Non-booking for antenatal care and risks for vertical HIV transmission among women in Chitungwiza, Zimbabwe: a cross-sectional study.

BACKGROUND: The success of prevention of mother to child transmission of HIV (PMTCT) programs dependents on pregnant women accessing antenatal care (ANC) services. Failure to access ANC throughout the course of pregnancy presents a missed opportunity to fully utilize PMTCT services and a high risk for vertical HIV transmission. Whilst not booking for ANC was about 6% in Zimbabwe, according to the 2015 Zimbabwe Demographic and Health Survey, it is important to determine the local burden of pregnant women both un-booked for ANC and living with HIV. in Chitungwiza city, to inform local response. This study aimed at determining the proportion of women un-booked for antenatal care and among them, the proportion of women who were with HIV and to identify risk factors associated with not-booking for ANC in Chitungwiza city in Zimbabwe. METHODS: A cross-sectional study was conducted involving a review of clinic records for 4400 women who received postnatal care at all 4 maternity clinics in Chitungwiza city between 01 January 2017 and 31 December 2017. Bivariate and multiple logistic regression analysis with Chi squared test were used to determine risk factors associated with booking status while adjusting for other study variables. All statistics tests' decisions were concluded at 5% level of significance. All data analysis was performed using STATA (version 13) statistical package. RESULTS: A total of 4400 women were attended to and of these, 19% were un-booked for ANC, while a total of 3% of the women were both un-booked and living with HIV. The women with HIV were 0.24 times less likely to book for ANC than HIV negative women, adjusted OR = 0.76 (95% CI: 0.61-0.98). Women aged 20-34 years were 1.3 times more likely to book than the teenagers, adjusted OR = 1.3 (95% CI: 1.04-1.62). CONCLUSION: The proportion of women not booked for ANC of 19% was unexpectedly high. With 3% of pregnant women in Chitungwiza having both HIV and no access to ANC, the risk for vertical HIV transmission remains. More need to be done to improve ANC access, targeting teenage mothers and those living with HIV who are more less likely to access ANC.

Importation and distribution of unregistered medicines in the public sector: similarities, differences, and shared challenges among Southern African Development Community (SADC) countries.

BACKGROUND: The purpose of the study was to assess the requirements for approval of the importation of unregistered medicines for use in the public sector in the Southern African Development Community (SADC) countries. METHODS: The study reviewed the legal provisions and requirements to be fulfilled when importing unregistered medicines for the public sector in SADC countries relative to two comparators drawn from countries with stringent regulatory systems through extant document analysis. The relative implementation index score was calculated and used to measure the level of implementing legal provisions and requirements to be fulfilled. Analysis was performed using the STATA software package. RESULTS: Approximately 13 out of 16 SADC countries had a relative implementation index below 50%. The aggregated implementation index across all SADC countries was 44%, ranging from 4 to 54%, while the two comparators had a relative implementation index of 81% and 85%, respectively. CONCLUSION: Implementing the minimum requirements for importing unregistered medicines for the public sector was deficient compared to the jurisdictions with stringent regulatory systems, and wide implementation gaps also existed within the SADC region.

Regulation of medicines advertisement in Zimbabwe: an assessment of the impact of pharmaceutical promotion on the prescribing behaviour of healthcare professionals.

BACKGROUND: The pharmaceutical industry plays a key role in drug discovery and is considered useful regards to informing the health care workers health care workers about new medicines. Investigations concerning health care workers to industry interactions are less common. The objective of this study is to determine levels of knowledge, attitude and perception towards regulation of pharmaceutical promotion among healthcare practitioners in Zimbabwe. METHODS: A cross-sectional study was used and 330 healthcare practitioners were enrolled into the study. Data collection was done through combined face-to-face interviews and web-based online survey. The relative importance index score and used as a measure of knowledge, attitude and perception levels towards pharmaceutical promotion. Univariate and bivariate analysis was performed using STATA software package. RESULTS: Our study estimated that 95%, 67%, and 90% of the healthcare practitioners in Zimbabwe have a favourable (i.e. > 65%) relative importance index score of knowledge, attitudes, and perception, respectively, towards regulation of pharmaceutical promotion. Further exploration of the data indicated that the factors that had an association with the knowledge, attitude and perception levels towards regulation of pharmaceutical regulation at 5% level of significance include health care workers' profession, gender, education level, the nature of the working institution and the number of prescriptions involved per week. CONCLUSION: In conclusion, the findings of this study highlighted that in general the health care workers in Zimbabwe have higher levels of knowledge, attitude and perception towards regulation of pharmaceutical promotion, though the attitudes levels weres a  bit lower compared to other domains.

Genotypic diversity of anogenital human papillomavirus in women attending cervical cancer screening in Harare, Zimbabwe.

Although anogenital cancers have been on a gradual rise in developing countries in the past few decades, they have been understudied. The objective was to investigate genotypic diversity of anogenital HPV amongst women reporting for routine cervical cancer screening in Harare in Zimbabwe. A cross-sectional study that enrolled 144 women ≥18 years from a cervical cancer-screening clinic was performed. Each woman provided a self-collected cervico-vaginal swab (VS) and a clinician-collected anal swab (CCAS). HIV testing was offered and cervical cytology was performed. Both VS and CCAS samples were HPV genotyped, using amplicon sequencing of the L1 gene region with Illumina technology. Mean age of the women was 39.9 (range 18-83 years, SD ± 11.0). HPV prevalence was 72% (104/144) in VS and 48% (69/144) in CCAS. The most common genotypes detected in both VS and CCAS were HPV18, HPV52, and HPV16. Sixty two percent of the subjects had multiple genotypic HPV infections. The odds of being HPV-positive among HIV-infected women were higher than in HIV-negative women in both the vagina and the anus (CCAS OR = 4.8; CI 2.4-9.8, P < 0.001) and (VS OR = 2.9; CI 1.3-6.4, P = 0.005). High HPV prevalence and diverse genotypes were detected in both the vagina and anus. Anal oncogenic HPV infection was common. HPV 52 was one of the most common oncogenic genotypes in both the vagina and anus. HIV co-infection played a significant role in the prevalence of HPV. These data have implications for design of primary and secondary programs for prevention of anogenital cancer in Zimbabwe.

Risk of mortality in HIV-infected COVID-19 patients: A systematic review and meta-analysis.

BACKGROUND: The relationship between HIV infection and COVID-19 clinical outcomes remains a significant public health research problem. We aimed to determine the association of HIV comorbidity with COVID-19 mortality. METHODS: We searched PubMed, Google Scholar and World Health Organization library databases for relevant studies. All searches were conducted from 1st to 7th December 2021. Title, abstract and full text screening was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality in HIV-infected COVID-19 patients was computed using a random-effects model. All analyses were performed using Meta and Metasens statistical packages available in R version 4.2.1 software package. The quality of included studies was assessed using the GRADE approach, Egger's test was employed to determine the risk of bias. RESULTS: A total of 16 studies were included in this review. Among the COVID-19 patients with HIV infection, the mortality rate due to COVID-19 was 7.97% (4 287/53,801), and among the COVID-19 patients without HIV infection, the mortality rate due to COVID-19 was 0.69% (127, 961/18, 513, 747). In the random effects model, we found no statistically significant relative risk of mortality in HIV-infected COVID-19 patients (RR 1.07, 95% CI 0.86-1.32). The between-studies heterogeneity was substantial (I2 = 91%, P < 0.01), while the risk of publication bias was not significant. CONCLUSION: Findings did not link HIV infection with an increased risk of COVID-19 mortality. Our results add to the conflicting data on the relationship between COVID-19 and HIV infection.

Risk Factors for COVID-19 Infection Among Healthcare Workers. A First Report From a Living Systematic Review and meta-Analysis.

Health care workers (HCWs) are more than ten times more likely to be infected with coronavirus infectious disease 2019 (COVID-19) than the general population, thus demonstrating the burden of COVID-19 among HCWs. Factors that expose HCWs to a differentially high-risk of COVID-19 acquisition are important to elucidate, enable appropriate public health interventions to mitigate against high risk and reduce adverse outcomes from the infection. We conducted a systematic review and meta-analysis to summarize and critically analyze the existing evidence on SARS-CoV-2 risk factors among HCWs. With no geographical limitation, we included studies, in any country, that reported (i) the PCR laboratory diagnosis of COVID-19 as an independent variable (ii) one or more COVID-19 risk factors among HCWs with risk estimates (relative risk, odds ratio, or hazard ratio) (iii) original, quantitative study design, and published in English or Mandarian. Our initial search resulted in 470 articles overall, however, only 10 studies met the inclusion criteria for this review. Out of the 10 studies included in the review, inadequate/lack of protective personal equipment, performing tracheal intubation, and gender were the most common risk factors of COVID-19. Based on the random effects adjusted pooled relative risk, HCWs who reported the use of protective personal equipment were 29% (95% CI: 16% to 41%) less likely to test positive for COVID-19. The study also revealed that HCWs who performed tracheal intubations were 34% (95% CI: 14% to 57%) more likely to test positive for COVID-19. Interestingly, this study showed that female HCWs are at 11% higher risk (RR 1.11 95% CI 1.01-1.21) of COVID-19 than their male counterparts. This article presents initial findings from a living systematic review and meta-analysis, therefore, did not yield many studies; however, it revealed a significant insight into better understanding COVID-19 risk factors among HCWs; insights important for devising preventive strategies that protect them from this infection. PROSPERO registration number: CRD42020193508 available for public comments via the link below https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193508).

Impact of Motivational Enhanced Adherence Counseling and Point-of-Care Viral Load Monitoring on Viral Load Outcome in Women on Life-Long ART: A Randomized Pilot Study.

We piloted the combined effectiveness of point-of-care viral load monitoring plus motivational enhanced adherence counseling (intervention) compared with routine care (control) in women identified at risk of virologic failure in the PROMOTE study in Zimbabwe. In an unblinded randomized study, consenting women with last viral load ≥200 copies/ml and/or pill count outside 90-110% range were randomized 1 : 1 to receive the intervention or continue routine care, comprising laboratory-based VL monitoring and standard EAC, from trained nurses and counsellors. Viral load was measured 0, 3, 6, and 12 months after enrolment. We compared viral suppression <200 copies/ml at 6 and 12 months between the arms through Fisher's exact test and sought associated factors by logistic regression with a 95% confidence interval (CI). Between December 2018 and July 2019, 50 women were enrolled (25 intervention and 25 controls) and followed until November 2020. At entry, 60% of the women were virally suppressed, 52% intervention vs. 68% control arm. Viral suppression was balanced between the two arms (p value = 0.248). At month 6 post study entry (primary endpont), 64% of the women retained in care were virally suppressed, 54% intervention vs. 76% control arm (p value = 0.124). At month12 post study entry (secondary endpoint), 69% of the women retained in care were virally suppressed, 67% intervention vs. 71% control arm women (p value = 0.739). More intervention women completed all scheduled sessions by month 6. Control group women were more likely to be virally suppressed at both timepoints. Only 25% had treatment switch by 12 months. Despite intense adherence support and viral load monitoring, sustained viral suppression remained elusive in women identified at risk of viral failure. These findings highlight the continued need for effective adherence intervention for women with unsuppressed HIV viral loads, efficient treatment switch strategies, as well as drug level monitoring.

Pharmacokinetic-pharmacodynamic modelling of atazanavir in hair among adolescents on antiretroviral treatment in Zimbabwe.

BACKGROUND: Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug's maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The objective of our study is to determine potency of atazanavir in hair, defined as atazanavir level in hair associated with 50% probability of failing to achieve viral load below 1000 copies/ml among adolescents, and explore the effect of participant specific variables on potency. METHODS: A secondary analysis was performed on data from a previous study conducted in HIV-infected adolescents failing 2nd line ART from Harare central hospital, Zimbabwe, between 2015 and 2016. We simulated atazanavir concentrations in hair using NONMEM (version 7.3) ADVAN 13, based on a previously established pharmacokinetic model. Logistic regression methods were used for PKPD analysis. Simulations utilising PKPD model focused on estimation of potency and exploring the effect of covariates. RESULTS: The potency of atazanavir in hair was found to be 4.5 ng/mg hair before adjusting for covariate effects. Participants at three months follow-up, reporting adequate adherence, having normal BMI-for-age, and cared for by mature guardians had increased potency of atazanavir in hair of 2.6 ng/mg, however the follow-up event was the only statistically significant factor at 5% level. CONCLUSION: Atazanavir in hair in the range 2.6 to 4.5 ng/mg is associated with above 50% probability of early viral load suppression. Adherence monitoring to adolescents with lower potency of atazanavir is recommended. The effect self-reported adherence level, BMI-for-age, and caregiver status require further evaluation.

Short Communication: Higher Tenofovir Concentrations in Hair Are Associated with Decreases in Viral Load and Not Self-Reported Adherence in HIV-Infected Adolescents with Second-Line Virological Treatment Failure.

Objective methods of measuring antiretroviral adherence are limited. We assessed the relationship between tenofovir disoproxil fumarate (TDF) hair concentrations, self-reported adherence, and virological outcomes in HIV-infected adolescents in Harare, Zimbabwe. HIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for >6 months with viral load (VL) ≥1,000 copies/mL were randomized to either modified directly administered antiretroviral therapy (mDAART) or standard of care. Hair and VL samples were collected at baseline and after 90 days. Treatment outcome was defined as TDF concentrations in hair. Virological suppression was defined as VL <1,000 copies/mL. Thirty-four adolescents had TDF concentrations measured at baseline and follow-up. Mean (median); range age was 16 (16); 13-18 years and 53% were females. Nineteen (56%) were randomized to mDAART. Mean (SD); range TDF concentrations were 0.03 (0.04); 0-0.17 ng/mg hair and 0.06 (0.06); 0-0.3 ng/mg hair at baseline and follow-up, respectively. Higher TDF concentrations were associated with decreased VL [regression coefficient (RC) 0.8; 95% confidence interval (CI) 0.7-1.0; p = .008] and mDAART (RC 0.5; 95% CI 0.3-1.0; p = .04), but were not associated with self-reported adherence and virological suppression (VL <1,000 copies/mL). Higher TDF hair concentrations were observed with virological decrease and an adherence intervention. Hair antiretroviral concentrations could be useful in triggering adherence interventions among adolescents with second-line virological failure.

Risk factors for COVID-19 among healthcare workers. A protocol for a systematic review and meta-analysis.

BACKGROUND: Evidence on the spectrum of risk factors for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among front-line healthcare workers (HCWs) has not been well-described. While several studies evaluating the risk factors associated with SARS-CoV-2 infection among patient-facing and non-patient-facing front-line HCWs have been reported since the outbreak of the coronavirus disease in 2019 (COVID-19), and several more are still underway. There is, therefore, an immediate need for an ongoing, rigorous systematic review that continuously assesses the risk factors of SARS-CoV-2 infection among front-line HCWs. OBJECTIVE: Here, we outline a protocol to serve as a guideline for conducting a living systematic review and meta-analysis to examine the burden of COVID-19 on front-line HCWs and identify risk factors for SARS-CoV-2 infection in patient-facing and non-patient-facing front-line HCWs. METHODS: The protocol was developed and reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The conduct of the proposed living systematic review and meta-analysis will primarily follow the principles recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking systematic reviews in healthcare, and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The systematic literature searches will be performed using the EBSCOhost platform by searching the following databases within the platform: Academic search complete, health source: nursing/academic edition, CINAHL with full text, Embase, PubMed, MEDLINE, Science Direct databases, Google Scholar, and; also a search in the China National Knowledge Infrastructure and the World Health Organization library databases for relevant studies will be performed. The searches will include peer-reviewed articles, published in English and Mandarin language irrespective of publication year, evaluating the risk for testing positive for C0VID-19, the risk of developing symptoms associated with SARS-CoV-2 infection, or both, among front-line HCWs. The initial review period will consider articles published since the onset of COVID-19 disease to the present and then updated monthly. Review Manager (RevMan 5.3) will be used to pool the odds ratios or mean differences for individual risk factors where possible. Results will be presented as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences, or standardised mean differences along with 95% confidence intervals, for continuous outcomes. The Newcastle-Ottawa Scale will be used to rate study quality, and the certainty of the evidence will be assessed by using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The results of the living systematic review and meta-analysis will be reported per the PRISMA guidelines. DISCUSSION: Though addressing the needs of front-line HCWs during the COVID-19 pandemic is a high priority, data to inform such initiatives are inadequate, particularly data on the risk factor disparities between patient-facing and non-patient-facing front-line HCWs. The proposed living systematic review and meta-analysis anticipate finding relevant studies reporting risk factors driving the SARS-CoV-2 infection rates among patient-facing and non-patient-facing front-line HCWs, thus providing subsidies for public health interventions and occupational health policies. The study results will be disseminated electronically, in print and through conference presentation, and key stakeholder meetings in the form of policy briefs. TRAIL REGISTRATION: PROSPERO registration number: CRD42020193508 available for public comments via the link below https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193508).

Brief Report: Ritonavir Concentrations in Hair Predict Virologic Outcomes in HIV-Infected Adolescents With Virologic Failure on Atazanavir-Based or Ritonavir-Based Second-Line Treatment.

BACKGROUND: Suboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe. METHODS: HIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load ≥1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as <1000 copies/mL after follow-up. RESULTS: Fifty adolescents (13-19 years) were enrolled in the study, and 42 adolescents had ritonavir concentrations measured in hair at baseline and at 90 days. Twenty-three participants (46%) were randomized to mDAART. Viral load suppression at follow-up [regression coefficient (standard error): -0.3 (0.1); 95% confidence interval (CI): -0.5 to -0.06; P = 0.01], self-reported adherence at follow-up [regression coefficient (standard error): 0.01 (0.005); 95% CI: 0.004 to 0.02; P = 0.006], and being male sex [regression coefficient (standard error): 0.3 (0.1); 95% CI: 0.08 to 0.5; P = 0.008] were associated with ritonavir concentrations in hair. The intervention, mDAART, was not associated with ritonavir concentrations [regression coefficient (standard error) 0.2 (0.1); 95% CI: -0.07 to 0.4; P = 0.2]. CONCLUSIONS: Ritonavir concentrations in hair predicted virological suppression and were associated with self-reported adherence and being male in this cohort of adolescents with treatment failure to atazanavir-based or ritonavir-based second-line ART. Measuring ritonavir concentrations in hair in adolescents on protease inhibitor-based regimens could assess adherence in this vulnerable group to avert subsequent virologic failure.

COVID-19 Prevalence among Healthcare Workers. A Systematic Review and Meta-Analysis.

Understanding the burden of SARS-CoV-2 infections among healthcare workers is a critical component to inform occupational health policy and strategy. We conducted a systematic review and meta-analysis to map and analayse the available global evidence on the prevalence of SARS-CoV-2 infections among healthcare workers. The random-effects adjusted pooled prevalence of COVID-19 among those studies that conducted the test using the antibody (Ab) method was 7% [95% CI: 3 to 17%]. The random-effects adjusted pooled prevalence of COVID-19 among those studies that conducted the test using the PCR method was 11% [95% CI: 7 to 16%]. We found the burden of COVID-19 among healthcare workers to be quite significant and therefore a cause for global health concern. Furthermore, COVID-19 infections among healthcare workers affect service delivery through workers' sick leave, the isolation of confirmed cases and quarantine of contacts, all of which place significant strain on an already shrunken health workforce.

A population pharmacokinetic model is beneficial in quantifying hair concentrations of ritonavir-boosted atazanavir: a study of HIV-infected Zimbabwean adolescents.

BACKGROUND: Adolescents experience higher levels of non-adherence to HIV treatment. Drug concentration in hair promises to be reliable for assessing exposure to antiretroviral (ARV) drugs. Pharmacokinetic modelling can explore utility of drug in hair. We aimed at developing and validating a pharmacokinetic model based on atazanavir/ritonavir (ATV/r) in hair and identify factors associated with variabilities in hair accumulation. METHODS: We based the study on secondary data analysis whereby data from a previous study on Zimbabwean adolescents which collected hair samples at enrolment and 3 months follow-up was used in model development. We performed model development in NONMEM (version 7.3) ADVAN 13. RESULTS: There is 16% / 18% of the respective ATV/r in hair as a ratio of steady-state trough plasma concentrations. At follow-up, we estimated an increase of 30% /42% of respective ATV/r in hair. We associated a unit increase in adherence score with 2% increase in hair concentration both ATV/r. Thinner participants had 54% higher while overweight had 21% lower atazanavir in hair compared to normal weight participants. Adolescents receiving care from fellow siblings had atazanavir in hair at least 54% less compared to other forms of care. CONCLUSION: The determinants of increased ATV/r concentrations in hair found in our analysis are monitoring at follow up event, body mass index, and caregiver status. Measuring drug concentration in hair is feasibly accomplished and could be more accurate for monitoring ARV drugs exposure.

Perspectives on oral pre-exposure prophylaxis use amongst female sex workers in Harare, Zimbabwe.

BACKGROUND: Pre-exposure prophylaxis (PrEP) could provide protection from human immunodeficiency virus (HIV) infection in sexually active persons at risk. Limited data are available in Zimbabwe with regard to the perceptions about PrEP amongst female sex workers (FSWs). OBJECTIVES: The aim of this study was to evaluate the knowledge levels of oral PrEP and the likelihood of its use amongst FSWs. METHOD: This was a cross-sectional study in the peri-urban areas of Harare, Zimbabwe. Human immunodeficiency virus-negative FSWs were interviewed to assess their awareness of and likelihood to use PrEP. The relative importance index was used to evaluate the levels of knowledge and the likelihood of, and barriers to, PrEP use. A set of 10 questions was designed and validated that evaluated participants' understanding of PrEP. A bivariate logistic regression model was utilised to identify predictors of PrEP use. RESULTS: A total of 131 FSWs with a median age of 25 years (interquartile range: 21-31) participated in this study. Of the 71 (54%) FSWs who had heard about PrEP, 46 (35%) participants had adequate knowledge of its use. A total of 102 (78%) participants revealed that they would be willing to continuously use PrEP if it was provided free of cost. Increasing age of the participants was associated with an increase in the likelihood of using PrEP (r = 0.0033, p = 0.038). More knowledge about PrEP increased the likelihood of its use (r = 0.21, p = 0.0153). This likelihood increased amongst participants with an unprotected sexual intercourse encounter in the preceding 3 months (r = 0.0448, p = 0.026). CONCLUSION: Knowledge of PrEP amongst FSWs was low. To increase the uptake of PrEP, there is a need to further sensitise FSWs about this intervention. Programmes should also promote awareness training in FSW subgroups that are less likely to use PrEP.

Evaluating an enhanced adherence intervention among HIV positive adolescents failing atazanavir/ritonavir-based second line antiretroviral treatment at a public health clinic.

Sustaining virological suppression among HIV-infected adolescents is challenging. We evaluated a home-based adherence intervention and characterized self-reported adherence, virological response and drug resistance among adolescents failing atazanavir/ritonavir (ATV/r)-based 2nd line treatment. METHODS: HIV-positive adolescents (10-18 years) on ATV/r-based 2nd line treatment with virological failure (viral load (VL) ≥1 000 copies/ml) were randomized to either standard care (SC) or SC with addition of modified directly administered antiretroviral therapy (mDAART) for 90 days. VL was measured and questionnaires were administered at study entry and at 3 months. Genotyping was done for participants with continued failure. Primary outcome was suppression to VL < 1 000 copies/ml. RESULTS: Fifty adolescents aged 10-18 years on 2nd line treatment for >180 days were enrolled, 23(46%) were randomized to mDAART and 27(54%) to SC. Fifty-four percent were female; mean age was 15.8 years; mean baseline VL was 4.8(log10) copies/ml; 40% reported adherence <80% in previous 1 month at baseline; 40% suppressed (VL <1 000 copies/ml) after follow-up. mDAART resulted in significantly increased self-reported adherence (RR= 0.1; 95% CI=0.02-0.8, p=0.023); closely following dosing schedule (RR= 4.8; 95% CI=1.6-13.8, p=0.004); VL decrease (p=0.031) and modest increase in virological suppression to <1 000 copies/ml (p=0.105). Genotyping in 28/30 participants with continued virological failure demonstrated high level atazanavir resistance (I50L, N88S and I84V) in 6(21%); 3(11%) of whom also had high level resistance to lopinavir and darunavir (V32I, I50L, I54V, 147V and V82A). DISCUSSION: The mDAART intervention modestly improved virological suppression among adolescents with ATV/r-based 2nd line treatment failure, significantly increased self-reported adherence and decreased viral load. High level ATV/r resistance was demonstrated. CONCLUSION: Targeting mDAART to adolescents who are virologically failing PI-based 2nd line treatment decreases viral load and increases self-reported adherence. Early drug-resistance testing could reduce morbidity and mortality.

Defining a Cutoff for Atazanavir in Hair Samples Associated With Virological Failure Among Adolescents Failing Second-Line Antiretroviral Treatment.

BACKGROUND: Adequate antiretroviral exposure is crucial to virological suppression. We assessed the relationship between atazanavir hair levels with self-reported adherence, virological outcomes, and the effect of a home-based adherence intervention in HIV-infected adolescents failing second-line antiretroviral treatment in Zimbabwe. METHODS: HIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for ≥6 months with viral load (VL) >1000 copies/mL were randomized to either standard care (control) or standard care plus modified directly administered antiretroviral therapy (intervention). Questionnaires were administered; VL and hair samples were collected at baseline and after 90 days in each group. Viral suppression was defined as <1000 copies/mL after follow-up. RESULTS: Fifty adolescents (10-18 years) were enrolled; 23 (46%) were randomized to intervention and 27 (54%) to control. Atazanavir hair concentration <2.35 ng/mg (lower interquartile range for those with virological suppression) defined a cutoff below which most participants experienced virological failure. Male sex (P = 0.03), virological suppression at follow-up (P = 0.013), greater reduction in VL (P = 0.006), and change in average self-reported adherence over the previous month (P = 0.031) were associated with adequate (>2.35 ng/mg) hair concentrations. Participants with virological failure were more likely to have suboptimal atazanavir hair concentrations (RR = 7.2, 95% CI: 1 to 51, P = 0.049). There were no differences in atazanavir hair concentration between the arms after follow-up. CONCLUSIONS: A threshold of atazanavir concentrations in hair (2.35 ng/mg), above which virological suppression was likely, was defined for adolescents failing second-line atazanavir/ritonavir-based ART in Zimbabwe. Male sex and better self-reported adherence were associated with adequate atazanavir hair concentrations. Antiretroviral hair concentrations may serve as a useful clinical tool among adolescents.

CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.

BACKGROUND: Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 µg/ml may result in virologic failure and above 4 µg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV. METHODS: Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses. RESULTS: CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels. CONCLUSION: This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe: Is There an Effect of the Mannose Binding Lectin Deficiency?

HIV infection remains a major global health burden since its discovery in 1983. Sub-Saharan Africa is the region hardest hit by the HIV/AIDS pandemic where 63% of the 33 million infected people live. While there is marked person-to-person variability in susceptibility, progression, and survival with HIV infection, there is a paucity of predictive diagnostics associated with these clinical endpoints. In this regard, the deficiency in plasma Mannose Binding Lectin (MBL) is a common opsonic defect reported to increase susceptibility infections, including HIV. To the best of our knowledge, we report here the first study on the putative role of MBL deficiency on HIV progression and survival in an African adult population. We hypothesized that MBL deficiency has a role to play in HIV infection by increasing HIV disease progression and decreasing survival. We assessed the role of MBL deficiency on HIV disease progression and survival in a Zimbabwean adult population enrolled in the Mupfure Schistosomiasis and HIV (MUSH) cohort. We analyzed blood samples for MBL levels, MBL2 genotypes, HIV-1 status, viral load, and CD4(+) T cell counts. Participants were followed for 3 years wherein the endpoints were measured at baseline, 6 weeks, and 3, 6, 12, 24, and 36 months. Disease progression was measured as the rate of decline in CD4(+) T cell counts and the rate of increase in HIV viral load. We assessed 197 HIV positive adults where 83% (164) were women with a median age of 31 years. Prevalence of plasma MBL deficiency (less than 100 µg/L) and MBL2 deficient genetic variants (A/O and O/O genotypes) was 21% (42 out of 197) and 39% (74 out of 190), respectively. We did not observe a significant role to explain individual variation in mortality, change of CD4(+) T cell count, and viral load by MBL plasma deficiency or MBL2 genetic variants from baseline to 3 years follow up period in this adult population. We suggest the need for global OMICS research and that the present findings attest to the large between-population variability in a host of factors that can predispose individuals susceptible to HIV progression and mortality. We therefore cannot recommend at this time the use of plasma MBL levels or MBL2 genetic variants as a prognostic marker in HIV infection, disease progression, and survival in this adult population in Africa.

Genetic variants of drug metabolizing enzymes and drug transporter (ABCB1) as possible biomarkers for adverse drug reactions in an HIV/AIDS cohort in Zimbabwe.

A study was conducted in an HIV/AIDS Zimbabwean cohort to assess possible associations of pharmacogenetic variants with common adverse drug reactions (ADRs) during anti-retroviral treatment (ART) and/or tuberculosis (TB) treatment. Genotype and allele frequencies for CYP2B6 G516T, CYP2B6 T983C, CYP2A6*17, ABCB1 rs10276036 C>T, NAT2*5 and NAT2*14 were similar to those reported in literature for other African populations. The CYP2B6 516TT genotype and male gender were significantly associated with occurrence of Efavirenz induced central nervous system disorders (OR 20.58, p=0.004) and the ABCB1 rs10276036TT genotype with Nevirapine induced skin hypersensitivity (OR 4.01, p=0.04). For Stavudine, time on treatment was the main factor in development of lipodystrophy (OR 1.06, p<0.0001). For isoniazid, increasing patient age was associated with peripheral neuropathy (OR 1.05, p=0.001). Although genetic polymorphisms may play a role in predicting occurrence of ADRs, this study also indicates that other factors (gender, age, treatment time) are crucial in predicting drug-induced adverse effects.