HAART reduces HIV-related morbidity and mortality [1,2]. Guidelines for HAART [3,4] recommend that HIV-infected pregnant women initiate HAART not only because of low CD4 cell counts but also to diminish the probability of mother-to-child transmission (MTCT), with a goal of full suppression of viral replication before delivery . HAART during pregnancy has lowered vertical transmission rates to below 2% [6,7].
The physiological changes associated with pregnancy affect all four components of drug disposition: absorption, distribution, metabolism and excretion. In general, plasma drug levels are lower during pregnancy than postpartum [8–14]. However, it is unclear whether lower concentrations induce virologic failure, increase MTCT, or cause more frequent treatment changes. Complications of pregnancy may resemble adverse effects of antiretrovirals (ARV); for instance, glucose intolerance (common to pregnancy and indinavir), vomiting (pregnancy and several ARV such as lopinavir, ritonavir, zidovudine, tenofovir or lamivudine) and mitochondrial toxicity [possibly increased by pregnancy, and a well recognized side effect of nucleoside reverse transcriptase inhibitors (NRTI), in particular of the combination of didanosine and stavudine] [15–20].
In this study, we describe the frequency of virologic failures and treatment changes in pregnant and nonpregnant women and, within the same women, before, during and after pregnancy in the Swiss HIV Cohort Study (SHCS).
The Swiss HIV cohort study
The ongoing multicentric SHCS, which is described in detail elsewhere [21,22], includes data on more than 14 000 patients. About one third of them are women. At 6-monthly intervals, information on clinical data, laboratory values and ART is collected. The reasons for treatment changes are classified by the treating physician as ‘failure’, ‘intolerance’ and ‘other reasons’ (mainly patients' wish or physicians' decision). Since January 1997, pregnant women are asked to participate in the Swiss Mother and Child HIV Cohort Study (MoCHiV), a subcohort of the SHCS, which specifically focuses on pregnant women and their children. Information about medical events and laboratory data is collected at each visit during pregnancy and at delivery. HIV viral load is determined using the Roche Amplicor HIV-1 Monitor assay. HAART was defined as a prescription of at least three antiretroviral drugs. Written informed consent was given by all participants and ethical committee approval was obtained in each centre.
Selection of patients
A flow diagram showing the patient selection and different analyses is shown in Fig. 1.
All pregnancies with known dates of conception and birth dates between January 1997 and July 2006 were included in the study. Virologic failure and treatment changes during pregnancy were compared in separate analyses in women starting HAART before or during pregnancy.
Start of HAART before pregnancy
Women starting HAART without previous antiretroviral therapy and who were treated for at least 3 months before conception were analysed. For every woman only the last pregnancy was included. In an interindividual comparison, pregnancies were matched to controls. A maximum of two non-pregnant women were chosen at random among women of the same age range (16–40 years) who were also on HAART for at least 3 months at the time the woman became pregnant. Matching criteria were: HIV transmission group (injecting drug use versus other), HIV viremia (<50, 50–399, >400 copies/ml) and CD4 cell count (±100 cells/μl) at the date of conception of the corresponding pregnant woman.
In an additional intraindividual comparison, we determined for each pregnancy a period of equal length before and after pregnancy. Only time periods in which the woman had been on HAART for at least 3 months at the beginning of the periods were included in the analysis.
Start of HAART during pregnancy
Women starting HAART during pregnancy were compared with non-pregnant women from the SHCS starting HAART since 1997. Both groups were treatment naive. Non-pregnant women were of comparable age (16–40 years) and had started HAART with a regimen commonly used during pregnancy, that is, women starting with efavirenz were excluded.
Women's characteristics were compared using the Chi-square test for categorical variables and the Wilcoxon test for continuous variables.
For women starting HAART before pregnancy to first treatment change (overall and cause specific) were compared using the Kaplan–Meier method and log rank test. Follow-up was censored at the delivery or at the end of a time period of equal length in non-pregnant women. Virologic failure was analysed by random-effect logistic regression with the matched pair as random-effect variable. Virologic failure was defined as at least one HIV viral load for at least 1000 copies/ml. The number of viral load determinations was included as an explanatory variable into the model.
For women starting HAART during pregnancy we performed a multivariable Cox regression with treatment change as the outcome. The analysis was adjusted for HIV transmission group, age and calendar year of starting HAART (<2000, ≥2000). Time was measured from the start of HAART, pregnant women were censored at birth and non-pregnant women were censored at the maximum time between start of HAART and delivery in pregnant women. In a secondary analysis, we evaluated the percentage of pregnant women reaching HIV viral load values below 400 copies/ml at delivery. We used Stata software (Version 9.2; Stata Corp., College Station, Texas, USA) for all analyses and all reported P values are two-sided.
Patient characteristics and descriptive analysis
Since 1997, a total of 422 pregnancies were recorded in the SHCS. Of these, 50 pregnancies (11.8%) were excluded because information on the exact time and duration of the pregnancy was lacking, leaving 372 pregnancies in 324 women for analysis (Fig. 1). Characteristics of excluded and included women were similar (Table 1).
In the majority of pregnancies (n = 220, 59.1%) ART was started before pregnancy. The median duration of ART before conception was 36 months [interquartile range (IQR): 19–60 months]. Among the 145 women starting ART during pregnancy, 10 (2.7%) started in the first trimester, 100 (26.9%) in the second and 35 (9.4%) in the third trimester. Two thirds (n = 26) of the women starting ART in the third trimester were diagnosed with HIV during pregnancy. Seven women (1.9%) did not receive any ART during pregnancy: one had spontaneously undetectable viremia, three were diagnosed as HIV positive at delivery and did not receive intrapartum zidovudine (AZT) and for the remaining three women no reason was documented. Women without antiretroviral therapy during pregnancy were excluded from subsequent analyses.
Overall, 115 (31.5%) of 365 women on ART changed their treatment during pregnancy. The reasons for first treatment change were immunologic or virologic failure and intolerance for 13 women each (3.6%), other reasons (such as patient's wish and physician's decision) for 77 (21.1%) and unknown for 12 (3.3%) women.
Three children (0.8%) became infected with HIV, the last in 2002. One of their mothers received AZT monotherapy and two had started HAART only 1 month before delivery. Viral load values at delivery were 6388 copies/ml, 43 100 copies/ml and in the third case viral load was undetectable 1 week before delivery.
Women starting HAART before pregnancy: comparison with nonpregnant women
Of the 131 pregnant women fulfilling the inclusion criteria, five could not be matched because of missing information regarding the matching criteria. Matching was successful for 122 pregnant women with 228 controls (for 16 cases only one control could be identified and for four women no suitable control was available). Matching ensured that pregnant and non-pregnant women were similar with regard to HIV transmission group (21 versus 22% injecting drug users), CD4 cell count (median 503 versus 505 cells/μl) and RNA levels at the time of conception (75% <50 copies/ml, 8% between 50 and 400 copies/ml, and 17% ≥400 copies/ml in both groups). Duration of follow-up and duration of ART was also similar in pregnant and non-pregnant women (4.4 years versus 4.0 years and 3.4 years versus 3.7 years). Pregnant women tended to be younger (median 33 versus 36 years, P = 0.001). Pregnant women changed their HAART regimen more often (log rank P = 0.04). Overall, 52 (42.6%) of pregnant women compared with 73 (32.0%) of matched controls changed the treatment during the time period. This was explained by more frequent switches due to replacement of efavirenz. No difference was found for treatment changes because of failure (n = 9, 7.4% in pregnant women, n = 11, 4.8% in non-pregnant women, P = 0.3) and intolerance (n = 10, 8.2% compared with n = 27, 11.8%, P = 0.3). When patients on efavirenz at the beginning of pregnancy were excluded from the analysis, the frequency of first treatment change was comparable (n = 42, 37.5% versus n = 59, 36.4%, P = 0.75). The most frequent adverse events leading to treatment change were gastrointestinal toxicity (n = 7 in pregnant women vs. n = 4 in nonpregnant women), fat redistribution (n = 0 versus n = 8) and toxicity on the nervous system (n = 0 versus n = 5). The risks of virologic failure tended to be lower in pregnant than in non-pregnant women [adjusted odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.25–1.09].
Women starting HAART before pregnancy: women as their own controls
Three women not on HAART for at least 3 months were excluded from this analysis (Fig. 1). One hundred and twenty-eight women already on HAART at the beginning of pregnancy were included in this analysis. The frequency for all cause-specific treatment changes (results not shown) and the frequency of virologic failure during pregnancy were similar as compared with a period of equal duration before and after pregnancy (adjusted OR = 1.04, 95% CI = 0.48–2.28).
Women starting HAART during pregnancy
A total of 107 women starting HAART for the first time during pregnancy (Fig. 1) were compared with 578 treatment naive non-pregnant women starting HAART in the SHCS. The characteristics of the two groups are shown in Table 2. The majority of pregnant women had no immunological indication for starting HAART (55% with CD4 cell counts >350 cells/μl compared with 24% in non-pregnant women).
Pregnant women changed their treatment regimens less often than non-pregnant women during a follow-up period of similar duration (log rank P = 0.008). This difference remained significant in the multivariable analysis [adjusted hazard ratio (HR) 0.46, 95% CI = 0.26–0.80, P = 0.006]. Treatment change due to intolerance was less frequent in pregnant women (adjusted HR 0.42, 95% CI = 0.19–0.94), whereas changes because of failure were rare in both the groups (none in pregnant women versus 1.9% in non-pregnant women, P = 0.27). A great majority (n = 100, 93%) of women starting HAART during pregnancy reached values below 400 copies/ml before delivery.
In this study, we compared outcomes of HAART in pregnant and non-pregnant women enrolled in the SHCS. We found that neither the risk of virologic failure nor the frequency of treatment change because of toxicity or virologic failure were increased during pregnancy. Most treatment changes were because of the substitution of the potentially teratogenic drug efavirenz.
In a previous SHCS study, up to 30% of the patients presented with CD4 cell counts below 200 cells/μl and between 5 and 10% with values below 50 cells/μl between 2001 and 2005 . During pregnancy, late presentation is of special concern as plasma HIV viral load is the main risk factor for MTCT . However, the overwhelming majority (n = 100, 93%) of women who started antiretroviral therapy for the first time during pregnancy reached viral load values less than 400 copies/ml around delivery. This percentage is higher than in a recent collaborative study , in which 73% of women reached viral suppression by the time of delivery. Only three pregnancies (0.8%) resulted in MTCT; treatment start was late or suboptimal in all three. AZT remained the principal prescribed NRTI during pregnancy and was used in 93% of all women. AZT was the first substance to be widely evaluated in the prevention of MTCT and it is still used, on the basis of efficacy studies and extensive experience [26,27]. With the exception of a few children with mitochondriopathy after AZT or 3TC or both exposures in a French cohort , several studies demonstrated that AZT had no long-term negative effect in AZT-exposed children [29,30].
Comparison with non-pregnant women
The comparison with non-pregnant women did not show an increased risk of virologic failure during pregnancy. This is reassuring, as several studies have shown that the plasma concentration of some protease inhibitors is decreased during pregnancy [12,31,32]. As a result, it was speculated that the risk of viral resistance and virologic failure could be increased during pregnancy and that therapeutic drug monitoring should be used [3,4]. Unfortunately, we had no data about adherence and drug levels during pregnancy. We were, therefore, unable to analyse the reasons and impact of potentially lower drug levels on treatment failure. Two previous studies in the United States showed that adherence to treatment was higher in pregnancy compared with postpartum [33,34]. Better adherence might thus have counter balanced any effect of physiological changes in our study, and this might also be the reason why in the interindividual comparison the risk of treatment failure tended to be lower in pregnant women. We did not find differences in the number of toxicity-related treatment modifications. This may be interpreted as indicating that drug-related side effects are not increased during pregnancy. Alternatively, physicians may be more reluctant to change a treatment if there is a potential risk of treatment failure with a new regimen.
Women starting HAART during pregnancy
Women starting HAART for the first time during pregnancy change therapy less often than comparable non-pregnant women. In this situation, where the protection of the unborn child is of utmost importance, patients and physicians may not want to risk virologic failure by changing a ‘treatment that works’, despite minor side effects. The marked differences in baseline CD4 cell counts – much higher values in pregnant women – may also lead to fewer frequent treatment changes in pregnant women and was the reason why no comparable control group on the basis of matched CD4 cell counts could be identified. Other studies have shown a decreased frequency of treatment switches with higher CD4 cell counts . Of note, we did not adjust the analysis for CD4 cell counts. Viral response could not be compared in pregnant and non-pregnant women as the follow-up time during pregnancy was limited and most of the non-pregnant women did not have viral load measurements at comparable time points.
Strengths and limitations
The large number of women participating in the SHCS is an important strength of our study. The SHCS population is representative of HIV-infected people in Switzerland, especially those in the advanced stage of the disease [21,36]. Eighty-eight percent of all pregnancies in the SHCS were included in this study. The characteristics of the excluded and included women were similar.
Women who were treatment naive at conception were compared with similar non-pregnant women. Results are therefore not confounded by previous antiretroviral therapy, which is known to be associated with a higher risk of virologic failure . In addition, women who were already on treatment at conception were compared to themselves, during a time when they were not pregnant. Both approaches lead to the same conclusion and both have advantages and disadvantages. Women who become pregnant might be different from nonpregnant women with respect to factors we were not able to control for. Comparisons of the same women over different time periods did not allow us to separate time effect from the effect of pregnancy.
Other limitations, common to both approaches, include the definition of virologic failure and the lack of more detailed information on reasons why physicians or patients decided to change the HAART regimen (the ‘other’ reasons). To define virologic failure, we used one viral load determination of more than 1000 copies/ml. This is in contrast to other studies in which virologic failure was defined as two consecutive viral load measurements above the detection limit (often 50, 400 or 500 copies/ml depending on the lower limit of quantification of the assay) after a positive response, or the absence of an undetectable viral load after 6 months of treatment [37,38]. This standard definition could not be used in our study as the frequency of viral load measurements differed between pregnant and non-pregnant women and because the pregnancy period was too short. The cut-off value of 1000 copies/ml was chosen to minimize the possibility of a viral ‘blip’ (defined as a single viral load value between the detection limit and 1000 copies/ml, not associated with virologic failure [39,40]). As the overall number of failures was small, the power of the study is limited. Larger studies are needed to confirm (or refute) our results. Finally, the reasons for virologic failure during pregnancy could not be assessed, as no data – especially about adherence and drug levels during pregnancy – were available.
Implications and conclusions
Information on virologic failure during pregnancy is of obvious importance to patients, their physicians and pharmacologists. In patients who were already taking HAART at the time of conception, pregnancy did not increase the risk of virologic failure. In patients who started treatment during pregnancy, treatment success was excellent, with 93% of patients reaching viral load values at less than 400 copies/ml at delivery. Larger studies or collaborative analyses of several cohorts are needed to obtain more precise estimates of the risk of virologic failure in pregnancy.
We would like to thank all participants of the Swiss HIV Cohort Study, all study physicians, study nurses and data managers whose participation made these analyses possible. We also would like to thank Matthias Egger, Michel Boulvain, Adriane Martin Hilber and Cornelia Staehelin for carefully reading the manuscript and helpful comments. This study has been financed in the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation.
The members of the Swiss HIV Cohort Study and the Swiss Mother and Child HIV Study are: C. Aebi, M. Battegay, E. Bernasconi, J. Böni, P. Brazzola, H.C. Bucher, Ph. Bürgisser, A. Calmy, S. Cattacin, M. Cavassini, J.-J. Cheseaux, G. Drack, R. Dubs, M. Egger, L. Elzi, M. Fischer, M. Flepp, A. Fontana, P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011- Lausanne), H.J. Furrer, C. Fux, A. Gayet-Ageron, S. Gerber, M. Gorgievski, C. Grawe, H. Günthard, Th. Gyr, H. Hirsch, B. Hirschel, I. Hösli, M. Hüsler, L. Kaiser, Ch. Kahlert, U. Karrer, C. Kind, Th. Klimkait, B. Ledergerber, G. Martinetti, B. Martinez, N. Müller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach, C. Rudin (Chairman of the MoChiV Substudy, Basel UKBB, Römergasse 8, CH-4058 Basel), P. Schmid, D. Schultze, J. Schüpbach, R. Speck, P. Taffé, A. Telenti, A. Trkola, P. Vernazza, R. Weber, D. Wunder, C.-A. Wyler, S. Yerly.
Authorship Statement: O.K. contributed to the design of the study, performed statistical analyses and wrote the first draft of the paper together with A.G.A. and B.M.T. B.M.T. and A.G.A. also contributed to the design of the study and contributed data. B.H. originally conceived the study design, contributed data and commented on earlier drafts of the paper. M.B. contributed to the design and the statistical analyses. All other authors contributed data and commented on earlier drafts of the paper. All authors have seen and approved the final version of the manuscript.
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