1 Background The roll out of ART has led to dramatic reductions in - PDF document

Beyond AIDS-related deaths: calculating the risk of non-communicable disease mortality attributable to HIV from verbal autopsy data C Calvert 1 , A Price 1, 3 , E Slaymaker 1 , G Reniers 1 , K Herbst 3 , D Michael 4 , S Clark 5 , B Zaba 1 , A Crampin 1, 2 1 London School of Hygiene and Tropical Medicine, London, UK 2 Malawi Epidemiology and Intervention Research Unit, Malawi 3 African Health Research Institute, UKZN, South Africa 3 Malawi Epidemiology and Intervention Research Unit, Malawi 4 National Institute for Medical Research, Mwanza, Tanzania 5 The Ohio State University, Columbus, USA 1

Background The roll out of ART has led to dramatic reductions in mortality in people living with HIV (PLHIV) in sub-Saharan Africa;(1, 2) however, mortality rates remain higher in PLHIV compared with HIV-negative people, despite evidence from high income settings suggesting that mortality rates in PLHIV with adequate viral suppression are the same as mortality rates in the general population.(3) Estimates from five studies in Eastern and Southern Africa indicate that, with wide availability of ART, the overall excess mortality attributable to HIV is between 22% and 46% amongst men living with HIV, with between 14% to 28% of mortality in HIV-positive women attributable to HIV.(4) This excess mortality attributable to HIV many be caused by: (1) the direct effect of HIV; (2) the effects of ART and; (3) other conditions, not traditionally classified as HIV-related, but which HIV increases the risk of (e.g. sepsis and malaria). Indeed, a study using information on deaths which occurred largely in the pre-ART era in Eastern and Southern Africa found that HIV increased the risk of all other causes of death,(5) including over 10-fold increase in the risk of a number of non-communicable diseases (NCDs), e.g. digestive cancers. Quantifying the extent to which HIV is associated with NCDs is of particular importance, due to the considerable burden of NCDs in areas of high HIV prevalence. Recent estimates suggest that there has been a 46% increase in the numbers of deaths due to NCDs in sub- Saharan Africa since 1990.(6) Several pathways exist by which HIV may increase the risk of mortality from NCDs. Firstly, some malignant cancers arise from HIV opportunistic infections including Kaposi sarcoma and HIV-associated lymphoma. Secondly, biological effects of HIV infection may increase the risk of certain NCDs. For example, HIV is linked with detrimental reductions in high density lipoproteins, important for transporting excess cholesterol to the liver.(7) Finally, some NCDs have been directly linked to ART use, including diabetes.(8) The increased risk of some NCDs, however, may be offset by lower body weights in PLHIV which lowers the risk of, for example, hypertension and diabetes. Methodological challenges, including limited data on causes of death in sub-Saharan Africa, the difficulty in ascertaining some NCD deaths and lack of information on HIV status, have hindered exploration of HIV as a risk factor for NCD mortality. The aim of our paper is to use standardised verbal autopsy data for individuals with known HIV status, to calculate rate ratios comparing NCD cause-specific mortality rates in HIV-positive and HIV-negative adults aged 15-59. To assess the impact of the HIV epidemic on NCD mortality at the population level, we will calculate population attributable fractions. Data and Research Methods Data Sources We used data from three study sites for this analysis: Karonga in Malawi, Kisesa in Tanzania, and uMkhanyakude in South Africa. These studies have all completed several rounds of demographic surveys, and conducted population-based HIV testing and verbal autopsies (VAs). Although similar data are collected, start dates, frequency of data collection and the level of detail of the information varies across studies. The methods of data collection for each study site are described in detail elsewhere.(9-11) Data Preparation Data analysts at each study site prepared the demographic surveillance site (DSS), HIV and VA data according to a standard specification. Each study extracted information including dates of entry to and exit from the study population, due to death or out-migration, and 2

information on the HIV test status of each study participant and signs and symptoms reported in a VA for the deceased. VA data were merged with the DSS data and only retained for analysis if linkage to a DSS death record was made. The VA and DSS data were also linked with HIV test data collected from sero-surveys. A number of assumptions were made when assigning HIV status which have been described in detail elsewhere.(12) Data from the time period before ART became available, which were only available for Kisesa, were excluded for this analysis, as were any data after the end of 2014. The cause of death attribution was done on the basis of VA interviews that were interpreted with the InSilicoVA tool.(13) Using InSilicoVA, estimates were generated for sub-populations defined by two broad age groups (below 60, and 60 or older), gender, and HIV status at the time of death. The individual-level cause-specific probabilities of death were then used to assign a main cause of death for each individual. This was assigned as the cause of death with the highest probability for each individual. Where no cause had greater than a 0.4 probability, the cause was assigned as indeterminate. For this analysis three main outcomes were defined: all NCD deaths; cancer-related deaths; and deaths related to cardiovascular disease. All NCD deaths comprised of deaths assigned to any of: cancer, severe anaemia, severe malnutrition, diabetes mellitus, acute cardiac disease, sickle cell with crisis, stroke, other and unspecified cardiac disease, chronic obstructive pulmonary disease, asthma, acute abdomen, liver cirrhosis, renal failure, epilepsy, and other and unspecified NCD. Cardiovascular disease included acute cardiac disease, stroke, and other and unspecified cardiac disease. Data Analysis Analyses were carried out using Stata 14. Using survival analysis, total person years, numbers of deaths and cause-specific mortality rates were estimated by HIV status for adults aged 15- 59. Rate ratios, comparing cause-specific mortality rates in PLHIV and HIV-negative people, were calculated. Where there was evidence that HIV increased the risk of NCD mortality, the percentage of deaths from that category of NCD (all, cancer or cardiovascular disease) which are attributable to HIV was subsequently calculated by subtracting the NCD mortality rate in the HIV-negative population from the NCD mortality rate in the total population with known HIV status. This difference was then divided by the overall NCD mortality rate in those with known HIV status, to give the percentage of NCD mortality attributable to HIV. Preliminary findings A total of 3,630 deaths with known HIV status to adults aged 15-59 were identified from the three studies. The majority of these deaths were from uMkhanyakude (N=2,765), with 496 deaths from Karonga and 369 from Kisesa. The percentage of the deaths identified in the DSS which received a VA varied across the sites with 100% VA coverage in Karonga, 95.0% in uMkhanyakude and 79.7% in Kisesa. There were limited data on the individual ART treatment status of these individuals who died; however, it has been estimated elsewhere that the percentage of adults 15-59 who had ever had ART in 2013 was 68.5% in Karonga, 64.6% in uMkhayakude and 30.7% in Kisesa.(12) The percentage of deaths attributed to NCDs varied from 8.5% in uMkhanyakude, to 23.1% and 26.4% in Kisesa and Karonga, respectively. Table 1 provides preliminary results, based on data up to 2014, of the NCD-related mortality rates by HIV status. In uMkhanykude, there was no evidence that HIV increased the rate of mortality attributable to all NCDs (p=0.76), but strong evidence to suggest that there was double the rate of mortality attributable to cancer in 3