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Sex Differences in Mortality and Loss Among 21,461 Older Adults on Antiretroviral Therapy in Sub-Saharan Africa

Agarwal, Mansi MPH; Lamb, Matthew R. PhD, MPH; Howard, Andrea A. MD, MS; Abrams, Elaine MD; El-Sadr, Wafaa M. MD, MPH; Elul, Batya PhD, MS

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2016 - Volume 73 - Issue 2 - p e33–e35
doi: 10.1097/QAI.0000000000001117
Letters to the Editor

Department of Epidemiology, Mailman School of Public Health, ICAP at Columbia University, Columbia University, New York, NY

Supported by U.S. Centers for Disease Control and Prevention, Identifying Optimal Models of HIV Care and Treatment Study, Grant Number 5U2GPS001537-03. U.S. Centers for Disease Control and Prevention, Identifying Optimal Models of HIV Care and Treatment, Grant Number 5U2GPS001537. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Presented at CROI 2014, March 3–6, 2014, Boston, MA.

The authors have no funding or conflicts of interest to disclose.

To the Editors:

The massive scale-up of antiretroviral therapy (ART) in sub-Saharan Africa (SSA) has resulted in substantial increases in life expectancy among people living with HIV (PLWH).1 This increase in life expectancy, coupled with a secondary HIV incidence peak observed in a multi-country study among older adults in the region,2,3 suggests that the number of PLWH ≥50 years will grow substantially in coming years. Indeed, the number of older PLWH in sub-Saharan Africa is projected to triple from 3.1 million in 2011 to 9.3 million by 2040.4

In a prior analysis using routinely collected data from a large multi-country HIV program in SSA, we found that adults aged ≥50 were increasingly represented among the population on ART.5 By 2010, older adults accounted for 12% of patients newly initiating ART and 16% of patients currently on ART. Additionally, the cumulative incidence of recorded death through one year after ART initiation was highest among patients aged ≥50 compared with younger individuals. Furthermore, the cumulative incidence of loss to follow-up (LTF) among patients on ART aged ≥50 was similar to that observed among those 40–49 years of age, but significantly lower than among those <40 years.

While those data highlighted the need to account for adults aged ≥50 years in HIV programs in SSA, age-specific data on determinants of mortality and LTF are also required so that programs can better support this growing population. Among the younger population of ART patients 15–49 years of age, patient sex has consistently emerged as an important determinant of poor outcomes, with men having a substantially higher risk of dying and being LTF than women across a range of programs and settings.6–8 To our knowledge, the relationship between sex and outcomes among older patients on ART has not been examined.

We used routinely collected de-identified patient-level data from 198 HIV clinics in Kenya (69 clinics), Mozambique (33 clinics), Rwanda (44 clinics), and Tanzania (52 clinics) to assess age- and sex-related differences in recorded all-cause mortality and LTF among adults ≥50 years of age who initiated ART between January 2005 and December 2010. All facilities provided HIV services per national guidelines, and received technical and financial support from ICAP-Columbia University through PEPFAR funding.

Patients were categorized into 5 strata reflecting age at the time of ART initiation: 50–54, 55–59, 60–64, 65–69, and ≥70 years. Given no prior research in this area, selection of age strata was not guided by pre-existing hypotheses but rather to facilitate exploratory analyses. Patients were considered LTF if they did not have a recorded visit for at least 6 months prior to the end of the observation period (December 2011) and were not known to have died or transferred to another facility. LTF patients were censored 15 days after their last recorded visit.

Cox Proportional Hazards models were used to describe the progression to death and LTF through 12 months after ART initiation. Sex and age differences in death and LTF were assessed in 3 ways. First, sex differences were examined for all patients. Second, sex differences were estimated in age-stratified models. Finally, differences by age were examined in separate models for males and females. All models controlled for the confounding effects of advanced HIV disease at ART initiation (CD4+ cell count <100 cells per cubic millimeter or WHO stage 4), entry point (inpatient vs. outpatient setting) and country; accounted for clustering of patients within clinics; and censored patients who were LTF (in mortality models) or died (in LTF models). Analyses were conducted using SAS 9.3. The Columbia University Medical Center, the US Centers for Disease Control and Prevention, and each of the participating countries provided ethical approval.

A total of 21,461 patients ≥50 years of age initiated ART between 2005 and 2010 at the 198 health facilities in this analysis: 10,800 were age 50–54, 5671 age 55–59, 2922 age 60–64, 1222 age 65–69 and 846 age ≥70. The proportion of female patients decreased with age from 53% of adults 50–54 years to 39% of those age ≥70. Across all age groups included, 6% of patients were diagnosed with HIV while receiving inpatient services, with a non-significant increasing trend by age (5% among those aged 50–54% to 8% among those aged ≥70 years) (P = 0.07). Median CD4+ cell count at ART initiation was 168 per cubic millimeter and similar across age groups. The incidence of mortality and LTF in the total population was 5.7% and 15.5%, respectively.

In unadjusted models among all patients on ART, men had significantly higher rates of recorded death through 12 months after ART initiation compared to women (HR = 1.49, 95% CI: 1.33 to 1.66) and LTF (HR = 1.25, 95% CI: 1.15 to 1.35). These sex differentials remained after adjusting for advanced HIV disease at initiation, point of entry, and country (Death: aHR = 1.38, 95% CI: 1.24 to 1.53; LTF: aHR = 1.23, 95% CI: 1.13 to 1.34) (Table 1). They also persisted when individual countries were removed from the analysis, and in country-specific models with the exception of Tanzania where no difference in the hazard of LTF was observed by sex (data not shown).



Models examining sex differences within age strata showed that men on ART also had significantly higher rates of death and LTF compared to women in the 50–54 age group (Death: aHR = 1.50, 95% CI: 1.29 to 1.76; LTF: aHR = 1.35, 95% CI: 1.18 to 1.53) and in the 55–59 age group (Death: aHR = 1.38, 95% CI: 1.07 to 1.78; LTF: aHR = 1.23, 95% CI: 1.08 to 1.39). Sex was not significantly associated with death or LTF within age strata among patients age ≥60.

Multivariable models stratified by sex also highlighted sex differences in the relationship between age and death and LTF. For women, there was an increasing association between age and recorded death among those 60–64 years of age (aHR = 1.40, 95% CI: 1.09 to 1.81), 65–69 years (aHR = 1.81, 95% CI: 1.26 to 2.60), and ≥70 years (aHR = 2.49, 95% CI: 1.70 to 3.65) compared to those aged 50–54 years. Similarly, the hazard of LTF was significantly higher for women aged 60–64 (aHR = 1.33, 95% CI: 1.14 to 1.54) and 65–69 (aHR = 1.31, 95% CI: 1.02 to 1.67) compared to those 50–54 years. No significant difference was observed in LTF between women 55–59 years (aHR = 1.08, 95% CI: 0.95 to 1.23) and those ≥70 years (aHR = 1.34, 95% CI: 0.97 to 1.85) compared to those 50–54 years. For men, while rates of recorded death were significantly higher among those 65–69 years of age (aHR = 1.47, 95% CI: 1.07 to 2.02), and ≥70 years (aHR = 1.52, 95% CI: 1.08 to 2.12) compared to those 50–54 years, differences in LTF were only observed among the oldest patients ≥70 years compared to those 50–54 years (aHR = 1.24, 95% CI: 1.03 to 1.51).

In this analysis of over 21,000 adults aged ≥50 years who initiated ART across diverse settings in 4 SSA countries, we found significant age- and sex-related differences in mortality and LTF. Men 50–59 years had higher rates of recorded death and LTF compared with women of the same age, echoing the pattern observed among PLWH aged 15–49 years.9–12 This may reflect similarities between younger men and those aged 50–59 years with regards to risk factors for poor outcomes such as frequent mobility,13,14 disease denial, and stigma.7,15,16 It may also result from overall higher non-HIV associated mortality among men relative to women due to higher prevalence of co-morbid conditions among men.17,18 However, the risk of death and LTF did not differ significantly between sexes aged ≥60 suggesting that factors contributing to sex differentials in death and LTF wane over the lifespan. Additionally, aging-related comorbidities may be more pronounced after age 60, thereby reducing sex differences as PLWH age.

As expected, mortality generally increased with age. While this can be partially explained by the natural aging process, we also observed sex differences in the relationship between age and death with elevated mortality rates beginning at age 60 for women versus age 65 for men. Further, the magnitude of the association between older age and reported mortality was substantially greater among women than men. This finding is surprising given that women have higher life expectancies than men in the 4 countries studied,19,20 and may reflect increased documentation of death among women than men.21

This study had several strengths including the use of routinely collected clinical data from a large multi-country program spanning more than 5 years. Also, sensitivity analyses examining sex differences in death and LTF by country and adjustment by country in multivariable analyses had little effect on the results, suggesting that our findings are robust across settings. Limitations include that 14% of participants were missing both CD4+ cell counts or WHO stage at ART initiation, and thus were included in the models as a “missing” category. However, there were no significant differences in missingness across older age groups suggesting non-differential misclassification bias. Additionally, as is common in studies of older patients, our study was subject to survivor bias which may have masked any sex differentials in outcomes after age 60.

In conclusion, our analysis suggests that sex differences in all-cause mortality and LTF observed among younger patients on ART are also observed among older patients aged 50–59, and that women on ART appear to have disproportionate risk of death as they age compared to men. As older adults will increasingly be represented in HIV care settings in SSA, further research is needed to understand determinants of mortality and retention in this important and growing population.

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