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ABSTRACT
BackgroundSub-Saharan Africa is the region most heavily affected by the HIV/AIDS epidemic. HIV increases the risk of developing cancer but the ascertainment of cancers in patients attending antiretroviral therapy (ART) treatment programs might be incomplete. To estimate the under-ascertainment of cancer we compared incidence rates of AIDS-defining cancers in South African HIV cohorts with and without cancer case ascertainment through record linkage with the National Cancer Registry.
MethodsWe used the data of adult (≥16 years) HIV-positive persons receiving care between 2004 and 2011 at one of four ART programs in South Africa. These programs collaborate with the International Epidemiologic Databases to Evaluate AIDS Southern Africa (www.iedea-sa.org) and collected data for AIDS-defining cancers but not for other cancers. To improve cancer ascertainment we probabilistically linked patient records (using first name, surname, age, and gender) from two HIV cohorts with the cancer records of the South African National Cancer Registry. We calculated incidence rates per 100,000 person-years after starting ART for the AIDS-defining cancers, i.e. Kaposi sarcoma (KS), invasive cervical cancer (ICC) and non-Hodgkin lymphoma (NHL). We compared incidence rates before and after inclusion of record linkage identified cancer cases using the attributable fraction of cancers identified with 95% confidence intervals (CI).
ResultsA total of 49,207 adults starting ART in South Africa were included. 65% of patients were female, median age at starting ART was 35 years (interquartile range 30-41 years). We identified a total of 471 incident cancer cases. With record linkage the incidence increased from 81 to 292 for KS, from 1 to 119 for NHL and 12 to 497 for ICC per 100,000 person-years. The attributable fraction of cancers identified was 72% (95% CI 63-79%) for KS, 98% (95% CI 94-99%) for NHL and 98% (95% CI 95-99%) for ICC.
ConclusionAscertainment of cancer in HIV program data in African settings is incomplete. This case study has shown that probabilistic record linkage to cancer registries is both feasible and essential for cancer ascertainment in HIV cohorts in South Africa.

AbstractIntroduction: To evaluate long‐term outcomes in HIV‐infected adolescents, it is important to identify ways of tracking outcomes after transfer to a different health facility. The Department of Health (DoH) in the Western Cape Province (WCP) of South Africa uses a single unique identifier for all patients across the health service platform. We examined adolescent outcomes after transfer by linking data from four International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA‐SA) cohorts in the WCP with DoH data.Methods: We included adolescents on antiretroviral therapy who transferred out of their original cohort from 10 to 19 years of age between 2004 and 2014. The DoH conducted the linkage separately for each cohort and linked anonymized data were then combined. The primary outcome was successful transfer defined as having a patient record at a facility other than the original facility after the transfer date. Secondary outcomes included the proportion of patients retained, with HIV‐RNA <400 copies/ml and CD4 > 500 cells/µl at 1, 2 and 3 years post‐transfer.Results: Of 460 adolescents transferred out (53% female), 72% transferred at 10–14 years old, and 79% transferred out of tertiary facilities. Overall, 81% of patients transferred successfully at a median (interquartile range) of 56 (27–134) days following transfer date; 95% reached the transfer site <18 months after transfer out. Among those transferring successfully, the proportion retained decreased from 1 to 3 years post‐transfer (90–84%). There was no significant difference between transfer and 1–3 years post‐transfer in the proportion of retained adolescents with HIV‐RNA <400 copies/ml and CD4 > 500 cells/µl except for HIV‐RNA <400 copies/ml at 3 years (86% vs. 75%; p = 0.007). The proportion virologically suppressed and with CD4 > 500 cells/µl was significantly lower at 1 and 2 years post‐transfer in those transferring at 15–19 vs. 10–14 years of age. Using laboratory data alone over‐estimated time to successful transfer.Conclusions: Linking cohort data to health information system data allowed efficient assessment of post‐transfer outcomes. Although >80% of adolescents transferred successfully with nearly 85% of them retained for 3 years post‐transfer, the decline in the proportion virologically suppressed and poorer outcomes in older adolescents are concerns.​

AbstractIntroduction: South Africa has the largest number of individuals living with HIV and the largest antiretroviral therapy (ART) programme worldwide. In September 2016, ART eligibility was extended to all 7.1 million HIV‐positive South Africans. To ensure that further expansion of services does not compromise quality of care, long‐term outcomes must be monitored. Few studies have reported long‐term mortality in resource‐constrained settings, where mortality ascertainment is challenging. Combining site records with data linked to the national vital registration system, sites in the International Epidemiology Databases to Evaluate AIDS Southern Africa collaboration can identify >95% of deaths in patients with civil identification numbers (IDs). This study used linked data to explore long‐term mortality and viral suppression among adults starting ART in South Africa.Methods: The study was a cohort analysis of routine data on adults with IDs starting ART 2004–2015 in five large ART cohorts. Mortality was estimated overall and by gender using the Kaplan‐Meier estimator and Cox's proportional hazards regression. Standardized mortality ratios (SMRs) were calculated by dividing observed numbers of deaths by numbers expected if patients had been HIV‐negative. Viral suppression in patients with viral loads (VLs) in their last year of follow‐up was the secondary outcome.Results: Among 72,812 adults followed for 350,376 person years (pyrs), the crude mortality rate was 3.08 (95% CI 3.02–3.14)/100 pyrs. Patients were predominantly female (67%) and the percentage of men initiating ART did not increase. Cumulative mortality 12 years after ART initiation was 23.9% (33.4% male and 19.4% female). Mortality peaked in patients enrolling in 2007–2009 and was higher in men than women at all durations. Observed mortality rates were higher than HIV‐negative mortality, decreasing with duration. By 48 months, observed mortality was close to that in the HIV‐negative population, and SMRs were similar for all baseline CD4 strata. Three‐quarters of patients had VLs in their last year, and 86% of these were virally suppressed.Conclusions: The South African ART programme has shown a remarkable ability to initiate and manage patients successfully over 12 years, despite rapid expansion. With further scale‐up, testing and initiating men on ART must be a national priority.

AbstractIntroduction: Chronic immune activation due to ongoing HIV replication may lead to impaired immune responses against opportunistic infections such as tuberculosis (TB). We studied the role of HIV replication as a risk factor for incident TB after starting antiretroviral therapy (ART).Methods: We included all HIV‐positive adult patients (≥16 years) in care between 2000 and 2014 at three ART programmes in South Africa. Patients with previous TB were excluded. Missing CD4 cell counts and HIV‐RNA viral loads at ART start (baseline) and during follow‐up were imputed. We used parametric survival models to assess TB incidence (pulmonary and extrapulmonary) by CD4 cell and HIV‐RNA levels, and estimated the rate ratios for TB by including age, sex, baseline viral loads, CD4 cell counts, and WHO clinical stage in the model. We also used Poisson general additive regression models with time‐updated CD4 and HIV‐RNA values, adjusting for age and sex.Results: We included 44,260 patients with a median follow‐up time of 2.7 years (interquartile range [IQR] 1.0–5.0); 3,819 incident TB cases were recorded (8.6%). At baseline, the median age was 34 years (IQR 28–41); 30,675 patients (69.3%) were female. The median CD4 cell count was 156 cells/µL (IQR 79–229) and the median HIV‐RNA viral load 58,000 copies/mL (IQR 6,000–240,000). Overall TB incidence was 26.2/1,000 person‐years (95% confidence interval [CI] 25.3–27.0). Compared to the lowest viral load category (0–999 copies/mL), the adjusted rate ratio for TB was 1.41 (95% CI 1.15–1.75, p < 0.001) in the highest group (>10,000 copies/mL). Time‐updated analyses for CD4/HIV‐RNA confirmed the association of viral load with the risk for TB.Conclusions: Our results indicate that ongoing HIV replication is an important risk factor for TB, regardless of CD4 cell counts, and underline the importance of early ART start and retention on ART.

Background: Having 90% of patients on antiretroviral therapy (ART) and achieving an undetectable viral load (VL) is 1 of the 90: 90: 90 by 2020 targets. In this global analysis, we investigated the proportions of adult and paediatric patients with VL suppression in the first 3 years after ART initiation. Methods: Patients from the IeDEA cohorts who initiated ART between 2010 and 2014 were included. Proportions with VL suppression (<1000 copies/ mL) were estimated using (1) strict intention to treat (ITT)-loss to follow-up (LTFU) and dead patients counted as having detectable VL; and (2) modified ITT-LTFU and dead patients were excluded. Logistic regression was used to identify predictors of viral suppression at 1 year after ART initiation using modified ITT. Results: A total of 35,561 adults from 38 sites/16 countries and 2601 children from 18 sites/6 countries were included. When comparing strict with modified ITT methods, the proportion achieving VL suppression at 3 years from ART initiation changed from 45.1% to 90.2% in adults, and 60.6% to 80.4% in children. In adults, older age, higher CD4 count preART, and homosexual/bisexual HIV exposure were associated with VL suppression. In children, older age and higher CD4 percentage pre-ART showed significant associations with VL suppression. Conclusions: Large increases in the proportion of VL suppression in adults were observed when we excluded those who were LTFU or had died. The increases were less pronounced in children. Greater emphasis should be made to minimize LTFU and maximize patient retention in HIV-infected patients of all age groups. ; U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases ; Eunice Kennedy Shriver National Institute of Child Health and Human Development ; National Cancer Institute ; Centers for Disease Control and Prevention, USA ; Agency for Healthcare Research and Quality, USA ; Health Resources and Services Administration, USA ; Canadian Institutes of Health Research, Canada ; Ontario Ministry of Health and Long Term Care ; Government of Alberta, Canada ; Intramural Research Program of the National Cancer Institute ; Australian Government Department of Health and Ageing ; UNSW, Kirby Inst, Sydney, NSW 2052, Australia ; Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA ; Fdn Huesped, Buenos Aires, DF, Argentina ; Univ Chile, Sch Med, Santiago, Chile ; Fdn Arriaran, Santiago, Chile ; Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa ; Childrens Hosp 2, Ho Chi Minh City, Vietnam ; Univ Cape Town, Dept Paediat & Child Hlth, Cape Town, South Africa ; Univ Calgary, Calgary, AB, Canada ; YRGCARE Med Ctr, Madras, Tamil Nadu, India ; Univ Fed Sao Paulo, Pediat Infect Dis Div, Escola Paulista Med, Sao Paulo, Brazil ; Johns Hopkins Univ, Dept Med, Div Infect Dis, Baltimore, MD USA ; Univ Stellenbosch, Dept Med, Div Infect Dis, Cape Town, South Africa ; Tygerberg Hosp, Cape Town, South Africa ; Univ Bern, Inst Social & Prevent Med, Bern, Switzerland ; Univ Fed Sao Paulo, Pediat Infect Dis Div, Escola Paulista Med, Sao Paulo, Brazil ; NCI: U01AI035004 ; NCI: U01AI035039 ; NCI: U01AI035040 ; NCI: U01AI035041 ; NCI: U01AI035042 ; NCI: U01AI037613 ; NCI: U01AI037984 ; NCI: U01AI038855 ; NCI: U01AI038858 ; NCI: U01AI042590 ; NCI: U01AI068634 ; NCI: U01AI068636 ; NCI: U01AI069432 ; NCI: U01AI069434 ; Centers for Disease Control and Prevention, USA: CDC-200-2006-18797 ; Centers for Disease Control and Prevention, USA: CDC-200-2015-63931 ; Agency for Healthcare Research and Quality, USA: 90047713 ; Health Resources and Services Administration, USA: 90051652 ; Canadian Institutes of Health Research, Canada: CBR-86906 ; Canadian Institutes of Health Research, Canada: CBR-94036 ; Canadian Institutes of Health Research, Canada: HCP-97105 ; Canadian Institutes of Health Research, Canada: TGF-96118 ; NCI: P30AI027757 ; NCI: P30AI027763 ; NCI: P30AI027767 ; NCI: P30AI036219 ; NCI: P30AI050410 ; NCI: P30AI094189 ; NCI: P30AI110527 ; NCI: P30MH62246 ; NCI: R01AA016893 ; NCI: R01CA165937 ; NCI: R01DA004334 ; NCI: R01DA011602 ; NCI: R01DA012568 ; NCI: R24AI067039 ; NCI: U01AA013566 ; NCI: U01AA020790 ; NCI: U01AI1031834 ; NCI: U01AI034989 ; NCI: U01AI034993 ; NCI: U01AI034994 ; NCI: M01RR000052 ; NCI: U54MD007587 ; NCI: UL1RR024131 ; NCI: UL1TR000004 ; NCI: UL1TR000083 ; NCI: UL1TR000454 ; NCI: UM1AI035043 ; NCI: Z01CP010214 ; NCI: Z01CP010176 ; NCI: U01AI069907 ; NCI: U01AI069923 ; NCI: U01AI069924 ; NCI: U01AI069918 ; NCI: F31DA037788 ; NCI: G12MD007583 ; NCI: K01A1093197 ; NCI: K23EY013707 ; NCI: K24DA000432 ; NCI: K24AI065298 ; NCI: KL2TR000421 ; NCI: N02CP055504 ; NCI: U01AI103390 ; NCI: U01AI103397 ; NCI: U01AI103401 ; NCI: U01AI103408 ; NCI: U01DA036935 ; NCI: U01HD032632 ; NCI: U10EY008057 ; NCI: U10EY008052 ; NCI: U10EY008067 ; NCI: U24AA020794 ; Web of Science

IntroductionThere is uncertainty regarding the completeness of death recording by civil registration and by health centres in South Africa. This paper aims to compare death recording by the two systems, in cohorts of South African patients receiving antiretroviral treatment (ART).MethodsCompleteness of death recording was estimated using a capture–recapture approach. Six ART programmes linked their patient record systems to the vital registration system using civil identity document (ID) numbers and provided data comparing the outcomes recorded in patient files and in the vital registration. Patients were excluded if they had missing/invalid IDs or had transferred to other ART programmes.ResultsAfter exclusions, 91,548 patient records were included. Of deaths recorded in patients files after 2003, 94.0% (95% CI: 93.3–94.6%) were recorded by civil registration, with completeness being significantly higher in urban areas, older adults and females. Of deaths recorded by civil registration after 2003, only 35.0% (95% CI: 34.2–35.8%) were recorded in patient files, with this proportion dropping from 60% in 2004–2005 to 30% in 2010 and subsequent years. Recording of deaths in patient files was significantly higher in children and in locations within 50 km of the health centre. When the information from the two systems was combined, an estimated 96.2% of all deaths were recorded (93.5% in children and 96.2% in adults).ConclusionsSouth Africa's civil registration system has achieved a high level of completeness in the recording of mortality. However, the fraction of deaths recorded by health centres is low and information from patient records is insufficient by itself to evaluate levels and predictors of ART patient mortality. Previously documented improvements in ART mortality over time may be biased if based only on data from patient records.

AbstractIntroductionThe World Health Organization (WHO) recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa.MethodsWe analysed data from 14 HIV treatment programmes in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in 2005 to 2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count <200 cells/mm3) or failing to suppress viral replication (>1000 HIV‐RNA copies/mL) after ART initiation. We used mixed effect logistic regression to assess time trends adjusted for age and sex.ResultsAmong 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017; the probability declined by 14% each year (odds ratio (OR) 0.86; 95% CI 0.86 to 0.86). Frequency of CD4 testing also declined. The percentage starting ART with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018; each year the probability declined by 20% (OR 0.80; 95% CI 0.80 to 0.81). VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested, but fewer than 2% were tested in the other four countries. The probability of VL testing after ART start increased only modestly each year (OR 1.06; 95% CI 1.05 to 1.06). The percentage with unsuppressed VL was 8.6%. There was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99 to 1.01).ConclusionsCD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub‐Saharan Africa.