Initiation of antiretroviral therapy among pregnant women in resource-limited countries: CD4+ cell count response and program retention
Toro, Patricia La; Katyal, Monicaa; Carter, Rosalind Ja; Myer, Landona,b; El-Sadr, Wafaa Ma; Nash, Denisa; Abrams, Elaine Ja; for the MTCT-Plus Initiative
aInternational Center for AIDS Care and Treatment Programs (ICAP), Columbia University Mailman School of Public Health, New York, New York, USA
bInfectious Diseases Epidemiology Unit, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Received 11 May, 2009
Revised 7 October, 2009
Accepted 6 November, 2009
Correspondence to Patricia L. Toro, MD, MPH, 722 West 168th Street, International Center for AIDS Care and Treatment Programs (ICAP), Columbia University Mailman School of Public Health, New York, NY 10032, USA. Tel: +1 212 342 0541; fax: +1 212 342 1824; e-mail: firstname.lastname@example.org
Objective(s): Few data are available from resource-limited countries on long-term outcomes of HIV-infected women who initiate antiretroviral therapy (ART) during pregnancy.
Design: Analysis of data from adult patients enrolled in the MTCT-Plus Initiative who initiated ART between 2003 and 2006 in seven countries in Sub-Saharan Africa and Thailand.
Methods: Mean population changes were assessed and multivariable mixed linear regression modeling was used to examine covariate effects on differences in absolute CD4+ cell count responses. Kaplan–Meier methods were used to examine program retention combining survival and losses to follow-up.
Results: Of 2229 individuals initiating ART, 1688 were women, of which 605 were pregnant (median gestational age 7 months), 1083 were not pregnant, and 541 were men. The average CD4+ response by 30 months on ART was 451 cells/μl among women who were pregnant at ART initiation as compared with 435 cells/μl among nonpregnant women (P = 0.53) and 349 cells/μl among men (P < 0.001). In multivariable analysis, lower CD4+ cell increase was independently associated with male sex, older age, and lower CD4+ cell count at initiation. After 30 months on ART retention was 0.85 with no retention differences between pregnant women, nonpregnant women, and men.
Conclusion: HIV-infected women in resource-limited countries who start ART during pregnancy have similar or better long-term CD4+ cell count responses as compared with other adults. These data support efforts to provide pregnant HIV-infected women with access to ART in resource-limited countries.
By the end of 2007, it is estimated that more than three million adults and children were reported to have initiated antiretroviral therapy (ART) in low and middle-income countries . The success of the ART rollout has been well documented in Sub-Saharan Africa where decreased HIV-related morbidity and mortality and a good immunological response have been consistently reported [2–14]. However, in comparison with well resourced settings, high early mortality rates during the first few months of treatment are likely due to ART initiation at an advanced stage of HIV disease. This suggests a need to initiate ART earlier in the disease course and to strengthen efforts to maintain patients in follow-up [15–19].
Women of reproductive age in resource-limited countries (RLCs) are often first identified as HIV-infected during pregnancy in the context of programs to prevent the mother-to-child transmission (PMTCT) of HIV and there is growing interest in the rapid initiation of ART during pregnancy for eligible women [20–23]. Although the ART scale-up has progressed rapidly over the last several years, PMTCT programs have lagged behind with limited coverage and a dependence on single-dose nevirapine (SD-NVP) [1,24,25]. It is estimated that only 30% of pregnant women living with HIV worldwide received any ART for PMTCT in 2007 . Despite the recognition that women with advanced HIV disease are more likely to transmit infection during pregnancy, delivery, and breastfeeding, and are at high risk for early death , few pregnant women are assessed for ART eligibility and initiated on therapeutic treatment during pregnancy . In 2007, only 12% of HIV-positive pregnant women in antenatal care were assessed to determine if they were eligible to receive ART for their own health .
Limited data are available to describe outcomes for treatment-eligible women initiating ART during pregnancy [28–31]. Martin et al.  reported an average increase of 133 cells/μl after 33 months of follow-up in a cohort of pregnant women in London. In Johannesburg, South Africa, 689 treatment-eligible women initiated ART at a mean gestation of 27 weeks and mean baseline CD4+ cell count of 154 cells/μl (range 6–784 cells/μl). For the 244 women who remained in the program 24 weeks or more, 80% gained at least 50 cells/μl and 41.4% gained 100–250 cells/μl .
Retention in care is also a critical issue for the woman as well as her baby. In a community-based ART clinic in Cape Town, South Africa, mortality rates for 318 pregnant and 1813 nonpregnant women initiating therapeutic ART were not significantly different, but a substantially higher lost to follow-up (LTF) rate was found in pregnant women; after 3 years on ART, 32% of pregnant women and 13% of nonpregnant women were no longer in care (P < 0.001 . Similarly, pregnancy was identified as a risk factor for LTF by Wang et al.  in a cohort of adult men and women initiating treatment at four South African community care sites.
The MTCT-Plus Initiative was one of the first HIV programs to offer ART to adults and children in Sub-Saharan Africa and Thailand [33,34]. In this report, we examine immunologic response, mortality, and program retention in a large cohort of ART-eligible pregnant and nonpregnant women, and men during the first 30 months of treatment.
The MTCT-Plus Initiative provided support to clinical programs in Cameroon, Cote d'Ivoire, Kenya, Mozambique, Rwanda, South Africa, Uganda, Zambia, and Thailand to implement HIV/AIDS care and treatment to families identified through perinatal HIV prevention services [33,34]. Pregnant or recently postpartum women (index women) identified as HIV-infected in PMTCT programs were invited to enroll in the MTCT-Plus Initiative through which they were offered comprehensive care and ART. Male partners and other household members of index women, if HIV-infected, were eligible for enrollment, as were their HIV-exposed and infected children. The Institutional Review Board of Columbia University approved the MTCT-Plus Initiative as a service delivery program.
At program entry, patients had a physical examination, WHO staging, and CD4+ cell count done locally. The CD4+ cell count was repeated every 6 months. Patients starting ART had more extensive laboratory tests, weekly clinical visits for 8 weeks, then monthly visits including intensive adherence counseling. Clinic visit attendance was tracked and outreach protocols were used to contact individuals who failed to attend scheduled visits. Adherence and psychosocial support were emphasized at each appointment and several programs had peer educator or patient support groups to enhance adherence.
ART eligibility was determined based on WHO and local guidelines. In 2003–2004, adults were considered eligible for ART if they met the following criteria: WHO stage 4 or CD4+ cell count 200 cells/μl or less or WHO stage 2 or 3 and CD4+ cell count 350 cells/μl or less. In January 2005, eligibility criteria were modified to exclude WHO stage 2 with CD4+ cell count 350 cells/μl or less. The recommended initial ART regimen included two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI (NNRTI) inhibitor . Generic formulations and fixed-dose combination tablets were procured if they were included on the WHO prequalification list .
The analysis included all treatment-naive adults (≥15 years of age) who initiated ART between February 2003 and July 2006 and had a minimum follow-up of 6 months, at which time the first follow-up CD4 test would be done. Observation was censored in January 2007. Adults who were receiving triple-drug ART at enrollment or had previous exposure to ART or initiated ART at a CD4+ cell count of more than 350 cells/μl were excluded from this analysis. The clinics in Mozambique and Cameroon collected data for only part of the observation period and thus were excluded from the analysis. The Cameroon program had been operational for less than 1 year and the Mozambique site did not report data for the entire study period. Women who received short-course PMTCT antiretroviral drugs (i.e. SD-NVP or short-course zidovudine (ZDV) ± SD-NVP) prior to initiating ART were considered treatment naive.
The analysis of CD4+ cell count response was restricted to patients with a ‘baseline’ CD4+ cell count measure (up to 13 weeks before or 4 weeks after ART initiation) and at least one follow-up measurement. The observed mean CD4+ cell count was determined at baseline and 6, 12, 18, 24, and 30 months following ART initiation with 95% confidence intervals (CIs). To be included in each post-initiation time point, patients had to have a CD4+ cell count measurement recorded within ±6 weeks of that date.
Linear mixed regression models were constructed to evaluate the association of CD4+ cell count change over time on ART with categorical covariates of interest, using all available CD4+ cell count measurements . Interaction terms were included to assess whether any associations changed over time. In order to test the consistency of potential effects of country of enrollment on CD4+ cell count response, country of enrollment was considered as a fixed-effect covariate. The final multivariate model included intercept and time since ART initiation as random effects with an unstructured covariance matrix to account for variation between individual patients. Model assumptions were evaluated and satisfied.
Person-years of follow-up were calculated from the date of ART initiation to the date of program loss or last visit before data censoring. Program loss was defined as documented death, voluntary withdrawal, or LTF; LTF was based either on at least three failed attempts to trace a patient following a missed appointment or failure to attend the program for more than 6 months after the last clinical visit or laboratory test. Retention and survival were described in terms of the number of events occurring within 100 person-years. Mortality-specific rates were calculated. Kaplan–Meier analysis and the log-rank test were used to assess differences in survival by sex–pregnancy status, age, WHO stage, CD4+ cell count at baseline, and country of enrollment.
Categorical variables were compared using Pearson's χ2 or Fisher's exact tests and the distributions of continuous variables were compared using Wilcoxon rank-sum tests. Analyses were performed using SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
A total of 6421 adults enrolled in the MTCT-Plus Initiative from 2003 to 2006. There were 2229 ART-naive individuals who initiated treatment by July 2006 and were included in this analysis (Fig. 1). Of these individuals, 1688 (76%) were women including 605 (36%) who were pregnant at ART initiation [median gestational age 7 months, interquartile range (IQR) 6–8]. The nonpregnant women started ART at a median time of 11 months postpartum (IQR 5–23). An additional 541 (24%) male partners also began ART. The median age for all patients initiating treatment was 30 years (IQR 27–34) and the median baseline CD4+ cell count was 155 cells/μl (IQR 95–195) (Table 1).
Men were significantly older than women irrespective of pregnancy status [median age 34 (IQR 31–39) vs. 29 years (IQR 26–33), P < 0.001] and had heavier weight [median 61 (IQR 55–67) vs. 57 kg (IQR 50–65), P < 0.001] than nonpregnant women. Overall, men had significantly higher rates of employment outside the home than women (72 vs. 29%, P < 0.001).
Pregnant women had a significantly lower median baseline CD4+ cell count than nonpregnant women (150 vs. 164 cells/μl, P < 0.001) but had lower WHO stage; 29% of nonpregnant women vs. 47% of pregnant women were WHO stage I (P < 0.001). Men had a lower median CD4+ cell count than women overall (146 vs. 158 cells/μl, P < 0.001). However, WHO stage did not differ significantly between men and women.
CD4+ cell count change following antiretroviral therapy initiation
Antiretroviral regimens included NVP for 2012 (90%) patients, with lamivudine (3TC) and either ZDV or stavudine (d4T). An additional 189 (9%) patients, including two pregnant women in their third trimester, started efavirenz with 3TC and either ZDV or d4T. Initial ART regimens were similar for men, pregnant women, and nonpregnant women.
A total of 1794 patients had both a baseline and at least one CD4+ cell count measurement after initiating ART. There were no significant differences in baseline CD4+ cell count or sex, pregnancy-status, age, WHO stage, education, employment, or housing conditions noted between the 2229 patients who initiated ART and the subgroup of 1794 patients included in the CD4+ cell count analysis. A total of 7889 CD4+ cell count measurements were recorded up to the 30-month visit following ART initiation with a median of four measurements (range 2–9) per patient.
Figure 2 shows the crude mean CD4+ cell count over time on ART stratified by sex and baseline pregnancy status. The mean baseline CD4+ cell count observed in the cohort was 149 cells/μl (95% CI 146–153) with significantly higher mean baseline CD4+ cell count [156 cells/μl (95% CI 151–161)] among nonpregnant women as compared with pregnant women [147 (95% CI 141–154), P = 0.04] and men [140 (95% CI 132–147), P < 0.001]. Pregnant women had a mean CD4+ cell count of 328 (95% CI 311–346), 370 (95% CI 350–390), 397 (95% CI 377–417), 441 (95% CI 414–468), and 451 (95% CI 414–488) at 6, 12, 18, 24, and 30 months, respectively, after ART initiation. Nonpregnant women had a similar, although less steep, increase in CD4+ cell count response over time. In comparison, men had an attenuated CD4+ cell count response to ART at each time point examined and overall (P < 0.001) as compared with women, regardless of pregnancy status.
In addition to sex and pregnancy status, age, baseline CD4+ cell count, and country of enrollment were each associated with a significant increase in CD4+ cell count (Table 2). After simultaneous adjustment for these factors in multivariate modeling, female sex/pregnancy (P = 0.003), younger age (P < 0.001), higher baseline CD4+ cell count (P < 0.001), and country of enrollment (P = 0.008) remained independently associated with change in CD4+ cell count over time.
Although there were no significant differences in predicted mean CD4+ cell count change from baseline between nonpregnant and pregnant women, there were significant sex differences. At 6 months and thereafter (Table 2), the predicted change in CD4+ cell count from baseline in pregnant women vs. men was 30 cells/μl (P < 0.001) and 20 cells/μl (P = 0.018) between nonpregnant women vs. men.
Baseline CD4+ cell count remained a strong predictor of CD4+ cell count over time on ART. At 6 months, the predicted CD4+ cell gain between the lowest baseline CD4+ cell count stratum (0–50 cells/μl) and the highest CD4+ cell count stratum (201–350 cells/μl) was 248 cells/μl. Over time this trend diminished, with the difference between these strata at 30 months equal to 170 cells/μl.
Predicted CD4 cell count response did not vary by WHO stage at baseline, but did vary by country. Participants from sites in Cote d'Ivoire had the greatest increase in CD4 cell count at 6 months and at every time point thereafter.
Retention in care after antiretroviral therapy initiation
As of January 2007, 1902 (85%) of the 2229 patients who initiated ART were alive and in active follow-up. Over 4193 person-years of follow-up, 77 (3.5%) patients were known to have died (1.8 per 100 person-years) and 192 (8.6%) patients were LTF (4.6 per 100 person-years). An additional 58 patients (2.6%) voluntarily withdrew from the program (1.4 per 100 person-years) due to change in place of residence (n = 17), seeking care elsewhere (n = 24), refusal of further participation (n = 8), inability to adhere to ART or the visit schedule (n = 6), or other reasons (n = 3). The mortality rates for pregnant women (17 deaths, 1.5 per 100 person-years), nonpregnant women (34 deaths, 1.7 per 100 person-years), and men (26 deaths, 2.4 per 100 person-years) were similar (P = 0.18). Mortality was associated with lower baseline CD4+ cell count (P < 0.001), higher baseline WHO stage (P < 0.001), and country of enrollment (P < 0.001), but not sex or pregnancy status.
Kaplan–Meier probability of program retention (death, LTF and withdrawal) was 0.85 overall, and was similar across sex and pregnancy groups: 0.82 for pregnant women, 0.87 for nonpregnant women, and 0.86 for males (log rank P = 0.10). Poorer program retention was associated with higher WHO stage (III or IV) at baseline (P < 0.001), but not CD4+ cell count.
This study is one of the first to report on immunologic outcomes, mortality, and program retention for ART-eligible women starting ART during pregnancy. We demonstrate a robust CD4+ cell count response during the first 2.5 years of treatment comparable to, if not better than, nonpregnant adults. Furthermore, we report low mortality and high retention for all patients initiating ART. These findings are particularly important as national PMTCT programs evolve to prioritize the identification and treatment of eligible pregnant women with therapeutic ART . The MTCT-Plus Initiative has previously documented the benefit of ART use during pregnancy in reducing the risk of MTCT .
In pregnant women who initiated ART, the mean observed CD4+ cell count increased from 147 cells/μl at baseline to 370 cells/μl at 12 months and 451 cells/μl at 30 months of follow-up. A similar, although less steep, trajectory was seen in nonpregnant women, whereas men initiating ART had a significantly smaller response over time reaching a mean CD4+ cell count of 300 and 349 cells/μl at 12 and 30 months, respectively. These findings are similar to other studies [3,4,39,40] in Africa demonstrating good immunologic response to ART. The Antiretroviral Therapy in Lower Income Countries (ART-LINC) collaboration found a median CD4+ cell count rise from 108 to 442 cells/μl after 60 months of treatment . Similarly, another multisite evaluation of Sub-Saharan treatment programs found that CD4+ cell count increased from 114 to 372 cells/μl at 3 years . Thus, our results suggest that the CD4+ cell count response to ART initiated during pregnancy is similar to the response of other nonpregnant adults.
CD4+ cell count, as well as WHO stage at start of ART, have consistently been identified as important determinants of response to therapy [27,42,43]. In this cohort, in addition to baseline CD4+ cell count, sex and pregnancy status, age, and country of enrollment were also associated with immunologic response. Median baseline CD4+ cell count for our cohort was notably higher than what many studies reported in the literature from similar settings, likely reflecting the programmatic mandate of MTCT-Plus to enroll pregnant and postpartum women and their HIV-infected partners [33,44]. Women with severe immunodeficiency or WHO stage 4 disease are less likely to become pregnant . Baseline CD4+ cell counts for nonpregnant women were somewhat higher than pregnant women in our cohort, but we hypothesize that this may be due to hemodilution, which occurs during pregnancy [46–48]. Also, women previously exposed to SD-NVP for PMTCT were analyzed as treatment-naive. Prior exposure to NVP has been demonstrated to reduce the likelihood of achieving viral suppression during subsequent treatment with an NNRTI-based regimen, particularly if started within 6 months of delivery . Clinical and immunologic outcomes appear to be less directly impacted by previous exposure, particularly when treatment is initiated later beyond delivery [50–52]. Although the median time of ART initiation in the postpartum cohort was 11 months, previous NVP exposure may have impacted early and long-term CD4+ outcomes, blunting the response in those women with more proximal exposure. By comparison, the cohort of men had significantly lower CD4+ cell counts at treatment initiation, which likely contributed to their muted immunologic response [53,54].
The country of enrollment was strongly associated with CD4+ cell count response over time (P < 0.001). Although all the sites used the same treatment protocols, some sites faced programmatic challenges such as staff retention, staff education/training, and effective execution of patient adherence protocols. Some sites were able to utilize additional resources within their clinic/institution to support adherence. Further, there may have been biological differences such as viral subtype, host factors, or underlying opportunistic infection rates that may have influenced the CD4+ cell response rate. It is unclear which, if any, of these site-level factors influenced CD4+ cell count over time, but it suggests that program and facility-level factors may play an important, independent role in influencing patient outcomes.
We noted lower mortality rates in our population of adults initiating ART as compared with other studies in the literature. Most programs have reported higher mortality rates, 5.5–9.7 per 100 person-years of follow-up, during the first few months of treatment attributed to the highly advanced disease status of many of the patients [16,55,56]. In comparison, there were only 17 documented deaths among women initiating ART during pregnancy (1.5 per 100 person-years), 34 deaths among nonpregnant women (1.7 per 100 person-years) and 26 deaths among men (2.4 per 100 person-years) in this cohort. Overall retention in care was high: 82% for pregnant women, 86% for men, and 87% of nonpregnant women at 30 months of follow-up. The healthier status of MTCT-Plus patients likely contributed to lower mortality risk and high retention rates, as it has been noted that a significant percentage of patients LTF in most cohort studies [30–32] have died. In addition, the MTCT-Plus model of care emphasized psychosocial support and adherence to care and treatment as critical components of the program. Sites supported through the MTCT-Plus Initiative were relatively well resourced with high provider–patient ratios and access to a wider range of supportive services.
This study has several strengths. Sites followed standardized MTCT-Plus protocols, received standardized MTCT-Plus training prior to start-up, and used standardized data collection forms. Furthermore, most patients initiated NNRTI-based ART, primarily with NVP, resulting in a relatively homogenous treatment population.
However, the study had several limitations. The data were derived from a clinical care program rather than a research study. Thus, there may have been variability across the program CD4+ cell counts, as measurements were done in local laboratories.
Another limitation is that the analysis of CD4+ cell count response to ART was limited to individuals with a baseline and at least one follow-up CD4+ cell count measurement. Thus, individuals who were at highest risk for poor outcomes were excluded from the analysis, either due to early death or their inability to return for follow-up visits. Those patients not included did not significantly differ from the analyzed cohort by baseline CD4+ cell count or sex, pregnancy-status, age, WHO stage, education, employment, or housing conditions. Further, these individuals were captured in the analysis of retention rates.
In summary, we have demonstrated that pregnant women as well as nonpregnant women and male partners who initiated first-line ART had excellent CD4+ cell count response and high retention in care during the first 2.5 years of follow-up. These findings lend support to the WHO recommendations for RLCs, which suggest initiation of ART in pregnant women if they are eligible for treatment .
Funding for the MTCT-Plus Initiative was provided by the Bill and Melinda Gates Foundation, the William and Flora Hewlett Foundation, the Robert Wood Johnson Foundation, the Henry J. Kaiser Family Foundation, the John D. and Catherine T. MacArthur Foundation, the David and Lucille Packard Foundation, the Rockefeller Foundation, and the Starr Foundation.
MTCT Plus Initiative: ACONDA FSU and Abobo clinics, Cote d'Ivoire (Dr Siaka Toure); Moi University College of Health Sciences Clinics, Kenya (Drs Robert Eintez and Joseph Mamlin); Nyanza Provincial General Hospital Clinic, Kenya (Dr Juliana Otieno); Treatment and Research AIDS Center, Rwanda (Dr Anita Assimwe); Cato Manor Clinic of UKZN, South Africa (Dr Anna Coutsoudous); Langa Health Clinic of Western Cape, South Africa (Dr Ivan Toms); Perinatal HIV Research Unit of University of Witswatersrand, South Africa (Dr James McIntyre); Thai Red Cross Clinic, Thailand (Dr Praphan Phanuphak); MU-JHU Cares Clinic, Uganda (Dr Philippa Musoke); St. Francis Hospital Clinic, Uganda (Dr Pius Okong); and Mtendere and Chelstone Health Clinics, Zambia (Dr Elizabeth Stringer).
P.T. was the primary writer of the manuscript and led the analysis. M.K. was the analyst/statistician. She reviewed and edited the manuscript. R.C. revised drafts and gave input throughout the analytic phase. W.E.-S. edited the manuscript and gave input throughout the writing process. L.M. edited the manuscript and gave specific input into issues of HIV treatment during pregnancy. D.N. advised during analysis. E.A. gave extensive editorial support and advised throughout the analysis.
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