To assess maternal disease progression over time, we used the Kaplan–Meier method to estimate the cumulative proportion of mothers who progressed to 1 of 4 surrogate disease end points at 6 and 12 months postpartum. Two of the end points described CD4+ lymphocyte decline from baseline at delivery: time to (1) CD4+ lymphocyte counts below 200 cells per microliter and (2) CD4+ lymphocyte counts below 350 cells per microliter. Women were censored at the time of ART initiation. The other 2 end points described progression to clinical AIDS or death from 6 weeks postpartum: (3) WHO clinical stage III or IV or death and a combined end point of (4) WHO clinical stage IV, CD4+ lymphocyte count below 200 cells per microliter, or death. Mothers were excluded from the analysis of the first 2 end points if they had delivery CD4+ lymphocyte counts below 200 and 350 cells per microliter, respectively, whereas the third analysis excluded those mothers who were stage III or IV at 6 weeks postpartum or who had started ART before 6 weeks; and finally, the fourth analysis excluded those mothers who were stage IV at 6 weeks, had taken ART before six weeks, or had CD4+ lymphocyte counts below 200 cells per microliter before 6 weeks. For the combined end points, 3 and 4, time to event was calculated as the minimum event time if a mother had more than one of the qualifying outcomes. For the third end point, women were censored at time of ARV initiation after 6 weeks or at the last visit through 12 months postpartum if they did not die or progress to WHO stage III or IV. For the fourth end point, women were censored at the time of ARV initiation after 6 weeks postpartum or at last CD4+ measure above the threshold of 200 cells per microliter through 12 months postpartum if they did not die or progress to WHO stage IV. Because ARV initiation is likely to be informative, a combined end point analysis was also performed where the time to event was the minimum visit in which the above thresholds (points 1–4) were crossed or ARV treatment was initiated. All participants in whom the end point was not observed were censored at their last visit time. Maternal death incidence was calculated by dividing the number of deaths by the total person-years through 12 months of follow-up and stratified by CD4+ lymphocyte counts at delivery.
From February 2007 to March 2010, 2025 women enrolled into HPTN 046, including 1430 (70.7%) with CD4+ lymphocyte counts above 350 cells per microliter (Table 1). WHO clinical staging was available at 6 weeks postpartum in 1945 women; 1855 (96%) were stage I or II. Women without WHO clinical staging at 6 weeks had similar demographic characteristics and baseline CD4+ lymphocyte counts compared with those with staging (data not shown). Twenty-eight percent of the women received triple ART regimens during pregnancy. Other baseline characteristics are summarized in Table 1.
Maternal disease progression rates both with censoring at ARV initiation and with ARV initiation included in the end point are summarized in Table 2. Among women who had CD4+ cell count results available at delivery and postpartum sampling (Table 2), 16 (4.3%) of those with counts between 350 and 549 cells per microliter dropped to below 200 cells per microliter by 1 year compared with 10 (1.6%) of those starting above 549 cells per microliter (Fig. 1A). Among women who had a CD4+ lymphocyte count between 400 and 549 cells per microliter at delivery, 116 (37%) dropped under 350 cells per microliter by 1 year after delivery, whereas 48 (7.4%) of those with a CD4+ cell count of ≥550 cells per microliter at delivery dropped below this threshold (Fig. 1B). When adding ARV initiation to the end point rather than censoring, rates of the end point of CD4+ count <200 cells per microliter or ARV initiation more than doubled for women with CD4+ counts between 350 and 549 cells per microliter but did not change appreciably for the end point including dropping to CD4+ count below 350 cells per microliter or for those starting above a CD4+ count of 550 cells per microliter (Figure 2). For women who started in stages I to III, 49 (4.3%) died or progressed to AIDS based on stage IV conditions or CD4+ lymphocyte count below 200 cells per microliter by 12 months after delivery, censoring for ARV initiation (Fig. 1C and D; Table 2). When including ARV initiation in the end point, 88 (7.7%) met the progression criteria. By 12 months, 83 (7.4%) women starting in clinical stage I or II progressed to stage III or IV, whereas 159 (13.4%) progressed to stage III or IV or initiated ARV. Of the 74 women initiating ARV by 12 months after delivery, 57 (77%) had nadir CD4+ lymphocyte counts below 200 cells per microliter before initiation, 10 (14%) were between 200 and 300 cells per microliter, and 7 (9%) remained above 300 cells per microliter. The reasons for initiation of ARV at higher CD4+ counts were not documented.
Twelve (1%) women who were not stage IV at their 6-week postpartum assessment developed 13 clinical stage IV end points by 12 months after delivery. These end points included 5 cases of extrapulmonary tuberculosis, 2 cases each of HIV wasting (>10% weight loss plus either unexplained diarrhea for over 30 days or chronic weakness and unexplained fever for over 30 days), Pneumocystis jiroveci pneumonia, and extrapulmonary cryptococcosis, and 1 case each of central nervous system toxoplasmosis and symptomatic HIV-associated nephropathy/cardiomyopathy. Sixteen (0.8%) of enrolled women died during the first year after delivery (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A443). Cause of death was unknown in 7 cases and had varied causes in the other 9. Only 1 of the 9 deaths (11%) with known causes was potentially secondary to an AIDS-defining condition and only 2 women who died had a CD4+ cell count below 200 cells per microliter at the visit before death. Maternal death rates per 100 person-years stratified by CD4+ lymphocyte count at delivery are shown in Table 3. The rates of death did not differ significantly by CD4 stratum, but number of events were low. Eleven (68.8%) of the deaths occurred among women with CD4+ lymphocyte counts over 350 cells per microliter at the visit before their death.
The pregnant and postpartum HIV-infected women enrolled to this trial were representative of the women seen at clinical research sites in sub-Saharan Africa7,8 and had a range of CD4+ lymphocyte counts at delivery, with 70% above 350 cells per microliter, the current threshold for initiation of ARV therapy in many countries.9 Less than 5% had stage III or IV disease at baseline, whereas 9% had CD4+ lymphocyte counts below 200 cells per microliter, suggesting that symptoms do not reliably indicate those most in need of ARV therapy. In addition, with the current CD4+ count threshold of 350 cells per microliter, symptoms will not identify many of those who need therapy.
Given the standard of care existing at the sites during the HPTN 046 trial, asymptomatic women with CD4+ lymphocyte counts above 350 cells per microliter did not meet WHO or country-specific criteria for ARV therapy. Within this context, we carefully monitored the women study participants for disease progression to initiate treatment if needed. This close follow-up also provided the opportunity to help inform future treatment recommendations. Women who were asymptomatic (WHO clinical stage I or II at baseline) had a relatively low risk (7.4%) of progressing to symptomatic HIV disease within 1 year postpartum, emphasizing the need for CD4+ lymphocyte testing to target therapy for those individuals at highest risk for disease progression in settings where universal treatment is unaffordable. Among women with CD4+ cell counts between 400 and 549 cells per microliter at baseline, 37% dropped to below 350 cells per microliter at 1 year, indicating a need for ARV therapy and suggesting that women in this range should be offered continuation of therapy after cessation of perinatal transmission risk. These findings are similar to data from the multicountry MTCT-Plus Initiative, which found that women stopping a variety of ARV regimens for prevention of perinatal transmission had a 46% risk of dropping below 350 cells per microliter by 24 months postpartum when the initial CD4+ cell count during pregnancy was 400–499 cells per microliter.10 A study from Haiti found that women stopping antiretroviral prophylaxis at delivery with a CD4+ lymphocyte count between 350 and 499 cells per microliter dropped to the threshold of 350 cells per microliter requiring therapy at a median of 19 months after delivery compared with a median of 71 months to reach this threshold among women with CD4+ cell counts at or above 500 cells per microliter at delivery.11 These data are also consistent with a study from Brazil, which showed that among women discontinuing ARV agents after delivery, the group with levels between 250 and 500 cells per microliter had a risk of progression to stage II or III events that was 2.5 times higher than women with CD4+ counts above 500 cells per microliter.12 The importance of CD4+ lymphocyte results for predicting progression were also shown in a study from Kenya demonstrating that CD4 counts and percentage during pregnancy were most predictive of mortality over the first 2 years postpartum compared with total lymphocyte count, hemoglobin, HIV RNA level, or body mass index.8
Among women in the 350–550 cells per microliter CD4+ lymphocyte group, continuation would also have benefits in reduction of heterosexual transmission to discordant partners. This conclusion is based on the results from a large randomized trial of discordant couples, which found that treating HIV-infected subjects with CD4+ lymphocyte counts between 350 and 550 cells per microliter reduced linked transmissions to partners by 96% as compared with delaying therapy until the CD4+ lymphocyte count drops below 250 cells per microliter or symptomatic illness occurred.3 Although earlier treatment at higher CD4+ levels above 550 cells per microliter may also reduce the risk of sexual transmission, the benefit in the group with higher counts has not been proven. Women beginning ARVs in pregnancy with CD4+ cell counts between 350 and 550 cells per microliter should be counseled about the potential benefit of reduced sexual transmission when they are considering whether or not to continue ARVs after delivery.
Intensive counseling for adherence to the regimen must be provided for women who choose to continue ARVs after cessation of mother-to-child HIV transmission risk, as adherence has been shown to decrease markedly once the incentive of transmission prevention has ended. A recent meta-analysis reported a pooled estimate of adequate adherence (>80% of doses) of 75.7% [95% confidence interval (CI): 71.5% to 79.7%] during pregnancy compared with 53.0% (95% CI: 32.8% to 72.7%, P = 0.005) during the postpartum period.4 This study included women from a range of low-, middle-, and high-income countries. Likewise, in several reports from African sites, HIV-infected women were at particularly high risk for loss to follow-up with ≥50% defaulting on their maternal child health appointments after delivery in some studies.13–16 Travel away from home to stay with family for several months after the birth of a child is common. In addition, many women have not disclosed their HIV status to partners or family members making adherence challenging, especially if residing with relatives.17 Poor adherence increases the risk of development of viral resistance and treatment failure.18 Concerns regarding development of resistance may be especially important, given the current WHO recommendations for efavirenz-based first-line therapies that require a single mutation for resistance.9 Clearly, support for adherence and follow-up after delivery will need to be intensified for women planning to continue ARV agents postpartum.
In our study, women with CD4+ lymphocyte counts of 550 cells per microliter or higher had a lower risk of disease progression with only 7.4% dropping below 350 cells per microliter and 1.6% below 200 cells per microliter by 1 year postpartum without ARVs. These results are consistent with data from the MTCT-Plus Initiative, which demonstrated that 18.5% of women with initial CD4+ cell counts above 500 cells per microliter during pregnancy progressed to counts below 350 cells per microliter by 24 months after delivery.10 The group of women with CD4+ cell counts above 550 cells per microliter would be expected to have a low risk of disease progression even with discontinuation of ARVs after pregnancy and breastfeeding, so could discontinue therapy if desired. These findings underscore the utility of CD4+ lymphocyte testing and suggest that in this group of women, more data are needed regarding the risks and benefits of continuing ARVs after risk of mother-to-child transmission of HIV has passed.
There is also a need for operational research that investigates better ways to achieve high levels of adherence to ARV drugs among both pregnant and postpartum women and to decrease loss to follow-up among HIV-infected pregnant women. In areas where implementation of universal treatment is currently not feasible for cost, supply, and logistic reasons, targeting therapy to groups at highest risk for disease progression and transmission to their infants based on their CD4+ cell counts remains necessary. Even with implementation of the strategy of starting lifelong therapy for all pregnant women, CD4+ lymphocyte testing may be helpful to target women with low CD4+ cell counts for increased support and provision of opportunistic infection prophylaxis. Events occurring among the postpartum women were rare but similar to those reported in the HPTN052 study discussed above, with deaths (0.8%) and extrapulmonary tuberculosis (0.2%) being the most frequent serious events in the current study.3 Causes of death were heterogeneous with only 2 cases occurring with proximate CD4+ lymphocyte counts under 200 cells per microliter and only 1 case (probable meningitis) likely AIDS defining. Other infections (malaria and hepatitis) and comorbidities (anemia, diabetes, pancreatitis, and cardiac failure) contributed to deaths, and some of these conditions may have been ameliorated by earlier ARV. Incomplete data on causes of death limit the conclusions that can be drawn.
Availability of ARV therapy for women with CD4+ lymphocyte counts below 200 cells per microliter in the current HPTN 046 study seems to have lowered the risk of death compared with earlier studies in similar populations. The HPTN 024 study, conducted among pregnant women in Malawi, Zambia, and Tanzania between 2001 and 2003, at a time when antiretroviral therapy was not widely available in those settings, reported death rates over the first year postpartum of 6.1 per 100 person-years among women with CD4+ lymphocyte counts below 200 cells per microliter at delivery, 1.1 per 100 person-years with CD4+ cell count of 200–500 cells per microliter, and 0.4 per 100 person-years for those with CD4+ cell counts over 500 cells per microliter. No deaths occurred among 331 HIV-uninfected women in the study.19 No ARV therapy was available to women after delivery in that study. In a retrospective review of a cohort of women delivering in Malawi in 2008 who received postpartum ARV therapy if they had WHO stage III or IV disease or CD4+ lymphocyte count below 250 cells per microliter, the mortality rate over 18–20 months postpartum was 4.24 deaths per 100 person-years among 173 consecutive HIV-infected women and 0 among HIV-uninfected delivering at the same sites.20
There are certain limitations to these findings including incomplete data on causes of death and lack of longer term follow-up. Data on the use of hormonal contraception are not available, but unlikely to have influenced the findings, based on data from Kenya among postpartum women that found no differences in CD4+ cell count or HIV RNA changes with use of hormonal contraceptives compared with no use.21 Despite these limitations, there are also a number of strengths of the HPTN 046 study including the large number of participants followed in 4 African countries and excellent retention that allowed careful monitoring of serial CD4+ lymphocyte counts and end point ascertainment over the first year after delivery. Because WHO and in-country guidelines in place during the study did not recommend ARV treatment for asymptomatic individuals with CD4+ cell counts above 200 cells per microliter, these data from HIV-infected women in the first year after delivery can help inform evolving guidelines about continuation of ARV after delivery.
Data from follow-up of the HIV-infected women enrolled to the HPTN 046 study are informative on the risk of disease progression among postpartum women in resource-limited settings. Women with CD4+ lymphocyte counts between 4000 and 550 cells per microliter in pregnancy had a 1 in 3 risk of progressing to indications for ARV therapy within 1 year of delivery based on the current WHO recommendations. Given these findings, this group of women should be counseled regarding the benefits of continuing ARVs after the need for ARVs for prevention of transmission is completed. Those who are interested in continuing ARVs should be provided with support for disclosure to family members, treatment adherence, and regular follow-up visits. Pending more data on long-term outcomes from ongoing trials, women with CD4+ lymphocyte counts above 550 cells per microliter could be presented with information regarding the potential benefits and risks of continuing ARVs and supported in their decision to stop or continue ARVs after the indication for prevention of mother-to-child transmission of HIV has ceased.
The authors thank the mothers and their children who participated in the study; the HPTN 046 study coordinators, counselors, clinicians, pharmacists, data quality and laboratory staff, and those responsible for recruitment and retention for their dedication and hard work on site; Thomas R. Fleming (University of Washington/Fred Hutchinson Cancer Research Center) for his contributions to study design and his strong support throughout study conduct; Scharla Estep (NIAID protocol pharmacist) for her help on pharmaceutical matters; and Avinash Shetty (Wake Forest University Health Sciences) for his contribution to study development and safety data review.
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HIV; postpartum; disease progression
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© 2013 by Lippincott Williams & Wilkins