Improvement studies for equitable and evidence-based innovation: an overview of the 'IM-SEEN' model.

BACKGROUND: Health inequalities are ubiquitous, and as countries seek to expand service coverage, they are at risk of exacerbating existing inequalities unless they adopt equity-focused approaches to service delivery. MAIN TEXT: Our team has developed an equity-focused continuous improvement model that reconciles prioritisation of disadvantaged groups with the expansion of service coverage. Our new approach is based on the foundations of routinely collecting sociodemographic data; identifying left-behind groups; engaging with these service users to elicit barriers and potential solutions; and then rigorously testing these solutions with pragmatic, embedded trials. This paper presents the rationale for the model, a holistic overview of how the different elements fit together, and potential applications. Future work will present findings as the model is operationalised in eye-health programmes in Botswana, India, Kenya, and Nepal. CONCLUSION: There is a real paucity of approaches for operationalising equity. By bringing a series of steps together that force programme managers to focus on groups that are being left behind, we present a model that can be used in any service delivery setting to build equity into routine practice.

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Baseline predictors of efavirenz-containing antiretroviral regimen adverse experiences.

PURPOSE: We aimed to identify modifiable, routinely available patient characteristics associated with adverse experiences potentially attributable to efavirenz-based regimens in patients in Botswana. METHODS: HIV-infected treatment naïve individuals starting a standard antiretroviral regimen including two nucleoside analog reverse transcriptase inhibitors and efavirenz in Botswana were enrolled in a prospective cohort. Adverse experiences were measured at 1 and 6 months using the efavirenz checklist, a 35-item instrument developed by the AIDS Clinical Trials Group. RESULTS: We enrolled 232 patients from 11 March 2010 to 17 March 2011. One hundred ninety-six were included in the month 1 analyses. Of the 196 included in the month 1 analyses, 157 (80%) completed the 6-month follow-up. Median efavirenz checklist score was 6 (interquartile range (IQR): 2-15) at month 1 and 1 (IQR: 0-5) at month 6. The median change in efavirenz checklist score from month 1-6 was -4 (IQR: -11 to -1), representing an improvement. Depressive symptoms, low CD4 count and less alcohol use were associated with improvement in adverse experiences over time. Low weight was associated with increased extent of adverse experiences at month 1 and 6. There was no confounding or effect modification. CONCLUSIONS: Clinicians may want to consider more intensive and tailored adverse experience education and management in patients based on depressive symptoms, CD4 count, and weight. Further assessment of the mechanism of the effect of alcohol use on adverse experiences, including analysis of CYP2B6 genotype and plasma efavirenz concentrations, is warranted.

Protocol for an automated, pragmatic, embedded, adaptive randomised controlled trial: behavioural economics-informed mobile phone-based reminder messages to improve clinic attendance in a Botswanan school-based vision screening programme.

BACKGROUND: Clinic non-attendance rates are high across the African continent. Emerging evidence suggests that phone-based reminder messages could make a small but important contribution to reducing non-attendance. We will use behavioural economics principles to develop an SMS and voice reminder message to improve attendance rates in a school-based eye screening programme in Botswana. METHODS: We will test a new theory-informed SMS and voice reminder message in a national school-based eye screening programme in Botswana. The control will be the standard SMS message used to remind parents/guardians to bring their child for ophthalmic assessment. All messages will be sent twice. The primary outcome is attendance for ophthalmic assessment. We will use an automated adaptive approach, starting with a 1:1 allocation ratio. DISCUSSION: As far as we are aware, only one other study has used behavioural economics to inform the development of reminder messages to be deployed in an African healthcare setting. Our study will use an adaptive trial design, embedded in a national screening programme. Our approach can be used to trial other forms of reminder message in the future. TRIAL REGISTRATION: ISRCTN 96528723 . Registered on 5 January 2022.

Sociodemographic characteristics of community eye screening participants: protocol for cross-sectional equity analyses in Botswana, India, Kenya, and Nepal.

Background: Attendance rates for eye clinics are low across low- and middle-income countries (LMICs) and exhibit marked sociodemographic inequalities. We aimed to quantify the association between a range of sociodemographic domains and attendance rates from vision screening in programmes launching in Botswana, India, Kenya and Nepal. Methods: We performed a literature review of international guidance on sociodemographic data collection. Once we had identified 13 core candidate domains (age, gender, place of residence, language, ethnicity/tribe/caste, religion, marital status, parent/guardian status, place of birth, education, occupation, income, wealth) we held workshops with researchers, academics, programme implementers, and programme designers in each country to tailor the domains and response options to the national context, basing our survey development on the USAID Demographic and Health Survey model questionnaire and the RAAB7 eye health survey methodology. The draft surveys were reviewed by health economists and piloted with laypeople before being finalised, translated, and back-translated for use in Botswana, Kenya, India, and Nepal. These surveys will be used to assess the distribution of eye disease among different sociodemographic groups, and to track attendance rates between groups in four major eye screening programmes. We gather data from 3,850 people in each country and use logistic regression to identify the groups that experience the worst access to community-based eye care services in each setting. We will use a secure, password protected android-based app to gather sociodemographic information. These data will be stored using state-of-the art security measures, complying with each country's data management legislation and UK law. Discussion: This low-risk, embedded, pragmatic, observational data collection will enable eye screening programme managers to accurately identify which sociodemographic groups are facing the highest systematic barriers to accessing care at any point in time. This information will be used to inform the development of service improvements to improve equity.

High-risk human papillomavirus prevalence in self-collected cervicovaginal specimens from human immunodeficiency virus (HIV)-negative women and women living with HIV living in Botswana.

BACKGROUND: The prevalence of high-risk human papillomavirus (hrHPV) is poorly described overall and in women living with HIV (WLWH) and HIV-negative women living in Botswana, a high HIV and cervical cancer-burden country. We conducted a pilot study of self-collection and high-risk HPV testing for cervical screening, from which data on HPV prevalence was available. METHODS: From five health facilities in the Kweneng East District, 1,022 women aged 30-49 years were enrolled to self-collect their cervicovaginal specimen for hrHPV testing by the Xpert HPV Test (Cepheid, Sunnyvale, CA, USA). Crude and age group-adjusted hrHPV prevalence by HIV status were calculated, and the relationship of hrHPV risk groups HPV16>HPV18/45>other hrHPV types) to the presence and severity of visible lesions. RESULTS: Of the 1,022 women enrolled, 1,019 (99.7%), 570 WLWH and 449 HIV-negative women, had hrHPV testing results. Crude hrHPV prevalences were 25.2% (95%CI = 21.2-29.4%) for HIV-negative women and 40.4% (95%CI = 36.3-44.5%) for WLWH. Age group-adjusted hrHPV prevalences were 23.7% (95%CI = 19.9-27.9%) for HIV-negative women and 41.3% (95%CI = 37.2-45.4%) for WLWH. Age group-adjusted prevalences of HPV16 (p<0.001), HPV18/45 (p<0.001), HPV31/33/35/52/58 (p<0.001), and HPV39/56/66/68 (p = 0.011) were greater among WLWH than HIV-negative women. Riskier hrHPV groups were more likely to have visible abnormalities (ptrend = 0.004) and visible abnormalities not eligible for cryotherapy (ptrend = 0.030). CONCLUSIONS: hrHPV infection was common among all women in the study living in Botswana, to a greater extent in WLWH than their HIV-negative counterparts. Strategies to triage hrHPV-positive women will be needed to avoid over-treating many women with benign hrHPV infections.

Vitamin D status, nutrition and growth in HIV-infected mothers and HIV-exposed infants and children in Botswana.

BACKGROUND: Poor vitamin D status is a global health problem and common in patients with human immunodeficiency virus (HIV) in high-income countries. There is less evidence on prevalence of vitamin D deficiency and nutrition and growth in HIV-infected and -exposed children in low- and middle-income countries. OBJECTIVES: To determine the vitamin D status in Batswana HIV-infected mothers and their children, differences among HIV-infected mothers and between HIV-exposed and -infected infants and children, and associations between vitamin D and disease-related outcomes, nutrition, and growth. METHODS: This was a cross-sectional study of HIV+ mothers and HIV-exposed infants and unrelated children (1-7.9 years). Serum 25-hydroxyvitamin D (25(OH)D) was measured, among other nutritional indicators, for mothers, infants and children. Vitamin D status for HIV-infected mothers and children, and an immune panel was assessed. History of HIV anti-retroviral medications and breastfeeding were obtained. Data were collected prior to universal combination antiretroviral therapy in pregnancy. RESULTS: Mothers (n = 36) had a mean serum 25(OH)D of 37.2±12.4ng/mL; 11% had insufficient (<20ng/mL), 17% moderately low (20.0-29.9ng/mL) and 72% sufficient (≥30ng/mL) concentrations. No infants (n = 36) or children (n = 48) were vitamin D insufficient; 22% of HIV- and no HIV+ infants had moderately low concentrations and 78% of HIV- and 100% of HIV+ infants had sufficient status, 8% of HIV- and no HIV+ children had moderately low concentrations and 92% of HIV- and 100% HIV+ children had sufficient concentrations. HIV+ children had significantly lower length/height Z scores compared to HIV- children. Length/height Z score was positively correlated with serum 25(OH)D in all children (r = 0.33, p = 0.023), with a stronger correlation in the HIV+ children (r = 0.47 p = 0.021). In mothers, serum 25(OH)D was positively associated with CD4% (r = 0.40, p = 0.016). CONCLUSIONS: Results showed a low prevalence of vitamin D insufficiency in Botswana. Growth was positively correlated with vitamin D status in HIV-exposed children, and HIV+ children had poorer linear growth than HIV- children.

Impact of Efavirenz Metabolism on Loss to Care in Older HIV+ Africans.

BACKGROUND AND OBJECTIVE: Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people. METHODS: We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care. RESULTS: Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants. CONCLUSION: Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.

Investigating Mediators of the Poor Pneumonia Outcomes of Human Immunodeficiency Virus-Exposed but Uninfected Children.

BACKGROUND: Human immunodeficiency virus-exposed but uninfected (HIV-EU) children have a higher mortality rate than the children of HIV-negative mothers (HIV-unexposed). Causal mediators of the poor health outcomes of HIV-EU children remain poorly defined. METHODS: We conducted a hospital-based prospective cohort study of children aged 1 to 23 months with clinically defined pneumonia. The children were recruited at a referral hospital in Gaborone, Botswana, between April 2012 and June 2016. The primary outcome, treatment failure at 48 hours, was assessed by an investigator blinded to the children's HIV-exposure status. We examined associations between HIV exposure and pneumonia outcomes in HIV-uninfected children. We next determined whether the effect of HIV exposure on outcomes was mediated by low-birth-weight status, nonbreastfeeding, malnutrition, in utero exposure to combination antiretroviral therapy, or pneumonia severity. RESULTS: A total of 352 HIV-uninfected children were included in these analyses, including 245 (70%) HIV-unexposed and 107 (30%) HIV-EU children. Their median age was 7.4 months, and 57% were male. Treatment failure occurred in 111 (32%) children, and 19 (5.4%) children died. HIV-EU children were more likely to fail treatment (risk ratio [RR], 1.57 [95% confidence interval (CI), 1.19-2.07]; P = .002) and had a higher in-hospital mortality rate (RR, 4.50 [95% CI, 1.86-10.85]; P = .001) than HIV-unexposed children. Nonbreastfeeding mediated 47% of the effect of HIV exposure on the risk of in-hospital death. CONCLUSIONS: HIV-EU children have worse pneumonia outcomes than HIV-unexposed children. Nonbreastfeeding mediates nearly half of the effect of HIV exposure on pneumonia mortality. Our findings provide additional evidence for a mortality benefit of breastfeeding by HIV-EU children.

Effects of sex and alcohol use on antiretroviral therapy outcomes in Botswana: a cohort study.

AIMS: To determine alcohol use effect on HIV treatment success and whether alcohol use mediates the relation between male sex and treatment failure. DESIGN: Longitudinal cohort study. SETTING: Eight HIV clinics in and near Gaborone, Botswana. PARTICIPANTS: A total of 938 HIV-infected treatment-naive adults initiating regimens containing the antiretroviral medication efavirenz between June 2009 and February 2013, including 478 (51%) males, median age 38 years, and plasma HIV RNA 4.9 log10 copies/ml. MEASUREMENTS: Primary outcome was a composite of treatment failure over 6 months including death, lost to care or plasma HIV RNA > 25 copies/ml. Exposures included alcohol use and gender. FINDINGS: Failure in 339 (36%) participants included 40 (4%) deaths, 194 (21%) lost to care and 105 (11%) with HIV RNA > 25 copies/ml. Both hazardous alcohol use in the past year [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) = 1.0, 1.9] and male sex (aOR = 2.1, 95% CI = 1.5, 2.9) were associated with failure. Hazardous alcohol use in the year prior to enrollment was more common in men (57%) than women (24%), P < 0.001. There was no difference in alcohol use effect on failure between sexes (P for interaction > 0.5). Controlling for hazardous alcohol use did not change the relation between sex and failure. CONCLUSION: Alcohol use among HIV-infected adults in Botswana appears to worsen HIV treatment outcomes. Alcohol use does not appear to have either a mediating or a moderating effect on the relation between gender and HIV treatment outcome failure.

CYP2B6 genotypes and early efavirenz-based HIV treatment outcomes in Botswana.

OBJECTIVES: To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes. DESIGN: Observational cohort study of HIV-infected adults initiating efavirenz-based regimens in Botswana. METHODS: The primary endpoint was a composite of death or loss to care or HIV RNA more than 25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured by using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint. RESULTS: A total of 801 individuals included 406 (51%) men, median age 37 years, median baseline CD4 cell count 195 cells/µl, and plasma HIV RNA 4.9 log10 copies/ml. 288 (36%) reached the endpoint, including 34 (4%) deaths, 151 (19%) lost to care, 11 (1%) lost to the study, but alive and in care, and 92 (11%) with plasma HIV RNA more than 25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences. CONCLUSION: Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate central nervous system toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.

Brief Report: CYP2B6 516G>T Minor Allele Protective of Late Virologic Failure in Efavirenz-Treated HIV-Infected Patients in Botswana.

BACKGROUND: CYP2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYP2B6 516G>T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana. SETTING: We performed a case-control study that included 1338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between July 2013 and April 2014. METHODS: Cases experienced late HIV failure, defined as plasma HIV RNA >1000 copies/mL after maintaining viral suppression (<400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA <400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G>T genotype. RESULTS: After adjustment for the confounding variables age and CD4 count, the CYP2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95% CI: 0.50 to 0.97. CONCLUSION: The CYP2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYP2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.

Vitamin D3supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial.

OBJECTIVES: Since vitamin D insufficiency is common worldwide in people with HIV, we explored safety and efficacy of high dose cholecalciferol (D3) in Botswana, and evaluated potential modifiers of serum 25 hydroxy vitamin D change (Δ25D). DESIGN: Prospective randomized double-blind 12-week pilot trial of subjects ages 5.0-50.9 years. METHODS: Sixty subjects randomized within five age groups to either 4000 or 7000 IU per day of D3 and evaluated for vitamin D, parathyroid hormone, HIV, safety and growth status. Efficacy was defined as serum 25 hydroxy vitamin D (25D) ≥32 ng/mL, and safety as no simultaneous elevation of serum calcium and 25D. Also assessed were HIV plasma viral RNA viral load (VL), CD4%, anti-retroviral therapy (ART) regime, and height-adjusted (HAZ), weight-adjusted (WAZ) and Body Mass Index (BMIZ) Z scores. RESULTS: Subjects were 50% male, age (mean±SD) 19.5±11.8 years, CD4% 31.8±10.4, with baseline VL log10 range of <1.4 to 3.8 and VL detectable (>1.4) in 22%. From baseline to 12 weeks, 25D increased from 36±9 ng/ml to 56±18 ng/ml (p<0.0001) and 68% and 90% had 25D ≥32 ng/ml, respectively (p = 0.02). Δ25D was similar by dose. No subjects had simultaneously increased serum calcium and 25D. WAZ and BMIZ improved by 12 weeks (p<0.04). HAZ and CD4% increased and VL decreased in the 7000 IU/d group (p<0.04). Younger (5-13y) and older (30-50y) subjects had greater Δ25D than those 14-29y (26±17 and 28±12 vs. 11±11 ng/ml, respectively, p≤0.001). Δ25D was higher with efavirenz or nevirapine compared to protease inhibitor based treatment (22±12, 27±17, vs. 13±10, respectively, p≤0.03). CONCLUSIONS: In a pilot study in Botswana, 12-week high dose D3 supplementation was safe and improved vitamin D, growth and HIV status; age and ART regimen were significant effect modifiers. TRIAL REGISTRATION: ClinicalTrials.gov NCT02189902.

Cervical cancer prevention in HIV-infected women using the "see and treat" approach in Botswana.

BACKGROUND: Cervical cancer is a major public health problem in resource-limited settings, particularly among HIV-infected women. Given the challenges of cytology-based approaches, the efficiency of new screening programs need to be assessed. SETTING: Community and hospital-based clinics in Gaborone, Botswana. OBJECTIVE: To determine the feasibility and efficiency of the "see and treat" approach using visual inspection acetic acid (VIA) and enhanced digital imaging (EDI) for cervical cancer prevention in HIV-infected women. METHODS: A 2-tier community-based cervical cancer prevention program was implemented. HIV-infected women were screened by nurses at the community using the VIA/EDI approach. Low-grade lesions were treated with cryotherapy on the same visit. Women with complex lesions were referred to our second tier specialized clinic for evaluation. Weekly quality control assessments were performed by a specialist in collaboration with the nurses on all pictures taken. RESULTS: From March 2009 through January 2011, 2175 patients were screened for cervical cancer at our community-based clinic. Two hundred fifty-three patients (11.6%) were found to have low-grade lesions and received same-day cryotherapy. One thousand three hundred forty-seven (61.9%) women were considered to have a normal examination, and 575 (27.3%) were referred for further evaluation and treatment. Of the 1347 women initially considered to have normal exams, 267 (19.8%) were recalled based on weekly quality control assessments. Two hundred ten (78.6%) of the 267 recalled women, and 499 (86.8%) of the 575 referred women were seen at the referral clinic. Of these 709 women, 506 (71.4%) required additional treatment. Overall, 264 cervical intraepithelial neoplasia stage 2 or 3 were identified and treated, and 6 microinvasive cancers identified were referred for further management. CONCLUSIONS: Our "see and treat" cervical cancer prevention program using the VIA/EDI approach is a feasible, high-output and high-efficiency program, worthy of considering as an additional cervical cancer screening method in Botswana, especially for women with limited access to the current cytology-based screening services.