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.

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 ).

HIV status disclosure patterns and male partner reactions among pregnant women with HIV on lifelong ART in Western Kenya.

Disclosure of HIV status to sexual partners in the context of prevention of mother-to-child transmission (PMTCT) may contribute to improved PMTCT outcomes. We administered a questionnaire to 200 women with HIV enrolled in a PMTCT study during pregnancy at 12 months after birth in Western Kenya between May-September 2017. Descriptive analysis of disclosure patterns and multivariate analysis of factors associated with male partner reactions is presented. Among 180 (90%) women who reported having a male partner, 95.5% reported disclosing their HIV status to that partner. The majority of women (82.8%) reported disclosure occurred within one year of their diagnosis, with 62.7% occurring within one week. The most common forms of disclosure were: self-disclosure (55.4%), during couple's HIV testing and counseling (CHTC) (31.5%), or at an antenatal care visit (7.7%). Most women (87.5%) reported that male partner reactions to their HIV status disclosure were positive. Those with negative reactions reported their partners were confused, annoyed, or threatened to leave, however there were no reports of intimate partner violence (IPV) or break ups. Disclosure via CHTC was associated with a positive male partner reaction compared to self-disclosure (adjusted OR (aOR) 20.2, 95% Confidence Interval (CI) 1.8-221.4). Those in concordant HIV status partnerships were more likely to have a positive reaction (aOR. 6.7, 95% CI 1.7-26.6). Women experiencing frequent verbal IPV were less likely to report a positive response (aOR 0.21, 95%CI 0.1-0.8). Most postpartum women with HIV in this cohort had disclosed to their male partners early after diagnosis and experienced a positive reaction. However, a minority had still not disclosed by 12 months after the birth and some experienced negative reactions to disclosure. The form of status disclosure and impact of intimate partner violence should be given greater attention within the context of PMTCT.

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.

"Closing the Gap": Provider Recommendations for Implementing Birth Point of Care HIV Testing.

Delays in traditional HIV DNA PCR testing for early infant diagnosis (EID) at 6 weeks of age result in late antiretroviral treatment (ART). Birth point of care (POC) testing is an emerging strategy with the potential to streamline EID services. We elicited providers' recommendations for introducing birth POC testing to guide strategies in Kenya and similar settings. We conducted formative interviews with 26 EID providers from four Kenyan hospitals prior to POC implementation. Providers discussed the need for comprehensive training, covering both EID and POC-specific topics for all key personnel. Providers highlighted equipment considerations, such as protocols for maintenance and safe storage. Providers emphasized the need for maternal counseling to ensure patient acceptance and most agreed that specimen collection for birth POC testing should occur in the maternity department and supported a multidisciplinary approach. Though most providers supported ART initiation based on a positive birth POC result, a few expressed concerns with result validity. To maximize implementation success, provider training, equipment security, maternal counseling, and logistics of testing must be planned and communicated to providers.

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 ).

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.

The Causal Effect of Tracing by Peer Health Workers on Return to Clinic Among Patients Who Were Lost to Follow-up From Antiretroviral Therapy in Eastern Africa: A "Natural Experiment" Arising From Surveillance of Lost Patients.

BACKGROUND.: The effect of tracing human immunodeficiency virus (HIV)-infected patients who are lost to follow-up (LTFU) on reengagement has not been rigorously assessed. We carried out an ex post analysis of a surveillance study in which LTFU patients were randomly selected for tracing to identify the effect of tracing on reengagement. METHODS.: We evaluated HIV-infected adults on antiretroviral therapy who were LTFU (>90 days late for last visit) at 14 clinics in Uganda, Kenya, and Tanzania. A random sample of LTFU patients was selected for tracing by peer health workers. We assessed the effect of selection for tracing using Kaplan-Meier estimates of reengagement among all patients as well as the subset of LTFU patients who were alive, contacted in person by the tracer, and out of care. RESULTS.: Of 5781 eligible patients, 991 (17%) were randomly selected for tracing. One year after selection for tracing, 13.3% (95% confidence interval [CI], 11.1%-15.3%) of those selected for tracing returned compared with 10.0% (95% CI, 9.1%-10.8%) of those not randomly selected, an adjusted risk difference of 3.0% (95% CI, .7%-5.3%). Among patients found to be alive, personally contacted, and out of care, tracing increased the absolute probability of return at 1 year by 22% (95% CI, 7.1%-36.2%). The effect of tracing on rate of return to clinic decayed with a half-life of 7.0 days after tracing (95% CI, 2.6 %-12.9%). CONCLUSIONS.: Tracing interventions increase reengagement, but developing methods for targeting LTFU patients most likely to benefit can make this practice more efficient.

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.

Retention in Care and Patient-Reported Reasons for Undocumented Transfer or Stopping Care Among HIV-Infected Patients on Antiretroviral Therapy in Eastern Africa: Application of a Sampling-Based Approach.

BACKGROUND: Improving the implementation of the global response to human immunodeficiency virus requires understanding retention after starting antiretroviral therapy (ART), but loss to follow-up undermines assessment of the magnitude of and reasons for stopping care. METHODS: We evaluated adults starting ART over 2.5 years in 14 clinics in Uganda, Tanzania, and Kenya. We traced a random sample of patients lost to follow-up and incorporated updated information in weighted competing risks estimates of retention. Reasons for nonreturn were surveyed. RESULTS: Among 18 081 patients, 3150 (18%) were lost to follow-up and 579 (18%) were traced. Of 497 (86%) with ascertained vital status, 340 (69%) were alive and, in 278 (82%) cases, updated care status was obtained. Among all patients initiating ART, weighted estimates incorporating tracing outcomes found that 2 years after ART, 69% were in care at their original clinic, 14% transferred (4% official and 10% unofficial), 6% were alive but out of care, 6% died in care (<60 days after last visit), and 6% died out of care (≥ 60 days after last visit). Among lost patients found in care elsewhere, structural barriers (eg, transportation) were most prevalent (65%), followed by clinic-based (eg, waiting times) (33%) and psychosocial (eg, stigma) (27%). Among patients not in care elsewhere, psychosocial barriers were most prevalent (76%), followed by structural (51%) and clinic based (15%). CONCLUSIONS: Accounting for outcomes among those lost to follow-up yields a more informative assessment of retention. Structural barriers contribute most to silent transfers, whereas psychological and social barriers tend to result in longer-term care discontinuation.

The potential to expand antiretroviral therapy by improving health facility efficiency: evidence from Kenya, Uganda, and Zambia.

BACKGROUND: Since 2000, international funding for HIV has supported scaling up antiretroviral therapy (ART) in sub-Saharan Africa. However, such funding has stagnated for years, threatening the sustainability and reach of ART programs amid efforts to achieve universal treatment. Improving health system efficiencies, particularly at the facility level, is an increasingly critical avenue for extending limited resources for ART; nevertheless, the potential impact of increased facility efficiency on ART capacity remains largely unknown. Through the present study, we sought to quantify facility-level technical efficiency across countries, assess potential determinants of efficiency, and predict the potential for additional ART expansion. METHODS: Using nationally-representative facility datasets from Kenya, Uganda and Zambia, and measures adjusting for structural quality, we estimated facility-level technical efficiency using an ensemble approach that combined restricted versions of Data Envelopment Analysis and Stochastic Distance Function. We then conducted a series of bivariate and multivariate regression analyses to evaluate possible determinants of higher or lower technical efficiency. Finally, we predicted the potential for ART expansion across efficiency improvement scenarios, estimating how many additional ART visits could be accommodated if facilities with low efficiency thresholds reached those levels of efficiency. RESULTS: In each country, national averages of efficiency fell below 50 % and facility-level efficiency markedly varied. Among facilities providing ART, average efficiency scores spanned from 50 % (95 % uncertainty interval (UI), 48-62 %) in Uganda to 59 % (95 % UI, 53-67 %) in Zambia. Of the facility determinants analyzed, few were consistently associated with higher or lower technical efficiency scores, suggesting that other factors may be more strongly related to facility-level efficiency. Based on observed facility resources and an efficiency improvement scenario where all facilities providing ART reached 80 % efficiency, we predicted a 33 % potential increase in ART visits in Kenya, 62 % in Uganda, and 33 % in Zambia. Given observed resources in facilities offering ART, we estimated that 459,000 new ART patients could be seen if facilities in these countries reached 80 % efficiency, equating to a 40 % increase in new patients. CONCLUSIONS: Health facilities in Kenya, Uganda, and Zambia could notably expand ART services if the efficiency with which they operate increased. Improving how facility resources are used, and not simply increasing their quantity, has the potential to substantially elevate the impact of global health investments and reduce treatment gaps for people living with HIV.

Understanding Sustained Retention in HIV/AIDS Care and Treatment: a Synthetic Review.

Sustained retention represents an enduring and evolving challenge to HIV treatment programs in Africa. We present a theoretical framework for sustained retention borrowing from ecologic principles of sustainability and dynamic adaptation. We posit that sustained retention from the patient perspective is dependent on three foundational principles: (1) patient activation: the acceptance, prioritization, literacy, and skills to manage a chronic disease condition, (2) social normalization: the engagement of a social network and harnessing social capital to support care and treatment, and (3) livelihood routinization: the integration of care and treatment activities into livelihood priorities that may change over time. Using this framework, we highlight barriers specific to sustained retention and review interventions addressing long-term, sustained retention in HIV care with a focus on Sub-Saharan Africa.

Experiences and perceptions of conditional cash incentive provision and cessation among people with HIV for care engagement: A qualitative study.

Background: Consistent engagement in HIV treatment is needed for healthy outcomes, yet substantial loss-to-follow up persists, leading to increased morbidity, mortality and onward transmission risk. Although conditional cash transfers (CCTs) address structural barriers, recent findings suggest that incentive effects are time-limited, with cessation resulting in HIV care engagement deterioration. We explored incentive experiences, perceptions, and effects after cessation to investigate potential mechanisms of this observation. Methods: This qualitative study was nested within a larger trial, AdaPT-R (NCT02338739), focused on HIV care engagement in western Kenya. A subset of participants were purposively sampled from AdaPT-R participants: adults with HIV who had recently started ART, received CCTs for one year, completed one year of follow-up without missing a clinic visit, and were randomized to either continue or discontinue CCTs for one more year of follow-up. In-depth interviews were conducted by an experienced qualitative researcher using a semi-structed guide within a month of randomization. Interviews were conducted in the participants' preferred language (Dholuo, Kiswahili, English). Data on patient characteristics, randomization dates, and clinic visit dates to determine care lapses were extracted from the AdaPT-R database. A codebook was developed deductively based on the guide and inductively refined based on initial transcripts. Transcripts were coded using Dedoose software, and thematic saturation was identified. Results: Of 38 participants, 15 (39%) continued receiving incentives, while 23 (61%) were discontinued from receiving incentives. Half were female (N = 19), median age was 30 years (range: 19-48), and about three-quarters were married or living with partners. Both groups expressed high intrinsic motivation to engage in care, prioritized clinic attendance regardless of CCTs and felt the incentives expanded their decision-making options. Despite high motivation, some participants reported that cessation of the CCTs affected their ability to access care, especially those with constrained financial situations. Participants also expressed concerns that incentives might foster dependency. Conclusions: This study helps us better understand the durability of financial incentives for HIV care engagement, including when incentives end. Together with the quantitative findings in the parent AdaPT-R study, these results support the idea that careful consideration be exercised when implementing incentives for sustainable engagement effects.

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.

Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer.

Purpose: Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. Materials and Methods: This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL. Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4. Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. Significance: Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME's effect on survival and chemotherapy tolerability.

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.).

A youth-centred approach to improving engagement in HIV services: human-centred design methods and outcomes in a research trial in Kisumu County, Kenya.

IntroductionInnovative interventions are needed to improve HIV outcomes among adolescents and young adults (AYAs) living with HIV. Engaging AYAs in intervention development could increase effectiveness and youth acceptance, yet research is limited. We applied human-centred design (HCD) to refine adherence-support interventions pretrial and assessed HCD workshop acceptability. METHODS: We applied an iterative, four-phased HCD process in Kenya that included: (1) systematic review of extant knowledge, (2) prioritisation of design challenges, (3) a co-creation workshop and (4) translation tables to pair insights with trial intervention adaptations. The co-creation workshop was co-led by youth facilitators employing participatory activities to inform intervention adaptations. Iterative data analysis included rapid thematic analysis of visualised workshop outputs and notes using affinity mapping and dialogue to identify key themes. We conducted a survey to assess workshop acceptability among participants. RESULTS: Twenty-two participants engaged in the 4-day workshop. Co-creation activities yielded recommendations for improving planned interventions (eg, message frequency and content; strategies to engage hard-to-reach participants), critical principles to employ across interventions (eg, personalisation, AYA empowerment) and identification of unanticipated AYA HIV treatment priorities (eg, drug holidays, transition from adolescent to adult services). We revised intervention content, peer navigator training materials and study inclusion criteria in response to findings. The youth-led HCD workshop was highly acceptable to participants. CONCLUSIONS: Research employing HCD among youth can improve interventions preimplementation through empathy, youth-led inquiry and real-time problem solving. Peer navigation may be most influential in improving retention when engagement with young people is based on mutual trust, respect, privacy and extends beyond HIV-specific support. Identifying opportunities for personalisation and adaptation within intervention delivery is important for AYAs. Patient engagement interventions that target young people should prioritise improved transition between youth and adult services, youth HIV status disclosure, AYA empowerment and healthcare worker responsiveness in interactions and episodic adherence interruptions.

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.

A Systematic Review of Immune Checkpoint Inhibitors in Non-Clear-Cell Renal Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as active therapies in the management of advanced RCC. While multiple studies have shown clinical activity of ICIs in clear cell histologies, the evidence to support their use in non-clear cell (ncc) subtypes is based on smaller prospective trials and retrospective analyses. OBJECTIVE: The objective of this review is to summarize the clinical outcomes of ICI-based therapies in ncc-subtypes and in tumors with sarcomatoid/rhabdoid features. METHODS: We performed a systematic literature search using PubMed, Google Scholar and ASCO databases. The keywords "renal cell cancer" and "immune checkpoint inhibitors" and equivalents were used and all original publications between July 2016 and July 2021 were included. RESULTS: We included a total of 14 publications, including two clinical trials and 12 case series. The most frequent histologies were papillary (up to 75-100%), unclassified (up to 34%) and chromophobe (up to 28%). ICI monotherapy showed some activity in both 1st and 2nd line with response rates up to 27%. ICI combination regimens yielded better activity than ICI monotherapy but, overall, a heterogeneous efficacy was noted across histologies. Overall, outcomes of ICIs were superior in tumors with sarcomatoid/rhabdoid features. CONCLUSION: The observed activity of ICI-based therapies was heterogeneous. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.