HIV epidemiology, prevention, treatment, and implementation strategies for public health.

The global HIV response has made tremendous progress but is entering a new phase with additional challenges. Scientific innovations have led to multiple safe, effective, and durable options for treatment and prevention, and long-acting formulations for 2-monthly and 6-monthly dosing are becoming available with even longer dosing intervals possible on the horizon. The scientific agenda for HIV cure and remission strategies is moving forward but faces uncertain thresholds for success and acceptability. Nonetheless, innovations in prevention and treatment have often failed to reach large segments of the global population (eg, key and marginalised populations), and these major disparities in access and uptake at multiple levels have caused progress to fall short of their potential to affect public health. Moving forward, sharper epidemiologic tools based on longitudinal, person-centred data are needed to more accurately characterise remaining gaps and guide continued progress against the HIV epidemic. We should also increase prioritisation of strategies that address socio-behavioural challenges and can lead to effective and equitable implementation of existing interventions with high levels of quality that better match individual needs. We review HIV epidemiologic trends; advances in HIV prevention, treatment, and care delivery; and discuss emerging challenges for ending the HIV epidemic over the next decade that are relevant for general practitioners and others involved in HIV care.

Low CD4 counts predict excessive weight gains during first-line treatment for HIV.

BACKGROUND: Weight gain is common after antiretroviral initiation, especially among females, those of black race and lower baseline CD4, although this may potentially be due to lower baseline weight. Use of tenofovir disoproxil fumarate or efavirenz can suppress weight gain. METHODS: Data were pooled from the ADVANCE (n = 1053), NAMSAL (n = 613) and WHRI001 (n = 536) trials investigating first-line regimen. Week 96 weight and body mass index (BMI) was stratified by baseline CD4. Multivariable models of weight change and incident obesity (BMI ≥30 kg/m2) were adjusted for baseline CD4, age, sex, tenofovir disoproxil fumarate, efavirenz, baseline BMI and trial. RESULTS: Participants across all treatment arms experienced weight gain from baseline to week 96, with baseline CD4 count, baseline HIV RNA, tenofovir alafenamide and dolutegravir use, and female sex significant predictors. Mean unadjusted weight change was highest with CD4 < 100 (+8.6 kg; SD = 8.2) and lowest with CD4 ≥ 350 (+3.0 kg; SD = 6.5). This weight gain in CD4 < 100 was highest for participants on tenofovir alafenamide-inclusive treatment, such that absolute weight at week 96 was highest in the CD4 < 100 group. Although not statistically significant, obesity rate (BMI ≥ 30 kg/m2) in those taking TAF/FTC + DTG with CD4 < 100 overtook that seen in CD4 ≥ 350, despite lower baseline obesity prevalence. The unadjusted findings were corroborated in multivariable longitudinal models. CONCLUSIONS: Participants with low CD4 may demonstrate significant 'overshoot' weight gain, in addition to 'return to health', with a trend towards increased risk of obesity when initiated on TAF/FTC + DTG. Use of tenofovir disoproxil fumarate and efavirenz were associated with smaller weight gains. Effective weight management strategies are needed, especially for individuals with low baseline CD4.

Cardiometabolic health in people with HIV: expert consensus review.

OBJECTIVES: To develop consensus data statements and clinical recommendations to provide guidance for improving cardiometabolic health outcomes in people with HIV based on the knowledge and experience of an international panel of experts. METHODS: A targeted literature review including 281 conference presentations, peer-reviewed articles, and background references on cardiometabolic health in adults with HIV published between January 2016 and April 2022 was conducted and used to develop draft consensus data statements. Using a modified Delphi method, an international panel of 16 experts convened in workshops and completed surveys to refine consensus data statements and generate clinical recommendations. RESULTS: Overall, 10 data statements, five data gaps and 14 clinical recommendations achieved consensus. In the data statements, the panel describes increased risk of cardiometabolic health concerns in people with HIV compared with the general population, known risk factors, and the potential impact of antiretroviral therapy. The panel also identified data gaps to inform future research in people with HIV. Finally, in the clinical recommendations, the panel emphasizes the need for a holistic approach to comprehensive care that includes regular assessment of cardiometabolic health, access to cardiometabolic health services, counselling on potential changes in weight after initiating or switching antiretroviral therapy and encouraging a healthy lifestyle to lower cardiometabolic health risk. CONCLUSIONS: On the basis of available data and expert consensus, an international panel developed clinical recommendations to address the increased risk of cardiometabolic disorders in people with HIV to ensure appropriate cardiometabolic health management for this population.

The cost of adding rapid screening for diabetes, hypertension, and COVID-19 to COVID-19 vaccination queues in Johannesburg, South Africa.

BACKGROUND: Non-communicable diseases (NCDs) are responsible for 51% of total mortality in South Africa, with a rising burden of hypertension (HTN) and diabetes mellitus (DM). Incorporating NCDs and COVID-19 screening into mass activities such as COVID-19 vaccination programs could offer significant long-term benefits for early detection interventions. However, there is limited knowledge of the associated costs and resources required. We evaluated the cost of integrating NCD screening and COVID-19 antigen rapid diagnostic testing (Ag-RDT) into a COVID-19 vaccination program. METHODS: We conducted a prospective cost analysis at three public sector primary healthcare clinics and one academic hospital in Johannesburg, South Africa, conducting vaccinations. Participants were assessed for eligibility and recruited during May-Dec 2022. Costs were estimated from the provider perspective using a bottom-up micro-costing approach and reported in 2022 USD. RESULTS: Of the 1,376 enrolled participants, 240 opted in to undergo a COVID-19 Ag-RDT, and none tested positive for COVID-19. 138 (10.1%) had elevated blood pressure, with 96 (70%) having no prior HTN diagnosis. 22 (1.6%) were screen-positive for DM, with 12 (55%) having no prior diagnosis. The median cost per person screened for NCDs was $1.70 (IQR: $1.38-$2.49), respectively. The average provider cost per person found to have elevated blood glucose levels and blood pressure was $157.99 and $25.19, respectively. Finding a potentially new case of DM and HTN was $289.65 and $36.21, respectively. For DM and DM + HTN screen-positive participants, diagnostic tests were the main cost driver, while staff costs were the main cost driver for DM- and HTN screen-negative and HTN screen-positive participants. The median cost per Ag-RDT was $5.95 (IQR: $5.55-$6.25), with costs driven mainly by test kit costs. CONCLUSIONS: We show the cost of finding potentially new cases of DM and HTN in a vaccine queue, which is an essential first step in understanding the feasibility and resource requirements for such initiatives. However, there is a need for comparative economic analyses that include linkage to care and retention data to fully understand this cost and determine whether opportunistic screening should be added to general mass health activities.

Secondary distribution of HIV self-test kits by HIV index and antenatal care clients: implementation and costing results from the STAR Initiative in South Africa.

BACKGROUND: Partner-delivered HIV self-testing kits has previously been highlighted as a safe, acceptable and effective approach to reach men. However, less is known about its real-world implementation in reaching partners of people living with HIV. We evaluated programmatic implementation of partner-delivered self-testing through antenatal care (ANC) attendees and people newly diagnosed with HIV by assessing use, positivity, linkage and cost per kit distributed. METHODS: Between April 2018 and December 2019, antenatal care (ANC) clinic attendees and people or those newly diagnosed with HIV clients across twelve clinics in three cities in South Africa were given HIVST kits (OraQuick Rapid HIV-1/2 Antibody Test, OraSure Technologies) to distribute to their sexual partners. A follow-up telephonic survey was administered to all prior consenting clients who were successfully reached by telephone to assess primary outcomes. Incremental economic costs of the implementation were estimated from the provider's perspective. RESULTS: Fourteen thousand four hundred seventy-three HIVST kits were distributed - 10,319 (71%) to ANC clients for their male partner and 29% to people newly diagnosed with HIV for their partners. Of the 4,235 ANC clients successfully followed-up, 82.1% (3,475) reportedly offered HIVST kits to their male partner with 98.1% (3,409) accepting and 97.6% (3,328) using the kit. Among ANC partners self-testing, 159 (4.8%) reported reactive HIVST results, of which 127 (79.9%) received further testing; 116 (91.3%) were diagnosed with HIV and 114 (98.3%) initiated antiretroviral therapy (ART). Of the 1,649 people newly diagnosed with HIV successfully followed-up; 1,312 (79.6%) reportedly offered HIVST kits to their partners with 95.8% (1,257) of the partners accepting and 95.9% (1,206) reported that their partners used the kit. Among these index partners, 297 (24.6%) reported reactive HIVST results of which 261 (87.9%) received further testing; 260 (99.6%) were diagnosed with HIV and 258 (99.2%) initiated ART. The average cost per HIVST distributed in the three cities was US$7.90, US$11.98, and US$14.81, respectively. CONCLUSIONS: Partner-delivered HIVST in real world implementation was able to affordably reach many male partners of ANC attendees and index partners of people newly diagnosed with HIV in South Africa. Given recent COVID-19 related restrictions, partner-delivered HIVST provides an important strategy to maintain essential testing services.

Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans With Human Immunodeficiency Virus.

BACKGROUND: Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterized the pharmacogenetics of dolutegravir exposure after ART initiation in the ADVANCE trial in South Africa. METHODS: Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using nonlinear mixed-effects modeling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). RESULTS: Genetic associations were evaluable in 284 individuals. Of 9 polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10-4), which was also associated with log10 bilirubin (P = 8.6 × 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = .02), as were bilirubin concentrations (P = 7.7 × 10-8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared with C/C. The lowest P value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10-7). CONCLUSIONS: In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.

Barriers to Uptake of Long-Acting Antiretroviral Products for Treatment and Prevention of HIV in Low- and Middle-Income Countries (LMICs).

Long-acting injectable antiretroviral therapy (LA ART) has been found to be non-inferior to daily oral ART in phase 3 clinical trials and is poised to soon enter routine clinical care. This treatment modality has the potential to address many barriers to daily oral ART adherence among people living with human immunodeficiency virus (HIV) and for HIV Pre-Exposure prevention. Data from the Patient Reported Outcomes (PROs) showed high rates of satisfaction, acceptability, tolerability and preference for the LA regimen, compared with the daily oral treatment. Once LA ART is available, access and uptake will be limited because of current knowledge gaps in the use of these agents and multiple challenges many specific to low-income and middle-income countries, where the epidemic is most concentrated and HIV prevention and treatment options are limited. These gaps will lead to multiple systems-level and individual-level barriers to implementation. Anticipating and addressing these gaps and barriers will help fulfill the promise of these agents against the pandemic.

Pharmacokinetic and pharmacogenetic associations with dolutegravir neuropsychiatric adverse events in an African population.

BACKGROUND: Dolutegravir has been associated with neuropsychiatric adverse events (NPAEs), but relationships between dolutegravir concentrations and NPAEs are unclear. OBJECTIVES: To determine in an African population whether a concentration-response relationship exists between dolutegravir and treatment-emergent NPAEs, and whether selected loss-of-function polymorphisms in genes encoding UDP-glucuronosyltransferase-1A1 (the major metabolizing enzyme for dolutegravir) and organic cation transporter-2 (involved in neurotransmitter transport and inhibited by dolutegravir) are associated with NPAEs. METHODS: Antiretroviral therapy-naive participants randomized to dolutegravir-based therapy in the ADVANCE study were enrolled into a pharmacokinetic sub-study. Primary outcome was change in mental health screening [modified mini screen (MMS)] and sleep quality from baseline to weeks 4, 12 and 24. Dolutegravir exposure was estimated using a population pharmacokinetic model. Polymorphisms analysed were UGT1A1 rs887829 and SLC22A2 rs316019. RESULTS: Data from 464 participants were available for pharmacokinetic analyses and 301 for genetic analyses. By multivariable linear regression, higher dolutegravir exposure was associated with worsening sleep quality only at week 12 [coefficient  = -0.854 (95% CI -1.703 to -0.005), P = 0.049], but with improved MMS score at weeks 12 and 24 [coefficient = -1.255 (95% CI -2.250 to -0.261), P = 0.013 and coefficient = -1.199 (95% CI -2.030 to -0.368), P = 0.005, respectively]. The UGT1A1 and SLC22A2 polymorphisms were not associated with change in MMS score or sleep quality. CONCLUSIONS: Only at week 12 did we find evidence of a relationship between dolutegravir exposure and worsening sleep quality. However, higher dolutegravir exposure was associated with improved MMS scores, suggesting a possible beneficial effect.

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

BACKGROUND: Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). METHODS: We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. RESULTS: There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. CONCLUSIONS: CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Pre-exposure prophylaxis (PrEP) in an era of stalled HIV prevention: Can it change the game?

Pre-exposure prophylaxis (PrEP) for HIV prevention has evolved significantly over the years where clinical trials have now demonstrated the efficacy of oral PrEP, and the field is scaling-up implementation. The WHO and UNAIDS have made PrEP implementation a priority for populations at highest risk, and several countries have developed guidelines and national plans accordingly, largely based on evidence generated by demonstration projects. PrEP presents the opportunity to change the face of HIV prevention by offering a new option for protection against HIV and disrupting current HIV prevention systems. Nevertheless, as with all new technologies, both practical and social requirements for implementation must be taken into account if there is to be sustained and widespread adoption, which will also apply to forthcoming prevention technologies. Defining and building success for PrEP within the scope of scale-up requires careful consideration. This review summarises where the PrEP field is today, lessons learned from the past, the philosophy and practicalities of how successful programming may be defined, and provides perspectives of costs and affordability. We argue that a successful PrEP programme is about effective intervention integration and ultimately keeping people HIV negative.

Performance of the Abbott RealTime MTB and MTB RIF/INH Assays in a Setting of High Tuberculosis and HIV Coinfection in South Africa.

South Africa is a country with a high incidence of tuberculosis (TB), complicated by coinfection with human immunodeficiency virus (HIV). The Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is used in South Africa as the test for the initial diagnosis of TB, and other molecular platforms such as the m2000 (Abbott Molecular, Des Plaines, IL, USA) are widely used for molecular monitoring of HIV load. The latter platform is now also equipped with the RealTime (RT) MTB and RealTime MTB RIF/INH assays for TB and first-line drug resistance screening but has not been evaluated in settings of HIV and TB coinfection. A prospective clinical validation study was conducted at a community health center in Johannesburg, South Africa, and consenting individuals with presumptive pulmonary TB were enrolled. The performance of the Abbott assays was compared with those of the Xpert MTB/RIF, liquid culture, drug susceptibility testing, and clinical case definitions. A statistical analysis was performed on 206 individuals (73% were HIV positive). The sensitivity and specificity of the RT MTB were 82.5% (confidence interval [CI], 67.2 to 92.7) and 93.1% (CI, 86.2 to 97.2) on raw sputum and 77.5% (CI, 61.5 to 89.2) and 95.1% (CI, 88.9 to 98.4) on concentrated sputum, respectively, compared with those from liquid culture. The RT MTB correctly identified 17/35 more smear-negative culture-positive specimens than the Xpert MTB/RIF. Both the RT MTB and the Xpert MTB/RIF displayed sensitivities >70% and specificities >90% in HIV-positive individuals. The available drug resistance results concurred with MTBDRplus and drug susceptibility profiles. The RT MTB assay has similar diagnostic performance to the Xpert MTB/RIF and is suited to testing presumptive TB patients coinfected with HIV. The existing laboratory information system connectivity, training, and technical support make this a viable polyvalent option to scale up TB alongside HIV laboratory testing services in South Africa.

The association between HIV (treatment), pregnancy serum lipid concentrations and pregnancy outcomes: a systematic review.

BACKGROUND: Observed adverse effects of antiretroviral therapy (ART) on the lipid profile could be of significance in pregnancy. This systematic review aims to summarize studies that investigated the association between HIV, ART and serum lipids during pregnancy and adverse pregnancy outcomes. METHODS: A systematic search was conducted in five electronic databases to obtain articles that measured serum lipid concentrations or the incidence of dyslipidaemia in HIV-infected pregnant women. Included articles were assessed for quality according to the Cochrane Risk of Bias Tool. The extracted data was analysed through descriptive analysis. RESULTS: Of the 1264 articles screened, 17 articles were included in this review; eleven reported the incidence of dyslipidaemia, and twelve on maternal serum lipid concentrations under the influence of HIV-infection and ART. No articles reported pregnancy outcomes in relation to serum lipids. Articles were of acceptable quality, but heterogenic in methods and study design. Lipid levels in HIV-infected women increased 1.5-3 fold over the trimesters of pregnancy, and remained within the physiological reference range. The percentage of women with dyslipidaemia was variable between the studies [0-88.9%] and highest in the groups on first generation protease inhibitors and for women on ART at conception. CONCLUSION: This systematic review observed physiologic concentrations of serum lipids for HIV-infected women receiving ART during pregnancy. Serum lipids were increased in users of first generation protease inhibitors and for those on treatment at conception. There was no information available about pregnancy outcomes. Future studies are needed which include HIV-uninfected control groups, control for potential confounders, and overcome limitations associated with included studies.

Sexual and reproductive health outcomes among female sex workers in Johannesburg and Pretoria, South Africa: Recommendations for public health programmes.

BACKGROUND: The sexual and reproductive health (SRH) status of female sex workers is influenced by a wide range of demographic, behavioural and structural factors. These factors vary considerably across and even within settings. Adopting an overly standardised approach to sex worker programmes may compromise its impact on some sub-groups in local areas. METHODS: Records of female sex workers attending clinic-, community-, or hotel-based health services in Johannesburg (n = 1422 women) and Pretoria (n = 408 women), South Africa were analysed. We describe the population's characteristics and identified factors associated with sexual and reproductive health outcomes, namely HIV status; previous symptomatic sexually transmitted infection (STI); modern contraceptive use and number of child dependents. RESULTS: The women in Johannesburg were less likely than those in Pretoria to have HIV (42.2% vs 52.9%), or previous symptomatic STIs (44.3% vs. 8.3%), and were 1.4 fold less likely to have child dependents (20.1% vs. 15.3%). About 43% of women in Johannesburg were Zimbabwean and 40% in Pretoria. Of concern, only about 15% of women in both sites were using modern contraceptives. Johannesburg women were also more likely to access health services at a hotel (85.0% vs. 80.6%) or clinic (5.7% vs. 0.5%), to have completed secondary education (57.1% vs. 36.0%), and moved house more than twice during the past year (19.6 vs. 2.0%). In both cities, risk of HIV rose rapidly with age (23.8%-58.2% vs. 22.0%-64.8%). Of interest, HIV prevalence was considerably higher in those with consistent condom use with one's main partner than inconsistent users. CONCLUSIONS: Sex worker populations are heterogeneous. Local health programmes must prioritise services that reflect the variety and complexity of sex worker needs and behaviours, and should be designed in consultation with sex workers. Segmenting sex worker populations according to age, country of origin and place of service delivery, and training healthcare providers accordingly, could help prevent new HIV infections, improve adherence to antiretroviral treatment and increase uptake of SRH services.

Accelerating the Uptake and Timing of Antiretroviral Therapy Initiation in Sub-Saharan Africa: An Operations Research Agenda.

Sydney Rosen and colleagues describe an operations research agenda to accelerating uptake of HIV treatment initiation.

Starter packs versus full prescription of antiretroviral drugs for postexposure prophylaxis: a systematic review.

BACKGROUND: The provision of starter packs for human immunodeficiency virus postexposure prophylaxis (PEP) is practiced in many settings to facilitate rapid initiation by nonexperts and encourage adherence. However, the impact of starter packs on PEP completion rates has not been systematically assessed. We systematically reviewed the evidence on outcomes associated with starter packs for PEP compared to full prescriptions. METHODS: Four databases and 2 conference abstract sites were searched up to December 2013; this search was updated in 1 database in June 2014. PEP completion rates, stratified by prescribing practice, were pooled using random-effects meta-analysis. RESULTS: Fifty-four studies provided data on 11 714 PEP initiations. Thirty-seven studies, including 3 randomized controlled trials (RCTs) and 34 observational cohorts, provided information on starter packs (although none of the RCTs specifically assessed starter packs), and 17 studies, including 2 RCTs and 15 observational cohorts, provided information on full prescriptions. Overall, outcomes were better when participants were offered a full 28-day course of PEP at initial presentation to healthcare, with fewer refusals (11.4% [95% confidence interval {CI}, 5.3%-17.5%] vs 22% [95% CI, 16.7%-28.1%]) and higher completion rates (70% [95% CI, 56.7%-77.3%] vs 53.2% [95% CI, 44.4%-62.2%]). More than a quarter (28% [95% CI, 21.4%-34.5%]) of individuals provided with a PEP starter pack failed to return for their subsequent appointment and therefore defaulted prior to receiving a full course of PEP. The quality of the evidence overall was rated as very low. CONCLUSIONS: The findings of this review suggest that starter packs do not improve adherence to PEP and may result in lower adherence and completion rates.

Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: a South African public hospital case series of over 1,000 women.

Advanced stage at diagnosis contributes to low breast cancer survival rates in sub-Saharan Africa. Living far from health services is known to delay presentation, but the effect of residential distance to hospital, the radius at which this effect sets in and the women most affected have not been quantified. In a periurban South African setting, we examined the effect of a geographic information system (GIS)-measured straight-line distance, from a patient's residence to diagnostic hospital, on stage at diagnosis in 1,071 public-sector breast cancer patients diagnosed during 2006-2012. Generalized linear models were used to estimate risk ratios for late stage (stage III/IV vs. stage I/II) associated with distance, adjusting for year of diagnosis, age, race and socioeconomic indicators. Mean age of patients was 55 years, 90% were black African and diagnoses were at stages I (5%), II (41%), III (46%) and IV (8%). Sixty-two percent of patients with distances >20 km (n = 338) had a late stage at diagnosis compared to 50% with distances <20 km (n = 713, p = 0.02). Risk of late stage at diagnosis was 1.25-fold higher (95% CI: 1.09, 1.42) per 30 km. Effects were pronounced in an underrepresented group of patients over age 70. This positive stage-distance association held to 40 km, and plateaued or slightly reversed in patients (9%) living beyond this distance. Studies of woman and the societal and healthcare-level influences on these delays and on the late stage at diagnosis distribution are needed to inform interventions to improve diagnostic stage and breast cancer survival in this and similar settings.