Determinants of survival of people living with HIV/AIDS on antiretroviral therapy in Brazil 2006–2015

Estimation of mortality is a key indicator of the performance of an HIV programme, however few large studies estimate survival on ART in Latin American countries and those that include Brazil, tend to focus on cohorts often based in urban areas such as Rio de Janeiro. [1, 2] Extrapolating findings from smaller cohort studies in Brazil to a national level is complex and requires consideration of the wider social and economic contexts. [3–7] Similarly, aggregating national data can distort our understanding of the mortality profile of people living with HIV (PLHIV), since the majority of HIV/AIDS cases come from the Southeast, a densely populated and affluent region of the country. [8]

In 2017, 48,000 new HIV infections and 14,000 AIDS-related deaths were estimated in Brazil, corresponding, respectively, to 48 and 37% of the total incidence and AIDS-mortality reported in Latin America. [9] The country’s AIDS Programme has adopted a policy of universal access to ART, becoming the first middle-income country to provide free health care and treatment. Over the past decade, the HIV/AIDS programme has undergone rapid expansion with 585,000 PLHIV on ART by September 2018, [10] improving the quality of life and life expectancy of PLHIV and reducing the incidence of opportunistic infections. [11, 12] However, the modest reductions in reported mortality rates disguise significant regional heterogeneities. AIDS mortality rates in North, North-East and Central regions have been increasing over the past ten years (2006-2016) whilst two north-eastern states (Amapá and Pará) experienced increases of 105.7 and 103% respectively. [13, 14]

Evidence of disparities in health outcomes by sex, risk group and region in PLHIV have been documented in Brazil. [5, 6, 12, 13, 15, 16] Intravenous drug users (IDUs) may be less likely to access ART and tend to enter into care late, consequently experiencing higher mortality rates [15], although some studies have found no significant difference between mortality rates in IDUs compared with non-IDUs. [3, 4] Additionally, the hazard of an AIDS death is higher in men compared with women and in heterosexual men compared with men who have sex with men (MSM). [7, 12]

The 2016 World Health Organization guidelines recommending early ART initiation to all PLHIV irrespective of CD4 cell count were based on a growing body of evidence showing the increased risk of AIDS or death associated with delaying treatment. [17] In fact Brazil introduced treatment for all in 2014, following rising CD4 eligibility thresholds from 200 cells per μL until 2009, 350 cells per μL until 2012 and 500 cells per μL in 2013. [18] In addition to the individual benefits, early treatment can also reduce the risk of HIV transmission to partners [19–22], impacting incidence at the population level. [23, 24] The current evidence consists mainly of cohort studies or randomised control trials conducted under experimental conditions. In many settings, only those with severe illness began ART with high CD4 cell counts, therefore we cannot expect the mortality profile of these individuals to appropriately reflect that of otherwise healthy PLHIV starting ART early. These estimates may therefore not be generalizable to the overall population of PLHIV using ART.

Three surveillance databases in Brazil (notification of HIV/AIDS cases, CD4 cell counts, ART dispensations) have been linked with vital registration data to provide information on over one million PLHIV, tracking individuals from diagnosis, through laboratory tests, treatment programmes and death. Here we present an analysis of survival in PLHIV on ART in Brazil over the past ten years. We examine mortality rates at six to twelve-month intervals adjusting for potential risk factors using individual-level data acquired from routine case-reporting.

Early ART initiation (amongst patients with CD4 cell counts ≥500 cells per μL) was associated with a 94% reduction in the risk of AIDS death during the first six months compared with starting at < 200 cells per μL. Older age or a history of intravenous drug use resulted in higher mortality rates consistent with earlier studies. [1, 12, 15, 27]

The poorer survival in the North may reflect differences in access to healthcare and is concerning as coinciding increases in incidence rates have also been reported in this region. [13, 14] Many of the larger, specialised services are in the Southeast, which has historically borne the greatest burden of the HIV epidemic. [28] In the large northern states, fewer clinics offer specialised care and patients may be at greater risk of non-adherence.

The relative effects of early treatment on survival were consistent after adjustments for other risk factors for mortality but the size of the effect varies by age, sex and region. The survival benefit from starting treatment early is greatest in women, younger ages and in the North region. Increasingly smaller gains are seen as age at ART initiation increases, with relative reductions in mortality rates of 78.4 and 81.8% in men and women aged 50 years starting treatment early (CD4 cell counts at ART initiation ≥500 versus < 200 cells per μL) compared with 89.1 and 90.7% in 20 year olds. When excluding individuals with less than one month of exposure to ART, there was a smaller impact of time on treatment relative to the first 1–6 months. This is likely due to the high mortality observed in this initial period, before viral loads are reduced by treatment.

Vital status is reported from the Mortality Information System database which has an estimated coverage of over 95% in 2000–2010 although misclassification of AIDS deaths may result in an underestimation of mortality rates. [29] Regional variations in misclassification of deaths also likely exist but to our knowledge, have not been well studied. [30] The majority of those lost to follow up are in recent years (68% of individuals LTFU are from 2012 onwards, see Supplementary Fig. 2). Patients classified as LTFU may still have been accessing care in the private sector despite failing to adhere to ART, which would not be reported in the Ministry of Health’s surveillance databases. Given the low rates of LTFU here (7.9%) coupled with the near completeness of linked vital registration data, we did not apply any additional correction factors to compensate for possible under-reporting of deaths.

We ignored co-morbidities and changes or interruptions in treatment, opting instead to provide generalised estimates which broadly take adherence patterns into account. Coverage of the ART dispensation system has been variable throughout the country and over time, but has remained consistently high (> 90%) between 2006 and 2015. [31] This is unlikely to significantly impact our findings here but may lead to under-estimations of the amount of time on ART for some people and bias our estimates of treatment impact upwards. The majority of those who initiated ART but were excluded from this analysis were missing CD4 cell count measurements. These individuals may have had poorer engagement with the health care system and may subsequently experience a worse prognosis.

Data on risk group are self-reported via the case-reporting surveillance system which records predominantly AIDS cases and may be misreported due to perceived stigma. The lower mortality rates in those missing information on risk group may be due to the absence of clinical symptoms which prompt individuals to seek healthcare and consequently be reported via this route. Additionally, case-reporting is lower in private healthcare facilities. The lower mortality rates amongst those without case-reports may reflect the fact that a greater proportion of them were being followed by private services. However, we expect the relative findings of highest survival in females and poorest survival in IDUs to remain applicable.

A key strength of this study is the use of real program data from three independent surveillance networks linked with vital registration. As these results do not rely on cohorts of individuals selected for inclusion or on data obtained from single sites, they will be broadly representative of the general population of PLHIV on ART in Brazil. We do not consider viral load here which could also be used as a predictor of mortality. An interesting next step could be the inclusion of both CD4 cell counts and viral load using Principal Component Analysis. [32]

The availability of early treatment in Brazil has led to increased linkage, higher median CD4 counts at ART initiation and 88% viral suppression in those treated [10]. Together with earlier studies demonstrating a significant reduction in mortality [8, 33, 34], lower incidence of AIDS-related and non-AIDS-related events [35] and a reduced risk of sexual transmission with early ART use [19, 36], these results provide further evidence supporting the implementation of early and lifelong ART in line with Brazilian and UNAIDS guidelines. [37] There is a need to evaluate the incidence of adverse effects resulting from the increased longer-term exposure to ART and the impact of early treatment initiation on long-term adherence, especially among high-risk populations.

Despite huge progress in early diagnosis and linkage to care, many vulnerable people at high risk are still not benefitting from early treatment and some of those, such as IDUs, experience disproportionately high mortality rates. In addition, 47.2% of those who died of AIDS-related causes between 2009 and 2013 had never accessed ART. [38] Brazil’s goal to end the AIDS epidemic by 2030 requires focussing prevention and treatment in these high-risk groups.

This study highlighted the disparities in mortality rates experienced by many PLHIV in Brazil due to age, sex, risk behaviour and geographical location. We showed the increased risk of mortality in males compared with females, in older age groups, those starting treatment at low CD4 counts and those living in regions outside the South-East or Central-West of Brazil. Starting treatment early (CD4 cell counts ≥500 cells per μL) significantly reduced the risk of AIDS death in the first six months of treatment and this survival benefit is greatest in women, younger age groups and people living in the North region. This study further emphasizes the benefits of early and lifelong treatment in PLHIV, a policy which has been implemented in Brazil since 2014, but many vulnerable people are still failing to access treatment early and experiencing unacceptably high AIDS mortality rates.