In a meta-analysis of three large HIV/HCV coinfection trials, women were more likely to experience an AETD or AEDM during HCV therapy in HIV infection. However, the observed types of adverse events were similar between sexes. Additionally, AETD and AEDM occurred earlier in women. When exploring the effect modification by sex, women on regimens containing an NNRTI without a PI experienced more adverse events requiring treatment discontinuation and women on AZT-containing regimens experienced more adverse events requiring interferon or ribavirin dose modification.
This is the first study to demonstrate that HIV-infected women on hepatitis C therapy experience more adverse events requiring treatment discontinuation. Although similar sex effects on treatment discontinuation have not been reported in HIV-uninfected HCV-positive women receiving interferon and ribavirin therapy (7
), hepatitis C monoinfection trials have demonstrated that women experience some adverse events (depression and anemia) more commonly than men (10
). The relatively lower proportion of women enrolled in the landmark registration trials (7
) may have precluded analysis of sex effects and discontinuation rates.
When examining the HIV literature, our findings of higher treatment discontinuations in women are similar to some (17
) but not all (14
) studies in HIV infection. In the CASCADE collaboration, women were more likely to discontinue ARV therapy (HR = 1.61, 95% CI: 1.15–2.27) (17
) while in the ICONA study group, women were twice as likely to discontinue treatment secondary to toxicity (18
). Conversely, three other studies did not find higher overall rates of treatment discontinuations among women (14
A sex effect on ARV modifications has also been noted in HIV studies; Currier and colleagues demonstrated that women were 1.25 times more likely to modify didanosine dosage (14
). In HIV infection, women are also more likely to experience adverse events while on therapy with descriptions of increased rates of rash and hepatitis with nevirapine (21
) and lactic acidosis with nucleoside analogues (22
). The reasons for heightened rates of adverse events in women are poorly understood. Differences in body weight and composition, renal clearance, cellular kinase activity, and P glycoprotein activity may all play a role.
Our finding that women on NNRTI regimens were more likely to discontinue HCV therapy than men is in agreement with other studies examining ARV regimen discontinuation in HIV infection. Women were more likely to discontinue efavirenz-based regimens with 38.8% (95% CI: 28.8% to 48.7%) stopping EFV by 48 weeks of treatment compared with 28.3% of men (95% CI: 23.4% to 33.2%) (23
). In our analysis, among women with AETD, women receiving NNRTI-based regimens had more depression. This finding, along with the findings that women are more likely to have elevated plasma efavirenz concentrations (24
), are more likely to have mood disorders (25
); and may be more likely to experience depression while on interferon therapy (11
) raise the possibility that neuropsychiatric side effects from interferon and efavirenz based regimens may be accentuated in women. These findings should be interpreted with caution in this study, however, as we did not have data on type of NNRTI regimen, and the number of women on NNRTI regimens who discontinued was small.
The finding that women were more likely to have AEDMs with AZT-containing regimens, and a subgroup analysis demonstrating that the majority of AEDM on AZT-containing regimens were hematologic are not unexpected. Women are at an increased risk of developing anemia during ribavirin therapy (10
) and our study suggests that AZT may also play a role in hematologic toxicities in women receiving ribavirin. In hepatitis C monoinfection trials, Sulkowski and colleagues found that the incidence of reaching a Hgb<10 g/dL was fourfold higher in women (10
) while an analysis of interferon alpha-2a trials also found that women were more likely to have anemia (26
). One study demonstrated higher levels of AZT in women (27
), suggesting a possible mechanism for the additive toxicity of ribavirin and AZT. Anderson and colleagues found that women had significantly higher intracellular concentrations of AZT with a female to male ratio of 2.3. Interestingly, we did not find a statistically significant sex difference in the rates of anemia leading to treatment discontinuation; the respective rates were small among both men and women, suggesting that these adverse events were well managed in this clinical trial setting.
We also found that older age was independently associated with the incidence of adverse events requiring treatment discontinuation and dose modification. This is supported by Sulkowski and colleagues (10
) who also found that older age was associated with hemoglobin decrease in hepatitis C monoinfection studies. The authors speculated that older age may impact hematopoetic reserves in bone marrow, leading to more bone marrow suppression than in younger subjects (10
One limitation of our analysis was the heterogeneity of treatment protocols. In ACTG 5071, ribavirin was dose-escalated from 600 mg to 800 mg, and subjects who experienced severe adverse events stopped therapy. This dose escalation, however, would only have masked severe adverse events. Additionally, the three protocols included varying regimens of interferon and ribavirin, with 40% of individuals receiving combination therapy with pegylated interferon and ribavirin. Subgroup analyses on this group with combination therapy, however, demonstrated similar results to that of all regimens. Another limitation of the study included the extensive use of ARVs (zidovudine and stavudine) that are less common in clinical practice today. Newer, more tolerable ARV regimens such as the nuclesos(t)ide transcriptase inhibitor combinations (i.e. tenofovir/emtricitabine and abacavir/lamivudine), boosted atazanavir, and raltegravir may lead to a reduced rate of adverse reactions attributable to concomitant ARV and HCV therapy. Analyses of these newer regimens with hepatitis C therapy, and their interactions with sex, are needed. We also acknowledge the presence of competing risks such as loss to follow-up, death, non-response, and unknown reasons for discontinuation. Therefore, time to adverse event requiring treatment discontinuation and time to first dose modification, respectively, were also analyzed in the competing risks setting, treating death, non-response, LFU and other known reason for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards model, and the conclusions on the effect of sex were the same in both analyses. Competing risks may have also reduced the observed adverse events and, if drop-out secondary to competing risks was associated with covariates, then confounding may have been introduced. Finally, the overall numbers of women experiencing AETDs and AEDMs were low at 69 and 175, respectively, leading us to interpret the interactions and subgroup analyses, including comparisons of types of adverse events between men and women, with caution.
In conclusion, women are more likely to experience adverse events leading to hepatitis C treatment dose modification and discontinuation in the setting of HIV/HCV coinfection. Women on NNRTI regimens were more likely to discontinue therapy and women on AZT-containing regimens were more likely to require dose modifications, suggesting an important sex-mediated role of ARV regimen on the impact of adverse events during hepatitis C therapy. ARV regimen may be an important predictor of treatment discontinuation and modification in women and should be further explored as predictors of adverse events in HIV/HCV coinfection trials.