In Côte d'Ivoire during 2004–2007, numbers of ART enrollees increased from <5,000 to 36,943. Trends in nationally representative ART program outcomes have not yet been reported.
We conducted a retrospective chart review to assess trends in patient characteristics and attrition [death or loss to follow-up (LTFU)] over time, among a nationally representative sample of 3,682 adults (≥15 years) initiating ART during 2004–2007 at 34 health facilities. Among ART enrollees during 2004–2007, median age was 36, the proportion female was 67%, the proportion HIV-2-infected or dually HIV-1&2 reactive was 5%, and median baseline CD4+ T-cell (CD4) count was 135 cells/µL. Comparing cohorts initiating ART in 2004 with cohorts initiating ART in 2007, median baseline weight declined from 55 kg to 52 kg (p = 0.008) and the proportion weighing <45 kg increased from 17% to 22% (p = 0.014). During 2004–2007, pharmacy-based estimates of the percentage of new ART enrollees ≥95% adherent to ART declined from 74% to 60% (p = 0.026), and twelve-month retention declined from 86% to 69%, due to increases in 12-month mortality from 2%–4% and LTFU from 12%–28%. In univariate analysis, year of ART initiation was associated with increasing rates of both LTFU and mortality. Controlling for baseline CD4, weight, adherence, and other risk factors, year of ART initiation was still strongly associated with LTFU but not mortality. In multivariate analysis, weight <45 kg and adherence <95% remained strong predictors of LTFU and mortality.
During 2004–2007, increasing prevalence among ART enrollees of measured mortality risk factors, including weight <45 kg and ART adherence <95%, might explain increases in mortality over time. However, the association between later calendar year and increasing LTFU is not explained by risk factors evaluated in this analysis. Undocumented transfers, political instability, and patient dissatisfaction with crowded facilities might explain increasing LTFU.
Citation: Auld AF, Ekra KA, Shiraishi RW, Tuho MZ, Kouakou JS, Mohamed F, et al. (2014) Temporal Trends in Treatment Outcomes for HIV-1 and HIV-2-Infected Adults Enrolled in Côte d'Ivoire's National Antiretroviral Therapy Program. PLoS ONE 9(5): e98183. https://doi.org/10.1371/journal.pone.0098183
Editor: Cristian Apetrei, University of Pittsburgh Center for Vaccine Research, United States of America
Received: March 4, 2014; Accepted: April 25, 2014; Published: May 27, 2014
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) (http://www.pepfar.gov/) through the United States Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Although the patient-level data do not include patient names, this IRB decision is in the interest of ensuring patient confidentiality. An individual may email the lead author (firstname.lastname@example.org) or the CDC division of Global HIV/AIDS science office (email@example.com) to request the data.
Similar to other countries in West Africa , , Côte d'Ivoire faces a dual epidemic of HIV-1 and HIV-2 . Current adult HIV-1 prevalence is estimated at 3% , while about 5% of HIV-infected adults are HIV-2 or HIV-1&2 dually reactive . Although the burden of the HIV-2 epidemic is limited , , antiretroviral therapy (ART) programs need to provide supplies and training for adequate identification and treatment of HIV-2, which differs from that of HIV-1 , complicating the program in an already challenging setting , where resources are limited and political instability has culminated in two civil wars in the last decade .
Despite these challenges, the Ministry of Health (MOH) and international partners, including the United States (U.S) President's Emergency Plan for Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), have increased numbers of ART enrollees about 20-fold from less than 5,000 to 104,750 during 2004–2012 . Although sub-national ART programs in Côte d'Ivoire have reported their treatment experience for the period 2004–2008 , , these previous reports cannot be considered nationally representative , . Investigating and reporting national ART program outcomes is important to provide a representative assessment of program quality and justify continued funding –. Describing program trends over time at a national level, and assessment of factors associated with national outcomes, can help to identify areas for national program improvement activities , .
Therefore, in 2009–2010, we conducted a retrospective, cohort study among a nationally representative sample of adult ART patients starting ART during 2004–2007, to describe trends in patient characteristics at ART initiation over time and trends in mortality and loss to follow-up (LTFU).
This study was approved by the Ivorian Ethics Review Committee (Comité National d'Éthique des Sciences de la Vie et de la Santé), the Institutional Review Board (IRB) of the U.S. Centers for Disease Control and Prevention (CDC), and the Harvard School of Public Health IRB. Patient informed consent was not required as only routine, anonymized, monitoring data were collected and analyzed.
Eligibility for ART
During 2004–2007, patients were eligible for ART when diagnosed as having World Health Organization (WHO) stage IV, WHO stage III with CD4 counts ≤350/µL, or WHO stage I/II with CD4 counts ≤200/µL . Prescription of co-trimoxazole (CTX) was indicated for all ART patients with CD4 count ≤350/µL.
For HIV-1-infected patients, recommended first-line ART regimens included stavudine (D4T) or zidovudine (AZT) with lamivudine (3TC) and either nevirapine (NVP) or efavirenz (EFV) or, a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen of AZT, 3TC and abacavir (ABC), if one of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was contra-indicated. For HIV-2-infected or dually reactive patients, recommended first-line therapy was D4T or AZT with 3TC and ritonavir-boosted indinavir (IND/r).
At ART initiation, monthly for the first 3 months, and quarterly thereafter, standardized MOH-recommended medical records were completed to monitor disease progression or improvement. Patients collected medications monthly from clinic pharmacies where the date of scheduled antiretroviral (ARV) pick-up appointments and actual ARV pick-updates were documented.
Study Design and Population
This was a retrospective cohort study. Patient-level data were abstracted from standardized, MOH-recommended medical records onto study questionnaires by trained abstractors from November 2009 through March 2010. Only medical records of adult patients, ≥15 years old at ART initiation, who started ART during 2004–2007, were eligible.
Sample size calculations were performed using Epi Info software (CDC, Epi Info 2008, Version 3.5.1, Atlanta, GA). To achieve a 95% confidence interval (CI) of +2.5% around the estimate for 12-month attrition, assuming a design effect of 1.5 , and a conservative (i.e., higher than expected) 12-month attrition percentage of 50% , a sample size of ≥2,301 patient records was needed. To meet the needs of a secondary analysis, aimed at assessing site-level predictors of patient outcomes, we aimed to sample 4,000 medical records.
Of 124 ART delivery sites in the country by December 31, 2007, 78 had provided ART to ≥50 adults. Only 833 (2.3%) of all 36,943 adult patients who had received ART by December 31, 2007, were enrolled at sites that had supported <50 patients on ART by this time. To maintain feasibility, 35 (45%) of the 78 eligible sites were randomly selected, using a two-stage sampling strategy. In stage one, the 78 eligible clinics were divided into three strata based on which organization was largely responsible for implementing the ART program at the site (non-governmental organization, MOH, or GFATM through MOH). Within these three strata, sub-strata were created according to site size (number of ART patients ever enrolled). Site size sub-strata were: small (50–250), medium (251–1,000), and large (>1,000). Within each substratum, SAS 9.2 (SAS Institute Inc., Cary, NC) was used to randomly sample facilities using probability-proportional-to-size sampling. Of the selected 35 clinics, 34 agreed to participate.
In stage two, simple random sampling was used to select 4,000 medical records from the 34 selected, consenting facilities. The total number of medical records selected in each sub-stratum was proportional to the number of eligible records in the corresponding sub-stratum in the general adult ART population by 2007.
The primary outcomes of interest after ART initiation were documented death and LTFU, and the secondary outcome of interest was the composite outcome of attrition (documented death or LTFU). A patient was considered LTFU if he/she was absent from the health facility in the 90 days preceding data abstraction, and if there was no documentation of death or transferal to another health facility. The date of LTFU was recorded as the date of the most recent visit. Transfers were censored from time-to-event analyses at the date of transfer. Data for time-to-event analysis (i.e. date of ART initiation and date and nature of the final outcome status) were complete.
Patient-level characteristics routinely captured on standard MOH medical records (Table 1) were considered a priori risk factors for inclusion in the multivariable models for each of the three outcomes — death, LTFU, and overall attrition. CD4 count and hemoglobin categories ,  and weight categories  were chosen based on published precedent. Suitability of the ART regimen was assigned according to published international guidelines , . ART adherence during months 0–6 of ART was estimated by timeliness to drug pick-up appointments (i.e., every day late for a pharmacy drug pick-up appointment during months 0–6 of ART was equivalent to one missed day of ART doses) –. Only site size was included as a site-level variable in this analysis , .
Data were analyzed using SAS 9.2 (SAS Institute Inc., Cary, NC), and STATA 11 (StataCorp, 2009, Stata Statistical Software, Release 11, College Station, TX). The anonymized dataset is available upon request from the analysis working group, comprising the corresponding author, members of the MOH, CDC, and the Elizabeth Glaser Pediatric AIDS Foundation.
Missing data, reported for each baseline covariate of interest in Table 1, were assumed to be missing at random (MAR), and were imputed using multiple imputation with chained equations . The ice – procedure in STATA was used to create 20 imputed datasets for each of the following outcomes: (1) documented death, (3) LTFU, and (3) overall attrition . The imputation model included the event indicator, all study variables, and the Nelson-Aalen estimate of cumulative hazard . For all analyses using imputed data, estimates were combined across the imputed datasets according to Rubin's rules  using the mim procedure in STATA .
To assess the association between baseline characteristics and year of ART initiation, linear, logistic, ordered, or multinomial logistic regression models, accounting for study design, were used for continuous, binary, ordinal, and nominal categorical variables, respectively. To assess the association between baseline characteristics and sex, unadjusted logistic regression, accounting for study design, was used.
A competing risks model was used to estimate 6-, 12-, and 24-month mortality and LTFU for each annual cohort of adults starting ART during 2004–2007 . Stacked cumulative incidence curves were used to illustrate cumulative probability of death and LTFU over time for each annual cohort of adults starting ART .
In time-to-event analysis, Cox proportional hazards regression models that controlled for study design were used to estimate crude and adjusted hazard ratios (AHR) and 95% confidence intervals (CI) for covariates of interest . The proportional hazards assumption was assessed using visual methods and the Grambsch and Therneau test . Kaplan-Meier curves were used to examine cumulative probability of retention (1-attrition) over time stratified by baseline variables.
Trends in Patient Characteristics at ART Initiation
Data from medical records of 3,682 eligible, adult ART patients were abstracted and analyzed. Year of ART enrollment for adult ART patients included in the study was 2004, 2005, 2006, and 2007, for 6%, 22%, 36% and 36%, respectively. During 2004–2007, 67% of patients were female, median age was 36 years, most patients (95%) were HIV-1-infected, 2% were HIV-2-infected, and 3% were HIV-1&2 dually reactive. These variables did not change significantly over time.
Overall, 59% of patients reported employment, but the proportion reporting employment declined from 65% to 56% during 2004–2007 (p = 0.027). Most patients had WHO stage III (58%) or IV (22%) with no significant changes over time (Table 1). Median ART enrollment weight was 53 kg, but declined from 55 kg to 52 kg during 2004–2007 (p = 0.008). Similarly, the proportion with very low weight (<45 kg) at ART initiation was 20% overall, but increased from 17% to 22% during 2004–2007 (p = 0.014). During 2004–2007, the proportion with hemoglobin <8 g/dL was 14% and this did not change over time. Median CD4 count overall was 135 cells/µL and did not change significantly over time (p = 0.363).
The proportion of patients prescribed CTX at ART initiation was 59% and this did not change significantly over time. The proportion achieving 95% adherence to pharmacy pick-up appointments decreased from 74% to 60% during 2004–2007 (p = 0.026). The proportion of patients prescribed sub-optimal ART regimens was 8% and did not change significantly over time (p = 0.245). The proportion of patients enrolling at smaller sites (sites with ≤1,000 enrollees) increased from 12% to 64% (p = 0.001) during 2004–2007.
Compared with females at ART enrollment, males had a higher median age (40 vs. 34, p<0.001), a higher prevalence of HIV-2 or dual HIV-1&2 reactivity (8% vs. 4%, p<0.001), and were more likely to report employment (82% vs. 47%, p<0.001). Compared with female ART enrollees, males had a higher median weight (57 kg vs. 50 kg, p<0.001) and a lower prevalence of severe anemia (HB <8 g/dL) (10% vs. 16%, p<0.001), but also a lower median CD4 count (119/µL vs. 146/µL, p<0.001). Adherence to ART <95% was not significantly different between males (33%) and females (35%, p = 0.553).
ART Regimen Prescription
Eighty-four different initial ART regimens were prescribed to ART enrollees during 2004–2007 (Table 2). Across all patients, D4T+3TC+NVP (44%) and D4T+3TC+EFV (23%), were the most common regimens prescribed.
Among 182 HIV-2-infected or dually reactive adults, optimal first-line therapy of two NRTIs and a boosted PI were prescribed to 41% of patients. Sub-optimal regimens were prescribed to the remaining 56% of HIV-2-infected or dually reactive adults: two NRTIs with an NNRTI were prescribed to 25%, triple NRTIs to 11%, two NRTIs with an unboosted PI to 10%, and monotherapy to 6% (Table 2).
Overall, 283 (8%) of all patients were prescribed sub-optimal regimens (Table 2). Sub-optimal ART regimen prescription was more common for HIV-2-infected or dually reactive patients compared with HIV-1-infected patients (56% vs. 5%, p<0.001).
Among 3,682 enrollees, 1,778 (49%) were alive on ART at the same facility by the time of data abstraction, 1,481 (40%) became LTFU, 216 (7%) died, and 207 (6%) had been transferred out to another facility. At 6, 12, 24, 36, 48, and 60 months after ART initiation, ART retention was 79%, 74%, 65%, 56%, 48%, and 46% respectively.
During 2004–2007, 12-month retention declined from 86% for 2004 ART enrollees, to 82% for 2005, 73% for 2006, and 69% for 2007 enrollees (Table 3, Figure 1). Declines in 12-month retention were due to increases in 12-month mortality from 2% to 4%, and LTFU from 12% to 28% for 2004 compared with 2007 enrollees. Similarly, rates of mortality increased from 1.5/100 person-years (PY) for 2004 enrollees to 3.9/100 PY for 2007 enrollees, while rates of LTFU increased from 9.2/100 PY for 2004 enrollees to 28.1/100 PY for 2007 enrollees (Table 4). Rates of overall attrition increased from 10.7/100 PY for 2004 enrollees to 32.0/100 PY for 2007 enrollees (Table 5).
Predictors of Outcomes
A 10-year increase in age at ART initiation was associated with an 11% reduction in LTFU risk (AHR 0.89; 95% CI, 0.83–0.96) but not mortality risk (Table 4). Male sex was borderline predictive of mortality (AHR 1.65; 95% CI, 0.98–2.76, p = 0.058) and was associated with LTFU (AHR 1.57; 95% CI, 1.31–1.89). HIV type was not associated with mortality or LTFU risk.
Compared with WHO stage I/II, WHO stage IV was predictive of mortality (AHR 3.07; 95% CI, 1.22–7.72), but not LTFU (Table 4). Compared with having a weight >60 kg, having a weight <45 kg was predictive of mortality (AHR 2.05; 95% CI, 1.22–3.46), and LTFU (AHR 1.90; 95% CI, 1.49–2.41). Compared with having a CD4>350 cells/µL at ART initiation, having a CD4<50 cells/µL was predictive of mortality (AHR 3.00; 95% CI, 1.13–7.95), but not LTFU.
Failure to prescribe CTX was associated with increased risk of LTFU (AHR 1.40; 95% CI, 1.12–1.75), but not documented mortality (Table 4).
Adherence to ART drug refill appointments <95% was associated with borderline increased mortality (AHR 2.08, 95% CI, 0.97–4.46, p = 0.058) and increased LTFU risk (AHR 1.51, 95% CI, 1.12–2.03).
In crude analysis, enrollment at smaller sites (<1,000 enrollees) was predictive of mortality, but this was not significant in multivariable analysis.
In crude analysis, year of ART enrollment was associated with both mortality and LTFU (Table 4). However, in adjusted analysis, year of enrollment was only associated with increasing LTFU rates and not mortality (Table 4).
Factors predictive of overall attrition in adjusted analysis included younger age, male sex (Figure 2A), very low weight (Figure 2B), CD4 count <50 cells/µL, failure to prescribe CTX at ART initiation, adherence to ART <95% (Figure 2C), and later calendar year of ART initiation (Figure 2 D, Table 5).
This is the first nationally representative evaluation of Côte d'Ivoire's adult ART program, and the first to evaluate trends in program outcomes over time, and has several important findings.
Declining ART Retention over Time
The most concerning finding of our analysis is the decrease in 12-month retention from 86% for 2004 ART enrollees to 69% for 2007 enrollees. Compared with average 12-month retention for African ART programs during 2004–2007 (75-80% , ), 12-month retention for ART enrollees in 2006 (72%) and 2007 (69%), was low.
The declining 12-month retention estimates are due to nearly three-fold increases in rates of LTFU (from 9.2–28.1/100 PY), and documented mortality (from 1.5–3.9/100 PY). While year of ART initiation was associated with both mortality and LTFU in unadjusted analysis, in multivariable analysis, controlling for other known predictors of death and LTFU, ART initiation year was only associated with LTFU.
The likely explanation for this finding is that other measured mortality risk factors were confounding the crude association between ART initiation year and mortality. Both prevalence of very low weight at ART initiation and non-adherence to ART in months 0-6 of ART, increased among successive annual cohorts of ART enrollees, and were associated with mortality. In contrast, measured risk factors for LTFU in this study do not explain the association between year of ART initiation and LTFU. This analysis has important implications for the program response to declining retention.
Program Response to Increasing Mortality
Addressing increasing prevalence of sub-optimal nutritional status and declining ART adherence may help program managers to reverse trends of increasing mortality rates. Increasing prevalence of nutritional insufficiency may be related to increasing food insecurity , which may be related to increasing political instability since the late 1990s that culminated in the second Ivorian civil war in 2011 . Alternately, expansion of the ART program to more rural areas, especially in the north of the country, where food insecurity is more common , might explain the worsening baseline nutritional status of ART enrollees. The increasing proportion of ART enrollees who report being unemployed (from 31% to 42% during 2004–2007) supports the theory that food insecurity might underpin increasing prevalence of sub-optimal nutritional status. In Côte d'Ivoire, where 23% of the population live on <$1.23/day , further research to evaluate the health benefits of integrated nutrition programs in adult ART clinics might be warranted –.
Addressing food insecurity, for example through clinic-based food assistance –, may also help to address the problem of declining ART adherence . Other interventions to improve adherence might include targeting patients who display sub-optimal pharmacy-based measures of adherence during months 0-6 of ART, with a package of adherence interventions including viral load testing , ; this targeted approach might improve adherence , reduce mortality , and reduce LTFU risk .
Program Response to Increasing LTFU
Identifying the causes of increasing LTFU rates in future studies is important to allow identification of possible interventions. Increasing rates of LTFU have been documented in other countries with rapidly expanding ART programs, including South Africa ,  and Mozambique . Two factors may be contributing to increasing LTFU: firstly, with increasing patient load, attention to timely, accurate maintenance of medical records may be compromised, resulting in missing entries for clinic visits or undocumented transfers , . Developing and implementing effective electronic monitoring systems, with dedicated data management personnel, could improve data quality and accuracy .
Secondly, with increasing patient-to-provider ratios, patient waiting times are increased, and waiting rooms become more crowded , –. This may be associated with patient and clinician dissatisfaction with clinic conditions, which may be one cause for increasing LTFU –. Reducing patient-to-provider ratios might be facilitated by several interventions including increasing the workforce, task shifting , or decreasing visit frequency for stable patients . One method to decrease visit frequency for stable patients is formation of community adherence support groups (CASG). CASGs comprise groups of 6–10 patients, who take turns to collect the group's ART medications from clinic pharmacies each month. In Mozambique a pilot project significantly reduced 12-month LTFU . Alternately, distribution of ART at locations closer to patient's homes might reduce patient and clinic burden and might improve retention .
Co-trimoxazole for ART Enrollees
In our study, failure to prescribe CTX to ART enrollees was associated with increased LTFU and overall attrition. It is unclear whether CTX reduced morbidity, which contributed to reductions in LTFU , , or whether clinician compliance with CTX prescription was a marker of higher quality clinical care. Regardless, there is considerable evidence , ,  supporting the need to prescribe CTX to all ART enrollees.
As has been documented in other African cohorts , , , , , males had a lower baseline median CD4 count than females, a higher risk of LTFU, and marginally increased mortality. Delayed presentation for care might be due to gender norms, which discourage men from admitting ill-health, while higher rates of LTFU might reflect differences in adherence to chronic care , , . However, higher background mortality among men in general, regardless of HIV status, might explain gender differences in mortality during ART follow-up . In Côte d'Ivoire's general population, mortality is higher among males than females (472 deaths/1,000 men vs. 385 deaths/1,000 women) . Increased male mortality is attributed to accidents, homicide, suicide , and increased opportunistic infections , , . In our cohort, higher male LTFU may also be due to underlying increased mortality , a proportion of which goes undocumented . However, further research is needed to inform intervention strategies.
In our study, as in others , , younger age was predictive of LTFU risk. Point estimates of LTFU rates were higher in adolescents (aged 15-<20 years at ART initiation) at 19.5/100 PY and young adults (aged 20-<25) at 24.4/100 PY, compared with adults aged 25-<75 at ART initiation (range: 0-18.7/100 PY). This may be because younger people are more mobile. In west Africa, migration for work is particularly common among adults in their twenties and thirties, especially among men . Increased risk for LTFU among adolescents has been documented in other studies . Possible cognitive impairment among perinatally infected children who start ART late as adolescents, lack of youth-friendly services, rigid scheduling, increasing responsibilities, and decreasing involvement of adult caregivers all contribute to the challenge of retaining adolescents and young adults on ART . Youth-specific retention interventions may be needed to keep young adults on ART in Côte d'Ivoire.
HIV-2 and Dual HIV-1&2 Reactivity
As in other countries , HIV-2 and dual reactivity were poorly managed, with 56% of affected patients prescribed sub-optimal first-line regimens. Similar to Burkina Faso , 25% of HIV-2-infected or dually reactive patients were prescribed NNRTI-containing regimens, to which HIV-2 is resistant –. A further 11% of patients were prescribed two NRTIs with an unboosted PI, which has been associated with poor treatment outcomes in Côte d'Ivoire  and Senegal , . Triple NRTI therapy is also not recommended , due to poor outcomes , , and risk of Q151M pan-NRTI resistance . Similarly, mono- and dual-therapy are associated with resistance and poor outcomes . Possible reasons for poor HIV-2 management include insufficient training of clinicians, and low availability of ritonavir-boosted regimens, either due to stock outs , or lack of a cold chain prior to availability of heat-stable lopinavir-ritonavir . Clinician training and drug supply and demand issues are being addressed .
Firstly, these analyses rely on routinely collected and sometimes incomplete data. Missing data on baseline patient characteristics likely introduced non-differential measurement error. Given the proportion of data missing for the adherence variable, prevalence of non-adherence and hazard ratios associated with non-adherence should be viewed with caution, although findings are in line with other publications from Côte d'Ivoire , . Secondly, our reported LTFU rate is likely an over-estimate due to the probability of undocumented death  or undocumented transfer  being observed as LTFU. Similarly, our reported mortality rate is likely an underestimate of true mortality . Finally, these data show trends for patients enrolled during 2004–2007 and trends may have changed in more recent years.
Increased prevalence of sub-optimal nutritional status and sub-optimal ART adherence, might explain increases in documented mortality over time. Earlier ART initiation before nutritional compromise and targeted adherence interventions might help reverse trends of increasing mortality. Further research to assess the survival benefit of food supplementation for food-insecure ART enrollees, might be warranted. Increasing LTFU rates are not explained by risk factors analyzed in this report. Undocumented transfers, political instability, or patient dissatisfaction with crowded facilities might explain increasing LTFU. Implementing electronic monitoring systems to improve data quality, and innovative LTFU-prevention strategies, possibly targeting men and younger patients, might reverse trends of increasing LTFU.
Disclaimer: The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views of the United States (U.S.) Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the U.S. Centers for Disease Control and Prevention or the U.S. Department of Health and Human Services.
Conceived and designed the experiments: AFA KAE RWS MZT JSK FM VE JE GA RM TVE. Performed the experiments: AFA KAE RWS MZT JSK FM VE JS JE GA RM TVE. Analyzed the data: AFA RWS JS. Contributed reagents/materials/analysis tools: AFA KAE RWS MZT JSK FM VE JS JE GA RM TVE. Wrote the paper: AFA KAE RWS MZT JSK FM VE JS JE GA RM TVE.
- 1. Tienen C, van der Loeff MS, Zaman SM, Vincent T, Sarge-Njie R, et al. (2010) Two distinct epidemics: the rise of HIV-1 and decline of HIV-2 infection between 1990 and 2007 in rural Guinea-Bissau. J Acquir Immune Defic Syndr 53: 640–647.
- 2. van der Loeff MF, Awasana AA, Sarge-Njie R, van der Sande M, Jaye A, et al. (2006) Sixteen years of HIV surveillance in a West African research clinic reveals divergent epidemic trends of HIV-1 and HIV-2. Int J Epidemiol 35: 1322–1328.
- 3. Djomand G, Greenberg AE, Sassan-Morokro M, Tossou O, Diallo MO, et al. (1995) The epidemic of HIV/AIDS in Abidjan, Cote d'Ivoire: a review of data collected by Projet RETRO-CI from 1987 to 1993. J Acquir Immune Defic Syndr Hum Retrovirol 10: 358–365.
- 4. Joint United Nations Programme on HIV/AIDS (2012) Report on the Global AIDS Epidemic. Available: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_with_annexes_en.pdf. Accessed 1 April 2013.
- 5. Toure S, Kouadio B, Seyler C, Traore M, Dakoury-Dogbo N, et al. (2008) Rapid scaling-up of antiretroviral therapy in 10,000 adults in Cote d'Ivoire: 2-year outcomes and determinants. AIDS 22: 873–882.
- 6. De Cock KM, Adjorlolo G, Ekpini E, Sibailly T, Kouadio J, et al. (1993) Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic. JAMA 270: 2083–2086.
- 7. Peterson K, Jallow S, Rowland-Jones SL, de Silva TI (2011) Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings. AIDS Res Treat 2011: 463704.
- 8. Harries K, Zachariah R, Manzi M, Firmenich P, Mathela R, et al. (2010) Baseline characteristics, response to and outcome of antiretroviral therapy among patients with HIV-1, HIV-2 and dual infection in Burkina Faso. Trans R Soc Trop Med Hyg 104: 154–161.
- 9. United Nations Development Programme (2011) The Conflict in Côte d'Ivoire and its Effect on West African Countries: A Perspective from the Ground. Available: http://www.crin.org/docs/Cote_d_Ivoire_vulnerable_groups.pdf. Accessed 29 March 2013.
- 10. Joint United Nations Programme on HIV/AIDS (2013) Global report: UNAIDS report on the global AIDS epidemic 2013. Available: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf. Accessed 17 February 2014.
- 11. Messou E, Kouakou M, Gabillard D, Gouesse P, Kone M, et al. (2011) Medication possession ratio: predicting and decreasing loss to follow-up in antiretroviral treatment programs in Cote d'Ivoire. J Acquir Immune Defic Syndr 57 Suppl 1S34–39.
- 12. Lowrance DW, Ndamage F, Kayirangwa E, Ndagije F, Lo W, et al. (2009) Adult clinical and immunologic outcomes of the national antiretroviral treatment program in Rwanda during 2004–2005. J Acquir Immune Defic Syndr 52: 49–55.
- 13. Auld AF, Mbofana F, Shiraishi RW, Sanchez M, Alfredo C, et al. (2011) Four-Year Treatment Outcomes of Adult Patients Enrolled in Mozambique's Rapidly Expanding Antiretroviral Therapy Program. PLoS One 6: e18453.
- 14. Government Accountability Office (2012) Designing evaluations - 2012 revision. Available: http://www.gao.gov/products/GAO-12-208G. Accessed 17 January 2013.
- 15. Institute of Medicine (2013) Evaluation of PEPFAR. Available: http://www.who.int/hiv/pub/progress_report2011/en/. Accessed 1 April 2013.
- 16. Montaner JS, Lima VD, Williams BG (2010) Evaluating outcomes of the President's Emergency Plan for AIDS Relief in Africa. Ann Intern Med 152: 131-132; author reply 132–133.
- 17. Boerma JT, Stanecki KA, Newell ML, Luo C, Beusenberg M, et al. (2006) Monitoring the scale-up of antiretroviral therapy programmes: methods to estimate coverage. Bull World Health Organ 84: 145–150.
- 18. Bennett S, Boerma JT, Brugha R (2006) Scaling up HIV/AIDS evaluation. Lancet 367: 79–82.
- 19. Rosen S, Fox MP, Gill CJ (2007) Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 4: e298.
- 20. Stringer J, Zulu I, Levy J, Stringer EM, Mwango A, et al. (2006) Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 296: 782–793.
- 21. Severe P, Juste MA, Ambroise A, Eliacin L, Marchand C, et al. (2010) Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 363: 257–265.
- 22. May M, Boulle A, Phiri S, Messou E, Myer L, et al. (2010) Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes. Lancet 376: 449–457.
- 23. World Health Organization (2010) Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach - 2010 revision. Available: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. Accessed 17 January 2013.
- 24. Fairley CK, Permana A, Read TR (2005) Long-term utility of measuring adherence by self-report compared with pharmacy record in a routine clinic setting. HIV Med 6: 366–369.
- 25. Lucas GM, Chaisson RE, Moore RD (1999) Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med 131: 81–87.
- 26. Grossberg R, Zhang Y, Gross R (2004) A time-to-prescription-refill measure of antiretroviral adherence predicted changes in viral load in HIV. J Clin Epidemiol 57: 1107–1110.
- 27. Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. New York: J. Wiley & Sons. 231 p.
- 28. Royston P (2004) Multiple imputation of missing values. The Stata Journal 4(3): 227–241.
- 29. Royston P (2005) Multiple imputation of missing values: update. The Stata Journal 5(2): 188–201.
- 30. Royston P (2005) Multiple imputation of missing values: update of ice. The Stata Journal 5(4): 527–536.
- 31. White IR, Royston P (2009) Imputing missing covariate values for the Cox model. Stat Med 28: 1982–1998.
- 32. Royston P, Carlin JB, White IR (2009) Multiple imputation of missing values: new features for mim. The Stata Journal 9(2): 252–264.
- 33. Wandeler G, Keiser O, Pfeiffer K, Pestilli S, Fritz C, et al. (2012) Outcomes of antiretroviral treatment programs in rural Southern Africa. J Acquir Immune Defic Syndr 59: e9–16.
- 34. Putter H, Fiocco M, Geskus RB (2007) Tutorial in biostatistics: competing risks and multi-state models. Stat Med 26: 2389–2430.
- 35. Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81: 515–526.
- 36. Fox MP, Rosen S (2010) Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007-2009: systematic review. Trop Med Int Health 15 Suppl 11–15.
- 37. Béchu N (2006) The impact of AIDS on the economy of families in Côte d'Ivoire: Changes in consumption among AIDS-affected households. Available: http://www.ceped.org/cdrom/orphelins_sida_2006/pdf/confront_aids_chapter_16.pdf. Accessed 7 January 2013.
- 38. World Food Programme (2011) World Food Programme - fighting hunger worldwide - Cote d'Ivoire. Available: http://www.wfp.org/countries/c%C3%B4te-d-ivoire/overview. Accessed 7 January 2013.
- 39. Tirivayi N, Koethe JR, Groot W (2012) Clinic-Based Food Assistance is Associated with Increased Medication Adherence among HIV-Infected Adults on Long-Term Antiretroviral Therapy in Zambia. J AIDS Clin Res 3: 171.
- 40. Tiyou A, Belachew T, Alemseged F, Biadgilign S (2012) Food insecurity and associated factors among HIV-infected individuals receiving highly active antiretroviral therapy in Jimma zone Southwest Ethiopia. Nutr J 11: 51.
- 41. Weiser SD, Gupta R, Tsai AC, Frongillo EA, Grede N, et al. (2012) Changes in food insecurity, nutritional status, and physical health status after antiretroviral therapy initiation in rural Uganda. J Acquir Immune Defic Syndr 61: 179–186.
- 42. Messou E, Chaix ML, Gabillard D, Minga A, Losina E, et al. (2011) Association between medication possession ratio, virologic failure and drug resistance in HIV-1-infected adults on antiretroviral therapy in Cote d'Ivoire. J Acquir Immune Defic Syndr 56: 356–364.
- 43. Wilson D, Keiluhu AK, Kogrum S, Reid T, Seriratana N, et al. (2009) HIV-1 viral load monitoring: an opportunity to reinforce treatment adherence in a resource-limited setting in Thailand. Trans R Soc Trop Med Hyg 103: 601–606.
- 44. Nachega JB, Hislop M, Dowdy DW, Lo M, Omer SB, et al. (2006) Adherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults. J Acquir Immune Defic Syndr 43: 78–84.
- 45. Nglazi MD, Lawn SD, Kaplan R, Kranzer K, Orrell C, et al. (2011) Changes in programmatic outcomes during 7 years of scale-up at a community-based antiretroviral treatment service in South Africa. J Acquir Immune Defic Syndr 56: e1–8.
- 46. Cornell M, Grimsrud A, Fairall L, Fox MP, van Cutsem G, et al. (2010) Temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across South Africa, 2002–2007. AIDS 24: 2263–2270.
- 47. Forster M, Bailey C, Brinkhof MW, Graber C, Boulle A, et al. (2008) Electronic medical record systems, data quality and loss to follow-up: survey of antiretroviral therapy programmes in resource-limited settings. Bull World Health Organ 86: 939–947.
- 48. Musheke M, Bond V, Merten S (2013) Deterrents to HIV-Patient Initiation of Antiretroviral Therapy in Urban Lusaka, Zambia: A Qualitative Study. AIDS Patient Care STDS.
- 49. Musheke M, Bond V, Merten S (2012) Individual and contextual factors influencing patient attrition from antiretroviral therapy care in an urban community of Lusaka, Zambia. J Int AIDS Soc 15 Suppl 11–9.
- 50. Duff P, Kipp W, Wild TC, Rubaale T, Okech-Ojony J (2010) Barriers to accessing highly active antiretroviral therapy by HIV-positive women attending an antenatal clinic in a regional hospital in western Uganda. J Int AIDS Soc 13: 37.
- 51. Dang BN, Westbrook RA, Rodriguez-Barradas MC, Giordano TP (2012) Identifying drivers of overall satisfaction in patients receiving HIV primary care: a cross-sectional study. PLoS One 7: e42980.
- 52. Tran BX, Nguyen NP (2012) Patient satisfaction with HIV/AIDS care and treatment in the decentralization of services delivery in Vietnam. PLoS One 7: e46680.
- 53. Roberts KJ (2002) Physician-patient relationships, patient satisfaction, and antiretroviral medication Adherence among HIV-infected adults attending a public health clinic. AIDS Patient Care STDS 16: 43–50.
- 54. Schneider J, Kaplan SH, Greenfield S, Li W, Wilson IB (2004) Better physician-patient relationships are associated with higher reported adherence to antiretroviral therapy in patients with HIV infection. J Gen Intern Med 19: 1096–1103.
- 55. Vahey DC, Aiken LH, Sloane DM, Clarke SP, Vargas D (2004) Nurse burnout and patient satisfaction. Med Care 42: II57–66.
- 56. Fairall L, Bachmann MO, Lombard C, Timmerman V, Uebel K, et al. (2012) Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial. Lancet 380: 889–898.
- 57. Harries AD, Zachariah R, Lawn SD, Rosen S (2010) Strategies to improve patient retention on antiretroviral therapy in sub-Saharan Africa. Trop Med Int Health 15 Suppl 170–75.
- 58. Decroo T, Telfer B, Biot M, Maikere J, Dezembro S, et al. (2011) Distribution of antiretroviral treatment through self-forming groups of patients in Tete Province, Mozambique. J Acquir Immune Defic Syndr 56: e39–44.
- 59. Koole O, Tsui S, Wabwire-Mangen F, Kwesigabo G, Menten J, et al.. (2012) Retention and risk factors for attrition among adults in antiretroviral treatment programs in Tanzania, Uganda and Zambia [Abstract MOAC0305]. XIX International AIDS Conference Washington D.C. July 22–27. Available: https://docs.google.com/viewer?a=v&q=cache:TWoCw06pt6IJ:pag.aids2012.org/PAGMaterial/aids2012/PPT/1411_2859/aids%2520july%25202012%2520koole%2520final.pptx+IAC+2012+olivier+koole+retention&hl=en&gl=us&pid=bl&srcid=ADGEESjSgUWPgjofBhkLNPnpYEmtTZHSSfGm1wZFltG9MahEWHUm8P1zgSZ4JhpPY3WMdlqQ7K64-N_SfdbGkk9jwgaz_0tD3zfFV5j9ruUO879xRGJfwydp-xWrkLazZqDiTQ5a9Jmh&sig=AHIEtbRU0FW-mWBE0uES8B5PZ8hdg9OYXg. Accessed 27 March 2013.
- 60. Lowrance D, Makombe S, Harries A, Yu J, Aberle-Grasse J, et al. (2007) Lower early mortality rates among patients receiving antiretroviral treatment at clinics offering cotrimoxazole prophylaxis in Malawi. J Acquir Immune Defic Syndr 46: 56–61.
- 61. Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, et al. (2010) Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort. Lancet 375: 1278–1286.
- 62. Cornell M, Myer L, Kaplan R, Bekker LG, Wood R (2009) The impact of gender and income on survival and retention in a South African antiretroviral therapy programme. Trop Med Int Health 14: 722–731.
- 63. United Nations (2008) World Population Prospects: the 2008 revision. Available: http://www.un.org/esa/population/publications/wpp2008/wpp2008_highlights.pdf. Accessed 1 February 2014.
- 64. Rajaratnam JK, Marcus JR, Levin-Rector A, Chalupka AN, Wang H, et al. (2010) Worldwide mortality in men and women aged 15–59 years from 1970 to 2010: a systematic analysis. Lancet 375: 1704–1720.
- 65. Owens IPF (2002) Sex Differences in Mortality Rate. Science 297: 2008.
- 66. Zuk M, McKean KA (1996) Sex differences in parasite infections: Patterns and processes. International Journal for Parasitology 26: 1009–1024.
- 67. Bisson GP, Gaolathe T, Gross R, Rollins C, Bellamy S, et al. (2008) Overestimates of survival after HAART: implications for global scale-up efforts. PLoS One 3: e1725.
- 68. Shimeles A (2010) Migration Patterns, Trends and Policy Issues in Africa. Available: http://www.afdb.org/fileadmin/uploads/afdb/Documents/Project-related-Procurement/WORKING%20119%20word%20document%20AA.pdf. Accessed 1 October 2013.
- 69. Zanoni BC, Mayer KH (2014) The Adolescent and Young Adult HIV Cascade of Care in the United States: Exaggerated Health Disparities. AIDS Patient Care STDS 28: 128–135.
- 70. Witvrouw M, Pannecouque C, Van Laethem K, Desmyter J, De Clercq E, et al. (1999) Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS 13: 1477–1483.
- 71. Witvrouw M, Pannecouque C, Switzer WM, Folks TM, De Clercq E, et al. (2004) Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir Ther 9: 57–65.
- 72. Isaka Y, Miki S, Kawauchi S, Suyama A, Sugimoto H, et al. (2001) A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors. Arch Virol 146: 743–755.
- 73. Adje-Toure CA, Cheingsong R, Garcia-Lerma JG, Eholie S, Borget MY, et al. (2003) Antiretroviral therapy in HIV-2-infected patients: changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of patients treated in Abidjan, Cote d'Ivoire. AIDS 17 Suppl 3S49–54.
- 74. Gottlieb GS, Badiane NM, Hawes SE, Fortes L, Toure M, et al. (2009) Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa. Clin Infect Dis 48: 476–483.
- 75. van der Ende ME, Prins JM, Brinkman K, Keuter M, Veenstra J, et al. (2003) Clinical, immunological and virological response to different antiretroviral regimens in a cohort of HIV-2-infected patients. AIDS 17 Suppl 3S55–61.
- 76. Ruelle J, Roman F, Vandenbroucke AT, Lambert C, Fransen K, et al. (2008) Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: analysis of the HIV-2 Belgium and Luxembourg database. BMC Infect Dis 8: 21.
- 77. Colson P, Henry M, Tivoli N, Gallais H, Gastaut JA, et al. (2005) Polymorphism and drug-selected mutations in the reverse transcriptase gene of HIV-2 from patients living in southeastern France. J Med Virol 75: 381–390.
- 78. Pasquet A, Messou E, Gabillard D, Minga A, Depoulosky A, et al. (2010) Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Cote d'Ivoire. PLoS One 5: e13414.