Survival following screening and preemptive antifungal therapy for subclinical cryptococcal disease in advanced HIV infection.

OBJECTIVES: Our study's primary objective was to compare 1-year survival rates between serum cryptococcal antigen (sCrAg)-positive and sCrAg-negative HIV-positive individuals with CD4+ cell counts less than 100 cells/µl without symptoms of meningitis in Zimbabwe. DESIGN: This was a prospective cohort study. METHODS: Participants were enrolled as either sCrAg-positive or sCrAg-negative and followed up for 52 weeks or less, with death as the outcome. Lumbar punctures were recommended to all sCrAg-positives and inpatient management with intravenous amphotericin B and high-dose fluconazole was recommended to those with disseminated Cryptococcus. Antiretroviral therapy was initiated immediately in sCrAg-negatives and after at least 4 weeks following initiation of antifungals in sCrAg-positives. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: We enrolled 1320 participants and 130 (9.8%) were sCrAg positive, with a median sCrAg titre of 1 : 20. Sixty-six (50.8%) sCrAg-positives had lumbar punctures and 16.7% (11/66) had central nervous system (CNS) dissemination. Cryptococcal blood cultures were performed in 129 sCrAg-positives, with 10 (7.8%) being positive. One-year (48-52 weeks) survival rates were 83.9 and 76.1% in sCrAg-negatives and sCrAg-positives, respectively, P = 0.011. Factors associated with increased mortality were a positive sCrAg, CD4+ cell count less than 50 cells/µl and having presumptive tuberculosis (TB) symptoms. CONCLUSION: Our study reports a high prevalence of subclinical cryptococcal antigenemia and reiterates the importance of TB and a positive sCrAg as risk factors for mortality in advanced HIV disease (AHD). Therefore, TB and sCrAg screening remains a crucial component of AHD package, hence it should always be part of the comprehensive clinical evaluation in AHD patients.

Clinical and bacteriological outcomes in patients with urinary tract infections presenting to primary care in Harare, Zimbabwe: a cohort study.

Background: Treatment for urinary tract infections (UTIs) is usually empiric and is based on local antimicrobial resistance data. These data, however, are scarce in low-resource settings. The aim of this study is to determine the impact of antibiotic treatment on clinical and bacteriological outcomes in patients presenting with UTI symptoms to primary care in Harare. Methods: This cohort study enrolled participants presenting with UTI symptoms to 10 primary healthcare clinics in Harare between July 2019 and July 2020. A questionnaire was administered and a urine sample was collected for culture. If the urine culture showed growth of ≥10 5 colony forming units/mL of a uropathogen, a follow up visit at 7-21 days was conducted. Results: The analysis included 168 participants with a median age of 33.6 years (IQR 25.1-51.4) and of whom 131/168 (78.0%) were female. Effective treatment was taken by 54/168 (32.1%) participants. The urine culture was negative at follow up in 41/54 (75.9%) of participants who took appropriate treatment and in 33/114 (28.9%, p<0.001) of those who did not. Symptoms had improved or resolved in 52/54 (96.3%) of those on appropriate treatment and in 71/114 (62.3%, p<0.001) of those without. Conclusion: The findings of this study show that effective treatment leads to symptom resolution and bacterial clearance in people presenting with UTIs to primary care. Although UTIs are not life-threatening and can resolve without treatment, they do impact on quality of life, highlighting the need for optimised treatment recommendations.

Spatial distribution of Mycobacterium Tuberculosis in metropolitan Harare, Zimbabwe.

INTRODUCTION: The contribution of high tuberculosis (TB) transmission pockets in propagating area-wide transmission has not been adequately described in Zimbabwe. This study aimed to describe the presence of hotspot transmission of TB cases in Harare city from 2011 to 2012 using geospatial techniques. METHODS: Anonymised TB patient data stored in an electronic database at Harare City Health department was analysed using geospatial methods. Confirmed TB cases were mapped using geographic information system (GIS). Global Moran's I and Anselin Local Moran's I (LISA) were used to assess clustering and the local Getis-Ord Gi* was used to estimate hotspot phenomenon of TB cases in Harare City for the period between 2011 and 2012. RESULTS: A total of 12,702 TB cases were accessed and mapped on the Harare City map. In both 2011 and 2012, ninety (90%) of cases were new and had a high human immunodeficiency virus (HIV)/TB co-infection rate of 72% across all suburbs. Tuberculosis prevalence was highest in the Southern district in both 2011 and 2012. There were pockets of spatial distribution of TB prevalence across West South West, Southern, Western, South Western and Eastern health districts. TB hot spot occurrence was restricted to the West South West, parts of South Western, Western health districts. West South West district had an increased peri-urban population with inadequate social services including health facilities. These conditions were conducive for increased intensity of TB occurrence, a probable indication of high transmission especially in the presence of high HIV co-infection. CONCLUSIONS AND RECOMMENDATIONS: Increased TB transmission was limited to a health district with high informal internal migrants with limited health services in Harare City. To minimise spread of TB into greater Harare, there is need to improve access to TB services in the peri-urban areas.

Utilization and outcomes of cervical cancer screening services in Harare City, 2012-2016: a secondary data analysis.

BACKGROUND: Visual inspection with acetic acid and cervicography (VIAC) is a method used to screen for cervical cancer. VIAC can be used as part of a "see and treat" strategy. Nine Harare city council health facilities offer VIAC free of charge with the aim of reducing morbidity and mortality from cervical cancer. Between 2014 and 2016, the number of women utilising VIAC dropped by 35%. We analysed records of clients who utilise VIAC at Harare city health facilities to characterise women accessing VIAC and their outcomes to make recommendations for improving the services. METHODS: We conducted a descriptive cross-sectional study using data collected for the Harare city VIAC program. We analysed all records of clients who utilised VIAC services at nine Harare city health facilities from 1 May 2012 to 31 December 2016. RESULTS: We analysed 46,217 records, the median age of the clients was 34 years [Q1 = 27: Q3 = 42]. Of the 46,217 clients screened, 3001 (6.5%) were VIAC positive, and 512 (1.1%) had suspicious of cancer lesions. The prevalence of VIAC positive ranged from 58 to 74 per 1000-screened clients over the 5 years. The prevalence of suspected cancer ranged from 9 to 14 per 1000-screened clients, and there was a general decrease in the prevalence between 2012 and 2016. Of the 3513 clients with VIAC positive or had suspicious of cancer lesions, 2090 (74.1%) did not receive treatment at the site where the screening took place. CONCLUSION: The majority of women who are accessing VIAC services in Harare are middle-aged, multiparous and married women. There is a treatment gap at most of the VIAC centres such that clients are referred to other centres for management. The objective of "see and treat" is not being realised.

Identifying high or low risk of mother to child transmission of HIV: How Harare City, Zimbabwe is doing?

BACKGROUND: Despite high antiretroviral (ARV) treatment coverage among pregnant women for prevention of mother-to-child transmission (PMTCT) of Human Immunodeficiency Virus (HIV) in Zimbabwe, the MTCT rate is still high. Therefore in 2016, the country adopted World Health Organization recommendations of stratifying pregnant women into "High" or"Low" MTCT risk for subsequent provision of HIV exposed infant (HEI) with appropriate follow-up care according to risk status. OBJECTIVE: The study sought to ascertain, among pregnant women who delivered in clinics of Harare in August 2017: the extent to which high risk MTCT pregnancies were identified at time of delivery; and whether their newborns were initiated on appropriate ARV prophylaxis, cotrimoxazole prophylaxis, subjected to early HIV diagnostic testing and initiated on ARV treatment. METHODS: Cross-sectional study using review of records of routinely collected program data. RESULTS: Of the 1,786 pregnant women who delivered in the selected clinics, HIV status at the time of delivery was known for 1,756 (98%) of whom 197 (11%) were HIV seropositive. Only 19 (10%) could be classified as "high risk" for MTCT and the remaining 90% lacked adequate information to classify them into high or low risk for MTCT due to missing data. Of the 197 live births, only two (1%) infants had a nucleic-acid test (NAT) at birth and 32 (16%) infants had NAT at 6 weeks. Of all 197 infants, 183 (93%) were initiated on single ARV prophylaxis (Nevirapine), 15 (7%) infants' ARV prophylaxis status was not documented and one infant got dual ARV prophylaxis (Nevirapine+Zidovudine). CONCLUSION: There was paucity of data requisite for MTCT risk stratification due to poor recording of data; "high risk" women were missed in the few circumstances where sufficient data were available. Thus "high risk" HEI are deprived of dual ARV prophylaxis and priority HIV NAT at birth and onwards which they require for PMTCT. Health workers need urgent training, mentorship and supportive supervision to master data management and perform MTCT risk stratification satisfactorily.

Enhanced adherence counselling and viral load suppression in HIV seropositive patients with an initial high viral load in Harare, Zimbabwe: Operational issues.

BACKGROUND: In people living with HIV (PLHIV) who are on anti-retroviral therapy (ART), it is essential to identify persons with high blood viral loads (VLs) (≥1000 copies/ml), provide enhanced adherence counselling (EAC) for 3 months and assess for VL suppression (<1000 copies/ml). OBJECTIVE: Our study objectives were to determine the proportion who had a high viral load in those people who underwent viral load testing between 1 August 2016-31 July 2017 at Wilkins Hospital, Harare, Zimbabwe. Of those with high viral load to assess; a) the proportion who enrolled for EAC, the demographic and clinical characteristics associated with enrolment for EAC and, b) the proportion who achieved viral load suppression and demographic, clinical characteristics associated with viral load suppression. DESIGN: Retrospective cohort study using routinely collected programme data. Data was collected from PLHIV who were on ART and had a high viral load from 1 August 2016 to 31 July 2017. RESULTS: Of 5,573 PLHIV on ART between 1 August 2016 and 31 July 2017, 4787 (85.9%) had undergone VL testing and 646 (13.5%) had high VLs. Of these 646, only 489 (75.7%) were enrolled for EAC, of whom 444 (69%) underwent a repeat VL test at ≥ 3 months with 201 (31.2%) achieving VL suppression. The clinical characteristics that were independently associated with higher probability of VL suppression were: a) undergoing 3 sessions of EAC; b) being on 2nd line ART. Initial VL levels >5,000 copies/ml were associated with lower probability of viral suppression. CONCLUSION: The routine VL testing levels were high, but there were major programmatic gaps in enrolling PLHIV with high VLs into EAC and achieving VL suppression. The full potential of EAC on achieving viral load suppression has not been achieved in this setting. The reasons for these gaps need to be assessed in future research studies and addressed by suitable changes in policies/practices.

Screening tool to identify adolescents living with HIV in a community setting in Zimbabwe: A validation study.

INTRODUCTION: A simple cost-effective strategy to pre-screen for targeted HIV testing can have substantial benefit in high burden and resource limited settings. A 4-item (previous hospitalisation, orphanhood, poor health status, and recurring skin problems) screening tool to identify adolescents living with HIV has previously shown high sensitivity in healthcare facility settings. We validated this screening tool in a community setting, in Harare, Zimbabwe in a community-based HIV prevalence survey. METHODS: A community-based HIV prevalence survey was conducted among individuals aged 8-17 years with guardian consent and child assent and residing in 7 communities during the period February 2015 to December 2015. Participants without previously diagnosed HIV were evaluated for the probability of having HIV using the screening tool. HIV status was defined using an anonymous HIV test which was done using Oral Mucosal Transudate (OMT). A questionnaire was also administered to ascertain self-reported HIV status and screening tool items. The validity of a 4-item screening tool was tested. Sensitivity and specificity of the screening tool was assessed against the HIV status based on OMT result. RESULTS: Prevalence survey participants were 5386 children who had an HIV test result, aged 8-17 years. However, 5384, who did not report testing HIV positive and responded to all screening tool item questions were included in the validation. Their median age was 12 (IQR: 10-15) years, 2515 (46.7%) were male. HIV prevalence was 1.3% (95% CI:1.0-1.8%). The 4-item screening tool had poor accuracy with an area under the receiver operating curve of 0.65(95% CI: 0.60-0.72) at a cut-off score≥1. Its sensitivity was 56.3% (95% CI:44.0-68.1%) and specificity of 75.1% (95% CI:73.9-76.3%), PPV of 2.9% (95% CI:2.1-3.9%) and a NPV of 99.2% (95% CI:98.9-99.5%). The number needed to test to diagnose one child using the screening tool was 55% lower than universal testing for HIV. CONCLUSION: Use of the 4-item screening tool could be a strategy that can be adopted to identify children living with HIV in a community setting in resource limited settings by reducing the number needed to test compared to universal testing since it is inexpensive, easy to administer and not harmful. However, screening items adapted to a community setting need to be explored to improve the performance of the screening tool.

Economic incentives for HIV testing by adolescents in Zimbabwe: a randomised controlled trial.

BACKGROUND: HIV testing is the important entry point for HIV care and prevention service, but uptake of HIV testing and thus coverage of antiretroviral therapy are much lower in older children and adolescents than in adults. We investigated the effect of economic incentives provided to caregivers of children aged 8-17 years on uptake of HIV testing and counselling in Harare, Zimbabwe. METHODS: This randomised controlled trial was nested within a household HIV prevalence survey of children aged 8-17 years in Harare. Households with one or more survey participants whose HIV status was unknown were eligible to participate in the trial. Eligible households were randomly assigned (1:1:1) to either receive no incentive, receive a fixed US$2 incentive, or participate in a lottery for $5 or $10 if the participant presented for HIV testing and counselling at a local primary health-care centre. The survey fieldworkers who enrolled participants were not blinded to trial arm allocation, but the statistician was blinded for analysis of outcome. The primary outcome was the proportion of households in which at least one child had an HIV test within 4 weeks of enrolment. HIV test uptake in the incentivised groups was compared with uptake in the non-incentivised group using logistic regression, adjusting for community and number of children as fixed effects and research assistant as a random effect. All analyses were by intention to treat. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201605001615280. FINDINGS: Between Aug 4, and Dec 18, 2015, 2050 eligible households were enrolled in the prevalence survey. 649 (32%) households were assigned no incentive, 740 (34%) households were assigned a $2 incentive, and 661 (32%) households were assigned to lottery participation. Children were unavailable in 148 households in the no-incentive group, 63 households in the $2 incentive group, and 81 households in the lottery group. 1688 households had at least one child with unknown HIV status and were enrolled into the trial. 22 households had no undiagnosed child, and one household refused consent. The primary outcome of HIV testing was assessed in 472 (28%) households in the no-incentive group, 654 (39%) households in the $2 incentive group, and 562 (33%) households in the lottery group. At least one child was HIV tested in 93 (20%) households in the no-incentive group, in 316 (48%) households in the $2 incentive group (adjusted odds ratio 3·67, 95% CI 2·77-4·85; p<0·0001), and in 223 (40%) of 562 households in the lottery group (2·66, 2·00-3·55; p<0·0001). No adverse events were reported. INTERPRETATION: Fixed incentives and lottery-based incentives increased the uptake of HIV testing by older children and adolescents, a key hard-to-reach population. This strategy would be sustainable in the context of vertical HIV infection as repeated testing would not be necessary until sexual debut. FUNDING: Wellcome Trust.

Community burden of undiagnosed HIV infection among adolescents in Zimbabwe following primary healthcare-based provider-initiated HIV testing and counselling: A cross-sectional survey.

BACKGROUND: Children living with HIV who are not diagnosed in infancy often remain undiagnosed until they present with advanced disease. Provider-initiated testing and counselling (PITC) in health facilities is recommended for high-HIV-prevalence settings, but it is unclear whether this approach is sufficient to achieve universal coverage of HIV testing. We aimed to investigate the change in community burden of undiagnosed HIV infection among older children and adolescents following implementation of PITC in Harare, Zimbabwe. METHODS AND FINDINGS: Over the course of 2 years (January 2013-January 2015), 7 primary health clinics (PHCs) in southwestern Harare implemented optimised, opt-out PITC for all attendees aged 6-15 years. In February 2015-December 2015, we conducted a representative cross-sectional survey of 8-17-year-olds living in the 7 communities served by the study PHCs, who would have had 2 years of exposure to PITC. Knowledge of HIV status was ascertained through a caregiver questionnaire, and anonymised HIV testing was carried out using oral mucosal transudate (OMT) tests. After 1 participant taking antiretroviral therapy was observed to have a false negative OMT result, from July 2015 urine samples were obtained from all participants providing OMTs and tested for antiretroviral drugs to confirm HIV status. Children who tested positive through PITC were identified from among survey participants using gender, birthdate, and location. Of 7,146 children in 4,251 eligible households, 5,486 (76.8%) children in 3,397 households agreed to participate in the survey, and 141 were HIV positive. HIV prevalence was 2.6% (95% CI 2.2%-3.1%), and over a third of participants with HIV were undiagnosed (37.7%; 95% CI 29.8%-46.2%). Similarly, among the subsample of 2,643 (48.2%) participants with a urine test result, 34.7% of those living with HIV were undiagnosed (95% CI 23.5%-47.9%). Based on extrapolation from the survey sample to the community, we estimated that PITC over 2 years identified between 18% and 42% of previously undiagnosed children in the community. The main limitation is that prevalence of undiagnosed HIV was defined using a combination of 3 measures (OMT, self-report, and urine test), none of which were perfect. CONCLUSIONS: Facility-based approaches are inadequate in achieving universal coverage of HIV testing among older children and adolescents. Alternative, community-based approaches are required to meet the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of diagnosing 90% of those living with HIV by 2020 in this age group.

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.