Hepatitis C Therapeutic Management Patterns Among Gastroenterologists in the United States: A National Survey

Sean P. Hurley, Matthew J. Hepburn, Michael Russo, Eric J. Lawitz

 

Background / Aim

Hepatitis C affects 1.8% of the population of the United States. The development of combination therapy for hepatitis C (pegylated-interferon and ribavirin) has allowed gastroenterologists to offer an effective therapeutic option, contingent upon adherence to the regimen. In order to assess clinical practice patterns of clinicians, a nationwide survey was conducted of gastroenterologists and hepatologists. Our hypothesis was that a majority of gastroenterologists would follow an acceptable approach to the management of patients with hepatitis C but substantial practice variation exists.

 

Methods

A thirty-one-question survey was mailed to 5000 gastroenterologists nationwide. Six questions assessed demographics of the respondents, while 25 questions focused on the management of patients with hepatitis C. Some of the major topic areas included therapeutic choices and the management of medication side effects.

 

Results

A total of 1002 surveys were returned of which 17.8% were returned. The therapy of choice (77% of respondents) is pegylated interferon and weight-based ribavirin. Ninety percent of respondents treat genotype 2 and 3 patients for 24 weeks. The data on early virologic response has resulted in 75% of respondents discontinuing therapy at 12 weeks if a 2 log or greater reduction in viral load is not achieved. Forty-five percent of respondents initially manage severe fatigue with dose reduction and 87% will also manage cytopenias with dose reduction. Forty-six percent of respondents will treat cytopenias with growth factors as the initial treatment strategy however insurance reimbursement limits their use more than 50% of the time in 14% of respondents. Twelve percent use gabapentin for myalgias/arthralgias and 12% will use pharmaceutical agents to combat fatigue (methylphenidate, modafenil, testosterone). Management of depression includes a 13% rate of prophylactic antidepressant use. Most (74%) of respondents will manage therapy-induced depression themselves. SSRI's are the agents of choice with fluoxetine and citalopram/escitalopram the most frequently prescribed.

 

Conclusion

Physicians' practice patterns are consistent with the recommendations of the 2002 NIH Consensus Statement. The primary strategy to manage adverse events is dose reduction. Alternative strategies to manage adverse events are being used across the United States. Prospective randomized placebo controlled trials are needed to critically examine the effectiveness of these alternative strategies.

 

The authors also noted:

  • Physicians in high-volume practices are less likely to reduce doses or discontinue therapy when managing side effects of therapy
  • Physicians who dose reduce or discontinue therapy as first line management of fatigue or cytopenias are less likely to have their patients complete therapy.

Induction-Dose of PEG-Interferon Alfa-2b in Combination with Ribavirin in HCV-Non-Responders to Prior Interferon or Interferon-Ribavirin Combination Therapy: Results of a French Multicenter RIBAPEG-NR Trial

Isabelle Rosa, Herve Hagege, Veronique Auray-Cartier, Philippe Cassan, Claire Wartelle, Jacques Denis, Jean Pierre Arpurt, Olivier Nouel, Dany Gargot, Bernard Nalet, Alex Pariente, Michel Chousterman, RIBAPEG-NR Study Group

 

Introduction

Retreatment with Peg-interferon (PEG-IFN) and ribavirin (RBV) in HCV-chronic infected patients who failed to respond to previous therapy yielded a sustained virologic response (SVR) rate of about 10%. This study was to determine whether better results could be achieved with an induction therapy using higher doses of PEG-IFN alfa-2b in combination with RBV.

 

Aim

The aim of this multicenter, randomized, open-label study was to assess the efficacy and safety of two regimens of PEG-IFN alfa-2b plus RBV in patients with prior non-response to interferon monotherapy or standard combination therapy.

 

Methods

Patients were randomly assigned to receive 1) PEG-IFN alfa-2b 2.0 μg/kg/wk plus RBV 800 mg daily x 8 weeks, then PEG-IFN alfa-2b 1.0 μg/kg/wk plus RBV 800 mg daily x 40 weeks, or 2) PEG-IFN alfa-2b 1.0 μg/kg/wk plus RBV 800 mg daily x 48 weeks. Patients were stratified according to HCV genotypes (1 vs non-1) and prior treatment (monotherapy vs combination therapy). Treatment was stopped if patients remained HCV RNA (+) at week 24.

 

Results

233 patients were enrolled in 53 centers : 118 in the induction group and 115 in the non-induction group. Baseline characteristics were as follows : genotype 1 : 69 %, HCV RNA titer > 800 000 IU/ml : 71%, fibrosis 3-4 : 52%, cirrhosis : 24 %, prior monotherapy : 42 %. At week 48, the virological response rate was significantly higher in the induction dose group (30.5% vs 20%, p= 0.045). At week 72, there was no difference in SVR rate in either group: 16% vs 15%. Predictive factors of SVR were the genotype non 1 (26% vs 11%, p=0.002) and prior IFN monotherapy treatment (21% vs 11%, p=0.002). Significantly more patients relapsed in the induction group : 14.4% vs 5.2% ( p=0.015).

 

Conclusion

End-of-treatment virological response is significantly higher in the induction group. However, the SVR is similar in both groups due to significantly more relapsers in the induction group. In this study, the benefit of an induction regimen with Peg-Intron is not demonstrated.  Therefore, it is suggested that a longer induction period or a longer treatment duration be considered in order to maintain the benefit of the induction regimen.

 

Differences in Physicians' Recommendations Regarding Over-The-Counter Analgesic Use in Patients with Chronic Liver Disease

Monica B. Awsare, Victor J. Navarro, Stanton Smullens, Barbara Turk, Douglas Drake, Steven K. Herrine

 

Background

There are currently no clear recommendations regarding the "safe" use of over-the-counter analgesics (OTCAs) in patients with chronic liver disease (CLD). As a result, physicians' perceptions of the safety of OTCAs in patients with CLD may differ.

 

Aim

To document physicians' perceptions regarding the safe use of OTCAs in patients with CLD.

 

Methods

A seven-question, web-based survey was sent to all 400 university health system physicians, representing all major specialties, with email accounts at our center. The survey queried recommendations regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP) in CLD patients, with and without cirrhosis. Survey options were "use without any special restrictions", "use but take less than recommended on the product label", "use but do not exceed what is recommended on the product label", and "do not use at all". Respondents were also asked their choice for cirrhotic patients with pain: APAP, NSAIDS, or "avoid any OTCA".

 

Results

A 20% response rate was obtained. Of the 79 total respondents, 18 were gastroenterologists (GIs); the remaining physicians (non-GIs) comprised primarily internists, family practitioners, and closely related specialties (38). Regarding the use of APAP in cirrhosis, 51% of non-GIs recommended "do not use at all" compared with none of GIs. Only 50% of GIs recommended using up to the maximum labeled dose of APAP. Regarding the use of NSAIDs in cirrhosis, 39% of non-GIs recommended "use but less than recommended on the product label" while 41% of GIs recommended not to use NSAIDs at all. All respondents were more permissive in regards to the use of OTCAs in chronic hepatitis without cirrhosis. Regarding treating pain in cirrhotics, 53% of non-GIs responded "avoid any OTCA" while the majority of gastroenterologists (75%) chose APAP. However, even among gastroenterologists, 19% chose to avoid any OTCA in cirrhotics.

 

Conclusion

1)     GIs and non-GIs greatly differ greatly in their perceptions of OTCA safety in patients with CLD. Despite the lack of evidence to justify these perceptions, we found that non-GIs perceive NSAIDs as safer than APAP in cirrhotics.

2)     This preference is troubling given the possibility of worsening a compensated or decompensated cirrhotic with NSAIDs.

3)     This data also suggests a concerning practice of under-treating pain in cirrhotic patients. These findings emphasize the need for more research and education in the use of OTCAs in CLD patients.

 

Treatment of Chronic Hepatitis C with Pegylated Interferon alfa-2a plus Ribavirin in Hemophiliac Patients

Reza Malekzadeh, Shahin Merat, Amir A. Sohrabpour, Siamak Khaleghi, Katakyoun Samimi-Rad

 

Introduction/ Aim

Hemophiliac patients who received clotting factors before mid to late 1980s were almost universally infected with hepatitis C. Since liver biopsy is associated with a high risk of bleeding in this population, we aimed to evaluate the success of a biopsy-independent treatment protocol.

 

Methods

In a prospective open-label study, 37 hemophiliac patients (35 male, 2 female) with chronic hepatitis C infection were enrolled. All patients were over 18 years of age and had positive HCV RNA and elevated ALT levels at baseline. Patients with HIV and HBV infection or other hepatic diseases were excluded. Liver biopsy was not performed due to the potential risks involved in hemophiliacs. The patients were planned to receive pegylated interferon alfa-2a, 180μg weekly and ribavirin 800mg daily for 48 weeks and be followed for at least 24 weeks after the end of treatment. Genotypes were determined when possible. Treatment was adjusted as necessitated by side effects.

 

Results

Two patients withdrew after 2 weeks due to severe flu-like symptoms. One patient died of a cerebrovascular accident on week 18 of treatment, considered to be unrelated to therapy. Two patients refused to stay on therapy after PCR turned negative at week 24 of treatment. Only 16 patients were genotyped. Genotypes 1a, 1b, 2b, and 3a were detected in 6, 2, 1, and 5 patients respectively and two patients were non-typable. In the remaining patients, HCV RNA became negative in all but one patient at the end of 48 weeks of treatment 96.9% (31/32). At 24 weeks after end of treatment, four more patients became viremic. The per-protocol and intention-to-treat rates for sustaind virologic response was 84.4% (27/32) and 73.0% (27/37) respectively. Dose reduction was necessary in 6 cases, 1 due to aggressive behavior, 3 due to neutropenia (neutrophil count < 750 /mm3), and 2 due to anemia (Hb < 10 g/dL).

 

Conclusion

A biopsy-independent protocol of combination therapy with pegylated interferon alfa-2a and ribavirin for 48 weeks in hemophiliac patients with chronic hepatitis C resulted in a very high rate of sustained virologic response. No life-threatening adverse effects were observed.

 

Risk Factors and Long-Term Evolution of Thyroid Dysfunction During Repeated Antiviral Treatments in 221 Patients with Chronic Hepatitis C

Xavier Moncoucy, Florence Leymarie, Stephane Levy, Brigitte Bernard-Chabert, Damien Jolly, Brigitte Delemer, Guillaume Cadiot, Marie-Daniele Diebold, Gerard Thiefin

 

Aim

The purpose of this study was to identify the predictive factors of dysthyroidism occuring during repeated antiviral treatments against chronic hepatitis C and to evaluate the long-term outcome of these patients.

 

Patients and methods

Patients treated for chronic hepatitis C between 1990 and 2001 were analyzed retrospectively. Patients with dysthyroidism before treatment and patients positive for hepatitis B surface antigen or human immunodeficiency virus antibodies were excluded. Serum thyroid-stimulating hormone (TSH) was measured before treatment and every 2 or 3 months during antiviral treatments. Dysthyroidism was defined by an abnormal serum TSH level checked twice.

 

Results

Two hundred twenty one consecutive patients were included. Among them, a hundred were treated twice, 21 had 3 treatments and 3 had 4 treatments. There was no significant difference in the frequency of dysthyroidism during the first and the second treatment, respectively 4,1% (n=9) and 6,2% (n=6). The female gender (p < 0,05) and the presence of anti-thyroid peroxydase or antimicrosome antibodies before antiviral treatment (p< 0,01) were predictive factors of dysthyroidism. The level of pretherapeutic serum TSH was statistically higher in the dysthyroidism group (p < 0,05). Treatment by interferon and ribavirin did not increase the risk of dysthyroidism compared to monotherapy by interferon. Pegylated interferon was not a risk factor compared with conventional interferon. Thirteen patients had hypothyroidism (2 of them as a result of biphasic thyroiditis) and 2 had hyperthyroidism. The antiviral treatment was continued in 11 out of 15 patients. Seven out of 13 patients with hypothyroidism required an indefinite treatment (range: 15 to 90 months).

 

Conclusions

In our series, about 5 % of patients with chronic hepatitis C had a dysthyroidism during interferon therapy. Predictive factors for dysthyroidism were female gender and positive thyroid antibodies before treatment. Absence of dysthyroidism at the time of first antiviral treatment does not preclude from the risk of dysthyroidism at the time of second treatment. Hypothyroidism requires indefinite opotherapy in about half of the cases.

 

Experience with Pegylated Interferon and Ribavirin Therapy for Hepatitis C Patients with Compensated Cirrhosis in an Urban VA Hospital

Abhinandana Anantharaju, Linda Piersall, JoAnn Stegmaier, Bernard Nemchausky, Frank Iber, Nikunj Shah

 

Background

Hepatitis C virus infection (HCV) & cirrhosis from HCV are more prevalent among US veterans than in the general population. The treatment with pegylated interferon (PI) & ribavirin (R) is the current standard of therapy for HCV. The SVR using PI & R in veterans with HCV is unknown. The patients with cirrhosis respond poorly to interferon therapy than noncirrhotics. In the general population, the SVR using PI & R in compensated HCV cirrhotics have been reported to be 43-44%. We evaluated the efficacy of combination therapy with PI & R in veterans with compensated HCV cirrhosis.

 

Methods

Seventy eight male veterans with HCV cirrhosis who initiated PIs (alfa 2a & 2b) & R combination therapy between May 2001 & October 2003 were evaluated. The patients who are still on treatment were excluded from the analysis. The PIs were used at standard doses & Ribavirin was given at a dose of 11 mg/kg. Patients were followed in a dedicated multidisciplinary HCV clinic. Routine labs & HCV-RNA levels were monitored. Genotypes & pretreatment liver biopsies were obtained. Erythropoietin & filgrastim were used as necessary.

 

Results

Fifty-five HCV cirrhotic patients (Child’s score 5.8 ± 1.2) met the inclusion criteria. The mean age was 55.1 ± 7.2 years. The Caucasians were 78.2%, African-Americans 18.2%, & Hispanics 3.6%. Forty-six patients received PI-2b & 9 patients received PI-2a. The mean duration of therapy was 35.0% ± 16.8 (range 4-48) weeks. Mean ALT & HCV RNA levels at entry were 118 ± 55.5 U/L & 8.6 ± 8.6 x 105 IU/ml respective. Patients with genotype 1 were 76.4%. Twenty (36.4%) patients demonstrated early viral response (EVR). Of which, 13 (23.6%) patients experienced an end of therapy viral response (ETR) & 6 (11.8%) patients had SVR. All 6 patients had completed 48-week therapy. Among those who completed 48-week therapy (n =31), the SVR was 19.4%. None of the patients without EVR showed ETR or SVR. Thirty-three (60%) patients had 45 incidences of side effects related to therapy. The side effects included psychiatric disturbances (22.2), anemia (28.9%), thrombocytopenia (15.6%), neutropenia (11.1%), & hypothyroidism (4.4%). None of the patients had decompensation during therapy. Seventeen patients did not complete 48-week therapy due to side effects.

 

Conclusions

The US veterans with compensated cirrhosis due to HCV show poor response (SVR by intent-to-treat 11.8%) to combination therapy with pegylated interferon and ribavirin than general population. Patients who have EVR and complete 48-week therapy achieve SVR.

 

Use of an Office-Based 2-Question Instrument for Detecting Depression in Hepatitis C Patients

David H. Winston, Donna C. Winston

 

Introduction

We have previously shown that the use of an office-based 2-question instrument (HEP-2Q), administered verbally by the gastroenterologist directly to the patient, is as effective as the Center for Epidemiologic Studies Depression Scale (CES-D) in detecting depression during treatment of hepatitis C (HCV) patients.

 

HEP-2Q

During the past year (administered at initial visit) OR Since your last visit (administered at all follow up visits--

 

1)     Have you been bothered by agitation, irritability, anger, crying, feeling down, sad, depressed or hopeless?

2)     Have you been bothered by little or no interest or pleasure in doing things and have you not been as involved with friends and family?"

 

We have now used the HEP-2Q in 109 HCV patients and found it to be a rapid, reliable, simple and effective tool for the gastroenterologist to use for diagnosing depression in HCV patients during treatment. None of the patients developed depression that was not first diagnosed through use of the HEP-2Q. Since screening for depression both before and during treatment of HCV has become an important management strategy in the therapy of HCV, we postulate that the use of the HEP-2Q will allow for early detection of depression by the office-based gastroenterologist. Antidepressants can then be more timely prescribed and help HCV patients adhere to and complete therapy.

Winston DH. Irish J Med Sci. 2003;172:S40-41

 

Conclusion

  • We have now used HEP-2Q in 109 patients and have found it to be a simple and effective tool for timely diagnosis of depression in the office-based clinical practice of HCV.
  • Based on the results, we postulate that the administration of the HEP-2Q by office based gastroenterologist will facilitate screening for depression in HCV patients. This should result in:
    • Early detection of depression
    • Anti-depressants being prescribed early in the course of depression before full blown depression develops

 

Interferon-Based Therapy of Chronic Hepatitis C in Adults with a History of Treated Malignancy

Maya Gambarin-Gelwan, Nancy Lau, Sara H. Olson, Sumera Dawood, Hans Gerdes, Robert C. Kurtz

 

Introduction

Chronic hepatitis C (CHC) is a common problem in cancer survivors. While interferon (IFN)-based therapy is currently the standard of care for patients with CHC, there is no data available on the outcome and tolerability of IFN-based therapy in this highly selected group of patients.

 

Aim

We undertook a retrospective review to evaluate the efficacy and side-effects (SE) of IFN-based therapy for CHC in patients with history of treated malignancies.

 

Methods

Demographic data, factors related to the HCV infection, co-infection with hepatitis B (HBV) and human immunodeficiency virus (HIV), alcohol use, stage of liver disease, and CHC treatment were reviewed.

 

Results

28 patients were identified (mean age 48.7 years) who fit our criteria. 68% were men. 71% were genotype 1. Three patients were co-infected with HBV, 5 co-infected with HIV. 54% had advanced stage fibrosis (stage III-IV) before treatment. 57% had a history of solid tumor. Twenty patients received chemotherapy, 6 received radiation therapy; 2 were bone marrow transplant recipients. The mean time from cancer-related treatment to IFN-based HCV therapy was 7.6 years. With the exception of two, all patients were in complete clinical remission from their primary malignancy. One patient had stable CML, the other had low-grade lymphoma (LGL) managed expectantly. 36% were treated with combination standard IFN-α and ribavirin (RBV); 57% with combination pegylated IFN (PEG IFN) and RBV; 7% with PEG IFN alone. 39% completed the course of therapy. Treatment was discontinued in 32% due to SE, and 25% due to the lack of virologic response. Therapy was discontinued after 4 weeks in the patient with LGL due to progression of lymphoma. An end of treatment response (ETR) was achieved in 39% . Sustained virologic response (SVR) was achieved in 31% (SVR data not yet available in 2 patients). Patients with advanced fibrosis had a worse outcome when compared to those with stage I-II (ETR 21 vs 55%; SVR 14 vs 55%, respectively). Treatment-induced SE were moderate, with flu-like symptoms and fatigue being the most common (75%). 36% required dose reduction; 25% required epoetin alfa injections. Therapy was discontinued in only one patient due to significant thrombocytopenia.

 

Conclusions

Patients with CHC, and history of treated cancer should be strongly considered for IFN-based therapy for HCV infection. Cancer survivors do not differ substantially in their response to IFN-based therapy or side-effects when compared with studies of patients without a past history of treated cancer.