Limited clinical trial data suggest that the safety and tolerability of hepatitis C virus (HCV) triple therapy (telaprevir/pegylated interferon/ribavirin) in patients infected with HIV is comparable to that observed in HCV monoinfected patients . Following the Food and Drug Administration approval of telaprevir for the treatment of HCV in HIV-negative patients in May 2011 [http://http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256299.htm (accessed 25 May 2011)]. we started off-label use of telaprevir in HIV-infected patients mainly through an industry-sponsored patient assistance program. This study reports the rate of grade IV adverse events; and HCV treatment discontinuation during HCV triple therapy in a university HIV-hepatitis clinic.
This is a retrospective cohort analysis of serious adverse events and treatment discontinuation rates attributable to HCV triple therapy. The study included all consecutive HIV/HCV coinfected patients treated for HCV using triple therapy at the University of California San Diego (UCSD), Owen hepatitis clinic. Upon Owen clinic enrollment, all patients provided written informed consent for the collection of data relevant to their clinical care and subsequent analysis. HCV treatment consisted of telaprevir 2250 mg/day (two tablets every 8 h) for the first 12 weeks; pegylated interferon 180 μg/week (single subcutaneous injection); and weight-based ribavirin except in patients with coexistent hematologic conditions in whom fixed ribavirin dose of 800 mg was used, for a total of 48 weeks of HCV therapy. The National Institutes of Health Division of AIDS grading system was used to rate severity of adverse events . Definitions of select grade IV adverse events included the following: anemia: hemoglobin level less than 6.5 g/dl or higher levels that required blood transfusion due to symptoms; neutropenia: absolute neutrophil count less than 500/μl; infections other than HIV that were considered life-threatening (e.g., septic shock); skin eruptions: extensive or generalized skin eruptions or Stevens–Johnson syndrome or toxic epidermal necrolysis; liver decompensation [development of ascites, encephalopathy, hepatic dysfunction (International Normalized Ratio of prothrombin time: INR >3.0 and direct hyperbilirubinemia >5.0 × upper normal limit)]; and neuropsychiatric [behavioral change potentially harmful to self and others (e.g. suicidal and homicidal ideation or attempt, acute psychosis)]. HCV treatment monitoring was conducted by a team of HIV physicians with certification in infectious diseases, HIV clinical pharmacists, a psychiatrist, and a substance counselor. Our pharmacists facilitated medication refills and assessed adherence in a structured interview at clinic visits. Assessment of barriers to care included evaluation of self-reported illicit substance and/or alcohol use within 3 months of HCV treatment initiation by completion of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) instrument  and subsequent evaluation by the substance abuse counselor; formal psychiatric evaluation; and unstable housing. Patients received weekly clinical and laboratory assessments during the first 4 weeks, biweekly until week 12, and then monthly until the end of HCV treatment, unless clinical circumstances dictated more frequent monitoring. The clinic protocol for management of anemia during the study period included step-wise dose reductions of ribavirin according to product label (200 mg/week) with concurrent use of erythropoietin (40 000 units/week) for hemoglobin levels of 10 g/dl or less. Severity of adverse events and rates of HCV treatment discontinuation were stratified according to the degree of liver fibrosis using the modified Ishak histological score system: minimal (F0-2) and advanced (F3-6) . We used χ 2 analysis or Wilcoxon-rank sum test to compare categorical or continuous variables, respectively, using NCCSS version 8.0 (Kaysville, Utah, USA).
Between 29 July 2011 and 12 October 2012, 24 HIV-1/HCV-genotype 1 coinfected patients were treated for HCV using triple therapy. Table 1 describes patient demographics, HCV genotype subtype, HCV viral load, interleukin-28B gene polymorphism allele genotype, prior HCV therapy status, CD4+ cell count, antiretroviral regimen, and liver fibrosis scores prior to HCV therapy initiation. Of the 10 patients who had received prior HCV therapy with pegylated interferon and ribavirin, all but one (who developed severe depression) had tolerated HCV treatment well (Table 1). Nineteen (79%) patients had remote history of intravenous drug use and three (13%) had hemophilia A. Seven patients (38%) had severe neuropsychiatric disease, but were cleared by our psychiatrist prior to HCV therapy. Two were actively using illicit substances (not intravenously) and one had unstable housing (Table 1). Four patients had other concurrent medical illnesses including psoriasis, epilepsy, factor V deficiency and β-thalassemia minor (patients 10, 14, 17, and 19, respectively in Table 1). Three HIV treatment-experienced patients with prior documented resistance to multiple HIV medications were switched to other combinations of antiretroviral therapy to minimize potential medication interactions with telaprevir (patient 6, 7, and 18 in Table 1). None of the patients had decompensated liver disease at the start of anti-HCV triple therapy. The median (range) of hemoglobin and serum creatinine prior to HCV treatment initiation were 14.6 g/dl (11.7–17.8) and 1.01 mg/dl (0.61–1.52), respectively. All patients had undetectable HIV viral load at the time of HCV therapy initiation.
The median (range) ribavirin dose at the time of HCV therapy initiation was 13.7 mg/kg (9.3–15.9). Eight patients had minimal liver fibrosis (F0–2/6) and 13 had advanced liver fibrosis (F3–6/6). Twelve patients (50%) developed grade IV adverse events and seven (29%) discontinued HCV therapy due to adverse events. Most adverse events that resulted in HCV treatment discontinuation were directly attributed to HCV treatment toxicity rather than exacerbation of underlying comorbidities (Fig. 1). Among the patients who developed life-threatening infections requiring hospital admission (n = 3), none were neutropenic. There was no significant difference between patients with minimal and those with advanced liver fibrosis in terms of the proportion of patients who developed severe adverse events [6/8 versus 8/13 (P = 0.53, χ 2 test)] or discontinued HCV therapy due to adverse events [4/8 versus 3/13 (P = 0.20, χ 2 test)]. Telaprevir directly contributed to severe adverse events in seven of 12 patients [anemia requiring blood transfusion (5) and dermatologic (2), including one case of hypersensitivity reaction]. The only patient who developed a hypersensitivity reaction presented with generalized skin rash with early vesicle formation and mucosal lesions concerning for early Stevens–Johnson syndrome 5 days after initiating HCV therapy. The patient denied ingesting any new or unusual foods or starting any other medication that could have accounted for his skin reaction. The median time (range) after HCV therapy initiation to require a blood transfusion was 5 weeks (4–16). None of the three patients with hemophilia required a blood transfusion. The initial median hemoglobin level (13.7 versus 14.9 g/dl, P = 0.36, Wilcoxon-rank sum test) and ribavirin dose (12.9 versus 13.7 mg/kg per day, P = 0.94, Wilcoxon-rank sum test) did not differ between patients who required a blood transfusion and those who did not. Of the 17 patients who continued HCV triple therapy without discontinuation due to severe adverse events, nine patients completed 48 weeks of treatment and remain HCV RNA-negative [4 weeks (n = 3), 12 weeks (n = 3), and 24 weeks (n = 3) after HCV treatment discontinuation], five did not respond to therapy, two developed HCV viral relapse, and one patient with ongoing substance abuse abandoned therapy after 24 weeks (Table 1). The HCV viral load of the five patients who did not respond to HCV therapy decreased more than 2 logs from baseline levels, but their HCV viral load was still more than 1000 IU/ml after 4 weeks of HCV triple therapy [median (range) 15 827 (2672–60927 IU/ml)]. Medication noncompliance was not judged to be an important factor in nonresponse. Three patients who discontinued HCV therapy before week 48, including the two patients with ongoing drug use, achieved HCV cure (patients 4, 12, and 14 in Table 1). None of the patients developed HIV viral breakthrough while on HCV therapy.
In this HIV clinic-based experience, a high rate of grade IV adverse events and treatment discontinuations were seen during HCV telaprevir-based treatment, despite a comprehensive multidisciplinary clinical monitoring system.
A phase II clinical trial for the treatment of HCV using telaprevir in HIV-infected patients found that adverse events were mostly mild in nature and that 8% discontinued treatment due to adverse events related to therapy . Reasons that could account for the present study's increased rate of adverse events include the following. First, clinical trials often exclude patients with ongoing medical and social barriers to care . In our study, 38% of patients had ongoing medical-neuropsychiatric-social comorbidities. Second, the use of weight-based ribavirin dosing may have been associated with higher rates of severe anemia, although we found no difference in the median initial ribavirin dose in patients who required a blood transfusion versus those who did not. Of note, at the time we made the decision to use weight-based ribavirin dosing, the ongoing phase 2b clinical trial of telaprevir in HIV-coinfected patients was using weight-adjusted ribavirin dose in some European centers . Third, if we had been more aggressive with ribavirin dose reduction, rates of severe anemia requiring blood transfusion may have been lower. The treatment of these patients was initiated before it was clear that aggressive ribavirin dose reduction would not affect the chances of achieving HCV sustained viral response . For example, if a patient was receiving 1200 mg of ribavirin and their hemoglobin decreased to 10 g/dl following 4 weeks of HCV triple therapy according to our protocol, we would have decreased ribavirin dose to 1000 mg instead of 600 mg as recent studies have shown .
The observed high rate of serious adverse events (50%) and treatment discontinuations (29%) occurred irrespective of liver fibrosis stage. But our small sample size of patients with available liver biopsy results (n = 21) provided only 10% power to detect the observed difference in proportion of HCV treatment discontinuation due to adverse events between patients with minimal versus advanced liver fibrosis as significant. Nevertheless, our findings are in line with those of a large population-based study in HCV-monoinfected patients with cirrhosis treated with telaprevir, in which higher rates of adverse events and treatment discontinuations were observed than in phase 3 clinical trials [7,8]. Furthermore, if the three patients in our cohort whose HCV viral load has remained undetectable 4 weeks after finishing HCV triple therapy ultimately achieve HCV sustained viral response after 12 weeks [http://http://www.natap.org/2012/HCV/041012_03.htm (accessed 25 April 2013)], then one in two of our HIV patients who were treated with telaprevir/pegylated interferon/ribavirin would be cured for HCV at the risk of one in two developing a serious adverse event.
In summary, our rate of HCV treatment discontinuation due to adverse events when using telaprevir/pegylated interferon/ribavirin in an HIV clinic-based setting was three times higher than the rate reported in a phase 2b clinical trial. Although more data are needed, careful consideration of the risks and benefits of therapy should be undertaken, given the high rate of severe adverse events and prospects for more efficacious and better-tolerated interferon-sparing therapy in the near future.
E.C. contributed to clinical care, study design, data collection, data analyses, and manuscript preparation. D.W. contributed to clinical care, study design care, and manuscript preparation. F.T., C.B., B.C., J.L., and L.H. contributed to study design and clinical care. Wm.C.M. contributed to study design and data analyses. All authors read and approved the final manuscript. The authors would like to thank Mr Joseph Montanez for providing substance counseling services to our patients.
This work was supported in part by the Clinical Investigation Core of the University of California San Diego Center for AIDS Research [AI036214], the CFAR Network of Integrated Clinical Systems (CNICS) [R24 AI067039-01A1], and the Pacific AIDS Education and Training Center (PAETC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
The authors have no conflict of interest.
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