Burden of HIV infection and HIV-associated morbidity in Zimbabwean adolescents

This thesis concerns the clinical epidemiology of HIV infection in Zimbabwean adolescents. Without treatment, there is a very high risk of death in the early years of life in HIV-infected infants. However, in recent years increasing numbers of adolescents have been presenting to health care services with symptomatic HIV infection and with features suggesting longstanding disease. Population-based surveys in Southern Africa have shown HIV prevalence rates among older children and adolescents to be much higher than would be anticipated if HIV-infants were not surviving early childhood. The burden and spectrum of HIV-associated morbidity among adolescents was investigated with two studies at secondary and primary care level, respectively. The main finding was of an extremely high prevalence of HIV infection at both levels of the health system, with HIV infection being the single most common cause of hospital admission and death among adolescents. Mother-to-child transmission was the most likely source of HIV infection in the majority, suggesting a substantial epidemic of older survivors of vertical HIV infection. Other countries with severe HIV epidemics may be experiencing a similar trend as their HIV epidemics mature. The lack of awareness of the possibility of survival to older childhood and adolescence with maternally-acquired, untreated HIV infection results in many missed opportunities for diagnosis, with HIV infection frequently not diagnosed until presentation with a severe HIV-related illness. The median CD4 count in 3 HIV-infected adolescents in primary care was 350cells/µl compared to a median CD4 count of 151cells/µl among hospitalised adolescents, suggesting that HIV testing in primary care identifies HIV-infected adolescents at an earlier stage of infection. Provider-initiated HIV testing and counselling in primary care was highly acceptable to adolescents and guardians. Provision of care has been adversely affected by under-appreciation of the numbers of surviving adolescents living with HIV, and the special needs of this age-group have not been distinguished from those of younger children. Young people who have acquired HIV perinatally are stigmatised by society who assume they must have acquired it through "bad" behaviour themselves, since it is not widely appreciated that long-term survival following vertical infection is possible. Immediate priorities are earlier diagnosis of HIV infection and improved management of HIV-infected adolescents. Possible areas of intervention are discussed in the final chapter. Similar studies are needed in neighbouring countries to investigate the generalisability of these findings

"It is not possible to go inside and have a discussion": how fear of stigma affects delivery of community-based support for children's HIV care.

Caregivers mediate children's access to HIV care and their adherence to treatment. Support for caregivers may improve health outcomes in children, but fear of HIV stigma and discrimination can affect both uptake and delivery of support services. Within a trial evaluating community-based support for caregivers of newly HIV diagnosed children in Harare, Zimbabwe, we conducted a longitudinal qualitative study to explore how stigma affected delivery and acceptance of the intervention. We conducted semi-structured interviews with 36 caregivers, 15 children, and 20 community health workers (CHWs). Children and caregivers described experiencing or witnessing stigma and discrimination, causing some to resist home visits by CHWs. Anxiety around stigma made it difficult for CHWs to promote key messages. In response, CHWs adapted the intervention by meeting caregivers outside the home, pretending to be friends or relatives, and proactively counteracting stigmatising beliefs. As members of local communities, some CHWs shared concerns about discrimination. HIV stigma can hinder "getting a foot over the threshold" in community-based programmes, particularly for households most affected by discrimination and thus least likely to engage with services. For community support programmes to be effective, stigma-related resistance should be addressed from the outset, including CHWs' own concerns regarding HIV stigma

Evaluation of the diagnostic accuracy of Computer-Aided Detection of tuberculosis on Chest radiography among private sector patients in Pakistan.

The introduction of digital CXR with automated computer-aided interpretation, has given impetus to the role of CXR in TB screening, particularly in low resource, high-burden settings. The aim of this study was to evaluate the diagnostic accuracy of CAD4TB as a screening tool, implemented in the private sector in Karachi, Pakistan. This study analyzed retrospective data from CAD4TB and Xpert MTB/RIF testing carried out at two private TB treatment and diagnostic centers in Karachi. Sensitivity, specificity, potential Xperts saved, were computed and the receiver operator characteristic curves were constructed for four different models of CAD4TB. A total of 6,845 individuals with presumptive TB were enrolled in the study, 15.2% of which had MTB + ve result on Xpert. A high sensitivity (range 65.8-97.3%) and NPV (range 93.1-98.4%) were recorded for CAD4TB. The Area under the ROC curve (AUC) for CAD4TB was 0.79. CAD4TB with patient demographics (age and gender) gave an AUC of 0.83. CAD4TB offered high diagnostic accuracy. In low resource settings, CAD4TB, as a triage tool could minimize use of Xpert. Using CAD4TB in combination with age and gender data enhanced the performance of the software. Variations in demographic information generate different individual risk probabilities for the same CAD4TB scores

Implementation and Operational Research: The Effectiveness of Routine Opt-Out HIV Testing for Children in Harare, Zimbabwe.

OBJECTIVE: HIV testing is the entry point to access HIV care. For HIV-infected children who survive infancy undiagnosed, diagnosis usually occurs on presentation to health care services. We investigated the effectiveness of routine opt-out HIV testing (ROOT) compared with conventional opt-in provider-initiated testing and counseling (PITC) for children attending primary care clinics. METHODS: After an evaluation of PITC services for children aged 6-15 years in 6 primary health care facilities in Harare, Zimbabwe, ROOT was introduced through a combination of interventions. The change in the proportion of eligible children offered and receiving HIV tests, reasons for not testing, and yield of HIV-positive diagnoses were compared between the 2 HIV testing strategies. Adjusted risk ratios for having an HIV test in the ROOT compared with the PITC period were calculated. RESULTS: There were 2831 and 7842 children eligible for HIV testing before and after the introduction of ROOT. The proportion of eligible children offered testing increased from 76% to 93% and test uptake improved from 71% to 95% in the ROOT compared with the PITC period. The yield of HIV diagnoses increased from 2.9% to 4.5%, and a child attending the clinics post intervention had a 1.99 increased adjusted risk (95% CI: 1.85 to 2.14) of receiving an HIV test in the ROOT period compared with the preintervention period. CONCLUSION: ROOT increased the proportion of children undergoing HIV testing, resulting in an overall increased yield of positive diagnoses, compared with PITC. ROOT provides an effective approach to reduce missed HIV diagnosis in this age group

Evaluation of the diagnostic accuracy of computer-aided detection of tuberculosis on chest radiography among private sector patients in Pakistan

The introduction of digital CXR with automated computer-aided interpretation, has given impetus to the role of CXR in TB screening, particularly in low resource, high-burden settings. The aim of this study was to evaluate the diagnostic accuracy of CAD4TB as a screening tool, implemented in the private sector in Karachi, Pakistan. This study analyzed retrospective data from CAD4TB and Xpert MTB/RIF testing carried out at two private TB treatment and diagnostic centers in Karachi. Sensitivity, specificity, potential Xperts saved, were computed and the receiver operator characteristic curves were constructed for four different models of CAD4TB. A total of 6,845 individuals with presumptive TB were enrolled in the study, 15.2% of which had MTB + ve result on Xpert. A high sensitivity (range 65.8-97.3%) and NPV (range 93.1-98.4%) were recorded for CAD4TB. The Area under the ROC curve (AUC) for CAD4TB was 0.79. CAD4TB with patient demographics (age and gender) gave an AUC of 0.83. CAD4TB offered high diagnostic accuracy. In low resource settings, CAD4TB, as a triage tool could minimize use of Xpert. Using CAD4TB in combination with age and gender data enhanced the performance of the software. Variations in demographic information generate different individual risk probabilities for the same CAD4TB scores

Engagement of private healthcare providers for case finding of tuberculosis and diabetes mellitus in Pakistan

Background: The rising co-epidemic of tuberculosis (TB) and diabetes mellitus (DM) is a challenge for constrained health systems in low and middle-income countries. Diabetes is a known risk factor for tuberculosis and associated with poor tuberculosis treatment outcomes, while tuberculosis is associated with worsening glycemic control. We investigated the performance of bi-directional TB and DM case finding approaches through a private-sector engagement model in Karachi, Pakistan.Methods: Between July 2016 and July 2018, private health care providers were engaged to generate referrals for bi-directional TB and DM screening at private diagnostic and treatment centers in Karachi, Pakistan. Individuals diagnosed with TB underwent glycated hemoglobin (HbA1c) testing at the time of anti-tuberculous treatment initiation and at three -month follow up stage. All individuals with a history of diabetes or random blood sugar of greater than 200 mg/dl were screened for TB using a chest X-ray and Xpert MTB/RIF.Results: A total of 6312 persons with tuberculosis were tested on HbA1c at treatment initiation, of whom 1516 (24%) were newly diagnosed with DM. About one third of those with HbA1c in the diabetic range (≥ 6.5%) at baseline were found to have a normal HbA1c (\u3c 5.7%) result at 3-month follow-up. A total of 3824 individuals with DM, of whom 2396 (63%) were known cases and 1428 (37%) were newly identified with random blood sugar \u3e 200 mg/dl, underwent chest x-ray and Xpert MTB/RIF testing, with 321 (13.4%) known and 54 (3.8%) new diabetics respectively identified with tuberculosis.Conclusion: This study demonstrates a high yield of TB and DM through bidirectional screening and the feasibility of engagement of private sector in finding missing cases of tuberculosis and diabetes. Given the high prevalence of undiagnosed DM in individuals with TB tuberculosis patients, there is a need to scale-up DM screening within TB programmes. Increased awareness of the high risk of TB among individuals with DM is needed among private health providers and screening for TB among diabetics should be strongly considered

Brief Report: Improving Early Infant Diagnosis Observations: Estimates of Timely HIV Testing and Mortality Among HIV-Exposed Infants.

BACKGROUND: Improving efforts toward elimination of mother-to-child transmission of HIV requires timely early infant diagnosis (EID) among all HIV-exposed infants, but the occurrence of timely EID and infant survival may be underascertained in routine, facility-bound program data. METHODS: From March 2015 to May 2015, we traced a random sample of HIV-positive mother and HIV-exposed infant pairs lost to follow-up for EID in facility registers in Zimbabwe. We incorporated updated information into weighted survival analyses to estimate incidence of EID and death. Reasons for no EID were surveyed from caregivers. RESULTS: Among 2651 HIV-positive women attending antenatal care, 1823 (68.8%) infants had no documented EID by 3 months of age. Among a random sample of 643 (35.3%) HIV-exposed infants lost to follow-up for EID, vital status was ascertained among 371 (57.7%) and updated care status obtained from 256 (39.8%) mothers traced. Among all HIV-infected mother-HIV-exposed infant pairs, weighted estimates found cumulative incidence of infant death by 90 days of 3.9% (95% confidence interval: 3.4% to 4.4%). Cumulative incidence of timely EID with death as a competing risk was 60%. The most frequently cited reasons for failure to uptake EID were "my child died" and "I didn't know I should have my child tested." CONCLUSIONS: Our findings indicate uptake of timely EID among HIV-exposed infants is underestimated in routine health information systems. High, early mortality among HIV-exposed infants underscores the need to more effectively identify HIV-positive mother-HIV exposed infant pairs at high risk of adverse outcomes and loss to follow-up for enhanced interventions

Phylogenetic and drug-resistance analysis of HIV-1 sequences from an extensive paediatric HIV-1 outbreak in Larkana, Pakistan

Introduction: In April 2019, an HIV-1 outbreak among children occurred in Larkana, Pakistan, affecting more than a thousand children. It was assumed that the outbreak originated from a single source, namely a doctor at a private health facility. In this study, we performed subtype distribution, phylogenetic and drug-resistance analysis of HIV-1 sequences from 2019 outbreak in Larkana, Pakistan.Methods: A total of 401 blood samples were collected between April-June 2019, from children infected with HIV-1 aged 0-15 years recruited into a case-control study to investigate the risk factors for HIV-1 transmission. Partial HIV-1 pol sequences were generated from 344 blood plasma samples to determine HIV-1 subtype and drug resistance mutations (DRM). Maximum-likelihood phylogenetics based on outbreak and reference sequences was used to identify transmission clusters and assess the relationship between outbreak and key population sequences between and within the determined clusters. Bayesian analysis was employed to identify the time to the most recent common recent ancestor (tMRCA) of the main Pakistani clusters.Results: The HIV-1 circulating recombinant form (CRF) 02_AG and subtype A1 were most common among the outbreak sequences. Of the treatment-naïve participants, the two most common mutations were RT: E138A (8%) and RT: K219Q (8%). Four supported clusters within the outbreak were identified, and the median tMRCAs of the Larkana outbreak sequences were estimated to 2016 for both the CRF02_AG and the subtype A1 clusters. Furthermore, outbreak sequences exhibited no phylogenetic mixing with sequences from other high-risk groups of Pakistan.Conclusion: The presence of multiple clusters indicated a multi-source outbreak, rather than a single source outbreak from a single health practitioner as previously suggested. The multiple introductions were likely a consequence of ongoing transmission within the high-risk groups of Larkana, and it is possible that the so-called Larkana strain was introduced into the general population through poor infection prevention control practices in healthcare settings. The study highlights the need to scale up HIV-1 prevention programmes among key population groups and improving infection prevention control in Pakistan

Loss to follow-up among children and adolescents growing up with HIV infection: age really matters.

INTRODUCTION: Globally, increasing numbers of HIV-infected children are reaching adolescence due to antiretroviral therapy (ART). We investigated rates of loss-to-follow-up (LTFU) from HIV care services among children as they transition from childhood through adolescence. METHODS: Individuals aged 5-19 years initiated on ART in a public-sector HIV clinic in Bulawayo, Zimbabwe, between 2005 and 2009 were included in a retrospective cohort study. Participants were categorized into narrow age-bands namely: 5-9 (children), 10-14 (young adolescents) and 15-19 (older adolescents). The effect of age at ART initiation, current age (using a time-updated Lexis expansion) and transitioning from one age group to the next on LTFU was estimated using Poisson regression. RESULTS: Of 2273 participants, 1013, 875 and 385 initiated ART aged 5-9, 10-14 and 15-19 years, respectively. Unlike those starting ART as children, individuals starting ART as young adolescents had higher LTFU rates after moving to the older adolescent age-band (Adjusted rate ratio (ARR) 1.54; 95% CI: 0.94-2.55) and similarly, older adolescents had higher LTFU rates after transitioning to being young adults (ARR 1.79; 95% CI: 1.05-3.07). In older adolescents, the LTFU rate among those who started ART in that age-band was higher compared to the rate among those starting ART at a younger age (ARR = 1.70; 95% CI: 1.05, 2.77). This however did not hold true for other age-groups. CONCLUSIONS: Adolescents had higher rates of LTFU compared to other age-groups, with older adolescents at particularly high risk in all analyses. Age-updated analyses that examine movement across narrow age-bands are paramount in understanding how developmental heterogeneity in children affects HIV outcomes

Evaluation of computer aided detection of tuberculosis on chest radiography among people with diabetes in Karachi Pakistan

Pakistan ranks fifth among high tuberculosis (TB) burden countries and also has seventh highest burden for diabetes mellitus (DM). DM increases the risk of developing TB and contributes to adverse TB treatment outcomes hence screening and integrated management for both diseases in high burden countries is suggested. Computer-Aided Detection for TB (CAD4TB) can potentially be used as triage tool in low resource settings to pre-screen individuals for Xpert MTB/RIF testing. The aim of this study was to evaluate the diagnostic accuracy and performance of CAD4TB software in people with diabetes (PWD) enrolled in a TB screening program in Karachi, Pakistan. A total of 694 individuals with a diagnosis of DM (of whom 31.1% were newly diagnosed) were screened with CAD4TB and simultaneously provided sputum for Xpert MTB/RIF testing. Of the 74 (10.7%) participants who had bacteriologically positive (MTB+) results on Xpert testing, 54 (73%) had a CAD4TB score \u3e70; and 155 (25%) participants who tested MTB-negative had scores \u3e70. The area under the receiver operator curve was 0.78 (95% CI: 0.77-0.80). Our study findings indicate that CAD4TB offers good diagnostic accuracy as a triage test for TB screening among PWD using Xpert MTB/RIF as the reference standard