One of the primary drawbacks of most studies evaluating the relationship of hepatotoxicity and ART during pregnancy is the lack of an HIV-infected, non-pregnant comparison group [3
]. Without this comparison group, one cannot determine if an increase in LEE with NVP use observed during pregnancy is associated with NVP, the pregnancy, or an interaction between these exposures. Our analysis suggests that a strong association between NVP and LEE was unlikely regardless of pregnancy status (adjusted RR 1.17, CI 0.80 – 1.70) and that pregnancy was a risk factor for LEE.
The only other study that examined the relationship between ART and hepatotoxicity in pregnant versus non-pregnant women compared outcomes of 186 pregnant and 186 non-pregnant women on nelfinavir- or nevirapine-containing regimens from 1997 through 2003 [13
]. This study reported that grade 2 or higher LEE occurred more frequently in pregnant women taking NVP (19.0%) than in non-pregnant women taking NVP (4.2%) (OR 5.3, CI 1.6-17.6); however, this association was not seen in those taking nelfinavir (OR 0.9, CI 0.2-3.4). In contrast to these results, our findings did not demonstrate an increase risk of LEE with NVP use regardless of pregnancy status with a much narrower confidence interval.
We also found pregnancy to be an independent risk factor in developing LEE, regardless of concurrent NVP use or prior ART and NVP exposure history. While prior studies have suggested that the risk of developing significant maternal toxicity from antiretroviral use in pregnancy to be relatively small [2
], pregnancy may provide a unique environment that predisposes women to drug-induced hepatotoxicity. Studies have demonstrated that women in general predominate among patients with drug-induced liver injury [14
]. A number of purported risk factors for developing hepatotoxicity are overrepresented in the pregnant population including CD4+ count > 250 cells/μL and ART naiveté, although these factors were not significantly associated with LEE in our analysis. Physiologic changes in pregnancy result in alterations in hepatic metabolism, primarily via induction of certain cytochrome P-450 enzymes, possibly resulting in increased susceptibility to drug-induced hepatotoxicity [15
]. Although the specific mechanism by which pregnancy may have increased the risk of LEE in our study is unclear, pregnancy has been shown to be an independent risk factor for developing hepatotoxicity in other diseases. Pregnant women with hepatitis E infection develop fulminant hepatic failure more frequently with associated mortality rates over 20% as compared to less than 0.1% in the non-pregnant population [18
]. Alterations in the Th1-Th2 balance towards Th2 predominance and impaired cellular immunity due to estrogen and progesterone have been hypothesized as possible explanations for this finding [20
Our study has limitations that should be considered. The frequency of liver enzyme assessment in the pregnant women was significantly greater than the non-pregnant women leading to possible assessment bias. We attempted to address this concern by reducing the sampling frequency in the pregnant women to match the non-pregnant women. Another limitation of this study is that we were unable to distinguish drug-induced hepatotoxicity from hepatotoxicity due to other causes. It is reasonable to assume a portion of patients in our study population had LEE independent of ART exposure. Approximately 3% of pregnant women have LEE due to conditions unique to pregnancy [21
]. It is possible that our inability to identify these causes of LEE in pregnancy may account for the association of LEE and pregnancy seen in our study. Despite these limitations, our analysis included a significantly larger population of women than the only other study that evaluated the association of NVP and LEE by pregnancy status [13
]. These limitations also do not significantly affect our finding that NVP use was not associated with LEE in both pregnant and non-pregnant women, even when stratifying by ART exposure history and CD4+ count.
Another limitation of this study is that all three cohort studies were conducted in the United States raising questions about generalisability of the findings, particularly to resource-limited settings. While this study cannot account for possible differences in these populations, it is interesting to note that the studies that initially suggested a possible increased risk of hepatotoxicity with NVP use in pregnant and non-pregnant populations were also performed in the United States and other developed countries [3
]. This concern has resulted in a reduction of use of NVP during pregnancy. Data from our study should be considered in assessing the recommendations for use of NVP in pregnancy. As noted in an FDA public health advisory for NVP [24
], there remain multiple reasons why NVP remains an important part of ART regimens worldwide: triple antiretroviral regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors, such as NVP, are standard of care for HIV treatment; many options are needed for HIV-infected patients since resistance to specific drugs or entire classes can develop; alternatives to NVP are limited by other toxicities, potential drug interactions, and by the risk of drug-related birth defects if given in the first trimester of pregnancy; NVP is chemically stable in environmental conditions where other antiretrovirals are not; symptomatic liver toxicity has not been reported in HIV-infected children; and NVP is available in a liquid formulation while many other antiretrovirals are not. Finally, it is important to emphasize that the hepatotoxicity noted in patients taking continuous NVP has not been seen when NVP is used as a single, intrapartum dose [25
While we support close monitoring of pregnant women for clinical or laboratory evidence of hepatotoxicity with any ART regimen, our results challenge the notion that NVP is uniquely associated with hepatotoxicity during pregnancy.