Emergence of acquired dolutegravir resistance in treatment-experienced people with HIV in Lesotho.

BACKGROUND: Since 2019, the World Health Organization has recommended dolutegravir-based antiretroviral therapy (ART) as the preferred regimen for HIV management. Large-scale programmatic transitioning to dolutegravir-based ART was subsequently implemented across Africa, often in the absence of recent viral load testing and without access to genotypic resistance testing (GRT) in case of viremia. METHODS: This study assessed for emerging dolutegravir resistance in the routine care Viral Load Cohort North-East Lesotho (VICONEL). We included pediatric and adult participants who changed from non-nucleoside transcriptase inhibitor- (NNRTI-) to dolutegravir-based ART and had at least one viral load assessment before and after the change. We sequenced available samples of participants fulfilling the additional virological criteria of having two viraemic episodes while taking dolutegravir, thereof at least one viral load ≥500 copies/mL taken ≥18 months after changing to dolutegravir. RESULTS: Among 15'349 participants, 157 (1.0%) met the virological criteria and GRT was successful for 85 (0.6%). Among these 85, eight (9.4%) had dolutegravir resistance, with two (2.4%) and six (7.1%) predicted to have intermediate and high-level dolutegravir resistance, respectively. One participant had two, two had one, and five had zero active drugs in their regimen. A GRT from before the change to dolutegravir is available for five of these eight participants: four had zero and one had one active drug in their NNRTI-based regimen. CONCLUSIONS: Nine percent of people with persistent or recurring HIV viremia ≥18 months after changing to dolutegravir-based ART had dolutegravir resistance. Detection and management of emerging dolutegravir resistance must be addressed across Africa.

Changes in Compliance with Bans on Tobacco Product Display and Advertising at Traditional and Modern Point-of-Sale Retailers in Depok, Indonesia, 2019-2021.

INTRODUCTION: Banning Point-of-Sale (POS) advertising and product display is an important tobacco control strategy. Depok, Indonesia enacted some regional tobacco control policies regulating the POS environment in 2021. This study examined changes in compliance before and after the implementation of these policies as of 2021. METHODS: Data collectors visited 180 modern retailers (hyper/supermarkets/convenience stores) and 147 traditional retailers (warungs) in 2019. The same retailers were re-visited in 2021. Data collectors assessed compliance with tobacco product display, and advertising regulations at POS, including if products were displayed in spaces to target minors (near candy or at a child's eye-level). Data were analyzed using McNemar and Mann-Whitney U tests. RESULTS: From 2019 to 2021, in modern retailers, tobacco product display (95.6% vs 52.2%) and product advertising (36.1% vs 3.9%) were significantly reduced (p<0.001). In traditional retailers, tobacco product display (94.6% in 2019, 91.2% in 2021, p>0.05) and product advertising (87.1% in 2019, 87.8% in 2021, p>0.05) remained common during both data collection periods. Tobacco products were commonly displayed in spaces to target minors in both modern retailers (43.3% in 2019, 34.4% in 2021, p>0.05) and traditional retailers (90.5% in 2019, 83.0% in 2021, p>0.05). CONCLUSIONS: Compliance with bans on tobacco product advertising and display at modern retailers improved significantly from 2019 to 2021; however, most modern retailers continue to display tobacco products in 2021. Traditional retailers remain largely non-compliant. Tobacco products are commonly displayed in areas that target minors. The enforcement of regional regulations should be strengthened, particularly among traditional retailers. IMPLICATIONS: In Depok, Indonesia, tobacco advertising and product display bans have been implemented; however, more work is needed to support compliance. Enforcement efforts, such as those carried out by civil police, can focus on tobacco product display bans in traditional and modern retailers, and traditional retailers need additional support to remove tobacco product advertising. Retailers may receive money from the tobacco industry for these advertisements. Creative solutions may include supporting retailers in finding alternative advertising revenue.

Clinical Risks for Chronic Lymphocytic Leukemia.

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures. Agent Orange and glyphosate herbicides have perhaps the most data to support their role. CLL is preceded by a precursor condition called monoclonal B-cell lymphocytosis (MBL), which could therefore be considered a risk factor, but which itself is likely caused by the same risk factors that ultimately give rise to CLL. Although virtually all people with CLL have a preceding MBL phase, most people with MBL will not develop CLL.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib.

First-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been associated with an increased risk for cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this manuscript, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N=1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Across the 10 studies, most patients (median age, 67 years) were male (66.3%), and most had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib versus ibrutinib. Despite a similar prevalence of pre-existing cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rate (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons/100 person-months; P<.0001) were lower with zanubrutinib than with ibrutinib, respectively. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons/100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib versus ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with the other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability over ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. CT# NCT03053440 NCT03336333 NCT03734016 NCT04170283 NCT03206918 NCT03206970 NCT03332173 NCT03846427 NCT02343120 NCT03189524.

Final 3-Year Study Outcomes from the Evaluation of the Zilver Vena Venous Stent for the Treatment of Symptomatic Iliofemoral Venous Outflow Obstruction (VIVO Clinical Study).

PURPOSE: To report 3-year outcomes from a prospective, multicenter, nonrandomized, single-arm study designed to assess the safety and effectiveness of the Zilver Vena Venous Stent for the treatment of symptomatic iliofemoral venous outflow obstruction. MATERIALS AND METHODS: The VIVO study included patients with symptomatic obstruction of 1 iliofemoral venous segment (ie, 1 limb), characterized by a Clinical, Etiological, Anatomic, Pathophysiology (CEAP) clinical classification of ≥3 or a Venous Clinical Severity Score (VCSS) for pain of ≥2. Patients were retrospectively grouped based on baseline clinical presentation as postthrombotic syndrome (PTS), nonthrombotic iliac vein (NIVL) obstruction, or acute deep vein thrombosis (aDVT). Clinical improvement was assessed by change in VCSS, Venous Disability Score, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) scores, and CEAP C classification. Stent performance was evaluated by rates of patency by ultrasound (US), freedom from clinically driven reintervention, and freedom from stent fracture. RESULTS: The 3-year results for the 243 patients in the VIVO cohort included a 90.3% rate of patency by US and a 92.6% rate of freedom from clinically driven reintervention. The 3-year rates of patency by US for the NIVL, aDVT, and PTS groups were 100%, 84.0%, and 86.1%, respectively. Sustained clinical improvement through 3 years was demonstrated by changes in VCSS, Venous Disability Score, CIVIQ-20, and CEAP C classification. No stent fractures were observed. CONCLUSIONS: The VIVO study demonstrated sustained high rates of patency and freedom from clinically driven reintervention and improvements in venous clinical symptoms through 3 years. Each patient group (NIVL, aDVT, and PTS) showed clinical improvement and sustained patency through 3 years; some variation existed among groups (eg, only the NIVL group had a 100% patency rate).

Efforts in Organized Medicine to Eliminate Harmful Race-Based Clinical Algorithms.

This survey study describes efforts to eliminate harmful race-based clinical algorithms among state or territorial medical associations and specialty societies in the US.

Venetoclax Initiation in Chronic Lymphocytic Leukemia: International Insights and Innovative Approaches for Optimal Patient Care.

Venetoclax, a highly selective, oral B-cell lymphoma 2 inhibitor, provides a robust targeted-therapy option for the treatment of chronic lymphocytic leukemia (CLL), including patients with high-risk del(17p)/mutated-TP53 and immunoglobulin heavy variable region unmutated CLL and those refractory to chemoimmunotherapy across all age groups. Due to the potent pro-apoptotic effect of venetoclax, treatment initiation carries a risk of tumor lysis syndrome (TLS). Prompt and appropriate management is needed to limit clinical TLS, which may entail serious adverse events and death. Venetoclax ramp-up involves gradual, stepwise increases in daily venetoclax dosing from 20 mg to 400 mg (target dose) over 5 weeks; adherence to on-label scheduling provides a tumor debulking phase, reducing the risk of TLS. The key components of safe venetoclax therapy involve assessment (radiographic evaluation and baseline blood chemistry), preparation (adequate hydration), and initiation (blood chemistry monitoring). In addition to summarizing the evidence for venetoclax's efficacy and safety, this review uses hypothetical patient scenarios based on risk level for TLS (high, medium, low) to share the authors' clinical experience with venetoclax initiation and present global approaches utilized in various treatment settings. These hypothetical scenarios highlight the importance of a multidisciplinary approach and shared decision-making, outlining best practices for venetoclax initiation and overall optimal treatment strategies in patients with CLL.

Social Communication and Parent Verbal Responsiveness Across Interaction Contexts in Toddlers on the Autism Spectrum.

PURPOSE: Interactions with caregivers during the ordinary activities that occur as families go about their everyday lives are critical to supporting children's acquisition of social communication and language skills. The purpose of this study was to examine child communication and parent verbal responsiveness across interaction contexts in 211 children (Mage = 20 months) on the autism spectrum (n = 121), with developmental delay (n = 46), or with typical development (n = 44). METHOD: Families participated in up to eight activities during an hour-long, video-recorded home observation. We tested differences in the strength of associations between diagnostic group and interaction context using linear mixed-effects models, with child rate per minute of communication and proportions of parent follow-in comments and directives as outcome variables. Child communicative functions expressed across contexts were also examined. RESULTS: Children across groups communicated at significantly higher rates per minute during book sharing and play with people compared to other interaction contexts. Most child communication was for the function of joint attention during book sharing, for social interaction during play with people, and for behavior regulation during necessary activities such as family chores and meals. On average, parents of children responded using proportionally more follow-in comments during book sharing and play compared to necessary activities, during which parents used more follow-in directives. CONCLUSION: Results provide a glimpse into the dyadic communication that may occur within everyday activities at home, which supports the need for future intervention research and may aid clinicians seeking to identify activities that serve as important contexts for intervention.

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL.

We retrospectively analyzed 609 chronic lymphocytic leukemia (CLL) patients treated with BTK inhibitors (BTKis) at Dana-Farber Cancer Institute from 2014 to 2022. Among them, 85 underwent next-generation sequencing (NGS) during or after BTKi therapy (ibrutinib, 64; acalabrutinib, 13; pirtobrutinib, 7; vecabrutinib, 1). Patients with NGS at progression (N=36, PD group) showed more 17p deletion, complex karyotype, and previous treatments including BTKi, compared to ongoing responders (N=49, NP group). 216 variants were found in 57 genes across both groups, with more variants in the PD group (158 variants, 70.3% pathogenic, P<0.001). The PD group had a higher incidence of pathogenic variants (70.3%, P<0.001), including 32 BTK(BTK C481S/F/R/Y, L528W, and T474I/L) and 4 PLCG2mutations. Notably, a high VAF L528W mutation was found in a first line ibrutinib-resistant patient. TP53, SF3B1, and NOTCH2mutations were also significantly more prevalent in the PD group (P<0.01, P<0.05, P<0.05). Additionally, MAPK pathway gene mutations trended more common and had higher VAFs in the PD group (P=0.041). T474 mutations were found in 4 of 6 patients progressing on pirtobrutinib, and BTK L528W mutation can arise with both covalent and non-covalent BTKi therapy. These results also suggest that RAS/RAF/MAPK pathway mutations may contribute to BTKi resistance.

Clinical Relevance of Human Immunodeficiency Virus Low-level Viremia in the Dolutegravir era: Data From the Viral Load Cohort North-East Lesotho (VICONEL).

Background: Human immunodeficiency virus low-level viremia (LLV) is associated with subsequent treatment failure at least with non nucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral therapy. Data on implications of LLV occurring under dolutegravir, which has largely replaced NNRTIs in Africa, are scarce, however. Methods: We included adults with human immunodeficiency virus in Lesotho who had ≥2 viral loads (VLs) taken after ≥6 months of NNRTI- or dolutegravir-based antiretroviral therapy. Within VL pairs, we assessed the association of viral suppression (<50 copies/mL) and low- and high-range LLV (50-199 and 200-999 copies/mL, respectively) with virological failure (≥1000 copies/mL) using a mixed-effects regression model. Participants could contribute VLs to the NNRTI and the dolutegravir group. Results: Among 18 550 participants, 12 216 (65.9%) were female and median age at first VL included was 41.2 years (interquartile range, 33.4-51.5). In both groups, compared with a suppressed VL, odds of subsequent virological failure were higher for low-range LLV (NNRTI: adjusted odds ratio; 95% confidence interval: 1.9; 1.4-2.4 and dolutegravir: 2.1; 1.3-3.6) and high-range LLV (adjusted odds ratio; 95% confidence interval, 4.2; 3.1-5.7 and 4.4; 2.4-7.9). Conclusions: In the dolutegravir era, LLV remains associated with virological failure, endorsing the need for close clinical and laboratory monitoring of those with a VL ≥50 copies/mL.

HIV viral suppression in children and adolescents two years after transition to dolutegravir: a multicentre cohort study.

BACKGROUND: Treatment failure is common among children and adolescents with HIV. Antiretroviral therapy (ART) containing dolutegravir has recently been rolled out across Africa, though long-term real-world data in paediatric populations are lacking. Here, we report treatment outcomes among children and adolescents in Lesotho who transitioned from non-nucleoside reverse transcriptase inhibitor- (NNRTI-) to dolutegravir-based ART through two years' follow-up. METHODS: Data were derived from two open cohort studies in Lesotho. Children and adolescents aged < 18 years who transitioned from NNRTI- to dolutegravir-based ART at least 18 months before data closure were included. We report viral load results <12 months before, 12 (window: 6-17) months after, and 24 (window: 18-29) months after transition to dolutegravir. Associations of pre-transition demographic and clinical factors with 24-month viraemia were assessed through multivariable logistic regression. RESULTS: Among 2126 included individuals, 1100 (51.7%) were female, median age at transition to dolutegravir was 14.0 years (interquartile range [IQR] 11.5-15.8), and median time taking ART at transition was 7.6 years (IQR 4.4-10.6). Among those with a viral load result at the respective time points, viral suppression to <50 copies/mL was achieved by 1635/1973 (82.9%) <12 months before, 1846/2012 (91.8%) 12 months after, and 1725/1904 (90.6%) 24 months after transition to dolutegravir. Pre-transition viraemia was associated with viraemia at 24 months, though >80% of individuals with pre-transition viraemia achieved resuppression to <50 copies/mL at 24 months. CONCLUSIONS: The proportion of children and adolescents with viral suppression increased after transition to dolutegravir, though further progress is needed to reach global targets.

Screening for problematic opioid use in the emergency department: Comparison of two screening measures.

Study objective: Earlier intervention for opioid use disorder (OUD) may reduce long-term health implications. Emergency departments (EDs) in the United States treat millions with OUD annually who may not seek care elsewhere. Our objectives were (1) to compare two screening measures for OUD characterization in the ED and (2) to determine the proportion of ED patients screening positive for OUD and those who endorse other substance use to guide future screening programs. Methods: A cross-sectional study of randomly selected adult patients presenting to three Midwestern US EDs were enrolled, with duplicate patients excluded. Surveys were administered via research assistant and documented on tablet devices. Demographics were self-reported, and OUD positivity was assessed by the DSM 5 checklist and the WHO ASSIST 3.1. The primary outcome was the concordance between two screening measures for OUD. Our secondary outcome was the proportion of ED patients meeting OUD criteria and endorsed co-occurring substance use disorder (SUD) criteria. Results: We enrolled 1305 participants; median age of participants was 46 years (range 18-84), with 639 (49.0%) Non-Hispanic, White, and 693 (53.1%) female. Current OUD positivity was identified in 17% (222 out of 1305) of the participants via either DSM-5 (two or more criteria) or ASSIST (score of 4 or greater). We found moderate agreement between the measures (kappa = 0.56; Phi coefficient = 0.57). Of individuals screening positive for OUD, 182 (82%) endorsed criteria for co-occurring SUD. Conclusions: OUD is remarkably prevalent in ED populations, with one in six ED patients screening positive. We found a high prevalence of persons identified with OUD and co-occurring SUD, with moderate agreement between measures. Developing and implementing clinically feasible OUD screening in the ED is essential to enable intervention.

Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

ABSTRACT: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

ABSTRACT: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.

A core outcome set for trials evaluating self-management interventions in people with severe mental illness and coexisting type 2 diabetes.

BACKGROUND: People with severe mental illness (SMI), such as schizophrenia, have higher rates of type 2 diabetes and worse outcomes, compared to those without SMI and it is not known whether diabetes self-management interventions are effective for people who have both conditions. Research in this area has been impeded by a lack of consensus on which outcomes to prioritise in people with co-existing SMI and diabetes. AIMS: To develop a core outcome set (COS) for use in effectiveness trials of diabetes self-management interventions in adults with both type 2 diabetes and SMI. METHODS: The COS was developed in three stages: (i) identification of outcomes from systematic literature review of intervention studies, followed by multi-stakeholder and service user workshops; (ii) rating of outcomes in a two-round online Delphi survey; (iii) agreement of final 'core' outcomes through a stakeholder consensus workshop. RESULTS: Seven outcomes were selected: glucose control, blood pressure, body composition (body weight, BMI, body fat), health-related quality of life, diabetes self-management, diabetes-related distress and medication adherence. CONCLUSIONS: This COS is recommended for future trials of effectiveness of diabetes self-management interventions for people with SMI and type 2 diabetes. Its use will ensure trials capture important outcomes and reduce heterogeneity so findings can be readily synthesised to inform practice and policy.

Pregnancy and STI/HIV prevention intervention preferences of South African adolescent girls: findings from a cultural consensus modelling qualitative study.

South African adolescent girls experience high rates of unintended pregnancy and sexually transmitted infections including HIV. To inform culturally-tailored dual protection interventions to prevent both unintended pregnancy and STIs/HIV, this study qualitatively examined girls' sexual health intervention preferences. Participants were aged 14-17 years old and Sesotho-speaking (N = 25). To elucidate shared cultural beliefs, individual interviews examined participants' perceptions about other adolescent girls' pregnancy and STI/HIV prevention intervention preferences. Interviews were conducted in Sesotho and translated into English. Two independent coders identified key themes in the data using a conventional content analysis approach with discrepancies resolved by a third coder. Participants indicated that intervention content should include efficacious pregnancy and STI/HIV prevention methods and ways to navigate peer pressure. Interventions should be accessible, avoid criticism and provide high-quality information. Preferred intervention formats included online, SMS/text, or delivery by social workers or older, knowledgeable peers, with mixed acceptability for delivery by parents or same-age peers. Schools, youth centres and sexual health clinics were preferred intervention settings. Results highlight the importance of cultural context in tailoring dual protection interventions to address the reproductive health disparities among adolescent girls in South Africa.