In this study, use of abacavir was not associated with reduced early or sustained virologic response, either overall or by HCV genotype. Among genotype 1- and 4-infected patients, median declines in HCV viral load over the initial 12 weeks of PEG-interferon plus ribavirin therapy were similar between abacavir users and non-users. In addition, in analyses performed among patients prescribed weight-based ribavirin dosages, no differences were observed in median HCV viral load declines at 12 weeks between abacavir users and non-users. In contrast, median declines in HCV viral load at 12 weeks for genotype 2 and 3 patients, all of whom received 800 mg/day of ribavirin, were substantially smaller among patients on abacavir, though there were no significant differences in early or sustained virologic response. Further, no other antiretroviral medications were associated with lack of virologic response.
Our results are consistent with a prior cohort study of 244 coinfected patients treated with PEG-interferon plus ribavirin at four hospitals in Spain (85% on ART; 49 on abacavir; 97% prescribed ≥13.2 mg/kg/day of ribavirin), which reported that patients receiving abacavir in the setting of weight-based ribavirin achieved similar sustained virologic response rates compared to non-users (46.2% versus 46.7%; OR, 1.03; 95% CI, 0.55 – 1.94) [13
]. The results of these studies suggest that the putative competitive effect between abacavir and ribavirin can be overcome with optimal weight-based ribavirin dosages.
Our findings differed from several other studies examining the association between abacavir use and HCV virologic response. A retrospective analysis of 154 coinfected subjects (22 receiving abacavir) enrolled in the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) HC02-Ribavic trial reported that abacavir use was an independent predictor of early virologic failure to combination HCV therapy (adjusted OR, 4.9; 95% CI, 1.5–16.1) [11
]. However, all patients in this trial received 800 mg/day of ribavirin. In addition, a retrospective cohort study of 493 coinfected patients (78% on ART; 115 receiving abacavir) prescribed PEG-interferon plus ribavirin at 10 Spanish hospitals also suggested that abacavir use reduced sustained virologic response rates (adjusted OR, 2.22; 95% CI, 0.9 – 5.4), particularly in the setting of low (<2.3 µg/mL) ribavirin plasma levels measured at 4 weeks of treatment (adjusted OR, 7.63; 95% CI, 1.4 – 41.7) [14
]. A second Spanish cohort study among 256 coinfected who received PEG-interferon plus ribavirin compared sustained virologic response rates between patients prescribed a nucleos(t)ide background consisting of abacavir plus lamivudine (70 patients) with tenofovir plus lamivudine or emtricitabine (186 patients) [13
]. Sustained virologic response rates were significantly lower in patients prescribed abacavir than tenofovir (20 [29%] versus 83 [45%]; adjusted OR, 2.6; 95% CI, 1.1 – 6.9) and particularly among those prescribed <13.2 mg/kg/day of ribavirin (3/15 [20%] versus 22/42 [52%]; p=0.03). Differences in ribavirin dosing and the study populations, which were exclusively European, might account for the disparate results between studies. Additionally, some studies were not restricted to subjects only receiving ART, which makes those results subject to confounding by indication [24
We observed that the initial 12-week HCV viral load decline in patients infected with HCV genotypes 2 or 3 was substantially smaller among abacavir users. Since these patients were all prescribed non-weight-based ribavirin dosages (i.e., 800 mg/day), it is possible that abacavir may interfere with ribavirin’s activity at these lower ribavirin dosages. The relatively small number of patients with genotypes 2 or 3 in this study limits our ability to draw definitive conclusions. Additional studies in coinfected patients with genotype 2 or 3 should be performed to examine if use of weight-based dosages of ribavirin can increase the viral load decline at 12 weeks.
Our analyses demonstrated that no other antiretroviral medications compromised early or sustained virologic responses to HCV therapy. In particular, our findings did not corroborate an earlier study reporting that use of ritonavir was associated with reduced early and sustained virologic response rates [25
]. In addition, elevations in pre-treatment total bilirubin have been reported to increase the risk of early virologic failure (adjusted OR, 4.5; 95% CI, 1.5 – 13.4) [11
]. Since the antiretroviral medication, atazanavir, can cause hyperbilirubinemia, use of this medication might reduce the risk of early virologic response. However, we found no association between atazanavir and HCV virologic non-response. Moreover, no other antiretroviral medication or classes were associated with lack of virologic response.
Our study had several limitations. First, the retrospective design of the study did not allow all potential confounders to be collected. Although a number of variables were evaluated and controlled for analytically, multivariable analyses may not entirely eliminate residual confounding from additional unmeasured factors, as is always true for all observational studies. In particular, we did not have information on the duration of HCV infection, since this was not routinely collected in medical records, and were unable to measure adherence to PEG-interferon and ribavirin therapy [10
], as pharmacy refill data were not available at all sites. We therefore could not examine the relationship between these variables and response to HCV therapy.
Second, although this study drew patients from six sites, some secondary analyses had small sample sizes. There was also a high overall rate of HCV treatment discontinuation, which contributed to the low sustained virologic response rates observed in this study. These factors limited our ability to identify potentially important associations. Our results should be interpreted with caution since early virologic response was the primary outcome, and the main strength of ribavirin is in the prevention of relapse, which is mainly reflected by rates of sustained virologic response. As additional studies of similar design are reported, formal methods of meta-analysis could be used to combine results across studies and perhaps add to the precision of our findings.
Third, patients who received abacavir more frequently prematurely discontinued HCV therapy, and the most common reason for withdrawal was virologic non-response. This increased rate of HCV treatment discontinuation might have been due to abacavir interfering with the antiviral activity of ribavirin, ultimately resulting in virologic non-response and withdrawal from therapy.
Finally, the study only included patients from the United States, and these results may not be generalizable to coinfected patients in other areas.
In conclusion, our study found that use of abacavir as well as other antiretrovirals was not associated with a lack of early or sustained virologic response. Additional studies are needed to determine if weight-based dosages of ribavirin can enhance HCV viral load declines among genotype 2 and 3 abacavir users.