Bayesian model via Sawtooth Software. RESULTS: One hundred and four respondents (37.5% men, 41.1 years mean age) preferred receiving care at a health facility, compared with home-delivery or a community meeting point (RU = 69.3, -16.2, and -53.1, respectively; p << 0.05); receiving those services from clinicians and pharmacists-as opposed to lay health workers or peers (RU = 21.5, 5.9, -24.5; p < 0.05); and preferred an individual support system over a group support system (RU = 15.0 and 4.2; p < 0.05). Likewise, patients strongly preferred longer intervals between both clinical reviews (RU = 40.1 and -50.7 for 6- and 1-month spacing, respectively; p < 0.05) and between ART collections (RU = 33.6 and -49.5 for 6- and1-month spacing, respectively; p < 0.05). CONCLUSION: Although health systems find community- and peer-based DSD models attractive, clinically stable patients expressed a preference for facility-based care as long as clinical visits were extended to biannual. These data suggest that multi-month scripting and fast-track models best align with patient preferences, an insight which can help prioritize use of different DSD models in the region.

Association between Primary Perioperative CEA Ratio, Tumor Site, and Overall Survival in Patients with Colorectal Cancer.

There are differences in the incidence, clinical presentation, molecular pathogenesis, and outcome of colorectal cancer (CRC) based on tumor location. Emerging research suggests that the perioperative carcinoembryonic antigen (CEA) ratio (post-op/pre-op CEA) is a prognostic factor for CRC patients. We aimed to determine the association between CEA ratio, tumor location, and overall survival (OS) among patients with CRC. We analyzed 427 patients who underwent resection for CRC at the University of Kansas Medical Center. After excluding those without pre- or post-operative CEA data, 207 patients were classified as either high (≥0.5) or low (<0.5) ratio. Primary outcomes were as follows: (1) OS stratified by CEA ratio; (2) OS stratified by tumor location; (3) OS stratified by tumor location among those with CEA elevation > 5 ng/mL at the time of recurrence. The Kaplan-Meier method was used to estimate survival rates. The median age was 62 years (inter-quartile range 51-71), 55% were male, 41% were smokers, 71% had left-sided tumors, the median pre-operative CEA was 3.1 ng/mL (inter-quartile range (IQR) 1.5-9.7), and 57% had a CEA ratio ≥0.5. The OS rates were 65.1% and 86.3% in patients with high versus low CEA ratios, respectively (log-rank p-value = 0.045). The OS rates were 64.4% and 77.3% in patients with right-sided vs. left-sided tumors, respectively (log-rank p-value = 0.5). Among patients with CEA levels greater than 5 at the time of recurrence, the OS rates were 42.9% and 43.4% in patients with right-sided vs. left-sided tumors, respectively (log-rank p-value = 0.7). There was a significantly higher survival among patients with low CEA ratios than among those with high CEA ratios. There was no difference in OS between left- versus right-sided tumors. Among patients with CEA elevation > 5 ng/mL at the time of recurrence, there was no difference in OS between left versus right-sided tumors. These findings warrant validation in a larger cohort as our sample size was limited.

Iterative Development of an mHealth Intervention to Support Antiretroviral Therapy Initiation and Adherence Among Female Sex Workers in Mombasa, Kenya.

Nurses have an integral role to play in achieving the 95-95-95 goals to stem the HIV epidemic. We used the Information-Motivation-Behavioral Skills (IMB) theoretical model to develop a nurse-delivered, mHealth intervention to support antiretroviral therapy adherence among female sex workers living with HIV in Mombasa, Kenya. Twenty-three purposively sampled female sex workers living with HIV participated in 5 focus group discussions to iteratively develop the message content as well as the format and structure of the nurse-delivered, text-based intervention. Focus group discussion interview guides were developed in accordance with the IMB model. Transcripts were analyzed according to IMB themes, and findings were used to develop the intervention. Information-oriented texts addressed concerns and misconceptions; motivation-oriented texts reinforced women's desires to feel healthy enough to engage in activities; and behavioral skills-oriented texts included strategies to remember medication doses. The nurse-delivered, theory-based, culturally tailored intervention to support medication adherence was evaluated.

Text messaging for maternal and infant retention in prevention of mother-to-child HIV transmission services: A pragmatic stepped-wedge cluster-randomized trial in Kenya.

BACKGROUND: Timely diagnosis of infant HIV infection is essential for antiretroviral therapy (ART) initiation. In a randomized controlled trial, we found the Texting Improves Testing (TextIT) intervention (a theory-based text messaging system) to be efficacious for improving infant HIV testing rates and maternal retention in prevention of mother-to-child HIV transmission (PMTCT) programs. Using an implementation science approach, we aimed to evaluate real-world effectiveness of the intervention. METHODS AND FINDINGS: In a pragmatic, cluster-randomized, stepped-wedge trial with 2 time periods of observation, we randomly allocated 10 clinics to begin implementing the intervention immediately and 10 clinics to begin implementing 6 months later. To approximate real-world conditions, inclusion criteria were broad. Women at clinics implementing the intervention received up to 14 text messages during pregnancy and after delivery and had the option to respond to text messages, call, or send inquiry text messages to a designated clinic phone. The primary outcomes were infant HIV testing and maternal retention in care during the first 8 weeks after delivery. We used modified Poisson regression with robust variance estimation to estimate the relative risk and 95% confidence intervals (CIs). Generalized estimating equations were applied on individual-level data to account for clustering by site. Between February 2015 and December 2016, 4,681 women were assessed for study participation, and 2,515 were included. Participant characteristics at enrollment did not differ by study arm. Overall median age was 27 years (interquartile range [IQR] 23-30), median gestational age was 30 weeks (IQR 28-34), 99% were receiving ART, and 87% who enrolled during intervention phases owned a phone. Of 2,326 infants analyzed, 1,466 of 1,613 (90.9%) in the intervention group and 609 of 713 (85.4%) in the control group met the primary outcome of HIV virologic testing performed before 8 weeks after birth (adjusted relative risk [aRR] 1.03; 95% CI 0.97-1.10; P = 0.3). Of 2,472 women analyzed, 1,548 of 1,725 (90%) in the intervention group and 571 of 747 (76%) in the control group met the primary outcome of retention in care during the first 8 weeks after delivery (aRR 1.12; 95% CI 0.97-1.30; P = 0.1). This study had two main limitations. Staff at all facilities were aware of ongoing observation, which may have contributed to increased rates of infant HIV testing and maternal retention in care at both intervention and control facilities, and programmatic initiatives to improve maternal and infant retention in care were ongoing at all facilities at the time of this study, which likely limited the ability to demonstrate effectiveness of the trial intervention. CONCLUSIONS: In this study, a larger proportion of infants in the intervention group received HIV testing compared with the control group, but the difference was small and not statistically significant. There was also a nonsignificant increase in maternal postpartum retention in the intervention periods. Despite the lack of a significant effect of the intervention, key lessons emerged, both for strengthening PMTCT and for implementation research in general. Perhaps most important, improving the implementation of usual care may have been sufficient to substantially improve infant HIV testing rates. TRIAL REGISTRATION: ClinicalTrials.gov Trial Number NCT02350140.

Acceptability of community-based mentor mothers to support HIV-positive pregnant women on antiretroviral treatment in western Kenya: a qualitative study.

BACKGROUND: Option B+ is a comprehensive antiretroviral treatment (ART) designed for HIV-infected pregnant/ postpartum women. However, barriers to implementing Option B+ and establishing long-term ART adherence while facilitating retention in prevention of mother to child transmission of HIV (PMTCT) services remain. Community-based mentor mothers (cMMs) who can provide home-based support for PMTCT services may address some of the barriers to successful adoption and retention in Option B+. Thus, we evaluated the acceptability of using cMMs as home-based support for PMTCT services. METHODS: Gender-matched in-depth interviews were conducted between September-November 2014 for HIV-infected pregnant/postpartum women and their male partners living in southwestern Kenya (n = 40); additionally, we conducted four focus groups involving 30 health workers (n = 70) within four health facilities. Audio-recordings were transcribed, translated, and then coded using a thematic analytical approach in which data were deductively and inductively coded with support from prior literature, identified themes within the interview guides, and emerging themes from the transcripts utilizing Dedoose software. RESULTS: Overall, the study results suggest high acceptability of cMMs among individual participants and health workers. Stigma reduction, improvement of utilization of health care services, as well as ART adherence were most frequently discussed potential benefits of cMMs. Participants pictured a cMM as someone acting as a role model and confidant, and who was over 30 years old. Many respondents raised concerns about breaches of confidentiality and inadvertent disclosure. Respondent suggestions to overcome these issues included the cMM working in different communities than where she lives and attending home-visits with no identifying clothing as an HIV-related health worker. CONCLUSIONS: The home-based cMM approach may be a beneficial and acceptable strategy for promoting ART adherence and retention within PMTCT services for pregnant/postpartum women living with HIV. Considering the risks of inadvertent disclosure of HIV-infected status and related negative consequences for pregnant/postpartum women living with HIV, similar cMM program designs may benefit from recognizing and addressing these risks. TRIAL REGISTRATION: The MOTIVATE! study was registered on July 7, 2015 at the ClinicalTrials.gov ( NCT02491177 ).

Adapting the HIV Infant Tracking System to Support Prevention of Mother-to-Child Transmission of HIV in Kenya: Protocol for an Intervention Development Pilot Study in Two Hospitals.

BACKGROUND: Despite progress to expand access to HIV testing and treatment during pregnancy in Kenya, gaps still remain in prevention of mother-to-child transmission of HIV (PMTCT) services. This study addresses the need for effective and scalable interventions to support women throughout the continuum of care for PMTCT services in low-resource settings. Our research team has successfully implemented the HIV Infant Tracking System (HITSystem), a Web-based, system-level intervention to improve early infant diagnosis (EID) outcomes. OBJECTIVE: This study will expand the scope of the HITSystem to address PMTCT services to bridge the gap between maternal and pediatric HIV services and improve outcomes. This paper describes the intervention development protocol to adapt and pilot an HITSystem version 2.0 to assess acceptability, feasibility, and preliminary PMTCT outcomes in Kenya. METHODS: This is a 3-year intervention development study to adapt the current HITSystem intervention to support a range of PMTCT outcomes including appointment attendance, antiretroviral therapy (ART) adherence, hospital deliveries, and integration of maternal and pediatric HIV services in low-resource settings. The study will be conducted in 3 phases. Phase 1 will elicit feedback from intervention users (patients and providers) to guide development and refinement of the new PMTCT components and inform optimal implementation. In Phase 2, we will design and develop the HITSystem 2.0 features to support key PMTCT outcomes guided by clinical content experts and findings from Phase 1. Phase 3 will assess complete PMTCT retention (before, during, and after delivery) using a matched randomized pilot study design in 2 hospitals over 18 months. A total of N=108 HIV-positive pregnant women (n=54 per site) will be enrolled and followed from their first PMTCT appointment until infant HIV DNA Polymerase Chain Reaction testing at the target age of 6 weeks (<7 weeks) postnatal. RESULTS: Funding for this study was received in August 2015, enrollment in Phase 1 began in March 2016, and completion of data collection is expected by May 2019. CONCLUSIONS: This protocol will extend, adapt, and pilot an HITSystem 2.0 version to improve attendance of PMTCT appointments, increase ART adherence and hospital-based deliveries, and prompt EID by 6 weeks postnatal. The HITSystem 2.0 aims to improve the integration of maternal and pediatric HIV services. TRIAL REGISTRATION: ClinicalTrials.gov NCT02726607; https://clinicaltrials.gov/ct2/show/NCT02726607 (Archived by WebCite at http://www.webcitation.org/78VraLrOb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13268.

Infant HIV testing at birth using point-of-care and conventional HIV DNA PCR: an implementation feasibility pilot study in Kenya.

BACKGROUND: Infant HIV diagnosis by HIV DNA polymerase chain reaction (PCR) testing at the standard 6 weeks of age is often late to mitigate the mortality peak that occurs in HIV positive infants' first 2-3 months of life. Kenya recently revised their early infant diagnosis (EID) guidelines to include HIV DNA PCR testing at birth (pilot only), 6 weeks, 6 months, and 12 months postnatal and a final 18-month antibody test. The World Health Organization (WHO) approved point-of-care (POC) diagnostic platforms for infant HIV testing in resource-limited countries that could simplify logistics and expedite infant diagnosis. Sustainable scale-up and optimal utility in Kenya and other high-prevalence countries depend on robust implementation studies in diverse clinical settings. METHODS: We will pilot the implementation of birth testing by HIV DNA PCR, as well as two POC testing systems (Xpert HIV-1 Qual [Xpert] and Alere q HIV-1/2 Detect [Alere q]), on specimens collected from Kenyan infants at birth (0 to 2 weeks) and 6 weeks (4 to < 24 weeks) postnatal. The formative phase will inform optimal implementation of birth testing and two POC testing technologies. Qualitative interviews with stakeholders (providers, parents of HIV-exposed infants, and community members) will assess attitudes, barriers, and recommendations to optimize implementation at their respective sites. A non-blinded pilot study at four Kenyan hospitals (n = 2 Xpert, n = 2 Alere q platforms) will evaluate infant HIV POC testing compared with standard of care HIV DNA PCR testing in both the birth and 6-week windows. Objectives of the pilot are to assess uptake, efficiency, quality, implementation variables, user experiences of birth testing with both POC testing systems or with HIV DNA PCR, and costs. DISCUSSION: This study will generate data on the clinical impact and feasibility of adding HIV testing at birth utilizing POC and traditional PCR HIV testing strategies in resource-limited settings. Data from this pilot will inform the optimal implementation of Kenya's birth testing guidelines and of POC testing systems for the improvement of EID outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03435887. Registered 26 February 2018.

Evaluation of the HIV Infant Tracking System (HITSystem) to optimise quality and efficiency of early infant diagnosis: a cluster-randomised trial in Kenya.

BACKGROUND: The HIV Infant Tracking System (HITSystem) is a web-based intervention linking providers of early infant diagnosis, laboratory technicians, and mothers and infants to improve outcomes for HIV-exposed infants. We aimed to evaluate the efficacy of the HITSystem on key outcomes of early infant diagnosis. METHODS: We did a cluster-randomised trial at six hospitals in Kenya, which were matched on geographic region, resource level, and volume of patients (high, medium, and low). We randomly allocated hospitals within a matched pair to either the HITSystem (intervention; n=3) or standard of care (control; n=3). A random number generator was used to assign clusters. Investigators were unaware of the randomisation process. Eligible participants were mothers aged 18 years or older with an infant younger than 24 weeks presenting for their first early infant diagnosis appointment. The primary outcome was complete early infant diagnosis retention, which was defined as receipt of all indicated age-specific interventions until 18 months post partum (for HIV-negative infants) or antiretroviral therapy initiation (for HIV-positive infants). Analysis was per protocol in all randomised pairs judged eligible, excluding infant deaths and those who moved or were transferred to another health facility. Modified intention-to-treat sensitivity analyses judged all infant deaths and transfers as incomplete early infant diagnosis retention. Separate multivariable logistic regression analyses were done with intervention group, hospital volume, and significant covariates as fixed effects. This trial is registered with ClinicalTrials.gov, number NCT02072603; the trial has been completed. FINDINGS: Between Feb 16, 2014, and Dec 31, 2015, 895 mother-infant pairs were enrolled. Of these, 87 were judged ineligible for analysis, 26 infants died, and 92 pairs moved or were transferred to another health facility. Thus, data from 690 mother-infant pairs were analysed, of whom 392 were allocated to the HITSystem and 298 to standard of care. Mother-infant pairs were followed up to Sept 30, 2017. Infants diagnosed as HIV-positive were followed up for a median of 2·1 months (IQR 1·6-4·8) and HIV-negative infants were followed up for a median of 17·0 months (IQR 16·6-17·6). Infants enrolled in the HITSystem were significantly more likely to receive complete early infant diagnosis services compared with those assigned standard of care (334 of 392 [85%] vs 180 of 298 [60%]; adjusted odds ratio [OR] 3·7, 95% CI 2·5-5·5; p<0·0001). No intervention effect was recorded at high-volume hospitals, but strong effects were seen at medium-volume and low-volume hospitals. Modified intention-to-treat analyses for complete early infant diagnosis were also significant (334 of 474 [70%] vs 180 of 334 [54%]; adjusted OR 2·0, 95% CI 1·4-2·7; p<0·0001). No adverse events related to study participation were reported. INTERPRETATION: The HITSystem intervention is effective and feasible to implement in low-resource settings. The HITSystem algorithms have been modified to include HIV testing at birth, and an adapted HITSystem 2.0 version is supporting HIV-positive pregnant women to prevent perinatal transmission and optimise maternal and infant outcomes. FUNDING: National Institute of Child Health and Human Development.

Maximizing adherence and retention for women living with HIV and their infants in Kenya (MOTIVATE! study): study protocol for a randomized controlled trial.

BACKGROUND: Successful completion and retention throughout the multi-step cascade of prevention of mother-to-child HIV transmission (PMTCT) remains difficult to achieve. The Mother and Infant Visit Adherence and Treatment Engagement study aims to evaluate the effect of mobile text messaging, community-based mentor mothers (cMMs), or both on increasing antiretroviral therapy (ART) adherence, retention in HIV care, maternal viral load suppression, and mother-to-child HIV transmission for mother-infant pairs receiving lifelong ART. METHODS/DESIGN: This study is a cluster randomized, 2 × 2 factorial, controlled trial. The trial will be undertaken in the western Kenyan counties of Migori, Kisumu, and Homa Bay. Study sites will be randomized into one of four groups: six sites will implement both text messaging and cMM, six sites will implement cMM only, six sites will implement text messaging only, and six sites will implement the existing standard of care. The primary analysis will be based on the intention-to-treat principle and will compare maternal ART adherence and maternal retention in care. DISCUSSION: This study will determine the impact of long-term (up to 12 months postpartum) text messaging and cMMs on retention in and adherence to ART among pregnant and breastfeeding women living with HIV in Kenya. It will address key gaps in our understanding of what interventions may successfully promote long-term retention in the PMTCT cascade of care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02491177 . Registered on 11 March 2015.

Participation in a clinical trial of a text messaging intervention is associated with increased infant HIV testing: A parallel-cohort randomized controlled trial.

OBJECTIVE: Text messages significantly improve uptake of infant HIV testing in clinical trial contexts. Women who were excluded from a randomized trial in Kenya were followed to create a comparison between women who were enrolled and did not receive the study SMS intervention and women who were screened but not enrolled. DESIGN: Parallel-cohort randomized controlled trial analysis. METHODS: We compared time to infant HIV testing between women in three groups: the Trial SMS group, the Trial Control group, and the Comparison Cohort comprised of women who were screened but not enrolled. RESULTS: Of the 1,115 women screened, 388 (35%) were eligible for trial enrollment, and were randomized to receive either intervention text messages (Trial SMS; N = 195) or continue usual care (Trial Control; N = 193). Among 727 women not enrolled in the study (Comparison Cohort), we obtained infant HIV testing data from clinic records for 510 (70%). The cumulative probability of infant HIV testing was highest in the Trial SMS group (92.0%; 95% CI 87.5-95.3), followed by the Trial Control group (85.1%; 95% CI 79.5-89.8), and lowest among women in the Comparison Cohort (43.4%; 95% CI 39.2-47.8). CONCLUSIONS: Both the Trial SMS group and the Trial Control group were significantly more likely to have their infants tested for HIV compared to the Comparison Cohort, providing evidence of a "clinical trial effect." This analysis suggests that SMS interventions should be implemented as an adjunct to consistent and engaged delivery of basic health services.

From 'half-dead' to being 'free': resistance to HIV stigma, self-disclosure and support for PMTCT/HIV care among couples living with HIV in Kenya.

In sub-Saharan Africa, self-disclosure of HIV-positive status may be a pivotal action for improving access to prevention of mother-to-child transmission services. However, understanding of HIV stigma and disclosure, and their effects on demand for care remains incomplete - particularly in the current context of new antiretroviral therapy guidelines. The purpose of this study was to explore these issues among self-disclosed couples living in southwest Kenya. We conducted 38 in-depth interviews with HIV-positive pregnant or postpartum women and their male partners. Of the 19 couples, 10 were HIV seroconcordant and 9 were serodiscordant. The textual analysis showed that HIV stigma continues to restrict full participation in community life and limit access to care by promoting fear, isolation and self-censorship. Against this backdrop, however, participants' narratives revealed varying forms and degrees of resistance to HIV stigma, which appeared to both produce and emerge from acts of self-disclosure. Such disclosure enabled participants to overcome fears and gain critical support for engaging in HIV care while further resisting HIV stigma. These findings suggest that programme interventions designed explicitly to stimulate and support processes of HIV stigma resistance and safe self-disclosure may be key to improving demand for and retention in HIV services.

Specification of implementation interventions to address the cascade of HIV care and treatment in resource-limited settings: a systematic review.

BACKGROUND: The global response to HIV has started over 18 million persons on life-saving antiretroviral therapy (ART)-the vast majority in low- and middle-income countries (LMIC)-yet substantial gaps remain: up to 40% of persons living with HIV (PLHIV) know their status, while another 30% of those who enter care are inadequately retained after starting treatment. Identifying strategies to enhance use of treatment is urgently needed, but the conceptualization and specification of implementation interventions is not always complete. We sought to assess the completeness of intervention reporting in research to advance uptake of treatment for HIV globally. METHODS: We carried out a systematic review to identify interventions targeting the adult HIV care cascade in LMIC dating from 1990 to 2017. We identified components of each intervention as "intervention types" to decompose interventions into common components. We grouped "intervention types" into a smaller number of more general "implementation approaches" to aid summarization. We assessed the reporting of six intervention characteristics adapted from the implementation science literature: the actor, action, action dose, action temporality, action target, and behavioral target in each study. FINDINGS: In 157 unique studies, we identified 34 intervention "types," which were empirically grouped into six generally understandable "approaches." Overall, 42% of interventions defined the actor, 64% reported the action, 41% specified the intervention "dose," 43% reported action temporality, 61% defined the action target, and 69% reported a target behavior. Average completeness of reporting varied across approaches from a low of 50% to a high of 72%. Dimensions that involved conceptualization of the practices themselves (e.g., actor, dose, temporality) were in general less well specified than consequences (e.g., action target and behavioral target). IMPLICATIONS: The conceptualization and Reporting of implementation interventions to advance treatment for HIV in LMIC is not always complete. Dissemination of standards for reporting intervention characteristics can potentially promote transparency, reproducibility, and scientific accumulation in the area of implementation science to address HIV in low- and middle-income countries.

The effect of facility-based antiretroviral therapy programs on outpatient services in Kenya and Uganda.

BACKGROUND: Considerable debate exists concerning the effects of antiretroviral therapy (ART) service scale-up on non-HIV services and overall health system performance in sub-Saharan Africa. In this study, we examined whether ART services affected trends in non-ART outpatient department (OPD) visits in Kenya and Uganda. METHODS: Using a nationally representative sample of health facilities in Kenya and Uganda, we estimated the effect of ART programs on OPD visits from 2007 to 2012. We modeled the annual percent change in non-ART OPD visits using hierarchical mixed-effects linear regressions, controlling for a range of facility characteristics. We used four different constructs of ART services to capture the different ways in which the presence, growth, overall, and relative size of ART programs may affect non-ART OPD services. RESULTS: Our final sample included 321 health facilities (140 in Kenya and 181 in Uganda). On average, OPD and ART visits increased steadily in Kenya and Uganda between 2007 and 2012. For facilities where ART services were not offered, the average annual increase in OPD visits was 4·2% in Kenya and 13·5% in Uganda. Among facilities that provided ART services, we found average annual OPD volume increases of 7·2% in Kenya and 5·6% in Uganda, with simultaneous annual increases of 13·7% and 12·5% in ART volumes. We did not find a statistically significant relationship between annual changes in OPD services and the presence, growth, overall, or relative size of ART services. However, in a subgroup analysis, we found that Ugandan hospitals that offered ART services had statistically significantly less growth in OPD visits than Ugandan hospitals that did not provide ART services. CONCLUSIONS: Our findings suggest that ART services in Kenya and Uganda did not have a statistically significant deleterious effects on OPD services between 2007 and 2012, although subgroup analyses indicate variation by facility type. Our findings are encouraging, particularly given recent recommendations for universal access to ART, demonstrating that expanding ART services is not inherently linked to declines in other health services in sub-Saharan Africa.