The Effects of Antiretroviral Therapy Scale-Up on Tuberculosis and Non-Communicable Diseases Health Service Utilization and Mortality Risk among the General Population in Rural South Africa, 2009-2014

The overall purpose of this dissertation was to examine evidence of spillover effects of HIV care and treatment service scale up in sub-Saharan Africa in the past decade. Particularly the focus was to quantify any effect HIV treatment initiation by a person living with HIV (PLHIV) may confer health benefits to the HIV negative population by increasing utilization of non-HIV services or reduce mortality risk. This dissertation had three primary aims. The first aim was to conduct a systematic review of the effect of increasing ART uptake in high HIV prevalence communities on use of non-HIV health services, including maternal, child, in/out-patient, non-HIV laboratory, and TB diagnosis and treatment services. Overall positive effects were found on the majority of health service indicators examined for non-HIV laboratory service utilization and Tuberculosis diagnosis and treatment services. We found negative associations on the majority of indicators examined for child health services. The existing evidence did not point to clear tendencies for maternal health services and outpatient and inpatient services. Restricting the sample to studies with stronger study designs for causal inference, the positive effect on non-HIV laboratory services and the negative impact on child health services held but evidence was mixed for TB diagnosis and treatment services, maternal health services and outpatient and inpatient services. The second aim of this dissertation was to conduct regression discontinuity quasi-experiments to determine whether exposure to health benefits from ART utilization by a person living with HIV (PLHIV) in a household affects uptake of TB, hypertension (HTN) and diabetes mellitus (DM) treatment by other household members with these conditions. The study was conducted in the comprehensive population cohort followed by the Africa Health Research Institute (AHRI) in Kwazulu-Natal (KZN), South Africa. We linked PLHIV engaged in HIV care to their cohabitating household members aged ≥15 years using a unique identifier for homesteads. Household ART utilization significantly increased treatment for diabetes (RR 1.90: 95% CI 1.07-3.40) but not for TB (RR 1.12: 95% CI 0.71-2.03) or hypertension (RR 1.31: 95% CI 0.97-1.77). The third aim of this dissertation was to use the same regression discontinuity design and KZN cohort data as in aim 2 to determine whether exposure to health benefits from ART utilization by PLHIV in a household reduces all-cause mortality of other household members. Overall, household ART utilization did not decrease all-cause mortality (Hazard Ratio (HR) 0.95: 95% CI 0.65-1.4), however, restricting the analysis to a narrow CD4+ cell count range around the regression discontinuity threshold showed reduced all-cause mortality by 67% (HR 0.43: 95% CI 0.22-0.85) among household members of PLHIV on ART; the reduced risk was driven largely by the significant reduction noted among female household members (HR 0.21: 95% 0.08, 0.56)

The START Study to evaluate the effectiveness of a combination intervention package to enhance antiretroviral therapy uptake and retention during TB treatment...

Background: Initiating antiretroviral therapy (ART) early during tuberculosis (TB) treatment increases survival; however, implementation is suboptimal. Implementation science studies are needed to identify interventions to address this evidence-to-program gap. Objective: The Start TB Patients on ART and Retain on Treatment (START) Study is a mixed-methods, cluster-randomized trial aimed at evaluating the effectiveness, cost-effectiveness, and acceptability of a combination intervention package (CIP) to improve early ART initiation, retention, and TB treatment success among TB/HIV patients in Berea District, Lesotho. Design: Twelve health facilities were randomized to receive the CIP or standard of care after stratification by facility type (hospital or health center). The CIP includes nurse training and mentorship, using a clinical algorithm; transport reimbursement and health education by village health workers (VHW) for patients and treatment supporters; and adherence support using text messaging and VHW. Routine data were abstracted for all newly registered TB/HIV patients; anticipated sample size was 1,200 individuals. A measurement cohort of TB/HIV patients initiating ART was recruited; the target enrollment was 384 individuals, each to be followed for the duration of TB treatment (6–9 months). Inclusion criteria were HIV-infected; on TB treatment; initiated ART within 2 months of TB treatment initiation; age ≥18; English- or Sesotho-speaking; and capable of informed consent. The exclusion criterion was multidrug-resistant TB. Three groups of key informants were recruited from intervention clinics: early ART initiators; non/late ART initiators; and health care workers. Primary outcomes include ART initiation, retention, and TB treatment success. Secondary outcomes include time to ART initiation, adherence, change in CD4+ count, sputum smear conversion, cost-effectiveness, and acceptability. Follow-up and data abstraction are complete. Discussion: The START Study evaluates a CIP targeting barriers to early ART implementation among TB/HIV patients. If the CIP is found effective and acceptable, this study has the potential to inform care for TB/HIV patients in high-burden, resource-limited countries in sub-Saharan Africa. Keywords: TB/HIV integration; implementation science; cost-effectiveness; acceptability; TB treatment succes

High Levels of Adherence and Viral Suppression in a Nationally Representative Sample of HIV-Infected Adults on Antiretroviral Therapy for 6, 12 and 18 Months in Rwanda

Background: Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART) in Africa. Methods: We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL) measurements. Multivariable logistic regression examined predictors of non-perfect (less than 100%) 30-day adherence and detectable VL (greater than 40 copies/ml). Results: Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months); younger age; reporting severe (vs. no or few) side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of less than 200 cells/µL); alcohol use; and attending sites which initiated ART services in 2003–2004 and 2005 (vs. 2006–2007); sites with ≥600 (vs. less than 600 patients) on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL. Conclusions: High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors

Declining Tuberculosis Incidence Among People Receiving HIV Care and Treatment Services in East Africa, 2007–2012

Background: Antiretroviral therapy (ART) reduces the risk of Tuberculosis (TB) among people living with HIV (PLWH). With ART scale-up in sub-Saharan Africa over the past decade, incidence of TB among PLWH engaged in HIV care is predicted to decline. Methods: We conducted a retrospective analysis of routine clinical data from 168,330 PLWH receiving care at 35 facilities in Kenya, Tanzania, and Uganda during 2003–2012, participating in the East African region of the International Epidemiologic Databases to Evaluate AIDS. Temporal trends in facility-based annual TB incidence rates (per 100,000 person years) among PLWH and country-specific standardized TB incidence ratios using annual population-level TB incidence data from the World Health Organization were computed between 2007 and 2012. We examined patient-level and facility-level factors associated with incident TB using multivariable Cox models. Results: Overall, TB incidence rates among PLWH in care declined 5-fold between 2007 and 2012 from 5960 to 985 per 100,000 person years [P = 0.0003] (Kenya: 7552 to 1115 [P = 0.0007]; Tanzania: 7153 to 635 [P = 0.0025]; Uganda: 3204 to 242 [P = 0.018]). Standardized TB incidence ratios significantly decreased in the 3 countries, indicating a narrowing gap between incidence rates among PLWH and the general population. We observed lower hazards of incident TB among PLWH on ART and/or isoniazid preventive therapy and receiving care in facilities offering TB treatment onsite. Conclusions: Annual TB incidence rates among PLWH significantly declined during ART scale-up but remained higher than the general population. Increasing access to ART and isoniazid preventive therapy and co-location of HIV and TB treatment may further reduce TB incidence among PLWH

Using mHealth for HIV/TB treatment support in Lesotho : enhancing patient–provider communication in the START study.

CAPRISA, 2017.Abstract available in pdf

Prevalence of and factors associated with late diagnosis of HIV in Malawi, Zambia, and Zimbabwe: Results from population-based nationally representative surveys

Introduction Late diagnosis of HIV (LD) increases the risk of morbidity, mortality, and HIV transmission. We used nationally representative data from population-based HIV impact assessment (PHIA) surveys in Malawi, Zambia, and Zimbabwe (2015–2016) to characterize adults at risk of LD and to examine associations between LD and presumed HIV transmission to cohabiting sexual partners. Methods We estimated the prevalence of LD, defined as CD4 count <350 cells/μL, among adults newly diagnosed with HIV during the surveys and odds ratios for associated factors. We linked newly diagnosed adults (index cases) to their household sexual partners and calculated adjusted odds ratios for associations between LD of the index case, viral load of the index case, and duration of HIV exposure in the relationship, and the HIV status of the household sexual partner. Results Of 1,804 adults who were newly diagnosed with HIV in the surveys, 49% (882) were diagnosed late. LD was associated with male sex, older age, and almost five times the odds of having an HIV-positive household sexual partner (adjusted odds ratio [aOR], 4.65 [95% confidence interval: 2.56–8.45]). Longer duration of HIV exposure in a relationship and higher viral load of the index case were both independently associated with higher odds of having HIV-positive household sexual partners. Individuals with HIV exposure of more than 5 years had more than three times (aOR 3.42 [95% CI: 1.63–7.18]) higher odds of being HIV positive than those with less than 2 years HIV exposure. The odds of being HIV positive were increased in individuals who were in a relationship with an index case with a viral load of 400–3499 copies/mL (aOR 4.06 [95% CI 0.45–36.46]), 3,500–9,999 copies/mL (aOR 11.32 [95% CI: 4.08–31.39]), 10,000–49,999 copies/mL (aOR 17.07 [95% CI: 9.18–31.72]), and ≥50,000 copies/mL (aOR 28.41 [95% CI: 12.18–66.28]) compared to individuals who were in a relationship with an index case with a viral load of <400 copies/mL. Conclusions LD remains a challenge in Southern Africa and is strongly associated with presumed HIV transmission to household sexual partners. Our study underscores the need for earlier HIV diagnosis, particularly among men and older adults, and the importance of index testing

Prevalence of nonsuppressed viral load and associated factors among HIV-positive adults receiving antiretroviral therapy in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017): results from population-based nationally representative surveys.

INTRODUCTION The global target for 2020 is that ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) will achieve viral load suppression (VLS). We examined VLS and its determinants among adults receiving ART for at least four months. METHODS We analysed data from the population-based HIV impact assessment (PHIA) surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017). PHIA surveys are nationally representative, cross-sectional household surveys. Data collection included structured interviews, home-based HIV testing and laboratory testing. Blood samples from PLHIV were analysed for HIV RNA, CD4 counts and recent exposure to antiretroviral drugs (ARVs). We calculated representative estimates for the prevalence of VLS (viral load <1000 copies/mL), nonsuppressed viral load (NVL; viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL) and rates of switching to second-line ART (protease inhibitors present) among PLHIV aged 15 to 59 years who participated in the PHIA surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe, initiated ART at least four months before the survey and were receiving ART at the time of the survey (according to self-report or ARV testing). We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART. RESULTS We included 9200 adults receiving ART of whom 88.8% had VLS and 11.2% had NVL including 8.2% who experienced VF and 3.0% who interrupted ART. Younger age, male sex, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married and residing in Zimbabwe, Lesotho or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female sex, shorter ART duration, higher CD4 count and alcohol use were associated with lower odds for VF and higher odds for interrupted ART. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART. CONCLUSIONS Countries are approaching global VLS targets for adults. Treatment support, in particular for younger adults, and people with higher CD4 counts, and switching of people to protease inhibitor- or integrase inhibitor-based regimens may further reduce NVL prevalence

The ENRICH study to evaluate the effectiveness of a combination intervention package to improve isoniazid preventive therapy initiation, adherence and completion among people living with HIV in Ethiopia: Rationale and design of a mixed methods cluster randomized trial

Background: Isoniazid preventive therapy (IPT) prevents tuberculosis among HIV-positive individuals, however implementation is suboptimal. Implementation science studies are needed to identify interventions to address this evidence-to-program gap. Objective: The ENRICH Study is a mixed methods cluster randomized trial aimed at evaluating the effectiveness and acceptability of a combination intervention package (CIP) to improve IPT implementation in Ethiopia. Design: Ten health centers were randomized to receive the CIP or standard of care. The CIP includes: nurse training and mentorship using a clinical algorithm, tool to identify IPT-eligible family members, and data review at multidisciplinary team meetings; patient transport reimbursement; and adherence support using peer educators and interactive voice response messages. Routine data were abstracted for all newly-enrolled IPT-eligible HIV-positive patients; anticipated sample size was 1400 individuals. A measurement cohort of patients initiating IPT was recruited; target enrollment was 500 individuals, to be followed for the duration of IPT (6–9 months). Inclusion criteria were: HIV-positive; initiated IPT; age ≥18; Amharic-, Oromiffa-, Harari-, or Somali-speaking; and capable of informed consent. Three groups were recruited from CIP health centers for in-depth interviews: IPT initiators; IPT non-initiators; and health care providers. Primary outcomes are: IPT initiation; and IPT completion. Secondary outcomes include: retention; adherence; change in CD4+ count; adverse events; and acceptability. Follow-up is complete. Discussion: The ENRICH Study evaluates a CIP targeting barriers to IPT implementation. If the CIP is found effective and acceptable, this study has the potential to inform TB prevention strategies for HIV patients in resource-limited countries in sub-Saharan Africa