The frequency of both grade 1 or higher (13.3%, CI 9.1 – 18.5%) and grade 3 or higher hepatotoxicity (0.5%, CI 0.01 – 2.5%) in pregnant women using NVP in our study is less than that reported in other studies. Hitti et al reported the phase I results of the PACTG 1022 trial which found a 29.4% rate of treatment discontinuation among the 17 pregnant patients taking NVP for suspected hepatotoxicity [5
]. However, one of the five patients who discontinued treatment developed only right upper quadrant pain with no LEE. This may reflect provider ascertainment bias in this non-blinded intervention study leading to premature discontinuation of therapy in the NVP group secondary to a preexisting concern that they were at increased risk for developing hepatotoxicity. The authors acknowledge in this study that the small sample size may have resulted in an overestimation of the actual incidence of hepatotoxicity. In a retrospective study, Lyons et al described grade 1 or higher LEE occurring in 34.1% of 85 women using NVP [7
]. These two studies and others [17
] have reported a 6.5-11.8% rate of grade 3 or higher hepatotoxicity, as compared to only 0.5% (CI 0.01 – 2.5%) in our study. Our lower rates of both grade 1+ and grade 3+ LEE are more similar to results reported in studies from Thailand [18
], Brazil [19
], Mozambique [16
] and London [20
]. While ethnic differences have been suggested as a possible factor in these discordant findings [20
], our study population was very similar to the ethnic composition of the PACTG 1022 study.
We observed no maternal deaths in our study of 1229 pregnant women on ART. This included 218 women taking NVP-containing regimens, 137 (62.8%) of whom were NVP naive. This is somewhat in contrast to reports of six maternal deaths associated with continuous NVP use in pregnancy [5
]. Reporting bias may play a role in this apparent difference in mortality as only one of these six deaths occurred in the setting of a prospective trial, while the remainders were case reports or personal communications. We also did not find an association between CD4+ count > 250 cells/μL and risk of hepatotoxicity in patients taking NVP in both univariate and multivariate analysis. The lack of evidence of an effect of CD4+ count on LEE is consistent with the largest review on NVP and hepatotoxicity which also was unable to demonstrate a CD4+ count cutoff in women that was associated with an increased risk of LEE [3
]. Individual genetic susceptibility may play an important role in the development of hepatotoxicity in relation to CD4+ cell count [21
Our study has potential limitations. First, confounding by indication may have occurred if clinicians avoided prescribing NVP to women at greatest risk for developing hepatotoxicity, leading to underestimation of risk in these patients. In our study, women using NVP during pregnancy were significantly less likely to be NVP naïve and thus may have differentially included women with tolerance to the hepatic effects of NVP. Still, the control group did generally have similar background characteristics to the NVP group, including baseline CD4+ cell counts. In addition, the majority of the data in this study were obtained prior to the FDA public advisory and NVP manufacturer's labeling changes (2005) warning against potential increased risks of hepatotoxicity making it less likely that these concerns biased the conclusions of this study. Finally, we attempted to control for confounding by indication through consideration of several potential confounding variables.
Another potential limitation was that we were unable to differentiate possible obstetrical causes of LEE from drug-induced hepatotoxicity. As such, it is reasonable to assume a portion of the patients in our study had LEE independent of their ART exposure. A 15 month prospective study of 4,377 deliveries found a 3% incidence of liver enzyme elevation during pregnancy [22
]. Pregnancy specific causes such as preeclampsia comprised the majority of these cases (67%), whereas drug toxicity accounted for less than 2% of the pregnancies with elevated liver enzymes. Other studies have shown that HIV infected pregnant women are not at significantly greater risk of developing these pregnancy conditions most often associated with liver dysfunction [23
]. Considering the incidence of LEE in our study (14%) was significantly higher than in the Ch'ng study (3%), it is reasonable to assume that the majority of the additional LEE was associated with ART use, although a causal association could not be proven.
In regards to the disproportionate contribution of women from P1025, a sensitivity analysis was performed that stratified the multivariate analysis by study (WITS and P1025) and no significant differences were seen from the combined analysis. This likely reflects the fact that the WITS and P1025 trials were both prospective, observational studies that are very similar on multiple levels such as inclusion and exclusion criteria, population characteristics, and frequency of study visits [12
]. In addition, by limiting the WITS population to those enrolled after 2002, we ensured that the schedule for LFT monitoring would be the same between the two trials and that the studies would cover the same calendar time frame.
Strengths of this study include the large number of women enrolled which provided statistical power to detect clinically important increases in risk, the inclusion of a reference group of HIV-infected pregnant women not on ARV, and the prospective and standardized nature of the data collection. Even if pregnant women are uniquely at increased risk for hepatotoxicity, our data suggest this risk is not substantially higher with NVP exposure as compared to other ART. The risk of hepatotoxicity associated with NVP use may be less than other studies have estimated and clinicians have feared. Specifically, the 95% confidence interval for the adjusted relative risk of any LEE among NVP unexposed versus NVP exposed women ranged from 0.64 to 1.57 which suggests that a substantial increase in risk of LEE with NVP use in pregnancy is unlikely ().
We would still exercise caution when administering any antiretroviral medication during pregnancy, with close clinical surveillance for symptoms of hepatotoxicity and laboratory monitoring for LEE, especially when initiating or altering a regimen. As with the decision to prescribe any medication, health care providers must carefully consider the risks and benefits of specific ART regimens and individualize therapy to each patient.