To the Editors:
After the introduction of first-generation direct acting antivirals, boceprevir and telaprevir (TVR), in the treatment armamentarium of genotype-1 hepatitis C virus (HCV) chronic infection, high rates of sustained virological response (SVR) are now commonly seen in clinical practice, ranging from 51% to 75%.1–4
Triple regimens with pegylated interferon alfa (PEG-IFNα), ribavirin (RBV), and the protease inhibitor TVR have been widely studied in HCV-infected patients, and to a lesser extent, in subjects with HIV coinfection.5–8
Eradication of chronic hepatitis C decreases the likelihood of end-stage liver disease, hepatocellular carcinoma, and death.9–11 This goal is even more relevant in HIV-infected patients, in whom end-stage liver disease, mostly related to HCV coinfection, has become a leading cause of mortality.12,13
Access to anti-HCV treatments has been often limited in HIV-infected patients, both for fear of more drug-related side effects, and for concern of reduced rates of SVR.14 Indeed, the efficacy of dual anti-HCV therapy with PEG-IFNα plus RBV was lower for HIV/HCV-coinfected patients, than for HCV-monoinfected subjects.15,16
The aim of this study was to assess, in a routine clinical setting, the effectiveness and safety of TVR plus PEG-IFNα/RBV in HCV-infected patients, coinfected, or not with HIV.
METHODS AND SETTING
This study was a retrospective collection of data of all HCV-infected patients who began TVR in combination with PEG-IFNα and RBV between December 2011 and January 2014 in the Infectious Disease Unit of San Gerardo Hospital in Monza, Italy.
The study was approved by the Institutional Review Board and conducted according to the ethical principles stated in the Declaration of Helsinki.
All the patients were treated with TVR (orally, 1125 mg twice daily or 750 mg 3 times a day), PEG-IFNα (subcutaneously, 180 μg once weekly) and RBV (orally, weight-adjusted dose). At the time of the analysis, all the subjects had completed the treatment with TVR (12 weeks).
Response to previous dual anti-HCV treatment was collected. Monoinfected patients who were naive to anti-HCV therapy or who previously relapsed after IFN and RBV, noncirrhotic and with undetectable levels of HCV RNA at weeks 4 and 12 (extended rapid virological response) were eligible for a shortened therapy of 24 weeks (response-guided therapy). All the others, including all coinfected patients, were treated with TVR/PEG-IFNα/RBV for 12 weeks, followed by PEG-IFNα and RBV for 36 weeks (total: 48 weeks).
HCV RNA was measured by polymerase chain reaction with a lower limit of detection of 12 IU/mL.
Data about demographics, medical conditions, previous HCV treatment history, fibrosis stage or presence of cirrhosis, laboratory values, and adverse events were collected from individual patients' medical charts (paper or electronic).
The χ2 test, Fisher exact test, and Student t test were used for comparison of discrete and continuous variables, respectively, between HIV-positive and HIV-negative individuals.
Patients' baseline characteristics are presented in Table 1, stratified by HIV status (monoinfected, n = 20; or coinfected, n = 15). All the patients were white. There was no statistically significant difference between HIV-positive and HIV-negative subjects regarding age, sex, prior treatment response, grade of fibrosis, or biochemical parameters, except for a higher prevalence of HCV genotype 1a over 1b in coinfected patients with respect to monoinfected subjects (80% versus 45%, respectively, P = 0.04).
About one-third of the patients (n = 12; 34%) was partial or null responder to a previous dual therapy. Fibrosis was divided according to Metavir score: only few patients had low-grade fibrosis (F0–F2, n = 3; 9%), whereas one-third (n = 12; 34%) had high-grade fibrosis or cirrhosis (F4).
All coinfected subjects had undetectable plasma HIV RNA and high CD4+ T-cell counts before starting treatment (median, 585 cells/mm3; interquartile range, 294–869).
Similar rates of virological response to anti-HCV treatment were seen in the 2 groups (Table 1). In particular, RVR was obtained in 12/15 (80%) coinfected and in 14/20 (70%) monoinfected patients (P = 0.70), end of treatment response in 8/11 (73%) coinfected versus 8/17 (47%) monoinfected subjects (P = 0.18), and SVR in 4/7 (57%) coinfected versus 7/16 (44%) monoinfected patients (P = 0.55).
The percentage of TVR discontinuation was 20% (3/15) and 35% (7/20), P = 0.46, in coinfected and monoinfected patients, respectively. TVR discontinuation was due to the occurrence of rash in 1 coinfected and 5 monoinfected patients (6.7% versus 25%, respectively, P = 0.20); rash was the most common reason for TVR interruption. Treatment failure during triple therapy occurred globally in 2 patients, 1 monoinfected and 1 coinfected. Other reasons for discontinuation were hospitalization for febrile neutropenia (1 patient) and incoercible vomiting leading the patient to stop only TVR (1 patient).
Side effects were common in both groups, in particular anemia, itching, anal discomfort, and rash. There was no statistically significant difference between coinfected and monoinfected patients in the incidence of anemia (67% versus 65%, respectively, P = 1.00) or severe (grade 3 or more) anemia (47% versus 35%, respectively), serious adverse events leading to hospitalization (13% versus 15%, respectively, P = 1.00) and anal discomfort (40% versus 30%, respectively, P = 0.54).
Interestingly, rash was seen less frequently in coinfected (2/10; 13%) than in monoinfected (10/20; 50%) subjects (P = 0.03) and only 1 HIV/HCV-coinfected patient developed severe (G3) rash, versus 4 monoinfected subjects. The occurrence of itching was less common in coinfected than in monoinfected patients (33% versus 66%, respectively), a difference not too far from being statistically significant (P = 0.06).
In our little cohort of patients with advanced HCV-related liver disease, we observed similar success rates of TVR between HIV/HCV-coinfected and HCV-monoinfected subjects, confirming that HIV coinfection is not reducing response rate to new anti-HCV treatments. In addition, we reported a reduced incidence of TVR-related rash in HIV-coinfected patients.
The rate of rash observed in monoinfected group (50%) is similar to what reported in TVR registration trials: 49%,1 50%,2 and 37%.4 Similarly, the percentage of coinfected patients who developed rash (13%) is the same rate found in the biggest trial to date available on patients with HIV/HCV coinfection treated with TVR (13%).7 These data were confirmed in other small studies focused on effectiveness and tolerability of TVR-containing regimens in coinfected patients.5,6,8 The lower incidence of rash seen in coinfected patients might be related to the immunological impairment and other immunological dysfunctions caused by HIV. It is interesting to note that notwithstanding the good viroimmunological control of all HIV/HCV-coinfected patients in our cohort, the 2 HIV subjects who developed rash had very high baseline CD4+ T-cell counts (1701 and 795 cells/mm3).
Although the small number of patients in our cohort suggests caution on interpretation, our data support the effectiveness of TVR in the treatment of HCV infection with advanced liver fibrosis. Moreover, direct comparison between HIV/HCV-coinfected and HCV-monoinfected subjects demonstrated similar rates of virologic response and adverse events, with a remarkably reduced incidence of rash in patients with HIV. These findings could favor increased clinicians' confidence in starting effective TVR-containing anti-HCV therapy in those who urgently need treatment, irrespective of HIV status. This could be crucial in settings with delayed access to new, less toxic, direct acting antivirals.
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