Feasibility and Acceptability of a Task-Shifted Intervention to Enhance Adherence to HIV Medication and Improve Depression in People Living with HIV in Zimbabwe, a Low Income Country in Sub-Saharan Africa.

Using a pilot trial design in an HIV care clinic in Zimbabwe, we randomised 32 adults with poor adherence to antiretroviral therapy and at least mild depression to either six sessions of Problem-Solving Therapy for adherence and depression (PST-AD) delivered by an adherence counsellor, or to Enhanced Usual Care (Control). Acceptability of PST-AD was high, as indicated by frequency of session attendance and through qualitative analyses of exit interviews. Fidelity was >80% for the first two sessions of PST-AD but fidelity to the adherence component of PST-AD dropped by session 4. Contamination occurred, in that seven patients in the control arm received one or two PST-AD sessions before follow-up assessment. Routine health records proved unreliable for measuring HIV viral load at follow-up. Barriers to measuring adherence electronically included device failure and participant perception of being helped by the research device. The study was not powered to detect clinical differences, however, promising change at 6-months follow-up was seen in electronic adherence, viral load suppression (PST-AD arm 9/12 suppressed; control arm 4/8 suppressed) and depression (Patient Health Questionnaire-4.7 points in PST-AD arm vs. control, adjusted p value = 0.01). Results inform and justify a future randomised controlled trial of task-shifted PST-AD.

New approaches to the diagnosis and treatment of cryptococcal meningitis.

Cryptococcal meningitis remains one of the leading causes of morbidity and mortality among immunosuppressed individuals, particularly those with advanced acquired immunodeficiency syndrome. The greatest burden of disease is in sub-Saharan Africa and Asia where there is limited access to diagnostics and treatment for the disease. The authors review the available tools for diagnosing cryptococcal meningitis and review treatment for cryptococcal meningitis, highlighting the evidence behind current treatment guidelines.

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.

Factors associated with CD4 + cell count recovery among males and females with advanced HIV disease.

OBJECTIVE: HIV/AIDS mortality remains significantly high in sub-Saharan Africa, mostly driven by opportunistic infections and advanced HIV disease (AHD). This study aimed to assess CD4 + cell count recovery following ART initiation and factors associated with immune reconstitution. METHODS: We conducted a prospective cohort study between 2015 and 2016. HIV-infected adults (≥18 years) with AHD (CD4 + cell count ≤100 cells/µl) receiving care at 20 outpatient HIV treatment facilities in Harare, Zimbabwe were enrolled. CD4 + cell count recovery (CD4 + cell count >200 cells/µl) was assessed following 12-month ART initiation and factors associated with immune reconstitution were investigated using logistic regression analysis. All statistical analyses were performed on Statistical Package for the Social Sciences (SPSS) version 23. RESULTS: 1320 participants were enrolled and 56.4% were males. The median (interquartile range, IQR) age was 37 (32-43) years. Tuberculosis was seen in 16.0%. Of the 739 participants that had CD4 + cell count at 12 months, CD4 + cell count recovery above 200 cells/µl was observed in 163 (22.1%) participants. Median (IQR) CD4 + cell count at 12-months increased to 127 (75-190) cells/µl from 31 (14-55) at baseline. Factors associated with CD4 + cell count recovery were younger age at baseline [odds ratio (OR) ≥40/<40  = 0.58, 95% confidence interval (CI): 0.40-0.85, P  = 0.005), sex (OR female/male  = 2.07, 95% CI: 1.44-2.99, P  < 0.0001) and baseline CD4 + cell count (OR ≥50/<50  = 1.60, 95% CI: 1.10-2.33, P  = 0.013). CONCLUSION: A significant proportion (77.9%) of patients seeking care with AHD in a resource limited setting failed to recover a CD4 + cell count >200 cells/µl. Male sex, older age and low CD4 + cell count at ART initiation were factors associated with poor immune reconstitution. Better differentiated care deliveries targeting this vulnerable population are critical for improving clinical outcomes and quality of life of the patients.

Investigating Attitudes, Motivations and Key Influencers for COVID-19 Vaccination Uptake among Late Adopters in Urban Zimbabwe.

The rapid development of vaccines in response to the COVID-19 pandemic has provided an effective tool for the management of COVID-19. However, in many African countries there has been a poor uptake of COVID-19 vaccines with only 32.5% first vaccine dose coverage compared to the WHO global target of 70%. As vaccine access improves, one of the important drivers of low uptake has been vaccine hesitancy, driven by levels of confidence, convenience, and complacency. Between 4 January-11 February 2022, we conducted a survey of vaccine late adopters to assess factors that influenced adults in Harare, Zimbabwe to present for their first COVID-19 vaccine dose almost 12 months after the vaccination program began. Of the 1016 adults enrolled, 50% were female and 12.4% had HIV co-infection. Binary logistic regression models were developed to understand factors associated with vaccine confidence. Women were more likely to have negative views about the COVID-19 vaccine compared to men (OR 1.51 (95%CI 1.16, 1.97, p = 0.002). Older adults (≥40 years) compared with youth (18-25 years) were more likely to have 'major concerns' about vaccines. When asked about their concerns, 602 (59.3%) considered immediate side effects as a major concern and 520 (52.1%) were concerned about long-term health effects. People living with HIV (PLWH) were more likely to perceive vaccines as safe (OR 1.71 (95%CI: 1.07, 2.74, p = 0.025) and effective (1.68 (95%CI: 1.07, 2.64, p = 0.026). Internet users were less likely to perceive vaccines as safe (OR 0.72 (95% CI: 0.55, 0.95, p = 0.021) compared to non-Internet users; and social media was a more likely source of information for youth and those with higher education. Family members were the primary key influencers for 560 (55.2%) participants. The most important reason for receiving the COVID-19 vaccine for 715 (70.4%) participants was the protection of individual health. Improving vaccine coverage will need targeted communication strategies that address negative perceptions of vaccines and associated safety and effectiveness concerns. Leveraging normative behavior as a social motivator for vaccination will be important, as close social networks are key influences of vaccination.

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.

Attitudes to Vaccine Mandates among Late Adopters of COVID-19 Vaccines in Zimbabwe.

Despite sufficient supply, <25% of the population in sub-Saharan Africa has received at least one dose of COVID-19 vaccine. Vaccine mandates have previously been effective in increasing vaccine uptake. Attitudes to COVID-19 vaccine mandates and vaccines for children in African populations are not well understood. We surveyed late-adopters presenting for COVID-19 vaccination one year after program initiation in Zimbabwe. Logistic regression models were developed to evaluate factors associated with attitudes to mandates. In total, 1016 adults were enrolled; 690 (67.9%) approved of mandating vaccination for use of public spaces, 686 (67.5%) approved of employer mandates, and 796 (78.3%) approved of mandating COVID-19 vaccines for schools. Individuals of lower economic status were twice as likely as high-income individuals to approve of mandates. Further, 743 (73.1%) participants indicated that they were extremely/very likely to accept vaccines for children. Approval of vaccine mandates was strongly associated with perceptions of vaccine safety, effectiveness, and trust in regulatory processes that approved vaccines. Vaccine hesitancy is an important driver of low vaccine coverage in Africa and can be mitigated by vaccine mandates. Overall, participants favored vaccine mandates; however, attitudes to mandates were strongly associated with level of education and socioeconomic status.

Vaccine Adverse Events Following COVID-19 Vaccination with Inactivated Vaccines in Zimbabwe.

Vaccination is one of the most effective methods for preventing morbidity and mortality from COVID-19. Vaccine hesitancy has led to a decrease in vaccine uptake; driven by misinformation, fear, and misperceptions of vaccine safety. Whole inactivated vaccines have been used in one-fifth of the vaccine recipients in Africa, however there are limited real-world data on their safety. We evaluated the reported adverse events and factors associated with reported adverse events following vaccination with whole inactivated COVID-19 vaccines-BBiBP-CorV (Sinopharm) and CoronaVac (Sinovac). A quantitative survey evaluating attitudes and adverse events from vaccination was administered to 1016 adults presenting at vaccination centers. Two follow-up telephone interviews were conducted to determine adverse events after the first and second vaccination dose. Overall, the vaccine was well tolerated; 26.0% and 14.4% reported adverse events after the first and second dose, respectively. The most frequent local and systemic adverse events were pain at the injection site and headaches, respectively. Most symptoms were mild, and no participants required hospitalization. Participants who perceived COVID-19 vaccines as safe or had a personal COVID-19 experience were significantly less likely to report adverse events. Our findings provide data on the safety and tolerability of whole inactivated COVID-19 vaccines in an African population, providing the necessary data to create effective strategies to increase vaccination and support vaccination campaigns.

Characterization of an HLA-C-restricted CTL response in chronic HIV infection.

HIV-specific CTL play an important role in the host control of HIV infection. HIV-nef may facilitate escape of HIV-infected cells from CTL recognition by selectively downregulating the expression of HLA-A and HLA-B molecules, while surface expression of HLA-C is unaffected. The HLA-C-restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA-C-restricted CTL in ten antiretroviral therapy-naïve Caucasian and African individuals with chronic HIV-1 infection (for at least 8 years; CD4 cell counts in the range of 50-350) who carried the HLA-Cw04 allele. HLA-Cw04-restricted CTL that recognize a conserved epitope within HIV-1 envelope (aa 375-383 SF9) were analyzed using IFN-gamma ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA-C-restricted CTL play an important role in the HIV-specific response, and can account for as much as 54% of the total response. HLA-C-restricted CTL are functionally and phenotypically identical to HLA-A- and HLA-B-restricted CTL. HLA-C-restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.

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.

Drug resistance and optimizing dolutegravir regimens for adolescents and young adults failing antiretroviral therapy.

OBJECTIVES: The integrase strand inhibitor dolutegravir (DTG) combined with tenofovir and lamivudine (TLD) is a single tablet regimen recommended for 1st, 2nd and 3rd-line public health antiretroviral therapy (ART). We determined drug resistance mutations (DRMs) and evaluated the predictive efficacy of a TLD containing regimen for viremic adolescents and young adults in Harare, Zimbabwe. METHODS: We sequenced plasma viral RNA from HIV-1-infected adolescents and young adults on 1st and 2nd-line ART with confirmed virologic failure (viral load >1000 copies/ml) and calculated total genotypic susceptibility scores to current 2nd, 3rd line and DTG regimens. RESULTS: A total of 160 participants were genotyped; 112 (70%) on 1st line and 48 (30%) on 2nd line, median (interquartile range) age 18 (15-19) and duration of ART (interquartile range) was 6 (4-8) years. Major DRMs were present in 94 and 67% of 1st and 2nd-line failures, respectively (P < 0.001). Dual class resistance to nucleotide reverse transcriptase inhibitors and nonnucleotide reverse transcriptase inhibitors was detected in 96 (60%) of 1st-line failures; protease inhibitor DRMs were detected in a minority (10%) of 2nd-line failures. A total genotypic susceptibility score of 2 or less may risk protease inhibitor or DTG monotherapy in 11 and 42% of 1st-line failures switching to 2nd-line protease inhibitor and TLD respectively. CONCLUSION: Among adolescents and young adults, current protease inhibitor-based 2nd-line therapies are poorly tolerated, more expensive and adherence is poor. In 1st-line failure, implementation of TLD for many adolescents and young adults on long-term ART may require additional active drug(s). Drug resistance surveillance and susceptibility scores may inform strategies for the implementation of TLD.

Identification of a novel HLA B*57 restricted cytotoxic T-lymphocyte epitope within HIV-1 rev.

HLA-B5701 and its related allele B5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B5701, B5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.

Evaluation of the FACSPresto, a New Point of Care Device for the Enumeration of CD4% and Absolute CD4+ T Cell Counts in HIV Infection.

INTRODUCTION: Enumeration of CD4+ T lymphocytes is important for pre-ART disease staging and screening for opportunistic infections, however access to CD4 testing in resource limited settings is poor. Point of care (POC) technologies can facilitate improved access to CD4 testing. We evaluated the analytical performance of a novel POC device the FACSPresto compared to the FACSCalibur as a reference standard and to the PIMA, a POC device in widespread use in sub-Saharan Africa. METHOD: Specimens were obtained from 253 HIV infected adults. Venous blood samples were analyzed on the FACSPresto and the FACSCalibur, in a subset of 41 samples additional analysis was done on the PIMA. RESULTS: The absolute CD4 count results obtained on the FACSPresto were comparable to those on the FACSCalibur with low absolute (9.5cells/µl) and relative bias (3.2%). Bias in CD4% values was also low (1.06%) with a relative bias of 4.9%. The sensitivity was lower at a CD4 count threshold of ≤350cells/µl compared with ≤500cells/µl (84.9% vs. 92.8%) resulting in a high upward misclassification rate at low CD4 counts. Specificity at thresholds of ≤350cells/µl and ≤500cells/µl were 96.6% and 96.8% respectively. The PIMA had a high absolute (-68.6cells/µl) and relative bias (-10.5%) when compared with the FACSCalibur. At thresholds of ≤350cells/µl and ≤500cells/µl the sensitivity was 100% and 95.5% respectively; specificity was 85.7% and 84.2% respectively. The coefficients of repeatability were 4.13%, 5.29% and 9.8% respectively. DISCUSSION: The analytic performance of the FACSPresto against the reference standard was very good with better agreement and precision than the PIMA. The FACSPresto had comparable sensitivity at a threshold of 500 cells/µl and better specificity than the PIMA. However the FACSPresto showed reduced sensitivity at low CD4 count thresholds. CONCLUSION: The FACSPresto can be reliably used as a POC device for enumerating absolute CD4 count and CD4% values.

AIDS-associated Kaposi sarcoma: outcomes after initiation of antiretroviral therapy at a university-affiliated hospital in urban Zimbabwe.

OBJECTIVE: To retrospectively investigate the outcomes of patients with AIDS-associated Kaposi sarcoma (AIDS-KS) after initiation of antiretroviral therapy (ART), under routine practice conditions, at a university-affiliated hospital in urban Zimbabwe. BACKGROUND: While studies from developed nations have demonstrated excellent outcomes for AIDS-KS patients treated with ART, few studies have examined the outcomes of African AIDS-KS patients after starting therapy. METHODS: A retrospective cohort of 124 AIDS patients initiating ART under routine practice conditions was studied. Thirty-one patients with AIDS-KS were matched 1:3 to 93 AIDS patients without KS (non-KS). The primary outcome was loss-to-care after initiation of therapy. Multivariate analysis was performed to identify significant predictors of loss-to-care. The percent change in weight at 6 months after starting ART was a secondary outcome. A sub-group analysis evaluated differences in pre-treatment variables between AIDS-KS patients retained-in-care compared to those lost-to-care. RESULTS: AIDS-KS patients had significantly greater 2-year proportional loss-to-care than matched non-KS AIDS patients (26.4% vs. 9.5%; p = 0.01) after initiation of ART. In multivariate analysis, the presence of KS (p = 0.02) was the only significant predictor of loss-to-care. AIDS-KS patients had significantly less weight gain after starting ART than non-KS AIDS patients (+3.4% vs. +6.4%; p = 0.03). AIDS-KS patients retained-in-care had significantly higher pre-treatment CD4+ lymphocyte counts than AIDS-KS patients lost-to-care (223 vs. 110 cells/mm(3); p = 0.04). CONCLUSIONS: In this retrospective study, AIDS-KS patients experienced significantly worse outcomes than matched non-KS AIDS patients after initiation of ART. AIDS-KS patients with higher pre-treatment CD4+ lymphocyte counts were more likely to be retained in care.

Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G.

Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (Kd = 2-45 microM), some interesting differences were observed. ILT2 generally bound with a 2- to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3- to 4-fold higher affinity than to classical MHCIs, suggesting that ILT/HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8+ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.