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CLINICAL SCIENCE: Epidemiology and Social

Effect of sex and age on outcomes among HIV-2-infected patients starting antiretroviral therapy in West Africa

Tchounga, Boris K.; Hønge, Bo L.; Eholie, Serge P.; Coffie, Patrick A.; Jespersen, Sanne; Wejse, Christian; Dabis, François; Geoffrey, Gottlieb S.; Ekouevi, Didier K. for the IeDEA West Africa collaboration

Author Information
doi: 10.1097/QAD.0000000000001232

Abstract

Introduction

HIV-2 infection is mainly localized in West Africa, with a limited spread to other parts of the world [1]. People infected with HIV-2 experience a longer asymptomatic phase, a slower immunologic progression, and a lower virologic replication compared with those infected with HIV-1 [2–4]. Because of the intrinsic resistance of HIV-2 to nonnucleoside reverse transcriptase inhibitors (NNRTIs), treatment options in resource-limited settings for HIV-2-infected individuals are limited and this may affect treatment sequencing in case of failure and long-term outcomes of these patients [5–7].

Similar to HIV-1 infection, more women than men are infected with HIV-2 [8–10], with a significantly advanced age at diagnosis and antiretroviral therapy (ART) initiation among HIV-2-infected individuals compared with HIV-1 [11]. In resource-limited settings, higher mortality [12–14] and loss to follow-up (LTFU) rates have been reported in men than in women among HIV-1-infected individuals [9,15–17], as well as an association between LTFU and mortality [18]. Many possible explanations such as baseline characteristics [19,20], late presentation (79% of HIV-1-infected individuals initiating ART with CD4+ cell count <200/μl), high viral load (>5 log), and suboptimal immunologic response [14,21] have been suggested, but the underlying causes of these findings remain poorly understood.

The relationship between ART outcomes and sex, as well as age have been well described among HIV-1-infected individuals in resource-limited settings, but very poorly studied in HIV-2-infected individuals because of lack of power related to a limited sample size of HIV-2 cohorts in each country. Considering the different disease pattern of HIV-2 infection compared with HIV-1, we evaluated mortality, LTFU, and associated determinants among ART-receiving HIV-2-infected individuals.

Methods

Study design, site, and population

This analysis was conducted among patients in the International Epidemiological Databases to Evaluate AIDS (IeDEA)–West Africa HIV-2 cohort that has been previously described [22]. This dynamic cohort is currently made up of 5193 HIV-2 and HIV-1/HIV-2 dually reactive individuals followed up in 15 West African clinics, in seven countries (Benin, Burkina Faso, Cote d’Ivoire, Guinea-Bissau, Mali, Senegal, and Togo). Patients were included in this cohort based on the results of the HIV testing performed according to the national algorithms of each participating country. The HIV diagnosis and the initial classification of patients of the IeDEA–West Africa HIV-2 cohort have been described elsewhere [23]. The study population considered for this analysis was HIV-2-monoinfected patients only, aged 16 years old and above, initiating ART between February 1997 and September 2014, and followed up till 15 May 2015. The routine care of patients (ART distribution and biological testing) follows the national HIV treatment guidelines of each country, most of them recommending ART initiation below 350 CD4+ cells/μl [22].

Variables and definition

Baseline characteristics used in this analysis refer to measurements recorded immediately before ART initiation for specific variables such as demographics (age, sex), disease progression (CD4+ cell count, WHO clinical stage) as well as clinical and biological parameters of patients [weight, haemoglobin (Hb)]. The following variables were transformed into categorical ones: age (16–39; 40–49; ≥50 years), initial CD4+ cell count (0–99; 100–199; 200–349; ≥350 cells/μl), Hb at enrolment (<7.5; 7.5–9.9; 10–12; >12 g/dl), BMI at enrolment (<18; 18–25; >25 kg/m2), and WHO clinical stage (I-II and III-IV).

Outcomes and definition

The primary outcome was all-cause mortality based on the living status reported at the closing date (15 May 2015) of the cohort's database for this analysis, after an active search by home visit, phone tracking of patients, or calling a close relative of the participant when the contact details were available.

Secondary outcome was LTFU, defined as a patient who was neither reported dead nor transferred out, and whose date of last visit was more than 6 months prior to the closing date of the cohort's database for this analysis (15 May 2015). Patients returning into care before the closing date of the cohort were not LTFU even when they had missed more than three consecutive visits (HIV care visits are usually programmed every 3 months).

Data collection and management

A dedicated case report file (CRF) was used to collect enrolment and follow-up data for all HIV-2-infected individuals included in the cohort. Follow-up characteristics (death or LTFU) were checked by social workers and notified to doctors who reported in the CRF. Data of each CRF were recorded in a local database built with Microsoft Access software (Microsoft Corporation, Redmond, Washington, USA).

Statistical analysis

Baseline characteristics and summary outcomes were compared between men and women and between age groups. Differences between proportions and medians were tested with Pearson's χ2 test or Mann–Whitney test. Probability and median survival time from the date of ART initiation to death or LTFU was estimated by Kaplan–Meier methods. Cox proportional hazards regression models were used to assess crude and adjusted hazard ratios (HRs) between baseline characteristics and outcomes (death or LTFU), over the first 24 months after ART initiation. For patients neither dead nor LTFU, the closing date of the follow-up was 15 May 2015. For patients who experienced death or LTFU during the observation period, the censor date was the date of the first event, meaning date of death for dead patients and date of the last visit for patients LTFU). Interactions between adjustment factors and sex or age were tested and possible confounders were checked. Univariable Cox models were performed to assess covariate effect; manual backwards selection method was performed to select significant covariates in a multivariable Cox model. The level of significance for all analyses was a two-sided P value of less than 0.05. All statistical analyses were performed with the statistical software package, Stata 11.0 software (Stata Corp, College Station, Texas, USA).

Ethics

The IeDEA–West Africa HIV-2 cohort's protocol has been approved by the national ethic committee of each participating country. All the patients gave their written consent or fingerprint if illiterate before being included in the cohort.

Results

Study population

As of 15 May 2015, the IeDEA–West Africa HIV-2 cohort comprised 5193 (see supplemental document 1: flow chart, https://links.lww.com/QAD/A970), including 2878 (55.4%) HIV-2-infected patients and 2315 (44.6%) HIV-1/HIV-2 dually reactive patients. Among them, 1825 HIV-2 singly infected patients met the eligibility criteria for this analysis, including 1102 (60.4%) women. Median age at ART initiation was 45.4 years [interquartile range (IQR; 38.0–52.0)]. Most of the patients came from Côte d’Ivoire (42.3%), Guinea-Bissau (23.2%), and Burkina Faso (18.5%) with the remaining 16.0% coming from Benin, Mali, Senegal, and Togo.

Baseline characteristics

Table 1 summarizes the baseline characteristics of the study population. At ART initiation, men were older in median than women (49 vs. 43 years, P = 0.000). The baseline clinical stage was reported for 877 (48%) patients and 663 of them (75.5%) were classified WHO stage I or II. The median CD4+ cell count at baseline was 185 cells/μl [IQR (95–297)], lower in men than women [160 cells/μl; IQR (79–262) vs. 204 cells/μl; IQR (105–337); P = 0.000]. At ART initiation, more men than women had a BMI less than 18 kg/m2, (12.2 vs. 9.3%, P = 0.015). The most commonly prescribed ART regimens were protease inhibitor-based regimens (66.6%), followed by triple- NRTI-based regimens (9.3%) and 436 (23.9%) patients initiated a suboptimal ART regimen (mainly NNRTI-based regimen) because of HIV-type misclassification at enrolment.

T1-16
Table 1:
Baseline characteristics of patients in the international epidemiological databases to evaluate AIDS HIV-2 Cohort according to sex from 2002 to 2014.

Follow-up characteristics and immunological response

The median follow-up duration was 28.8 months [IQR (9.8–58.9)] with no difference between sex and age groups, and the at-risk period was estimated to 5915 person-years of observation (pyo). The median CD4+ cell count was 185 cells/μl at baseline, and increased to 263, 283, and 290 cells/μl, at 6, 12, and 24 months, respectively. The median CD4+ cell count was higher in woman than in men at 6 months [289 (172–472) vs. 229 (150–344); P = 0.0003], 12 months [292 (196–475) vs. 273 (180–396); P = 0.033], and 24 months [337 (195–530) vs. 259 (170–379); P = 0.0001].

Mortality

There were 221 (12.1%) deaths during the observation period and the overall mortality rate was 3.7/100 pyo [95% confidence interval (CI; 3.2–4.2)]. The cumulative estimated risk of death at 6, 12, and 24 months after ART initiation was 4.1 [95% CI (3.2–5.1)], 5.5% [95% CI (4.4–6.5)], and 7.7% [95% CI (6.4–8.9)], respectively. Over the first 24 months after ART initiation (2687 pyo), 140 (7.7%) patients were dead and the mortality rate was 5.2/100 pyo [95% CI (4.4–6.1)], higher in men than in women [7.4/100 pyo; 95% CI (5.9–9.3) vs. 3.9/100 pyo; 95% CI (3.0–4.9), log-rank test P = 0.001] (Fig. 1a). Mortality was also associated with age at ART initiation (log-rang test, P value = 0.026). Figure 1b shows a higher probability of death among people initiating ART at 50 years or older compared with those initiating ART at a younger age (Fig. 1b).

F1-16
Fig. 1:
Effect of sex and age on mortality among antiretroviral therapy-receiving HIV-2-infected individuals in West Africa.(a) Mortality according to sex among HIV-2 infected individuals receiving ART. (b) Mortality after ART initiation among HIV-2 infected individuals according to age. ART, antiretroviral therapy.

Factors associated with mortality

Table 2 shows the results of the multivariable model assessing factors associated with mortality. Male sex was associated with higher mortality than female sex [adjusted HR (aHR) = 1.98; 95% CI (1.40–2.82), P < 0.001]. A borderline significant association appeared between mortality and age at least 50 years [aHR = 1.44; 95% CI (0.96–2.16)] compared with age 40–49 years. Regarding clinical and biological baseline characteristics, initiating ART between 2007 and 2010 [aHR = 1.72; 95% CI (1.11–2.66)] or between 2011 and 2014 [aHR = 2.16; 95% CI (1.33–3.51)] was associated with higher mortality compared with initiating treatment before 2007. CD4+ cell count at ART initiation between 100 and 199 cells/μl [aHR = 3.25; 95% CI (1.34–7.85)] compared with CD4+ cell count at least 350 cells/μl was significantly associated with higher mortality. Similar associations with mortality were found for initial Hb level between 9.9 and 7.5 g/dl [aHR 2.38; 95% CI (1.30–4.35)] compared with initial Hb level at least 12 g/dl and with initial BMI less than 18 kg/m2 [aHR = 2.06; 95% CI (1.24–3.40)] compared with BMI between 18 and 25 kg/m2. Mortality was neither associated with the country of origin of each specific cohort nor with the initial ART regimen after adjusting on other baseline characteristics.

T2-16
Table 2:
Effect of sex, age, and other factors on mortality and loss to follow-up during the first 24 months after antiretroviral therapy initiation (multivariable final Cox models).

Loss to follow-up

After 24 months, 469 (25.7%) patients were LTFU and the estimated risk of being LTFU at 6, 12, and 24 months after ART initiation was 10.8% [95% CI (9.4–12.3)], 16.7% [95% CI (14.9–18.4)], and 25.7% [95% CI (23.7–18.7)], respectively. The probability of being LTFU after 24 months on ART did not significantly vary according to sex (log-rank test, P value = 0.310) but varied according to age, with people aged 16–39 and those aged at least 50 having higher probability (log-rank test, P value = 0.007) of being LTFU than those aged 40–49 (Fig. 2a and 2b).

F2-16
Fig. 2:
Effect of sex and age on loss to follow-up probability among antiretroviral therapy-receiving HIV-2-infected individuals in West Africa.(a) Loss to follow-up probability according to sex among HIV-2 infected individuals receiving ART. (b) Loss to follow-up probability after ART initiation among HIV-2 infected individuals according to categories of age. ART, antiretroviral therapy.

Factors associated with loss to follow-up

In a multivariable model, after adjusting for demographic, clinical, and laboratory baseline characteristics, male sex [aHR = 1.20; 95% CI (0.99–1.47), P value = 0.058] and being aged 16–39 or at least 50 compared with 40–49 years old [aHR = 1.28; 95% CI (1.02–1.61)] was associated with LTFU (Table 2). In addition, ART initiation in 2007–2010 [aHR = 1.47; 95% CI (1.15–1.88)] or in 2011–2014 [aHR = 2.33; 95% CI (1.79–3.02)] compared with before 2007 was associated with LTFU. Initial Hb level less than 7.5 g/dl [aHR = 1.48; 95% CI (1.03– 2.15)] compared with more than 12 g/dl and initial BMI less than 18 kg/m2 [aHR = 1.69; 95% CI (1.19–2.41)] compared with 18–25 kg/m2 were also associated with LTFU, whereas initial WHO stage and CD4+ cell count were not associated with LTFU.

Death and loss to follow-up

During the first 24 months of follow-up, 609 (33.4%) individuals died (n = 140) or became LTFU (n = 469). The retention probability was 85.0% [95% CI (83.4–86.6)] at 6 months, 77.9% [95% CI (75.9–79.8%)] at 12 months, and 66.6% [95% CI (64.5–68.8)] at 24 months. The retention probability at 24 months was higher among women compared with men (68.9% [95% CI (66.0–71.6%)] vs. 63.2% [95% CI (59.6–66.7%)], respectively, P value = 0.007) (Fig. 3a). Retention was also higher among patients aged 16–39 [65.5%; 95% CI (61.4–69.4)] and those aged 40–49 [71.4%; 95% CI (67.9–74.8)] compared with those aged at least 50 [61.9%; 95% CI (57.8–65.9)] (Fig. 3b).

F3-16
Fig. 3:
Effect of sex and age on retention among antiretroviral therapy-receiving HIV-2-infected individuals in West Africa.(a) Retention probability according to sex among HIV-2-infected individuals receiving ART. (b) Retention probability according to age groups among HIV-2-infected individuals receiving ART. ART, antiretroviral therapy.

Over the first 24 months on ART, factors associated with death and LTFU in multivariable analysis after adjusting for other baseline characteristics were male sex [aHR = 1.39; 95% CI (1.17–1.65), P value = 0.000], age at least 50 years [aHR = 1.31; 95% CI (1.08–1.60), P value = 0.006], ART initiation after 2007 [aHR = 2.21; 95% CI (1.76–2.78)], initial Hb level less than 7.5 g/dl [aHR = 1.49; 95% CI (1.06–2.09), P value = 0.01], and initial BMI less than 18 kg/m2 [aHR = 1.87; 95% CI (1.40–2.49)].

Discussion

This study reports on HIV-2 ART-programme outcomes according to sex and age in a large West African multicountry cohort. The overall number of deaths was 221 (12.1%), for a global mortality rate of 3.7/100 pyo [95% CI (3.2–4.2)]. Over the first 24 months after ART initiation, the mortality rate was estimated to be 5.2/100 pyo with a death probability of 7.7%. Men had higher mortality rate than women, especially those initiating ART at an advanced age. Approximately, one-quarter of the patients were LTFU after 24 months on ART, and the retention rate was only 66%. Male sex, advanced age at ART initiation, ART initiation after 2007, low initial Hb level, and low BMI were associated with mortality and with LTFU at 24 months, whereas low initial CD4+ cell count was only associated with mortality.

In our study, among ART-receiving HIV-2-infected individuals, the crude mortality rate was high, around 12% after a median follow-up duration of 28.8 months and one-third of deaths occurred during the first 6 months after starting ART. Thus, despite the differences in disease progression between HIV-1 and HIV-2, the estimates of mortality in ART-receiving HIV-2-infected individuals appear to be comparable with what is seen in HIV-1 infection in sub-Saharan Africa (SSA) [24–27]. Like in HIV-1 infection, late presentation (20% of patients with CD4+ cell count <100 cells/μl) could explain this high mortality rate in HIV-2-infected individuals receiving ART. The suboptimal immune recovery (only +100 CD4+ cells/μl after the first 24 months of ART), which is ∼two times lower in our cohort than that observed in HIV-1-infected individuals over the same period [26], may also play a role in this high mortality rate. In addition, men were more likely to die than women in our cohort, as has been reported in ART-receiving HIV-1-infected individuals [10,13,14]. Baseline clinical and laboratory characteristics have been identified as possible factors explaining this sex difference in mortality in HIV-1-infected individuals [12,18–20,28]. Similar associated factors were found in our study, especially the CD4+ cell counts that were lower in men than in women at ART initiation, indicating higher rates of late presentation among men. Age is another cofactor frequently cited to explain the difference in mortality among ART-receiving men and women. Many surveys identified the older age of men compared with women at ART initiation, as a reason for sex difference in mortality [9,13,14,29]. In our cohort, more men than women initiated ART after the age of 50 and this age difference could also partly explain the difference in mortality between men and women. Individuals initiating ART after 2007 in our cohort had higher mortality than those initiating ART earlier. This result contrast with findings from other HIV-1 studies, reporting a tremendous decline in mortality and LTFU with the scaling-up of ART programmes [12,28,29]. One possible explanation for our finding could be the potential for the lower likelihood of being captured in programmatic databases for patients who started ART prior to 2007, and died or who were lost to follow-up soon after entering care, compared with patients who survived.

Our study found a tremendous increase of LTFU in HIV-2-infected adults at 6, 12, and 24 months after ART initiation. Many other surveys from SSA reported similar or higher rates of LTFU among HIV-1-infected individuals receiving ART [14,17,18,29]. In these studies, LTFU was associated with age at ART initiation, male sex, low BMI, low Hb level, and sometimes with low CD4+ cell count at ART initiation [14,17,18,29]. All these factors are also known to be associated with mortality in HIV-1-infected individuals, and many studies report that 30–40% of patients LTFU are misclassified deaths [13,18,30]. Our analysis retrieved the same factors associated with LTFU among HIV-2-infected individuals receiving ART, and we speculate that a considerable number of patients LTFU in our cohort may be misclassified deaths.

Retention in care is a major outcome to assess success of ART delivery programmes as it takes into accounts both deaths and LTFU. A 2007 meta-analysis among HIV-1-infected patients on ART in SSA reported retention of 75.0% at 12 months and 61.6% at 24 months [31]. More recently, a 2012 systematic review on retention and LTFU among HIV-infected patient in SSA reported a retention rate of 65% [95% CI (58–73)] among ART-receiving individuals after 3 years of follow-up [32]. The results in HIV-2-infected patients are similar with a retention rate of 77.9% at 12 months and 66% at 24 months and lower retention among men. This low retention in care suggests high ART discontinuation and the possible development of ART resistance. ART resistance is of concern, especially for HIV-2-infected individuals in SSA, who initiate ART with a protease inhibitor-based regimen, but have limited or no access to effective second-line ART [33–35].

Some limitations should be considered when interpreting our study results. First, we used data from routine HIV care that usually included significant levels of missing data even after data queries. Second, the death assessment was limited to hospital reports or patient's family notification, mainly because of the weakness of the national death registries from contributing IeDEA–West Africa countries. Furthermore, HIV-2 viral load data were not routinely available to assess whether those who died or were LTFU had virologic failure.

This study underscores the fact that like in HIV-1 cohorts, HIV-2 ART-receiving men are more likely to die and have a lower retention rate than women. There is an urgent need to improve HIV-2 programmatic outcomes, reduce mortality and LTFU, educate clinicians and programmes about low retention rates, and explore interventions to improve the cascade of care for both men and women infected with HIV-2.

Acknowledgements

We thank the fieldwork teams, the study sites, and Eric Balestre for their effort. We are indebted to all of the HIV-positive people who agreed to participate in this present study as well as to the health workers and PAC-CI who performed the data collection.

This work was supported by the following institutes: the US National Cancer Institute (NCI); the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); and the US National Institute of Allergy and Infectious Diseases (NIAID) as part of IeDEA (grant 5U01AI069919).

Author contribution: Study design: B.K.T., D.K.E., P.A.C., G.S.G., S.P.E. and F.D. Data collection: S.P.E., B.L.H., C.W., and S.J. Statistical analysis: B.K.T. and Eric Balestre. Manuscript drafting: B.K.T., D.K.E., and P.A.C. Critical reading: D.K.E., G.S.G., B.K.T., B.L.H., Eric Balestre, S.P.E., P.A.C., C.W., S.J., and F.D.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

antiretroviral therapy; HIV-2; loss to follow-up; mortality; sex; West Africa

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