Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Psychological distress among healthcare workers accessing occupational health services during the COVID-19 pandemic in Zimbabwe.

BACKGROUND: Healthcare workers (HCWs) have experienced anxiety and psychological distress during the COVID-19 pandemic. We established and report findings from an occupational health programme for HCWs in Zimbabwe that offered screening for SARS-CoV-2 with integrated screening for comorbidities including common mental disorder (CMD) and referral for counselling. METHODS: Quantitative outcomes were fearfulness about COVID-19, the Shona Symptom Questionnaire (SSQ-14) score (cutpoint 8/14) and the number and proportion of HCWs offered referral for counselling, accepting referral and counselled. We used chi square tests to identify factors associated with fearfulness, and logistic regression was used to model the association of fearfulness with wave, adjusting for variables identified using a DAG. Qualitative data included 18 in-depth interviews, two workshops conducted with HCWs and written feedback from counsellors, analysed concurrently with data collection using thematic analysis. RESULTS: Between 27 July 2020-31 July 2021, spanning three SARS-CoV-2 waves, the occupational health programme was accessed by 3577 HCWs from 22 facilities. The median age was 37 (IQR 30-43) years, 81.9% were women, 41.7% said they felt fearful about COVID-19 and 12.1% had an SSQ-14 score ≥ 8. A total of 501 HCWs were offered referral for counselling, 78.4% accepted and 68.9% had ≥1 counselling session. Adjusting for setting and role, wave 2 was associated with increased fearfulness over wave 1 (OR = 1.26, 95% CI 1.00-1.60). Qualitative data showed high levels of anxiety, psychosomatic symptoms and burnout related to the pandemic. Mental wellbeing was affected by financial insecurity, unmet physical health needs and inability to provide quality care within a fragile health system. CONCLUSIONS: HCWs in Zimbabwe experience a high burden of mental health symptoms, intensified by the COVID-19 pandemic. Sustainable mental health interventions must be multisectoral addressing mental, physical and financial wellbeing.

The transient effect of a peer support intervention to improve adherence among adolescents and young adults failing antiretroviral therapy in Harare, Zimbabwe: a randomized control trial.

BACKGROUND: Adolescents and young adults living with HIV in sub Saharan Africa are at high risk of poor adherence to antiretroviral therapy (ART) and virologic failure (VF). METHODS: We conducted a randomized control trial among adolescents and young adults on ART with VF to assess the effectiveness of a community-based peer support intervention aimed at improving VF. Viral load (VL) levels were obtained at 12, 24 and 36 weeks. A subset of the participants had baseline HIV drug resistance (HIVDR) genotyped using Sanger sequencing. RESULTS: The participants' median (interquartile range (IQR)) age was 18.1 (IQR: 15.1-20.0) years and half (50.5%, n = 107) were male. At week 24, the proportion of subjects with a detectable viremia was significantly lower in the intervention arm than in the standard of care (SOC) arm (76.0% (n = 79) vs. 89.0% (n = 96), p = 0.013). At Week 36, there remained a difference in the proportion of subjects with a detectable VL between the intervention arm (68.3%, n = 71) and SOC arm (79.6%, n = 86), which was trending towards statistical significance (p = 0.059). There was no difference in the probability of having a detectable VL over time between the intervention and SOC groups (adjusted odds ratio: 1.14, p = 0.439). Baseline HIVDR was observed in 44.0% of the participants in the intervention and 56.0% in the SOC group (p = 0.146). CONCLUSION: A transient effect of the peer support intervention in improving VF was observed among adolescents and young people failing ART. TRIAL REGISTRATION: This study is registered with www.clinicaltrials.gov under the reference number: NCT02833441.

Diagnostic Accuracy of Pan-Degenerate Amplification and Adaptation Assay for HIV-1 Drug Resistance Mutation Analysis in Low- and Middle-Income Countries.

HIV drug resistance (HIVDR) is a barrier to sustained virologic suppression in low- and middle-income countries (LMICs). Point mutation assays targeting priority drug resistance mutations (DRMs) are being evaluated to improve access to HIVDR testing. In a cross-sectional study (June 2018 to September 2019), we evaluated the diagnostic accuracy of a simple and rapid HIVDR assay (the pan-degenerate amplification and adaptation [PANDAA] assay targeting the mutations K65R, K103NS, M184VI, Y181C, and G190A) compared to Sanger sequencing and next-generation sequencing (NGS). Plasma samples from adolescents and young adults (aged 10 to 24 years) failing antiretroviral therapy (viral load, >1,000 copies/ml on 2 consecutive occasions 1 month apart) were analyzed. Sensitivity and specificity of the PANDAA assay were determined by a proprietary application designed by Aldatu Biosciences. Agreement between genotyping methods was evaluated using Cohen's kappa coefficient. One hundred fifty samples previously characterized by Sanger sequencing were evaluated using PANDAA. For all DRMs detected, PANDAA showed a sensitivity and specificity of 98% and 94%, respectively. For nucleotide reverse transcriptase inhibitor DRMs, sensitivity and specificity were 98% (95% confidence interval [CI], 92% to 100%) and 100% (94% to 100%), respectively. For non-nucleotide reverse transcriptase inhibitor DRMs, sensitivity and specificity were 100% (97% to 100%) and 76% (61% to 87%), respectively. PANDAA showed strong agreement with Sanger sequencing for K65R, K103NS, M184VI, and G190A (kappa > 0.85) and substantial agreement for Y181C (kappa = 0.720). Of the 21 false-positive samples genotyped by PANDAA, only 6 (29%) were identified as low-abundance variants by NGS. With the high sensitivity and specificity to detect major DRMs, PANDAA could represent a simple and rapid alternative HIVDR assay in LMICs.

Tenofovir-associated kidney disease in Africans: a systematic review.

BACKGROUND: Data on chronic kidney disease development in HIV infection is important towards building a comprehensive knowledge of HIV, ageing and polypharmacy in Africa. Several previous studies on tenofovir-associated kidney disease in Africa have shown conflicting results. This review summarises what is known about the development of kidney disease in HIV-positive African patients on tenofovir disoproxil fumarate (TDF)-containing ART. We set out to document the occurrence of kidney disease in HIV-positive Africans on TDF-containing ART in population-based studies and to evaluate the renal safety of TDF in Africans. METHODS: We conducted a systemic review using published studies which were identified through a computerized search of original research using the Medline/PubMed database, EMBASE, EBM Reviews, Proquest Google Scholar and Global Health reported from inception until 5 October 2017. Two reviewers independently abstracted the data and performed quality assessment of the included studies. We screened 595 articles and included 31 in the qualitative analysis performed. RESULTS: A total of 106 406 patients (of whom 66,681 were on Tenofovir) were involved in these 31 studies with sample sizes ranging from 30 to 62,230. Duration on tenofovir-containing ART ranged from those initiating ART at baseline to those who received TDF for up to 9 years. All but one of the studies involved only patients 16 years and older. The studies had differing definitions of kidney dysfunction and were of variable study design quality. The documented outcomes had substantial discrepancies across the studies, most likely due to methodological differences, study size and disparate outcome definitions. CONCLUSIONS: Our review identified studies in Africans reporting statistically significant renal function decline associated with TDF use but the clinical significance of this effect was not enough to contraindicate its continued use in ART regimens. Consistent with studies in other populations, patients are at greater risk if they have pre-existing renal disease and are more advanced in age. More research is needed on paediatric populations under 16 years of age. Trial registration This review was registered on Prospero (registration number CRD42018078717).

A Simple Phosphate-Buffered-Saline-Based Extraction Method Improves Specificity of HIV Viral Load Monitoring Using Dried Blood Spots.

Although Roche COBAS Ampliprep/COBAS TaqMan (CAP/CTM) systems are widely used in sub-Saharan Africa for early infant diagnosis of HIV from dried blood spots (DBS), viral load monitoring with this system is not practical due to nonspecific extraction of both cell-free and cell-associated viral nucleic acids. A simplified DBS extraction technique for cell-free virus elution using phosphate-buffered saline (PBS) may provide an alternative analyte for lower-cost quantitative HIV virus load (VL) testing to monitor antiretroviral therapy (ART). We evaluated the CAP/CTM v2.0 assay in 272 paired plasma and DBS specimens using the cell-free virus elution method and determined the level of agreement, sensitivity, and specificity at thresholds of target not detected (TND), target below the limit of quantification (BLQ) (<20 copies/ml in plasma or <400 copies/ml in DBS), and VL of <1,000 copies/ml, and VL of <5,000 copies/ml. Reported plasma VL ranged from TND, or <20, to 5,781,592 copies/ml, and DBS VL ranged from TND, or <400, to 467,600 copies/ml. At <1000 copies/ml, agreement between DBS and plasma was 96.7% (kappa coefficient, 0.93; P < 0.0001). The mean difference between DBS and plasma VL values was -1.06 log10 copies/ml (95% confidence interval [CI], -1.17, -0.97; P < 0.0001). At a treatment failure threshold of >1,000 copies/ml, the sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) were 92.7%, 100%, 100%, and 94.3%, respectively. PBS elution of DBS offers a sensitive and specific method for monitoring plasma viremia among adults and children on ART at the WHO-recommended threshold of >1,000 copies/ml on the Roche CAP/CTM system.

Prevalence of chronic conditions and multimorbidity among healthcare workers in Zimbabwe: Results from a screening intervention.

The burden of non-communicable diseases (NCDs) in southern Africa is expanding and is superimposed on high HIV prevalence. Healthcare workers are a scarce resource; yet are vital to health systems. There are very limited studies on the burden of chronic conditions among healthcare workers in Africa, and none exploring multimorbidity (≥2 chronic conditions). We describe the epidemiology of infectious (HIV) and non-communicable chronic conditions, and multimorbidity, among Zimbabwean healthcare workers. Healthcare workers (≥18 years) in eight Zimbabwean provinces were invited to a voluntary, cross-sectional health-check, including HIV, diabetes, hypertension and mental health screening. Statistical analyses described the prevalence and risk factors for multimorbidity (two or more of HIV, diabetes, hypertension or common mental disorder) and each condition. Missing data were handled using multiple imputation. Among 6598 healthcare workers (July 2020-July 2022) participating in the health-check, median age was 37 years (interquartile range 29-44), 79% were women and 10% knew they were living with HIV. Half had at least one chronic condition: 11% were living with HIV, 36% had elevated blood pressure, 12% had elevated HbA1c and 11% had symptoms of common mental disorder. The overall prevalence of multimorbidity was 15% (95% CI: 13-17%); 39% (95% CI: 36-43%) among people aged 50 and older. Whilst most HIV was diagnosed and treated, other chronic conditions were usually undiagnosed or uncontrolled. Limiting our definition of multimorbidity to two or more screened conditions sought to reduce bias due to access to diagnosis, however, may have led to a lower reported prevalence than that found using a wider definition. Half of healthcare workers screened were living with a chronic condition; one in seven had multimorbidity. Other than HIV, most conditions were undiagnosed or untreated. Multisectoral action to implement contextually relevant, chronic disease services in Africa is urgently needed. Specific attention on health workers is required to protect and retain this critical workforce.

Evaluation of a comprehensive health check offered to frontline health workers in Zimbabwe.

Health workers are essential for a functioning healthcare system, and their own health is often not addressed. During the COVID-19 pandemic health workers were at high risk of SARS-CoV-2 infection whilst coping with increased healthcare demand. Here we report the development, implementation, and uptake of an integrated health check combining SARS-CoV-2 testing with screening for other communicable and non-communicable diseases for health workers in Zimbabwe during the COVID-19 pandemic. Health checks were offered to health workers in public and private health facilities from July 2020 to June 2022. Data on the number of health workers accessing the service and yield of screening was collected. Workshops and in-depth interviews were conducted to explore the perceptions and experiences of clients and service providers. 6598 health workers across 48 health facilities accessed the service. Among those reached, 5215 (79%) were women, the median age was 37 (IQR: 29-44) years and the largest proportion were nurses (n = 2092, 32%). 149 (2.3%) healthcare workers tested positive for SARS-CoV-2. Uptake of screening services was almost 100% for all screened conditions except HIV. The most common conditions detected through screening were elevated blood pressure (n = 1249; 19%), elevated HbA1c (n = 428; 7.7%) and common mental disorder (n = 645; 9.8%). Process evaluation showed high acceptability of the service. Key enablers for health workers accessing the service included free and comprehensive service provision, and availability of reliable point-of-care screening methods. Implementation of a comprehensive health check for health workers was feasible, acceptable, and effective, even during a pandemic. Conventional occupational health programmes focus on infectious diseases. In a society where even health workers cannot afford health care, free comprehensive occupational health services may address unmet needs in prevention, diagnosis, and treatment for chronic non-communicable conditions.

Effects of Gender and Baseline CD4 Count on Post-Treatment CD4 Count Recovery and Outcomes in Patients with Advanced HIV Disease: A Retrospective Cohort Study.

Presentation to care with advanced HIV disease (AHD) is a significant problem in sub-Saharan Africa. We evaluated factors associated with immune recovery among individuals presenting to care with AHD in Zimbabwe. We conducted a retrospective evaluation of outcomes among adult (>18 years old) individuals with AHD (CD4 count ≤200 cells/mm3) receiving care at 18 outpatient primary care clinics in Harare, Zimbabwe. Baseline and 12-month CD4 count data were extracted from medical records. CD4 count recovery (defined as CD4 count >200 cells/mm3) after 12 months on non-nucleotide reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) regimen was determined and factors associated with CD4 count recovery were established using logistic regression. All statistical analysis was performed on SPSS v23. A total of 1,338 participant records were included in the analysis. The median interquartile range (IQR) age was 37 (30-43) years and 52% were females. The baseline median (IQR) CD4 count was 50 (28-75) cells/mm3 and was significantly lower among patients with history of cryptococcal meningitis compared to those without [25 (10-52) vs. 52 (32-77), respectively; p = .0009]. The median (IQR) CD4 count at 12 months after ART initiation increased from 50 (28-75) at baseline to 180 (92-290) cells/mm3. Immune recovery with a CD4 count >200 cells/mm3 was observed in 181/417 (43%). Male gender and low baseline CD4 count were strong predictors of poor immunological recovery on ART. Immunological recovery following ART initiation was 43% among individuals with AHD. Male patients are most vulnerable to persistent immunological failure. Clinical Trial Registration number: NCT02434172.

Exploring COVID-19 vaccine uptake among healthcare workers in Zimbabwe: A mixed methods study.

With COVID-19 no longer categorized as a public health emergency of international concern, vaccination strategies and priority groups for vaccination have evolved. Africa Centers for Diseases Prevention and Control proposed the '100-100-70%' strategy which aims to vaccinate all healthcare workers, all vulnerable groups, and 70% of the general population. Understanding whether healthcare workers were reached during previous vaccination campaigns and what can be done to address concerns, anxieties, and other influences on vaccine uptake, will be important to optimally plan how to achieve these ambitious targets. In this mixed-methods study, between June 2021 and July 2022 a quantitative survey was conducted with healthcare workers accessing a comprehensive health check in Zimbabwe to determine whether and, if so, when they had received a COVID-19 vaccine. Healthcare workers were categorized as those who had received the vaccine 'early' (before 30.06.2021) and those who had received it 'late' (after 30.06.2021). In addition, 17 in-depth interviews were conducted to understand perceptions and beliefs about COVID-19 vaccines. Of the 2905 healthcare workers employed at 37 facilities who participated in the study, 2818 (97%, 95% CI [92%-102%]) reported that they had received at least one vaccine dose. Geographical location, older age, higher educational attainment and having a chronic condition was associated with receiving the vaccine early. Qualitatively, (mis)information, infection risk perception, quasi-mandatory vaccination requirements, and legitimate concerns such as safety and efficacy influenced vaccine uptake. Meeting the proposed 100-100-70 target entails continued emphasis on strong communication while engaging meaningfully with healthcare workers' concerns. Mandatory vaccination may undermine trust and should not be a substitute for sustained engagement.

Exploring COVID-19 vaccine uptake among healthcare workers in Zimbabwe: A mixed methods study.

With COVID-19 no longer categorized as a public health emergency of international concern, vaccination strategies and priority groups for vaccination have evolved. Africa Centres for Diseases Prevention and Control proposed the '100-100-70%' strategy which aims to vaccinate all healthcare workers, all vulnerable groups, and 70% of the general population. Understanding whether healthcare workers were reached during previous vaccination campaigns and what can be done to address concerns, anxieties, and other influences on vaccine uptake, will be important to optimally plan how to achieve these ambitious targets. In this mixed-methods study, between June 2021 and July 2022 a quantitative survey was conducted with healthcare workers accessing a comprehensive health check in Zimbabwe to determine whether and, if so, when they had received a COVID-19 vaccine. Healthcare workers were categorized as those who had received the vaccine 'early' (before 30.06.2021) and those who had received it 'late' (after 30.06.2021). In addition, 17 in-depth interviews were conducted to understand perceptions and beliefs about COVID-19 vaccines. Of the 3,086 healthcare workers employed at 43 facilities who participated in the study, 2,986 (97%, 95% CI [92%-100%]) reported that they had received at least one vaccine dose. Geographical location, older age, higher educational attainment and having a chronic condition was associated with receiving the vaccine early. Qualitatively, (mis)information, infection risk perception, quasi-mandatory vaccination requirements, and legitimate concerns such as safety and efficacy influenced vaccine uptake. Meeting the proposed 100-100-70 target entails continued emphasis on strong communication while engaging meaningfully with healthcare workers' concerns. Mandatory vaccination may undermine trust and should not be a substitute for sustained engagement.

Chronic lung disease in adolescents with delayed diagnosis of vertically acquired HIV infection.

BACKGROUND: Long-term survivors of vertically acquired human immunodeficiency virus (HIV) infection are reaching adolescence in large numbers in Africa and are at high risk of delayed diagnosis and chronic complications of untreated HIV infection. Chronic respiratory symptoms are more common than would be anticipated based on the HIV literature. METHODS: Consecutive adolescents with presumed vertically acquired HIV attending 2 HIV care clinics in Harare, Zimbabwe, were recruited and assessed with clinical history and examination, CD4 count, pulmonary function tests, Doppler echocardiography, and chest radiography (CXR). Those with suspected nontuberculous chronic lung disease (CLD) were scanned using high-resolution computed tomography (HRCT). RESULTS: Of 116 participants (43% male; mean age, 14 ± 2.6 years, mean age at HIV diagnosis, 12 years), 69% were receiving antiretroviral therapy. Chronic cough and reduced exercise tolerance were reported by 66% and 21% of participants, respectively; 41% reported multiple respiratory tract infections in the previous year, and 10% were clubbed. More than 40% had hypoxemia at rest (13%) or on exercise (29%), with pulmonary hypertension (mean pulmonary artery pressure >25 mm Hg) in 7%. Forced expiratory volume in 1 second (FEV(1)) was <80% predicted in 45%, and 47% had subtle CXR abnormalities. The predominant HRCT pattern was decreased attenuation as part of a mosaic attenuation pattern (31 of 56 [55%]), consistent with small airway disease and associated with bronchiectasis (Spearman correlation coefficient (r(2) = 0.8) and reduced FEV(1) (r(2) = -0.26). CONCLUSIONS: Long-term survivors of vertically acquired HIV in Africa are at high risk of a previously undescribed small airway disease, with >40% of unselected adolescent clinic attendees meeting criteria for severe hypoxic CLD. This condition is not obvious at rest. Etiology, prognosis, and response to treatment are currently unknown.

Diagnostic Accuracy of Point of Care Cryptococcal Antigen Lateral Flow Assay in Fingerprick Whole Blood and Urine Samples for the Detection of Asymptomatic Cryptococcal Disease in Patients with Advanced HIV Disease.

Cryptococcal disease (CD) is a leading cause of mortality among individuals with advanced HIV disease (AHD). Screening with serum cryptococcal antigen (sCrAg) lateral flow assay (LFA) enables early detection of subclinical disease but requires venipuncture and laboratory processing. Clinic-based point of care (POC) CrAg screening tests using urine or fingerprick whole blood could facilitate early diagnosis of CD. We evaluated the diagnostic performance of POC clinic-based fingerprick whole blood and urine CrAg compared to the gold standard laboratory sCrAg LFA in screening for CD among asymptomatic individuals with CD4 counts of <200 cells/µL in Harare, Zimbabwe. sCrAg positive participants who consented to a lumbar puncture also had cerebrospinal fluid (CSF) CrAg testing and titers for CSF-positive specimens. A total of 1,333 individuals were screened, and over half (56.6%) were males. The median (interquartile range) CD4 count was 27.5 (11-46) cells/µL. We found a sensitivity of 63.8% (95% CI: 54.8-72.1) and specificity of 84.0% (95% CI: 81.7-86.0) for urine CrAg, and a sensitivity of 48.0% (95% CI: 39.1-57.1) and specificity of 99.5% (95% CI: 98.9-99.8) was found for fingerprick whole blood. The sensitivity of both POC CrAg tests increased in individuals with sCrAg titers of ≥1:160, CD4 count of <50 cells/µL and disseminated central nervous system (CNS) disease. Clinic-based POC urine and fingerprick whole blood CrAg testing performed better in screening for CD among AHD patients with CNS disease. More sensitive assays to identify AHD patients with asymptomatic CD are needed. IMPORTANCE Cryptococcal disease (CD) remains a leading cause of morbidity and mortality among individuals with advanced HIV disease (AHD). Identifying point of care (POC) approaches to screening for CD in asymptomatic individuals is important to guide therapeutic management. We evaluated the use of POC fingerprick whole blood and urine testing for cryptococcal disease in patients with AHD as compared with laboratory-based serum antigen testing. POC fingerprick whole blood and urine testing had low sensitivity and specificity in asymptomatic individuals with AHD. Most analysis has focused on evaluating test performance in symptomatic individuals. Here we show that POC testing with whole blood and urine samples should not be used to screen for asymptomatic CD in AHD.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

A primary care level algorithm for identifying HIV-infected adolescents in populations at high risk through mother-to-child transmission.

OBJECTIVE: To present an algorithm for primary-care health workers for identifying HIV-infected adolescents in populations at high risk through mother-to-child transmission. METHODS: Five hundred and six adolescent (10-18 years) attendees to two primary care clinics in Harare, Zimbabwe, were recruited. A randomly extracted 'training' data set (n = 251) was used to generate an algorithm using variables identified as associated with HIV through multivariable logistic regression. Performance characteristics of the algorithm were evaluated in the remaining ('test') records (n = 255) at different HIV prevalence rates. RESULTS: HIV prevalence was 17%, and infection was independently associated with client-reported orphanhood, past hospitalization, skin problems, presenting with sexually transmitted infection and poor functional ability. Classifying adolescents as requiring HIV testing if they reported >1 of these five criteria had 74% sensitivity and 80% specificity for HIV, with the algorithm correctly predicting the HIV status of 79% of participants. In low-HIV-prevalence settings (<2%), the algorithm would have a high negative predictive value (≥ 99.5%) and result in an estimated 60% decrease in the number of people needing to test to identify one HIV-infected individual, compared with universal testing. CONCLUSIONS: Our simple algorithm can identify which individuals are likely to be HIV infected with sufficient accuracy to provide a screening tool for use in settings not already implementing universal testing policies among this age-group, for example immigrants to low-HIV-prevalence countries.

Perception of risk of vertically acquired HIV infection and acceptability of provider-initiated testing and counseling among adolescents in Zimbabwe.

OBJECTIVES: We investigated attitudes toward provider-initiated HIV testing and counseling (PITC) in the suburbs of Harare, Zimbabwe, where late presentation after mother-to-child HIV transmission (MTCT) is a major cause of adolescent mortality. METHODS: Adolescents (10-18 years) attending 2 primary clinics were offered PITC. Participants completed a questionnaire investigating acceptability of PITC, and in-depth interviews with 41 adolescents and 30 guardians explored understanding of long-term survival after MTCT. RESULTS: Of 506 participants, 16 were known to be HIV-positive; of the remaining 490, only 5 (1%) declined HIV testing. Infected adolescents and their guardians often anticipated a positive result and reported being advised by relatives (but not health workers) to be tested because of chronic illness, especially if parents or siblings had died or were HIV-infected. However, HIV-negative participants were not aware that long-term survival following MTCT could occur. All adolescents felt that HIV diagnosed at their age would be assumed to have been sexually acquired regardless of the true mode of transmission. CONCLUSIONS: Including late diagnosis of MTCT in pretest counseling and health educational messages may facilitate PITC for older children and adolescents, especially for those who have not had their sexual debut.

Community SARS-CoV-2 seroprevalence before and after the second wave of SARS-CoV-2 infection in Harare, Zimbabwe.

BACKGROUND: By the end of July 2021 Zimbabwe, has reported over 100,000 SARS-CoV-2 infections. The true number of SARS-CoV-2 infections is likely to be much higher. We conducted a seroprevalence survey to estimate the prevalence of past SARS-CoV-2 in three high-density communities in Harare, Zimbabwe before and after the second wave of SARS-CoV-2. METHODS: Between November 2020 and April 2021 we conducted a cross-sectional study of randomly selected households in three high-density communities (Budiriro, Highfield and Mbare) in Harare. Consenting participants answered a questionnaire and a dried blood spot sample was taken. Samples were tested for anti-SARS-CoV-2 nucleocapsid antibodies using the Roche e801 platform. FINDINGS: A total of 2340 individuals participated in the study. SARS-CoV-2 antibody results were available for 70·1% (620/885) and 73·1% (1530/2093) of eligible participants in 2020 and 2021. The median age was 22 (IQR 10-37) years and 978 (45·5%) were men. SARS-CoV-2 seroprevalence was 19·0% (95% CI 15·1-23·5%) in 2020 and 53·0% (95% CI 49·6-56·4) in 2021. The prevalence ratio was 2·47 (95% CI 1·94-3·15) comparing 2020 with 2021 after adjusting for age, sex, and community. Almost half of all participants who tested positive reported no symptoms in the preceding six months. INTERPRETATION: Following the second wave, one in two people had been infected with SARS-CoV-2 suggesting high levels of community transmission. Our results suggest that 184,800 (172,900-196,700) SARS-CoV-2 infections occurred in these three communities alone, greatly exceeding the reported number of cases for the whole city. Further seroprevalence surveys are needed to understand transmission during the current third wave despite high prevalence of past infections. FUNDING: GCRF, Government of Canada, Wellcome Trust, Bavarian State Ministry of Sciences, Research, and the Arts.

Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa.

BACKGROUND. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. METHODS. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged > or = 18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. RESULTS. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm(3) (interquartile range, 17-69 cells/mm(3)). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1-7.23). The study was terminated early by the data safety monitoring committee. CONCLUSIONS. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.

Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe.

BACKGROUND: Mother-to-child transmission of human immunodeficiency virus (HIV) infection was extremely common in southern Africa during the 1990s, and a substantial minority of infected infants have survived to reach adolescence undiagnosed. Studies have shown a high prevalence of HIV infection in hospitalized adolescents who have features associated with long-standing HIV infection, including stunting and frequent minor illnesses. We therefore investigated the epidemiology of HIV infection at the primary care level. METHODS: Adolescents (aged 10-18 years) attending two primary care clinics underwent HIV and Herpes simplex virus-2 (HSV-2) serological testing, clinical examination, and anthropometry. All were offered routine HIV counseling and testing. Patients attending for acute primary care (APC) who were HIV infected were asked about their risk factors. RESULTS: Five hundred ninety-four participants were systematically recruited (97% participation), of whom 88 (15%) were attending for antenatal care. HIV infection prevalence was higher among APC attendees than among antenatal care attendees (17% vs 6%; P < .007), but for the prevalence of HSV-2 infection, a marker of sexually acquired HIV, the converse was true (4% vs 14%; P < .002). Seventy (81%) of 86 HIV-positive APC attendees were previously undiagnosed. They had a broad range of presenting complaints, with a median CD4 cell count of 329 cells/microL (interquartile range, 176-485 cells/microL) and a high prevalence of stunting, compared with the corresponding prevalence among HIV-negative attendees (40% vs 12%; P < .001). Maternal transmission was considered to be likely by 69 (80%) of the 86 HIV-positive APC attendees, only one of whom was HSV-2 positive. CONCLUSIONS: Unrecognized HIV infection was a common cause of primary care attendance. Routine HIV counseling and testing implemented at the primary care level may provide a simple and effective way of identifying older long-term survivors of mother-to-child transmission before the onset of severe immunosuppression and irreversible complications.