Liver disease currently represents one of the leading causes of mortality in HIV-infected individuals in Western countries, where antiretroviral therapy is widely used.1 Chronic hepatitis C virus (HCV) is the major contributor to this adverse outcome, given the high prevalence of coinfection due to shared routes of transmission of HIV and HCV,2 the accelerated course of liver fibrosis in this population,3 and the increased risk of liver toxicity using antiretroviral agents in coinfected individuals.4 For all these reasons, treatment of chronic hepatitis C in HIV patients is currently viewed as a priority.5 Unfortunately, the rate of sustained virological response (SVR) to current hepatitis C therapy is lower in coinfected than in HCV-monoinfected individuals, overall ranging from 25% to 50%.6-10 As a result, a growing number of HIV/HCV-coinfected patients in developed countries have failed a first course of hepatitis C therapy. In the subset of these individuals with advanced liver fibrosis, waiting for new drugs against hepatitis C11 may be challenged by earlier development of decompensated liver disease, forcing consideration of liver transplantation as the only option. The recent report of a lower 5-year survival of HIV/HCV liver transplanted patients compared with HCV-monoinfected individuals is further worrisome news for these patients.
Retreatment of chronic hepatitis C has been attempted in HCV-monoinfected individuals12-14 and in HIV/HCV-coinfected patients.15-17 The chances of achievement of SVR following a second course of hepatitis C therapy depend very much of the treatment modality under which failure occurred, whether premature treatment discontinuation was forced due to side effects, if failure was due to HCV relapse following the end of therapy, or which HCV genotype was involved.5 Herein, we report the final results of a prospective study in which HIV/HCV-coinfected patients with history of a prior failure to a suboptimal hepatitis C therapy were re-treated with a 12-month course of pegylated interferon (pegIFN) plus weight-based ribavirin (RBV).
PATIENTS AND METHODS
All consecutive HIV/HCV-coinfected patients with positive serum HCV-RNA who had previously been exposed to a suboptimal course of hepatitis C therapy attended at our institution were prospectively included in the PILOT study (NCT00530972). The definition of prior suboptimal hepatitis C therapies included any of the following regimens: (1) conventional IFN monotherapy, (2) conventional IFN plus RBV, and (3) pegIFN plus fixed 800 mg/d RBV. Moreover, suboptimal therapy was considered for any length of hepatitis C treatment given for less than 12 months for any reason, mainly premature discontinuations due to potentially manageable side effects.
Hepatitis C Treatment and Monitoring
Subcutaneous pegIFN alpha-2a 180 g/wk plus oral RBV (1000 mg/d if <75 kg, 1200 mg if ≥75 kg) was given to all patients regardless of HCV genotype. Following international guidelines for the treatment of chronic hepatitis C in HIV patients,5 subjects who did not show a decline above 2 logs in serum HCV-RNA at week 12, discontinued treatment and were considered as nonresponders. Likewise, patients who did not attain serum HCV-RNA < 10 IU/mL at week 24 of treatment were also considered as nonresponders and interrupted therapy. SVR was applied to the subset of patients who persisted with undetectable viremia 24 weeks upon completion of treatment. Dose adjustments for either pegIFN or RBV were made following standard recommendations. Erythropoietin was not available.
Liver fibrosis was estimated using hepatic stiffness determined using transient elastometry (FibroScan, Echosens, Paris, France). Following recommendations from prior studies,18,19 values used to make Metavir estimates were as follows: <6.2 kPa for F0-F1; 6.2-9.1 kPa for F2; 9.2-15 kPa for F3, and >15 kPa for F4. Patients with F3-F4 Metavir estimates were considered as having advanced liver fibrosis. Elastometric measurements were performed at baseline and every 6 months since then. Liver fibrosis progression between baseline and last hepatic stiffness measurements was defined as a change from F0 to F2 Metavir estimates to F3-F4 or when increases above 30% in liver stiffness (kPa) were recognized in patients with baseline advanced liver fibrosis. On the other hand, liver fibrosis improvement was considered for declines of at least one point in the Metavir score in patients with F2-F4 baseline estimates or reductions above 30% in liver stiffness values (kPa) in subjects with baseline F0-F1 Metavir estimates.
Main demographics were recorded at baseline in a chart specially designed for this study. Serum HCV-RNA was measured using a commercial real-time PCR assay (Cobas Taqman, Roche, Pleasanton, CA), which has a lower detection limit of 10 IU/mL. HCV genotypes were assessed using a commercial reverse hybridization method (InnoLiPA HCV II; Innogenetics, Ghent, Belgium). Plasma trough concentrations of RBV were measured at weeks 4 and 12 using high-performance liquid chromatography, as described elsewhere20 testing blood drawn before the morning drug dose.
Descriptive values are expressed as percentages and means (±SD). Comparisons were made using the chi-square test for proportions, and parametric or nonparametric tests for continuous variables. Response to hepatitis C therapy was calculated by intention-to-treat analysis, in which missing results were considered as failures. Univariate and multivariate analyses were performed to identify demographics, clinical and laboratory parameters, HCV variables, and HIV factors which could be associated with the achievement of SVR. The best discriminatory cut-off for RBV plasma trough concentration at weeks 4 or 12 predicting SVR was similarly investigated. Finally, all variables with P values <0.1 in univariate analyses were introduced in a final logistic regression model. All data were recorded and analyzed using the SPSS v15.0 software package (SPSS Inc, Chicago, IL).
A total of 52 HIV/HCV-coinfected patients were included in the study. The main characteristics of the study population are depicted in Table 1. The mean age was 43 years old, mean body weight was 72 kg, and 82% were men. The mean CD4 count was 671 cells/μL, as 92% of patients were under antiretroviral therapy and 91% had undetectable plasma HIV-RNA. With respect to chronic hepatitis C, more than two-thirds of patients were infected by HCV genotypes 1 or 4, 77% had high baseline serum HCV-RNA (>500,000 IU/mL), and 56% had advanced liver fibrosis. Up to 51% of patients had previously been exposed to pegIFN and only 39% were prior HCV relapsers.
Five patients (9%) interrupted treatment prematurely, 4 of them due to serious side effects (pneumonia, anemia, depression, intense flu-like symptoms) and one was lost to follow-up. Four patients required RBV dose reductions during treatment.
Efficacy and Predictors of SVR
Overall, 16 (30.8%) out of 52 enrolled patients achieved SVR. It was 19.5% in HCV genotypes 1/4 carriers and 72.7% in patients infected with HCV genotypes 2/3 (P = 0.002). Other baseline differences between patients who achieved SVR and those who did not are recorded in Table 1. Overall, patients with high baseline serum HCV-RNA and advanced liver fibrosis were less likely to respond to pegIFN plus RBV. A trend for higher response was seen in prior relapsers compared with nonresponders (P = 0.07). Interestingly, no significant differences were found considering distinct prior treatment modalities. SVR was attained overall by 27% of patients with prior pegIFN failure (16% in prior nonresponders and 35% in relapsers), but it declined to 9% when considering only HCV genotype 1 prior nonresponders.
Table 2 records the results of the univariate and multivariate analysis in which all factors influencing the achievement of SVR were considered. Interestingly, infection with HCV genotypes 2/3 versus 1/4 was the major determinant of SVR to a second course of hepatitis C therapy. The only other variable which remained as significantly independently associated with the achievement of SVR was RBV plasma trough concentrations at week 4.
RBV Plasma Trough Concentrations and SVR
RBV levels at weeks 4 and 12 were both significantly associated with SVR (Table 2). However, only RBV measurements at week 4 remained as independently associated with the achievement of SVR in the multivariate analysis. The area under receiver operating curve (AUROC) curve for RBV trough concentrations at week 4 and SVR allowed to explore the best threshold in RBV plasma trough concentration to discriminate SVR and non-SVR; it was 2.07 μg/mL, with negative and positive predictive values of 83.3% and 45.8%, respectively (P = 0.02).
Changes in Liver Fibrosis Estimates
Liver fibrosis estimates using transient elastometry were available for all patients. The mean time before initiating treatment was 16 weeks and the mean time for the last measurement upon completion of therapy was 25 months. None of the 16 patients who achieved SVR showed liver fibrosis progression. In contrast, 27% of those who did not attain SVR showed liver fibrosis progression (P = 0.04; Fig. 1).
This study shows that retreatment of chronic hepatitis C with pegIFN plus weight-based RBV in HIV-infected individuals who failed a prior course of suboptimal hepatitis C therapy may permit to reach SVR in nearly one-third of patients. As expected, patients infected with HCV genotypes 2/3 had better chances of response (73%) than HCV genotypes 1/4 carriers (20%). These results are overall encouraging, since prior studies testing the efficacy of hepatitis C retreatment in HIV/HCV-coinfected patients have all reported lower response rates, ranging from 16% to 30%.15-17 Our findings are particularly relevant because the main characteristics of patients enrolled in all these trials are quite similar, with no differences in HIV disease stage, around 70% of patients infected with HCV genotypes 1/4, half of them with advanced liver fibrosis, and more than 60% with nonresponse (instead of relapse) to prior hepatitis C therapy. Of note, 51% of our patients already had received pegIFN, although with a fixed 800 mg/d of RBV. The experience in HCV-monoinfected patients with prior nonresponse or relapse has shown that response rates to retreatment are not much better, being around 25% when suboptimal therapies were given in the past12,13 but declining to 18% when failure occurred under pegIFN.14 In our series, SVR was attained overall by 27% of patients with prior pegIFN failure, 16% in prior nonresponders and 35% in relapsers, but it declined to 9% when considering only HCV genotype 1 prior nonresponders. A limitation of our study to be acknowledged is that we do not know the proportion of prior truly virological nonresponders because at the time the first course of hepatitis C therapy was given, early quantitative assessment of serum HCV-RNA had not been done in most cases.
The benefit of providing appropriate RBV exposure seems largely to account for the relatively good results in our study. Although the importance of high RBV dosing to maximize SVR has already been demonstrated in HCV-monoinfected patients,21,22 it is now clear that adequate RBV exposure is even more crucial in HIV/HCV-coinfected patients, in whom the antiviral effect of interferon is diminished.23,24 Patients who attained RBV plasma trough concentrations above 2.07 μg/mL at week 4 of treatment had the highest chance of SVR, regardless any other variable but HCV genotype. Overall, the negative predictive value of SVR was 83% when RBV plasma levels at week 4 were below this threshold. A recent study found similar results, reporting a threshold of 2 μg/mL in RBV plasma trough concentrations at week 4 as independent predictor of SVR.25 Altogether these observations support that in difficult-to-treat chronic hepatitis C patients, including anyone with prior nonresponse or relapse, seems to be crucial to exceed certain RBV plasma levels during the first weeks of therapy to maximize the chances of HCV clearance.
Liver fibrosis progression did not occur in patients who achieved SVR over 2 years following the end of retreatment, whereas 23% of patients who failed hepatitis C retreatment showed liver fibrosis progression during the same period. These data are interesting because the 2-year delay in assessment of liver fibrosis should have avoided any anti-inflammatory effect of IFN,26 supporting that HCV clearance was the main responsible of halting liver fibrosis progression in responders. Given that 56% of our study population showed advanced liver fibrosis at baseline, our results highlight the importance of eradicating HCV to prevent liver disease progression in this population. With longer follow-up, other studies have shown that liver fibrosis may revert,27 with a clear diminished risk of hepatic clinical events,28 even in cirrhotics.29
In summary, retreatment of chronic hepatitis C in HIV-infected individuals with prior exposure to a suboptimal course of hepatitis C therapy may be considered as a reasonable option. It may be the preferred alternative for the subset of patients with advanced liver fibrosis in whom the potential benefit derived from using new antivirals against HCV still has to be proven and will require waiting for long time. Maximizing RBV exposure seems to be crucial in these patients. If HCV clearance is attained, liver fibrosis progression will be halted and hepatic clinical events reduced.
1. Weber R, Sabin C, Friis-Møller N, et al. Liver-related deaths in persons infected with the HIV
: the D:A:D study. Arch Intern Med
2. Alter M. Epidemiology of viral hepatitis and HIV
co-infection. J Hepatol
3. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in HIV
and hepatitis C
virus coinfected patients. The Multivirc Group. Hepatology
4. Soriano V, Puoti M, Garcia-Gasco P, et al. Antiretroviral drugs and liver injury. AIDS
5. Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV
and hepatitis C
virus: 2007 updated recommendations from the HCV-HIV
International Panel. AIDS
6. Chung R, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin
versus interferon alfa-2a plus ribavirin
for chronic hepatitis C
-coinfected persons. N Engl J Med
7. Torriani F, Rodriguez-Torres M, Rockstroh J, et al. Peginterferon Alfa-2a plus ribavirin
for chronic hepatitis C
virus infection in HIV
-infected patients. N Engl J Med
8. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin
, for chronic hepatitis C
-infected patients: a randomized controlled trial. JAMA
9. Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin
compared with interferon alfa-2b plus ribavirin
for treatment of HIV
/HCV co-infected patients. AIDS
10. Nunez M, Miralles C, Berdun MA, et al. Role of weight-based ribavirin
dosing and extended duration of therapy in chronic hepatitis C
-infected patients: the PRESCO trial. AIDS Res Hum Retroviruses
11. Soriano V, Peters M, Zeuzem S. New therapies for HCV infection. Clin Infect Dis
12. Poynard T, Schiff E, Terg R, et al. Sustained viral response (SVR) is dependent on baseline characteristics in the re-treatment of previous alfa interferon/ribavirin
non-responders: final results of the EPIC3 program. 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy. Abstract 988.
13. Shiffman M, Di Bisceglie A, Lindsay K, et al. Peginterferon alfa-2a and ribavirin
in patients with chronic hepatitis C
who have failed prior treatment. Gastroenterology
14. Jensen D, Freilich B, Adreone P, et al. Pegylated interferon alfa-2a (40 KD) plus ribavirin
(RBV) in prior non-responders to pegylated interferon alfa-2b (12KD)/RBV: final efficacy and safety outcomes of the REPEAT study. Program and abstracts of the58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, MA. Abstract LB4.
15. Myers R, Benhamou Y, Bochet M, et al. Pegylated interferon alpha 2b and ribavirin
virus-coinfected non-responders and relapsers
to IFN-based therapy. AIDS
16. Rodriguez-Torres M, Rodriguez-Orengo J, Rios-Bedoya C, et al. Efficacy and safety of peg-IFN alfa-2a with ribavirin
for the treatment of HCV/HIV
coinfected patients who failed previous IFN based therapy. J Clin Virol
17. Crespo M, Mira JA, Pineda JA, et al. Efficacy of pegylated interferon and ribavirin
for re-treatment of chronic HCV infection in HIV
co-infected patients failing a previous standard interferon-based regimen. J Antimicrob Chemother
18. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C
19. de Ledinghen V, Douvin C, Kettaneh A, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV
virus-coinfected patients. J Acquir Immune Defic Syndr
20. Morello J, Rodriguez-Novoa S, Cantillano A, et al. Measurement of ribavirin
plasma concentrations by high-performance liquid chromatography using a novel solid-phase extraction method in patients treated for chronic hepatitis C
. Ther Drug Monit
21. Lindahl K, Stahle L, Bruchfeld A, et al. High-dose ribavirin
in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C
22. Hornfeldt E, Stahle L, Schvarcz R, et al. Response to high ribavirin
dose in combination with peg-IFN alfa-2a for treatment of HCV genotype 1 previous non-responders. Hepatology
23. Dixit N, Layden-Almer J, Layden T, et al. Modeling how ribavirin
improves interferon response rates in hepatitis C
virus infection. Nature
24. Ramos B, Nunez M, Rendon A, et al. Critical role of ribavirin
for the achievement of early virological response to HCV therapy in HCV/HIV
-coinfected patients. J Viral Hepat
25. Maynard M, Pradat P, Gagnieu M, et al. Prediction of sustained virological response by ribavirin
plasma concentration at week 4 of therapy in hepatitis C
virus genotype 1 patients. Antivir Ther
26. Soriano V, Labarga P, Ruiz-Sancho A, et al. Regression of liver fibrosis in hepatitis C
-coinfected patients after treatment with pegylated interferon plus ribavirin
27. Barreiro P, Labarga P, Martin-Carbonero L, et al. Sustained virological response following HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV
-coinfected patients. Antivir Ther
28. Soriano V, Maida I, Garcia-Samaniego J, et al. Long-term follow-up of HIV
-infected patients with chronic hepatitis C
virus infection treated with interferon-based therapies. Antivir Ther
29. Mallet V, Gilgenkrantz H, Serpaggi J, et al. The relationship of regression of cirrhosis to outcome in chronic hepatitis C
. Ann Intern Med