This analysis shows that pregnant women who are referred to an adult ART service for treatment initiation may face significant delays in initiating ART. As a result of these delays, a sizable proportion of women in this setting did not initiate ART before delivery. Among women who did initiate ART during the antenatal period, there was substantial variability in the delays from women’s first screening at the ART clinic to starting therapy, but the duration of systemic delays before ART initiation was not associated with improved patient outcomes on treatment. Given the urgency of ART initiation in pregnancy to prevent vertical HIV transmission, these data have important implications for the design of ART services for eligible pregnant women.
The median delay from screening at the ART clinic to ART initiation was 21
days (IQR, 14–29). When coupled with a median gestation at screening of 27
weeks, most women received 8
weeks or less of therapy prior to delivery. While the duration of ART required in pregnancy to achieve viral suppression is influenced by pre-ART viraemia and the antiretroviral drugs used, most studies show that at least 12–20
weeks of therapy is required to achieve viral suppression in most women and in turn minimize the risk of vertical HIV transmission [9
]. Following from this, while we did not measure viral suppression at delivery or infant HIV outcomes as part of this routine service, it is likely that a proportion of the women had significant viraemia and, therefore, were at increased risk of HIV transmission at the time of delivery [21
Here we analyzed the delay from screening to initiation of ART as a proxy for the time available for patient preparation before starting therapy. This delay may influence patient preparation in two related ways. First, increased time before starting ART provides time for formal patient counseling sessions, as group counseling sessions take place at regularly scheduled intervals each week at the ART clinic. Second, it is possible that some period of time before ART initiation may be useful to help some patients adjust individually to the need to start lifelong therapy, as ART initiation is accompanied by psychosocial stressors related to HIV stigma and disclosure, and may be particularly complex in the context of pregnancy [22
]. It is important to note that the delay variable used here cannot distinguish these two constructs, and we do not have measures of the number of counseling sessions attended nor any markers of patients’ perceived readiness to initiate therapy. Nonetheless, the overall delay between screening and ART initiation is a useful indirect measure of both phenomena in combination.
Although delays from ART screening to initiation limited the total duration of ART received before delivery, these data suggest that there was no apparent benefit to these delays on maternal outcomes. Levels of retention in care appeared relatively low but viral suppression was relatively high among those retained. However neither of these outcomes varied according to the length of delay from screening to ART initiation. This finding is in keeping with the general literature on patient preparation before ART initiation: while there are hypotheses that delaying ART initiation for patient preparation contributes to improved outcomes [15
], there are few empirical data that support these hypotheses [18
]. In the absence of such an association, the benefits of delaying ART initiation in pregnancy for adherence preparation and counseling are unclear.
This is one of the first studies to investigate the impact of systemic delays before ART initiation during pregnancy on ART outcomes. There are other populations of HIV-infected individuals in which systemic delays to ART initiation contribute to avoidable morbidity and mortality, including adults with advanced immunosuppression [24
], individuals with tuberculosis [25
], and perinatally-infected infants [26
] (although there are other clinical situations in which rapid ART initiation may lead to clinical deterioration [27
]). In each of these groups, observational evidence followed by definitive randomized controlled trials has shown that the risks associated with delayed ART initiation are outweighed by the benefits of expedited therapy. Timing of ART initiation in pregnancy is quite different from these examples, however: HIV-infected pregnant women are usually relatively healthy; the short-term benefits of rapid ART initiation are primarily in reducing transmission risk; and the principle threats to the retention of pregnant women on ART may be loss to follow-up and inadequate adherence rather than morbidity and mortality. In this light, while these results could be interpreted to support a ‘test-and-treat’ approach to ART in pregnancy [28
] - where all HIV-infected pregnant women are initiated on ART immediately, regardless of clinical or immunological status – these findings should be interpreted with care. In particular, the data come a group of women with relatively low CD4 cell counts (median, 142 cells/μL) attending a single, relatively large ART clinic in South Africa. The results may not be generalizable to other geographic settings and populations of pregnant women, and there is a clear need for additional investigation of any ‘test-and-treat’ approach to manage HIV in pregnancy.
The findings reported here should be viewed in light of several important limitations. Because information was taken from a retrospective review of patient records, we do not have available several measures of interest, in particular data on deliveries, neonatal health, and infant HIV testing outcomes. In addition, women commonly arrived at the ART clinic having taken zidovudine PMTCT prophylaxis for several weeks, clouding the interpretation of ‘baseline’ pre-ART viral loads. After ART initiation, viral load testing was conducted according to women’s duration on ART and there was not viral load testing at the time of delivery; thus we have little insight into the overall proportion of women who achieved viral suppression by delivery. Moreover we do not have detailed information on the precise reasons why ART initiation was expedited in some women and delayed in others: if the reasons underlying the length of this delay are associated with women’s outcomes on ART, this may represent an important, unmeasured confounding factor. Such confounding by indication is commonplace throughout clinical research [30
], including studies of the timing of ART initiation [31
], and can only be comprehensively addressed through randomized studies [32
Despite these limitations, this study has important implications for services to initiate ART in eligible pregnant women. There are well-established risks associated with delaying ART initiation in pregnancy, in terms of vertical transmission of HIV [10
] as well as maternal morbidity and mortality [33
]. While a potential benefit associated with delayed ART initiation has been suggested in terms of improved maternal outcomes on treatment (due to increased time for patient preparation), these data suggest no such benefit. In turn, the need to expedite ART in pregnancy is likely to outweigh the putative benefits of delaying therapy for patient education. Although patient education and counseling is a critical part of ART initiation, the usefulness of delaying ART until after patient education and counseling is complete is unclear. This points in turn to the need for strategies to initiate ART as quickly as possible in the context of pregnancy, but few models for this exist, and any intervention strategy must address the multiple factors that combine to delay ART initiation in pregnancy [34