Once Initiated Haart Therapy Should Be Continued
Introduction
Although not the only factor [1], maternal HIV cell-free viral load is a major predictor of mother-to-child transmission of HIV. In the pre-HAART era, a number of studies examined the relationship between HIV transmission rates in nonbreastfeeding women and viral load. In the Women and Infants Transmission study (WITS), no transmissions were documented among women with a viral load of less than 1000 HIV RNA copies/ml, whereas rates of more than 60% were seen in untreated women with viral loads more than 100 000 copies/ml [2]. Other studies returned similar data, except that transmissions at less than 1000 copies/ml were documented with a rate of 5% reported in a meta-analysis [3]. Zidovudine monotherapy (ZDVm) reduced this risk by 67% regardless of viral load [4], whereas the combination of ZDVm and prelabour caesarean section (PLCS) achieved 1% transmission risk [5]. This has led to the widespread use of PLCS as part of prevention of mother-to-child transmission (PMTCT) strategies across western Europe [6], even as HAART became widely recommended for PMTCT. Whereas the additional benefit of PLCS persists even with maternal viral loads less than 400 HIV RNA copies/ml [7], national data from the UK and Ireland demonstrate that when treatment with HAART results in a viral load less than 50 HIV RNA copies/ml by the time of delivery, the risk of transmission is as low as 0.1% (3/2117) [8]. In women on HAART, no difference in transmission was seen with PLCS (0.7%) compared with planned vaginal delivery (0.7%). During this period (2000–2006), British HIV Association guidelines recommended PLCS unless maternal viral load was less than 50 HIV RNA copies/ml [9,10]. North American guidelines allow for a vaginal delivery if HIV viral load is less than 1000 copies/ml [11]. In either setting, achieving this threshold is essential to ensure both low rates of HIV transmission and the safe option of an intended vaginal delivery. Although some HIV-infected pregnant women have conceived on HAART, a significant proportion initiate treatment during pregnancy, primarily to reduce the MTCT risk and the recommendations for when HAART is initiated vary from 10–12 weeks [11] to by 28 weeks gestation [12]. Given that the recommended mode of delivery is substantially influenced by maternal viral load at the time of delivery, we here address the question of timing and type of antiretroviral therapy to achieve either target viral load to confidently allow vaginal delivery and demonstrate that therapy should be tailored to the patient.
Methods
A retrospective cohort study included data on all HIV-positive women commencing HAART during pregnancy, whether as short-term highly active antiretroviral therapy (START) for PMTCT or for maternal health with the intention of continuing after delivery, and delivering between January 2000 and March 2009, at one of five centres. The five centres (four from London and one from Brighton, UK) were chosen as they are HIV tertiary referral centres with a high HIV MTCT caseload and are members of the London HIV Perinatal Research Group. HAART was defined as at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), in combination with either a boosted protease inhibitor, a nonnucleoside reverse transcriptase inhibitor (NNRTI), or a third NRTI. As regimens containing unboosted protease inhibitors are no longer recommended in the UK, these were excluded.
Data were extracted from clinical, pharmacy, and pathology databases, as well as medical note review. Data from separate sites were linked using unique completely anonymized identifiers and combined into a single database for analysis. Data collected included age, ethnicity, gestation at initiation of HAART, HIV clade, and resistance mutations (major protease inhibitor, NRTI, and NNRTI mutations according to the Stanford database), hepatitis co-infection, transmission category, previous use of HAART, choice and timing of HAART, baseline CD4 cell count, baseline HIV viral load and delivery viral load, and date of delivery. All laboratory data were obtained from Clinical Pathology Accredited diagnostic laboratories and the HIV viral load assays all had a lower limit of detection (LLD) of 50 HIV RNA copies/ml plasma or less. Data on delivery viral loads were analysed with two cut-offs: less than 50 and less than 1000 copies/ml.
Time since starting HAART until actual date of delivery for each of the outcomes (viral load <50 and <1000 copies/ml) was estimated using survival analysis and in patients who did not achieve the outcome data were censored at date of delivery.
Kaplan–Meier plots were used to explore associations between baseline HAART viral load values grouped into quartiles and time to viral load less than 50 copies/ml. In addition, viral loads were also grouped into four strata that were clinically defined. The log–rank test was used to test for differences in time to viral load less than 50 copies/ml in viral load quartile groups.
Quantitative variables were categorized using quartiles and where necessary separate categories with missing data were created, so that no degrees of freedom were lost when building multivariable models.
Associations between prognostic variables that were grouped using quartiles and viral load less than 50 copies/ml were assessed using test for trend across the quartile-grouped categories.
For each outcome, univariate Cox's proportional hazards model was used to assess associations between prognostic or confounding variables and each of the outcomes. All variables found to be significant in univariate Cox's proportional hazards model (P < 0.15) were then selected to build a multivariable model. Cox's proportional hazards multivariable model presented shows significant independent predictors of each of the outcomes after adjusting for prognostic, confounding, and/or residual effects of variables. Tests of interactions between co-variables were performed and, where significant interactions were found between co-variables, these have been discussed in the text. The final multivariable model(s) presented have been tested for proportionality assumption using the Schoenfeld test. All data analyses were performed in SAS version 9.1.3 (SAS Institute Inc., Cary, North Carolina, USA) and all P values presented are two tailed.
Results
Of the 439 eligible women at the participating centres, 378 had sufficient data to be included in the analysis. Their demographics, which did not differ from those excluded, are shown in Table 1. The median age at conception was 30 years (range 14.7–49.8) and 70.9% were of black African ethnicity. Resistance and subtyping information was only available for 266 of 378 (70.3%) and 263 of 378 (69.6%) of women, respectively, as this was not a routine investigation at the start of the study period. Only 33 (8.7%) were infected with clade B HIV, the predominant subtypes being C (22.5%) and CRF_02_AG (18.3%). Nineteen (5%) of women had resistance-associated mutations prior to initiation of HAART. Ninety women (23.8%) had been treated with antiretroviral therapy before this pregnancy. Median pretreatment viral load was 8243 HIV RNA copies/ml [interquartile range (IQR) 2341–32 640] and median CD4+ lymphocyte count was 330 cells/μl [3] (IQR 195–470). The baseline characteristics of the 378 women included in the study are shown in Table 1. The median gestational age at initiation of HAART was 23.3 weeks (IQR 20.4–26.3, range 1–39 weeks).
Baseline characteristics and demographics of study women.
Overall, 292 (77.2%) women achieved a documented viral load less than 50 copies/ml by delivery. The effect of baseline viral load on the proportion of women remaining with a detectable viral load over time on HAART for the different viral load strata is shown in Fig. 1. The relationship between baseline viral load and the proportion of women reaching this viral load was highly significant.
Log–rank survival plot showing viral load (VL) less than 50 copies antepartum.
In univariate analysis, age, clade, ethnicity, genotypic resistance, injecting drug use, previous HAART, and hepatitis co-infection were not significantly associated with achieving a viral load of less than 50 copies/ml. Baseline CD4+ lymphocyte count was associated with achieving this target in univariate analysis. Baseline CD4+ lymphocyte counts in the lower quartile (<195 cells/μl) resulted in 69% less than 50 copies/ml by delivery compared with 85% of those in the upper quartile (>470 cells/μl) [hazard ratio = 2.5; 95% confidence interval (95% CI) 1.8–3.49; P < 0.01]. The results of univariate analysis are shown in Table 2.
Univariate Cox's proportional hazards regression model showing likelihood of antepartum undetectable since HAART initiation.
Univariate Cox's proportional hazards regression model showing likelihood of antepartum undetectable since HAART initiation.
Multivariate Cox's proportional hazards regression model adjusted for injecting drug use, age at conception, ethnicity, baseline CD4 cell count, gestation at initiation, and whether regimen was START or intended to continue showed baseline viral load impacted on the likelihood of achieving a viral load less than 50 and less than 1000 copies/ml by the time of delivery. Baseline viral load was also associated with the likelihood of achieving less than 50 copies/ml by 36 weeks gestation, the time when decisions around mode of delivery are often finalised (Table 3). The significant effect of increasing viral load on the probability of achieving an acceptable threshold remains.
Multivariable Cox's proportional hazards regression model for achieving viral load less than 50 copies/ml by delivery and 36 weeks of gestation, and viral load less than 1000 copies/ml by delivery.
Furthermore, assessment of the data by baseline viral load grouped into clinically defined strata and by gestation at initiation of HAART showed that when baseline viral load is less than 10 000 copies/ml, the gestational age at initiation of HAART is unlikely to affect success up to 26.3 weeks gestation; however, when viral load is more than 10 000 copies/ml, then deferring HAART past 20.4 weeks is significantly associated with a reduced likelihood of reaching the target by delivery (P = 0.011). When baseline viral load was more than 100 000 copies/ml, the likelihood of reaching a viral load of less than 50 copies/ml was low (37%: hazard ratio 0.31) even if HAART was started before 20 weeks gestation (Table 4). Of the 43 women who commenced HAART with a viral load of more than 100 000 copies/ml, those who achieved a viral load less than 50 by delivery initiated HAART at median of 17.7 weeks, compared with those not reaching an undetectable level of 22.5 weeks. When baseline viral load grouped into unbiased quartile grouped strata was analysed, 87% of the women in the lower three quartiles (<32 640 copies/ml) achieved less than 50 copies/ml by the time of delivery compared with only 46% in the upper quartile (P < 0.01).
Likelihood of viral load less than 50 copies/ml by delivery at different gestations of initiation of HAART as demonstrated by hazard ratio.
Finally, multivariate Cox's proportional hazards regression model showed the choice of therapy was significantly associated with the proportion of women reaching a viral load less than 50 copies/ml delivery. Overall boosted protease inhibitor therapy (n = 246) resulted in 80% less than 50 HIV RNA copies/ml compared with 72% of those using NNRTI-based therapy (n = 129). The hazard ratio for NNRTI-based HAART compared with protease inhibitor-based HAART was 0.7 (95% CI 0.52–0.94; P = 0.016). In all but one case, nevirapine was the chosen NNRTI. Lopinavir/ritonavir was the most common boosted protease inhibitor prescribed (n = 171, 70%), followed by saquinavir/ritonavir (n = 67, 27%) and atazanavir/ritonavir (n = 8, 3%). In those women (n = 96) starting HAART in the earliest quartile of gestation (prior to 20.4 weeks), 49 commenced protease inhibitor-based therapy and 47 NNRTI-based therapy.
Discussion
The results from our study indicate that, for women with a viral load of more than 10 000 copies/ml and especially for those with a viral load of more than 100 000 copies/ml, the probability of achieving targets of either less than 50 or less than 1000 copies/ml by the time of delivery is compromised by delaying initiation of START beyond 20.4 weeks gestation. Women with viral loads less than 10 000 copies/ml should commence START by 26.3 weeks to optimize the probability of successful therapy. Viral load at initiation of HAART was the most important determinant of achieving an undetectable viral load by delivery, and the worst outcomes were seen in the uppermost viral load quartile of more than 32 000 copies/ml. British guidelines currently recommend commencing START between 20 and 28 weeks [13] and the median starting gestational age in the UK and Ireland cohort 2000–2006 was 25.6 weeks (IQR 22.4–28.9) [8]. Other national and international guidelines provide similar recommendations for the initiation of START. The German–Austrian guidelines 2008 update recommend 28 weeks [12]. The European AIDS Clinical Society recommend week 28 [14], or earlier if the viral load is high, although how early is not specified. The World Health Organisation recommends commencement of START, where available, by week 28, whilst recognising possible benefits of reduced MTCT with earlier treatment [15]. These data may be particularly relevant when the availability of PLCS is limited. Our study suggests that in terms of achieving an undetectable viral load by delivery, several guidelines may not afford women commencing START enough time to reach this goal. In contrast, the USA DHHS 2010 guidelines recommend initiating START at between 10 and 12 weeks gestation regardless of HIV viral load [11].
The timing of START in pregnancy requires careful consideration. Despite reassuring safety data with first exposure in any trimester [16], it is generally considered prudent to minimize foetal drug exposure. Tolerance of HAART may be impacted by nausea and vomiting in pregnancy and time to adjust to newly diagnosed infection and make informed choices is also desirable. These data suggest that women with a HIV viral load less than 10 000 copies/ml can reasonably delay START to 26.3 weeks without compromising the probability of achieving an undetectable viral load by delivery. However, some studies, such as a French case–control study of transmissions in women with a low delivery viral load, have suggested that delayed START may result in early in-utero transmission, particularly in women with high baseline viral loads [17]. The USA DHHS perinatal guidelines September 2011 amendment acknowledges these data, recommends early commencement of HAART if the viral load is high, and further suggests that early and sustained virological control is likely to reduce the risk of transmission in all women [11]. Furthermore, it is clear that the speed of viral decay is not the same for all HAART regimens. In particular, integrase inhibitors such as raltegravir have been shown to produce more rapid virological control than comparative NNRTI regimens [18]. They may therefore be an attractive option for PTMCT, particularly in women with high viral load or late gestational presentation if safety can be assured.
The European Collaborative Study group examined the time to an undetectable HIV viral load in 240 pregnant women starting HAART at median of 23 weeks gestation (IQR 18–27) [19]. Overall 73% of women achieved a viral load less than LLD, but this could have been less than 50 or less than 400 copies/ml depending on the assay used. They also found that baseline viral load was a predictor of the speed of achieving viral suppression by delivery. Up to 50% of those with a baseline viral load more than 100 000 copies/ml and 70% of those with a baseline viral load more than 10 000 copies/ml achieved a viral load less than 400 copies/ml by delivery. Their data did not find a difference between NNRTI and protease inhibitor regimens in terms of successful treatment, but did find that the time to undetectable viral load was shorter in the NNRTI group, particularly if the baseline viral load was more than 10 000 copies/ml. Our data showed slightly more success overall in the protease inhibitor arm. The major differences between the ECS and our data are that all our patients on a protease inhibitor regimen were taking a ritonavir-boosted protease inhibitor, and the LLD of our assays was uniformly 50 copies/ml or less.
A more recent analysis of the WITS cohort examined outcomes from 1998 to 2005 in 630 HIV-1-infected women commencing HAART in pregnancy [20]. Again, the LLD of most assays used was less than 400 copies/ml, and two thirds of the cohort were treated with the unboosted protease inhibitor nelfinavir, which is now difficult to access and not routinely used. Overall 48% of women with detectable virus initiating HAART during pregnancy still had a detectable (>400 copies/ml) viral load at delivery, although this is not stratified for gestational age at initiation of HAART. They found an increase in the likelihood of detectable HIV at delivery with increasing baseline viral load, with an adjusted hazard ratio of 1.35–1.52 for every log10 above 400 copies/ml. An association with the type of HAART regimen was not supported in multivariate analysis.
Limitations of our study are that it is both retrospective and observational, and we were unable to obtain sufficient reliable data on drug adherence and therapeutic drug levels. As with any nonrandomized study, we cannot exclude confounding from factors not considered in our analysis. Furthermore, for some stratifications of viral load and gestation at initiation of HAART, the absolute numbers in some subcategories are relatively small, for example, only 96 patients commenced HAART prior to 20.4 weeks gestation. Nonetheless, this is one of the largest studies investigating the likelihood of achieving a viral load less than LLD by the point of delivery, and has the advantage of using contemporary regimens and viral load assays.
With the increasing trend to advocate for vaginal delivery in HIV-positive pregnant women, regardless of the viral load cut-off used for this recommendation, the data from this study and both the ECS and WITS cohorts suggest that a significant proportion of women do not reach these targets, especially if the baseline viral load is high. Our study further defines these groups and provides information detailing the effect of gestation at initiation of HAART.
HAART commenced during pregnancy, which is most effective as part of widespread HIV antenatal screening at a population level, has markedly reduced the rates of MTCT of HIV when freely available. Increasingly, with wider worldwide access to HAART, many women will be using this as part of a START regimen, but often in settings when a caesarean section is not a viable option. Whether adhering to USA DHHS guidelines [11], which do not attribute further risk reduction to caesarean section if the viral load on HAART is less than 1000 copies/ml, or the British HIV Association Guidelines [13], which currently recommend a more stringent cut off of less than 50 copies/ml, it is clear that HAART must be commenced with sufficient time to reach these goals if vaginal delivery is likely or intended.
We conclude that women with a viral load of more than 10 000 copies/ml should commence HAART by 20.4 weeks, and women with a viral load of more than 100 000 should start HAART without delay. In women with a viral load less than 10 000 copies/ml an undetectable viral load should be achieved by delivery provided START is not deferred beyond 26 weeks gestation. However, this should be balanced against the possible increased risk of in-utero transmission with a delayed start, or the risk of transmission should premature rupture of membranes occur prior to the commencement of therapy in a pregnancy where the gestational age of the fetus is compatible with survival. Current UK and other guidelines for when to commence START may therefore limit the chance of vaginal delivery. If the current trend for vaginal delivery is maintained, we suggest guidelines take these data into account when recommending the timing of START.
Acknowledgements
Conflicts of interest
Comprehensive Biomedical Research Centre support at Imperial College Healthcare NHS Trust (G.P.T.).
P.J.R. has received travel and conference expenses from MSD, BMS, ViiV, and Tibotec. D.H. has received honorarium for presentations, lectures, and travel from BMS and Janssen. Y.G. has received honoraria for lectures and presentations by Gilead, Janssen, MSD, BMS, and ViiV. J.A. has received consultancy fees from Gilead, Abbott, BMS, and Johnson and Johnson. G.P.T. has received consultancy fees from the WHO, and a research grant from Abbott. A.d.R. has received consultancy fees from BMS, and honoraria for lectures from BMS, Janssen, and MSD. C.N. has received conference registration from ViiV. P.K., U.H., and S.M. have no conflicts of interest to declare.
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Keywords:
HAART; HIV; mother-to-child transmission; pregnancy; treatment; viral load
Source: https://journals.lww.com/aidsonline/Fulltext/2012/06010/When_should_HAART_be_initiated_in_pregnancy_to.5.aspx
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