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A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART. [ABSTRACT FROM AUTHOR]

The use of holding regimens for people living with HIV (PLWH) without effective antiretroviral options can have effects on outcomes and future treatment options. We aimed to investigate the use of holding regimens for PLWH in Asian countries. Data from adults enrolled in routine HIV care in IeDEA Asia-Pacific cohorts were included. Individuals were considered to be on holding regimen if they had been on combination antiretroviral therapy for at least 6 months, had two confirmed viral loads (VL) ≥1000 copies/mL, and had remained on the same medications for at least 6 months. Survival time was analyzed using Fine and Gray's competing risk regression. Factors associated with CD4 changes and VL <1000 copies/mL were analyzed using linear regression and logistic regression, respectively. A total of 425 PLWH (72.9% male; 45.2% high-income and 54.8% low-to-middle-income country) met criteria for being on a holding regimen. From high-income countries, 63.0% were on protease inhibitors (PIs); from low-to-middle-income countries, 58.4% were on non-nucleoside reverse transcriptase inhibitors (NNRTIs); overall, 4.5% were on integrase inhibitors. The combination of lamivudine, zidovudine, and efavirenz was the most commonly used single regimen (n = 46, 10.8%), followed by lamivudine, zidovudine, and nevirapine (n = 37, 8.7%). Forty-one PLWH (9.7%) died during follow-up (mortality rate 2.0 per 100 person-years). Age >50 years compared to age 31–40 years (sub-hazard ratio [SHR] 3.29, 95% CI 1.45–7.43, p = 0.004), and VL ≥1000 copies/ml compared to VL <1000 copies/mL (SHR, 2.14, 95% CI 1.08–4.25, p = 0.029) were associated with increased mortality, while higher CD4 counts were protective. In our Asia regional cohort, there was a diversity of holding regimens, and the patterns of PI vs. NNRTI use differed by country income levels. Considering the high mortality rate of PLWH with holding regimen, efforts to extend accessibility to additional antiretroviral options are needed in our region. [ABSTRACT FROM AUTHOR]

Objectives: We investigated weight changes following antiretroviral therapy (ART) initiation, the development of metabolic syndrome (MetS) and its association with all‐cause mortality among Asian adults living with HIV. Methods: Participants enrolled in a regional Asian HIV‐infected cohort with weight and height measurements at ART initiation were eligible for inclusion in the analysis. Factors associated with weight changes and incident MetS (according to the International Diabetic Federation (IDF) definition) were analysed using linear mixed models and Cox regression, respectively. Competing‐risk regression models were used to investigate the association of MetS with all‐cause mortality. Results: Among 4931 people living with HIV (PLWH), 66% were male. At ART initiation, the median age was 34 [interquartile range (IQR) 29–41] years, and the median (IQR) weight and body mass index (BMI) were 55 (48–63) kg and 20.5 (18.4–22.9) kg/m2, respectively. At 1, 2 and 3 years of ART, overall mean (± standard deviation) weight gain was 2.2 (±5.3), 3.0 (±6.2) and 3.7 (±6.5) kg, respectively. Participants with baseline CD4 count ≤ 200 cells/µL [weight difference (diff) = 2.2 kg; 95% confidence interval (CI) 1.9–2.5 kg] and baseline HIV RNA ≥ 100 000 HIV‐1 RNA copies/mL (diff = 0.6 kg; 95% CI 0.2–1.0 kg), and those starting with integrase strand transfer inhibitor (INSTI)‐based ART (diff = 2.1 kg; 95% CI 0.7–3.5 kg vs. nonnucleoside reverse transcriptase inhibitors) had greater weight gain. After exclusion of those with abnormal baseline levels of MetS components, 295/3503 had incident MetS [1.18 (95% CI 1.05–1.32)/100 person‐years (PY)]. The mortality rate was 0.7 (95% CI 0.6–0.8)/100 PY. MetS was not significantly associated with all‐cause mortality in the adjusted model (P = 0.236). Conclusions: Weight gain after ART initiation was significantly higher among those initiating ART with lower CD4 count, higher HIV RNA and an INSTI‐based regimen after controlling for baseline BMI. Greater efforts to identify and manage MetS among PLWH are needed. [ABSTRACT FROM AUTHOR]

Missed clinic visits can lead to poorer treatment outcomes in HIV-infected patients. Suboptimal antiretroviral therapy (ART) adherence has been linked to subsequent missed visits. Knowing the determinants of missed visits in Asian patients will allow for appropriate counselling and intervention strategies to ensure continuous engagement in care. A missed visit was defined as having no assessments within six months. Repeated measures logistic regression was used to analyse factors associated with missed visits. A total of 7100 patients were included from 12 countries in Asia with 2676 (37.7%) having at least one missed visit. Patients with early suboptimal self-reported adherence <95% were more likely to have a missed visit compared to those with adherence ≥95% (OR = 2.55, 95% CI(1.81-3.61)). Other factors associated with having a missed visit were homosexual (OR = 1.45, 95%CI(1.27-1.66)) and other modes of HIV exposure (OR = 1.48, 95%CI(1.27-1.74)) compared to heterosexual exposure; using PI-based (OR = 1.33, 95%CI(1.15-1.53) and other ART combinations (OR = 1.79, 95%CI(1.39-2.32)) compared to NRTI+NNRTI combinations; and being hepatitis C co-infected (OR = 1.27, 95%CI(1.06-1.52)). Patients aged >30 years (31-40 years OR = 0.81, 95%CI(0.73-0.89); 41-50 years OR = 0.73, 95%CI(0.64-0.83); and >50 years OR = 0.77, 95%CI(0.64-0.93)); female sex (OR = 0.81, 95%CI(0.72-0.90)); and being from upper middle (OR = 0.78, 95%CI(0.70-0.80)) or high-income countries (OR = 0.42, 95%CI(0.35-0.51)), were less likely to have missed visits. Almost 40% of our patients had a missed clinic visit. Early ART adherence was an indicator of subsequent clinic visits. Intensive counselling and adherence support should be provided at ART initiation in order to optimise long-term clinic attendance and maximise treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: HIV continues to have a disproportionate impact on specific populations in Malaysia, particularly men who have sex with men (MSM). HIV self-testing (HIVST) is a strategy that has been shown to scale up HIV testing rates. However, it faces shortcomings because of concerns about self-efficacy, result interpretation, and lack of counseling and linkage to care. This underscores the need for an innovative approach that integrates HIVST with timely counseling, expert guidance, and referrals to enhance engagement in relevant HIV prevention or treatment., Objective: This study aims to describe the protocol used in developing and testing a web-based platform (ie, CINTAI) providing an HIVST kit and real-time e-counseling to support online-to-offline linkage to HIV care services for MSM in Malaysia., Methods: The methods are reported according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guidelines. In phase I, we will adapt existing HIVST web-based platforms to create a new online-to-offline HIVST and counseling platform called "CINTAI" for Malaysian MSM. In phase II, we will use a type 1 hybrid implementation trial design to determine the feasibility, acceptability, and preliminary efficacy of "CINTAI" compared with treatment as usual among Malaysian MSM, with assessments conducted over 6 months. Multilevel implementation factors will also be collected to guide future adoption and scale-up. We will enroll 78 MSM in the pilot randomized controlled trial. Baseline characteristics will be tested for homogeneity between groups using appropriate statistical tests. A generalized linear mixed model with random subject effects will account for within-subject correlation. Treatment assignment, time, interaction, and confounders will be included. The proportion of MSM tested for HIV over 6 months and other outcomes (pre-exposure prophylaxis for HIV or antiretroviral therapy linkage, HIV risk behaviors, and chemsex harm reduction) will be compared using linear contrasts., Results: We completed phase I of the proposed study in April 2024 and started phase II in May 2024, with 15 participants recruited (7 in the CINTAI and 8 in the treatment-as-usual groups). On the basis of a series of formative works completed during phase I, we developed a fully functional, web-based platform that provides a digital platform for MSM in Malaysia to order HIVST kits for free and to receive HIV counseling, followed by offline linkage to HIV prevention services (if HIV negative) or HIV treatment services (if HIV positive)., Conclusions: Despite being at high risk for HIV transmission, MSM in Malaysia have alarmingly low testing and linkage to HIV care services, prompting the need for innovative approaches to support HIV prevention efforts. If found to be feasible and acceptable, CINTAI can be easily adapted for a range of health outcomes and health care delivery services for MSM, including adaptation to other low- and middle-income countries., International Registered Report Identifier (irrid): DERR1-10.2196/60962., (©Antoine Khati, Jeffrey A Wickersham, Kamal Gautam, Kiran Paudel, Panyaphon Phiphatkhunarnon, Sin How Lim, Kirthana Puniamurthy, Frederick L Altice, Nittaya Phanuphak, Iskandar Azwa, Roman Shrestha. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 23.10.2024.)

Background: Globally, transgender women have been disproportionately affected by the HIV epidemic, including in Malaysia, where an estimated 11% of transgender women are living with HIV. Available interventions designed specifically to meet transgender women's needs for HIV prevention are limited. Mobile health, particularly smartphone mobile apps, is an innovative and cost-effective strategy for reaching transgender women and delivering interventions to reduce HIV vulnerability., Objective: This study aims to adapt a theory-based mobile health HIV prevention smartphone app, HealthMindr, to meet the unique needs of transgender women in Malaysia. We conducted theater testing of the HealthMindr app with transgender women and key stakeholders and explored barriers to transgender women's uptake of HIV pre-exposure prophylaxis (PrEP)., Methods: From February to April 2022, a total of 6 focus group (FG) sessions were conducted with 29 participants: 4 FG sessions with transgender women (n=18, 62%) and 2 FG sessions with stakeholders (n=11, 38%) providing HIV prevention services to transgender women in Malaysia. Barriers to PrEP uptake and gender-affirming care services among transgender women in Malaysia were explored. Participants were then introduced to the HealthMindr app and provided a comprehensive tour of the app's features and functions. Participants provided feedback on the app and on how existing features should be adapted to meet the needs of transgender women, as well as any features that should be removed or added. Each FG was digitally recorded and transcribed. Transcripts were coded inductively using Dedoose software (version 9.0.54; SocioCultural Research Consultants, LLC) and analyzed to identify and interpret emerging themes., Results: Six subthemes related to PrEP barriers were found: stigma and discrimination, limited PrEP knowledge, high PrEP cost, accessibility concerns, alternative prevention methods, and perceived adverse effects. Participants suggested several recommendations regarding the attributes and app features that would be the most useful for transgender women in Malaysia. Adaptation and refinement of the app were related to the attributes of the app (user interface, security, customizable colors, themes, and avatars), feedback, and requests for additional mobile app functional (appointment booking, e-consultation, e-pharmacy, medicine tracker, mood tracker, resources, and service site locator) and communication (peer support group, live chat, and discussion forum) features., Conclusions: The results reveal that multifaceted barriers hinder PrEP uptake and use among transgender women in Malaysia. The findings also provide detailed recommendations for successfully adapting the HealthMindr app to the context of Malaysian transgender women, with a potential solution for delivering tailored HIV prevention, including PrEP, and increasing accessibility to gender-affirming care services., (©Kamal Gautam, Roman Shrestha, Sihlelelwe Dlamini, Belle Razali, Kiran Paudel, Iskandar Azwa, Rumana Saifi, YuHang Toh, Hazriq Justin Lim, Ryan Sutherland, Arjee Restar, Nittaya Phanuphak, Jeffrey A Wickersham. Originally published in JMIR Formative Research (https://formative.jmir.org), 13.08.2024.)

Background: The HIV epidemic continues to grow fastest among men who have sex with men (MSM) in Malaysia in the presence of stigma and discrimination. Engaging MSM on the internet using chatbots supported through artificial intelligence (AI) can potentially help HIV prevention efforts. We previously identified the benefits, limitations, and preferred features of HIV prevention AI chatbots and developed an AI chatbot prototype that is now tested for feasibility and acceptability., Objective: This study aims to test the feasibility and acceptability of an AI chatbot in promoting the uptake of HIV testing and pre-exposure prophylaxis (PrEP) in MSM., Methods: We conducted beta testing with 14 MSM from February to April 2022 using Zoom (Zoom Video Communications, Inc). Beta testing involved 3 steps: a 45-minute human-chatbot interaction using the think-aloud method, a 35-minute semistructured interview, and a 10-minute web-based survey. The first 2 steps were recorded, transcribed verbatim, and analyzed using the Unified Theory of Acceptance and Use of Technology. Emerging themes from the qualitative data were mapped on the 4 domains of the Unified Theory of Acceptance and Use of Technology: performance expectancy, effort expectancy, facilitating conditions, and social influence., Results: Most participants (13/14, 93%) perceived the chatbot to be useful because it provided comprehensive information on HIV testing and PrEP (performance expectancy). All participants indicated that the chatbot was easy to use because of its simple, straightforward design and quick, friendly responses (effort expectancy). Moreover, 93% (13/14) of the participants rated the overall chatbot quality as high, and all participants perceived the chatbot as a helpful tool and would refer it to others. Approximately 79% (11/14) of the participants agreed they would continue using the chatbot. They suggested adding a local language (ie, Bahasa Malaysia) to customize the chatbot to the Malaysian context (facilitating condition) and suggested that the chatbot should also incorporate more information on mental health, HIV risk assessment, and consequences of HIV. In terms of social influence, all participants perceived the chatbot as helpful in avoiding stigma-inducing interactions and thus could increase the frequency of HIV testing and PrEP uptake among MSM., Conclusions: The current AI chatbot is feasible and acceptable to promote the uptake of HIV testing and PrEP. To ensure the successful implementation and dissemination of AI chatbots in Malaysia, they should be customized to communicate in Bahasa Malaysia and upgraded to provide other HIV-related information to improve usability, such as mental health support, risk assessment for sexually transmitted infections, AIDS treatment, and the consequences of contracting HIV., (©Min Hui Cheah, Yan Nee Gan, Frederick L Altice, Jeffrey A Wickersham, Roman Shrestha, Nur Afiqah Mohd Salleh, Kee Seong Ng, Iskandar Azwa, Vimala Balakrishnan, Adeeba Kamarulzaman, Zhao Ni. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 26.01.2024.)

Background: We validated the Data collection on Adverse events of anti-HIV Drugs (D:A:D) full-risk and short-risk score models for chronic kidney disease (CKD) in the Asian HIV cohorts., Settings: A validation study among people living with HIV (PLHIV) aged ≥18 years among the cohorts in the Asia-Pacific region., Methods: PLHIV with a baseline estimated glomerular filtration rate > 60 mL/min/1.73 m were included for validation of the D:A:D CKD full version and short version without cardiovascular risk factors. Those with <3 estimated glomerular filtration rate measurements from baseline or previous exposure to potentially nephrotoxic antiretrovirals were excluded. Kaplan-Meier methods were used to estimate the probability of CKD development. The area under the receiver operating characteristics was also used to validate the risk score., Results: We included 5701 participants in full model {median 8.1 [interquartile range (IQR) 4.8-10.9] years follow-up} and 9791 in short model validation [median 4.9 (IQR 2.5-7.3) years follow-up]. The crude incidence rate of CKD was 8.1 [95% confidence interval (CI): 7.3 to 8.9] per 1000 person-years in the full model cohort and 10.5 (95% CI: 9.6 to 11.4) per 1000 person-years in the short model cohort. The progression rates for CKD at 10 years in the full model cohort were 2.7%, 8.9%, and 26.1% for low-risk, medium-risk, and high-risk groups, and 3.5%, 11.7%, and 32.4% in the short model cohort. The area under the receiver operating characteristics for the full-risk and short-risk score was 0.81 (95% CI: 0.79 to 0.83) and 0.83 (95% CI: 0.81 to 0.85), respectively., Conclusion: The D:A:D CKD full-risk and short-risk score performed well in predicting CKD events among Asian PLHIV. These risk prediction models may be useful to assist clinicians in identifying individuals at high risk of developing CKD.

Background: The World Health Organization recommends continuation with the failing second-line regimen if third-line option is not available. We investigated treatment outcomes among people living with HIV in Asia who continued with failing second-line regimens compared with those who had treatment modifications after failure., Methods: Treatment modification was defined as a change of two antiretrovirals, a drug class change or treatment interruption (TI), all for >14 days. We assessed factors associated with CD4 changes and undetectable viral load (UVL <1,000 copies/ml) at 1 year after second-line failure using linear and logistic regression, respectively. Survival time was analysed using competing risk regression., Results: Of the 328 patients who failed second-line ART in our cohorts, 208 (63%) had a subsequent treatment modification. Compared with those who continued the failing regimen, the average CD4 cell increase was higher in patients who had a modification without TI (difference =77.5, 95% CI 35.3, 119.7) while no difference was observed among those with TI (difference =-5.3, 95% CI -67.3, 56.8). Compared with those who continued the failing regimen, the odds of achieving UVL was lower in patients with TI (OR=0.18, 95% CI 0.06, 0.60) and similar among those who had a modification without TI (OR=1.97, 95% CI 0.95, 4.10), with proportions of UVL 60%, 22% and 75%, respectively. Survival time was not affected by treatment modifications., Conclusions: CD4 cell improvements were observed in those who had treatment modification without TI compared with those on the failing regimen. When no other options are available, maintaining the same failing ART combination provided better VL control than interrupting treatment.