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Treatment of Hepatitis C Virus (HCV) Infection: The Interferon Story

By Michael Marco

July 9-14, 2000

The irony, then, is that patients with the lowest likelihood of progression and who need therapy the least are precisely the ones who are most likely to respond and benefit most. In contrast, those who have features correlating with more progressive disease, who require therapy the most, are the ones least likely to respond and to benefit.
-- JL Dienstag, The Natural History of Chronic Hepatitis C and What Should We Do About It?

Current therapies are still unsatisfactory and should be limited to patients who have evidence of moderately severe or progressive disease.
-- JH Hoofnagle, Therapy of Chronic Hepatitis C


Introduction
Endpoints: Criteria and Definitions
IFN Monotherapy
Combination Therapy: Interferon + Ribavirin
Factors Predictive of a Response to Therapy
Side Effects
IFN Histologic Improvement in Responders & Non-responders and its Implications
HCV Treatment of Selected Patients and Populations
Patients with Acute HCV
HCV Patients with Persistenly Normal ALT Levels
HCV Patients with Cirrhosis
Children and the Elderly with HCV
HIV/HCV Coinfected Patients
Conclusion
References


Introduction

There are limited treatment options for people with HCV. For approximately 70% of HCV-infected individuals in the United States and Europe, currently approved treatments are seemingly ineffective (McHutchinson 1998; Poynard 1998). For the rest, however, treatment can result in what some people would consider a "cure." Interferon-alpha (IFN) was the gold standard of treatment for HCV for many years, and now IFN in combination with the nucleoside analog ribavirin is the regimen of choice. There are as many arguments to recommend starting treatment as there are to wait for safer and more effective ones.

In this chapter, I will analyze existing treatment data of FDA-approved therapies in order to examine questions of who should start, when to start, and when to stop anti-HCV therapy. If physicians treating HCV do not know all of this by heart, they should. It is imperative they be able to communicate this information so their patients can make informed decisions about when and if to start treatment. According to Willis Maddrey, "The appropriate education of the patient is both an obligation and an opportunity for the physician" (Maddrey 1999).


Endpoints: Criteria and Definitions

Before discussing results from treatment studies, it is important to first define the criteria used to establish response rates. Until recently, investigators used numerous terms and definitions to describe treatment response, and this lack of standardization makes it difficult to compare study results (Lindsay 1997).

A beneficial response to therapy has been based on three endpoints:

They are measured at two separate time points:


IFN Monotherapy

Interferon is a naturally occurring protein secreted by mammalian cells. It has antiviral, anti- inflammatory and immunoregulatory properties (Borden 1981). Its exact mechanism of action against HCV is incompletely understood. (See the "HCV Virology" chapter for more information.)

In 1986, and before the HCV virus was identified (it was simply named non-A non-B hepatitis), Hoofnagle and colleagues at the National Institutes of Health (NIH) conducted the first study of IFN treatment for HCV (Hoofnagle 1986). Data from this and subsequent randomized controlled trials of IFN documented a reduction in ALT levels and improvement in liver histology. (There was no viral load monitoring since no one knew what virus was being treated.)

IFN was approved by the Food and Drug Administration (FDA) in 1991 for the treatment of chronic HCV at the dose of three million units (MU) subcutaneously (injection under the skin) three times a week (tiw) for six months. In 1997, the FDA granted marketing approval for IFN extended dosing of 12 to 24 months. IFN is also indicated for the treatment of hairy cell leukemia, AIDS-related Kaposi's sarcoma, chronic myelogenous leukemia (Roferon-A), malignant melanoma (Intron-A), follicular lymphoma (Intron-A), and condylomata acuminata (Intron-A) (PDR 2000).

Between 1986 and 2000, over 100 studies of IFN monotherapy for the treatment of HCV were conducted. Overall, a six-month course of IFN at 3 MU tiw has been shown to induce a biochemical end of therapy response (ETR) of 40-50% and sustained response (SR) of 15-20%. Virologic ETR is usually 30-40%, and the SR drops to 10-20% (NIH Consensus Panel 1997). Biochemical and virologic responses have usually been accompanied by histologic improvement (Poynard 1996; Marcellin 1997; Shiffman 1997).

While an SR is seen in ~20% of individuals on IFN monotherapy, these sustained responses are usually durable and considered by some as a "cure." Marcellin and colleagues studied 80 French HCV patients who had sustained a biochemical and virologic response to IFN monotherapy for at least 12 months (Marcellin 1997). Patient's serum and liver tissue samples underwent PCR analysis, ALT levels were measured, and liver biopsies were performed at least once over a six-year period. During a mean follow-up of four years (range: 1-7.6 years), 93% of patients had persistently normal ALT levels, 96% remained undetectable, 62% had normal or nearly normal histologic findings, and liver HCV RNA was undetectable in all 27 patients tested. According to Marcellin:

The absence of detectable liver HCV RNA 1 to 5 years after treatment is consistent with the view that HCV infection may be cleared with interferon-alpha therapy in patients with chronic hepatitis C. (Marcellin 1997)

There has been considerable debate about the optimal dose and duration of IFN monotherapy. In the U.S. IFN is approved for treating HCV at the 3-MU dose; the 6-MU dose is indicated only for retreatment of IFN-relapsers (PDR 2000). In Europe, however, the 6 MU tiw dose is indicated for the first three months, followed by the 3 MU dose. Poynard and colleagues conducted a meta-analysis using 37 randomized controlled trials to evaluate the benefits of higher dose (6 MU vs. the standard 3 MU) and longer treatment duration of IFN monotherapy (12 months vs. 6 months) (Poynard 1996). Using only biochemical endpoints in the analysis, the ETR for the 6-MU dose was not statistically different from the 3-MU dose, but the 12-month course was shown to generate a 16% increase over the 6-month course (9% vs. 23%; P<0.001).

These data assisted a panel of expert international hepatologists at the NIH Consensus Development Conference in 1997 in recommending the dosage of 3 MU tiw for 12 months. An interim assessment at three months was recommended. If a patient's ALT level had not normalized and HCV RNA was still detectable, "interferon therapy should be stopped, because further treatment is unlikely to induce a response" (NIH Consensus Panel 1997). If either the ALT was normal or the HCV RNA was undetectable, continuation of treatment for the full 12 months was recommended.

The NIH Consensus Panel, which convened before the results of the combination IFN/ribavirin studies had been published, made the following judgments:

IFN therapy is indicated for chronic HCV in patients 18 to 60 years of age who have:

Indication for IFN therapy is less clear for patients who:

IFN therapy is not indicated for patients with:

IFN therapy is contraindicated for patients with:

Last, therapy should not be limited (forbidden) by:

There are many different commercially available interferons which have been evaluated in HCV studies: IFN alfa-2b (Intron A, Schering-Plough); IFN alfa-2a (Roferon-A, Hoffmann-La Roche); IFN alfa-n1 (Wellferon, Glaxo Wellcome); consensus interferon (Infergen, Amgen). According to the NIH Consensus Panel, "All forms of interferon appear to have similar efficacy in chronic hepatitis C" (NIH Consensus Panel 1997).


Combination Therapy: Interferon + Ribavirin

Ribavirin is a synthetic guanosine [nucleoside] analog which has in vitro activity against a range of RNA and DNA viruses (Patterson 1990). In monotherapy studies in patients with chronic HCV, ribavirin has been shown to decrease ALT levels, yet had no HCV antiviral activity (Bodenheimer 1997). Also tested in HIV antiviral studies, ribavirin monotherapy demonstrated no clinical antiviral activity (Roberts 1990); nonetheless, it has demonstrated profound synergistic effect with IFN in improving response rates in chronic HCV studies. Its exact mechanism of action, however, remains incompletely understood.

Combination IFN and ribavirin (IFN/RBV) was initially studied in pilot and phase I-II studies of patients who were either untreated or had experienced relapse; results suggested that IFN/RBV was more effective than IFN alone (Schvacz 1995; Schalm 1997; Reichard 1998).

Two large, multicenter, randomized trials comparing IFN/RBV with IFN in untreated patients with chronic hepatitis C were conducted in the U.S., Canada, and Europe (McHutchinson 1998; Poynard 1998). The U.S. study conducted by McHutchinson and colleagues randomized 912 patients, and the international study by Poynard and colleagues randomized 832 patients. For discussion and presentation, results of these studies are usually combined because of the similarity of design, monitoring, endpoints, and virologic testing.

Patients were included in these studies if they had documented chronic HCV (both anti-HCV and HCV RNA in serum), raised ALT levels, compensated liver disease (non-cirrhotic), biopsy-proven chronic hepatitis, and no contraindication to therapy or other serious medical illnesses (i.e., decompensated cirrhosis, cytopenia, autoimmune disease). The U.S. study randomized patients to four treatment arms:

A. IFN (3 MU tiw) for 24 weeks
B. IFN (3 MU tiw) for 48 weeks
C. IFN (3 MU tiw) + RBV (1000 or 12001 mg/day) for 24 weeks
D. IFN (3 MU tiw) + RBV (1000 or 1200 mg/day) for 48 weeks

The international study randomized its patients to the equivalent of arms B, C, and D. Arm A (IFN monotherapy for 24 weeks) was not included.

The virologic end of treatment response (ETR) and sustained response (SR) for all 1,744 patients from both studies are listed in the charts below:

Virologic SR rates (primary endpoint = HCV RNA <100 copies/mL) were significantly better in the combination IFN/RBV arms than in the IFN monotherapy arms. Normalization of ALT levels (a secondary endpoint) closely mirrored virologic response rates. Normalization of ALT levels was associated with achievement of undetectable HCV viral loads. Likewise, the percentage of patients with documented histologic improvement (another secondary endpoint) was markedly better in patients in the combination treatment arms: IFN 24W = 44%; IFN 48W = 41%; IFN/RBV 24W = 57%; and IFN/RBV 48W = 61%.

Results of these studies suggest two things: 1) IFN/RBV combination therapy is superior to IFN monotherapy; and 2) the 1997 NIH Consensus Panel was correct in its recommendation that IFN monotherapy should be administered for 48 weeks rather than 24 weeks (NIH Consensus Panel 1997).

As impressive as these results appear, a majority of HCV patients on combination therapy do not have a 50% chance of clearing virus. An analysis of factors predictive of response to therapy sheds light on which patients do well and which fair poorly on IFN/RBV therapy.


Factors Predictive of a Response to Therapy

Host Factors
Using logistic regression analysis, three host factors were found to be independent positive predictors of SR: 1) female sex; 2) lesser degree of fibrosis on baseline liver biopsy; and 3) age < 40 years (observed only in the international study). Note: Patients with alcohol dependency were excluded from the studies.

Viral Factors
Two viral features, HCV RNA copy number and HCV genotype, were overwhelmingly the strongest predictors of response. Patients with genotype 2 or 3 had approximately double the virologic response rate of those with genotype 1. The chart below details virologic SR rates according to genotypes2:

Thus, while genotype 1 accounts for about 75% of U.S. HCV infections (MJ Alter 1999), and has no prognostic value in HCV natural history if untreated (Poynard 1997; Khan 2000), it is the strongest prognostic indicator for successful response to therapy. The 51-55% SR virologic response rate seen for all study patients immediately drops more than 20% to a disappointing 30% SR rate if only persons with genotype 1 are analyzed. Conversely, two-thirds of the genotype 2/ 3 patients successfully achieve an SR. It is quite possible that some individuals with genotype 1 are resistant to IFN.

Baseline HCV RNA was also identified as a strong predictor of a virologic SR. While HCV RNA is a strong predictor of treatment outcome, it has no correlation with the natural history of the disease in those not on treatment (Lau 1993; Poynard 1997; De Moliner 1998). Patients with a high baseline HCV RNA (considered >2 million copies/mL), faired worse than the patients with low baseline HCV RNA (< 2 million copies/mL). In the combination therapy arms, the virologic SR was 46% for those with low HCV RNA levels compared to 38% for those with high pretreatment viral loads (P < 0.05). The chart below documents the virologic SR rates in genotype 1 patients from the IFN/RBV arms according to baseline HCV RNA:

Approximately 62% and 70% of the patients in the international and U.S. studies, respectively, had baseline HCV RNA > 2 million copies. Likewise, 59% and 72% of patients in the International and U.S. studies, respectively, had genotype 1 HCV. A majority (~2/3) of patients in these studies, had negative prognostic factors and were only able to achieve a 27% virologic SR. Thus, patients considering therapy should be given in understandable language as much information as possible, including 1) virologic status (e.g., HCV RNA level and genotype); 2) histologic status (e.g., stage and grade); 3) results of past studies broken down by good and poor viral and host prognostic factors; 4) known side effects (constitutional, psychological, and hematological); 5) U.S. and European guideline indications for therapy (e.g., "those with progressive disease"); and 6) HCV natural history data (i.e., estimated time to cirrhosis) if untreated. Only then can patients make an informed decision regarding the risks and benefits of starting treatment.

Optimal Course of Therapy: New Guidelines
In both studies, all patients who achieved a virologic SR were HCV RNA-undetectable by week 24. This suggests that if a patient is not undetectable by week 24, he or she never will be, and therapy can be discontinued (Hoofnagle 2000). Interestingly, 14% of the combination therapy patients who had detectable HCV RNA at the 12-week interim analysis went on to achieve an SR (4% and 10% in the 24-week and 48-week arms, respectively) (Poynard 2000). Thus, the old guideline of stopping IFN monotherapy at week 12 (the "3-months rule") if HCV RNA is still detectable, should be replaced by the "6-month stop rule" when combination therapy is used (Hoofnagle 2000).

The NIDDK, in its continual update of the 1997 NIH Consensus Panel's recommendations, has proposed new treatment guidelines for the use of combination IFN/RBV in patients with chronic HCV (NIDDK 2000). The new guidelines in a treatment algorithm are listed below:

NIDDK's Algorithm for Treatment of Patients with Chronic HCV
Make the diagnosis based on aminotransferase elevations, anti-HCV and HCV RNA in serum, and chronic hepatitis shown by liver biopsy.
~
Assess for suitability of therapy and contraindications.
~
Test for HCV genotype.
~
Discuss side effects and possible outcomes of treatment.
~
Start therapy with alpha interferon 3 million units by subcutaneous injection thrice daily and oral ribavirin 1,000 or 1,200 mg daily.
~
At weeks 1, 2, and 4 and then at intervals of every 4 to 8 weeks thereafter, assess side effects, symptoms, blood counts and aminotransferases.
~
At 24 weeks, assess aminotransferase levels and HCV RNA. In patients with genotypes 2 and 3, stop therapy. In patients with genotype 1, stop therapy if HCV RNA is still positive, but continue therapy for a total of 48 weeks if HCV RNA is negative, retesting for HCV RNA at the end of treatment.
~
After therapy, assess aminotransferases at 2- to 6-month intervals. In responders, repeat HCV RNA testing 6 months after stopping.

(NIDDK 2000)


In a recent publication, Poynard and colleagues contend that in order to minimize relapse, treatment duration of IFN/RBV in naive patients should be based on several prognostic factors rather than simply the patient's genotype (Poynard 2000). In an analysis of the 1,774 patients from the U.S. and international IFN/RBV registrational studies (McHutchinson 1998; Poynard 1998), five independent prognostic factors were associated with a virological sustained response: genotype 2 or 3; baseline HCV RNA <3.5 million copies/mL; no or portal fibrosis; female gender; and <40 years of age.

After all patients have completed 24 weeks of combination therapy, Poynard and colleagues recommend:

While genotype remains the most significant prognostic factor, this study documents that basing a decision of treatment duration on "one factor among the five is an over-simplification that could lead to errors in different populations and subgroups" (Poynard 2000).


Side Effects

IFN and RBV both have their own well-documented toxicities. The table below lists the known side effects of both drugs:


Major and Minor Side Effects of IFN and Ribavirin
DrugSide Effects
Interferon (side effects):Fatigue, malaise, myalgias (nuscle aches), headaches, poor appetite
Depression, irritability, anxiety, emotional lability
Difficulty concentrating, forgetfulness, sleeplessness
Thrombocytopenia, neutropenia
Alopecia (hair loss), shortness of breath
Nasal congestion, sore throat, cough, rigors (shivering; hot/cold flashes), pruritus (itching), skin rash
Ribavirin (side effects):Hemolytic anemia (destruction of red blood cells); decrease in hemoglobin of 2-4 g/dl in the first 1-2 weeks;
pruritus (itching); skin rash; shortness of breath;
fetal loss or fetal abnormalities
Ribavirin (serious side effects):Bacterial infections; induction of autoantibodies and autoimmune disease; severe depression; psychosis; disorientation; suicide (attempted and actual);
vision or hearing loss; tinnitus (ringing/buzzing in the ear); seizures; acute renal or heart failure
(PDR 2000)


Most side effects are mild to moderate and can be managed with counseling, dose reduction, and specific treatments, including G-CSF for neutropenia and epogen for anemia. Because of the risk of fetal abnormalities, it is imperative that women and men use adequate birth control while using ribavirin and for six months afterwards. If men and women cannot practice adequate birth control, ribavirin must not be used!

In the large, multicenter international and U.S. IFN/RBV studies, side effects were more common in the IFN/RBV combination arm than in the IFN monotherapy arm. Dose reduction was required in 13% of patients receiving IFN compared to 17% of those receiving IFN/RBV. Discontinuation of treatment was more common in the 48-week combination therapy arms than in the 48-week IFN monotherapy arms (20% vs. 8%; P<0.05) (McHutchinson 1998; Poynard 1998).

The flu-like symptoms (fever, headache, fatigue) are pronounced in patients receiving IFN. Pre-medication with Tylenol, aspirin, or Advil can help somewhat in lessening these side effects. Most importantly, the reports of acute depression and attempted and actual suicides on IFN must be discussed with patients. Psychological monitoring and possibly a 6 to 12 month course of an antidepressant should be considered.

The 1999 EASL Consensus Statement thoroughly lists contraindications for both IFN and RBV (EASL 1999):


Absolute contraindications to IFN: Present or past psychosis or severe depression; neutropenia and/or thrombocytopenia; organ transplantation (except liver); symptomatic heart disease; decompensated cirrhosis; uncontrolled seizures
Relative contraindications to IFN: Uncontrolled diabetes; autoimmune disorders, especially thyroiditis
Absolute contraindications to RBV: End-stage renal failure; anemia; hemoglobinopathies; severe heart disease; pregnancy; no reliable method of contraception
Relative contraindications to RBV: Uncontrolled arterial hypertension; old age


Treatment of IFN Relapsers and Non-responders
An IFN relapser is different from an IFN non-responder. The former are those who achieved either a virologic (HCV RNA) or a biological response (ALT) at the end of treatment but were unable to sustain the response off therapy for six months. IFN non-responders are those who failed to achieve either a virologic or biochemical response during treatment. Some patients, however, may have had undetectable HCV RNA at certain times while on therapy.

Davis and colleagues conducted a large, international, multicenter trial randomizing 345 IFN biochemically relapsing HCV patients to receive either IFN monotherapy or IFN/RBV for 24 weeks (Davis 1998). Primary endpoints were virologic and histologic, but not biochemical. The results are listed in chart on the next page:


IFN vs. IFN/RBV in IFN Biochemical Relapsers: Treatment Results
CharacteristicIFN (N = 172) IFN/RBV (N = 173)P
Virologic SR8 (5%)84 (49%)<0.001
Biochemical SR8 (5%)81 (47%)<0.001
Virologic + Biochemical SR8 (5%)81 (47%)<0.001
Histologic Improvement57/138 (41%)87/139 (63%)
Genotype
  Genotype 13/94 (3%)29/98 (30%)¥
  Genotype non-15/78 (6%)55/75 (73%)
Baseline HCV RNA Level
  >2 million copies/mL2/131 (2%)*54/128 (42%)**
  <2 million copies/mL6/41 (15%)30/45 (67%)
¥ P<0.001 vs. other genotypes.
ý P=0.003 vs. HCV RNA <2 million copies/mL
Ý P=0.006 vs. HCV RNA <2 million copies/mL


Obviously, combination therapy is more effective than IFN for retreating IFN relapsers. This study, however, has been questioned for using only 24 weeks of treatment rather than 48 weeks (Hoofnagle 2000). In light of results from the U.S. and international combination therapy studies, it appears that those with genotype non-1 virus will do well with 24 weeks of combination therapy, but those with genotype 1 or high viral loads may be better treated with a 48-week course of therapy.

Follow-up data on the virologic sustained responders from the three registrational IFN/RBV studies (Davis 1998; McHutchinson 1998; Poynard 1998) were presented at the 1999 Annual Meeting of the American Association for the Study of Liver Disease (Davis 1999). Five hundred and fifty-eight of the 2,089 (38.5%) patients in the three studies achieved a virologic SR: 445 to IFN/RBV and 103 to IFN. At the time of analysis, 316 had at least 6 months off-study follow-up. Nine of the 316 (2.8%) had relapsed (became HCV RNA-detectable). While this is a small number of relapsers, and more follow-up time is needed, no significant differences were observed between those who were treatment-naive vs. prior relapser, on IFN vs. IFN/RBV, or with different genotypes or pre-treatment viral loads.

There are little data on the retreatment of IFN non-responders. A study by Heathcote and colleagues took patients who had either relapsed on or never responded to 3 MU of IFN-alfa 2b or 9 micrograms of consensus IFN (CIFN) and randomized them to receive a higher dose of CIFN (15 micrograms) for 24 or 48 weeks (Heathcote 1998). The prior relapsers on the 48 week treatment arm had a significantly higher SR rate than patients in the 24 week arm. There was no significant difference between the two non-responder arms. The virologic SR rates are documented in the chart below:

The response rates documented for prior non-responders may appear low, but they are still improvements over the 1% to 2% response rates seen in other studies where non-responders attempted retreatment with IFN (Marriott 1992; Alberti 1997).

A number of small to medium size IFN/RBV studies have been conducted in IFN non-responders. Cheng and colleagues recently conducted a meta-analysis of 8 randomized controlled trials with a total of 729 patients (Cheng 2000). The overall biochemical and virologic SR rates were 13.3% and 13.7%, respectively.

HCV treatment guidelines are mixed and relatively unhelpful when it comes to advising IFN non-responders. The EASL guidelines, published in 1999, contend, "there are no clear data to indicate that retreatment will be beneficial." The updated NIDDK management guidelines only advises relapsers to consider a 24-week course of combination therapy, but give no guidance to non-responders. They do, however, state the obvious truth: "New medications and approaches to treatment are needed" (NIDDK 2000).


IFN Histologic Improvement in Responders & Non-responders and its Implications

Does histologic improvement prevent the development of hepatocellular carcinoma (HCC; liver cancer) and improve survival? Do patients not achieving a virologic SR on IFN benefit histologically? And, are there any reasons a relapser or non-responder would want to continue on IFN? Nobody knows the exact answers; all three questions remain controversial.

In a retrospective cohort study, Imai and colleagues from Japan studied 563 HCV cirrhotic patients (Imai 1998). All were biopsied, and 419 initiated IFN monotherapy between 1992 and 1993, while 144 served as controls. The endpoint was HCC, and an SR was defined only as a normalization of ALT levels. After a median follow-up of close to four years, 28 (6.7%) and 19 (13.2%) of the IFN-treated patients and controls, respectively, developed HCC (P = 0.04). Only 1 of the 151 IFN patients who achieved an SR developed HCC. The relative risk (RR) for the development of HCC in patients with an SR was 0.06 (95% CI, 0.01-0.46). There was no statistically significant reduction in the relative risk of HCC in the non-responders (RR = 0.51; 95% CI, 0.20-1.27). These data are interesting, and the reduction in HCC in responders appears somewhat promising; however, this was a retrospective cohort study with many limitations. The authors correctly point out two flaws: 1) the wide 95% confidence intervals, stating, "The results suggest that the effect of interferon on the incidence of hepatocellular carcinoma was not very strong;" and 2) insufficient data collection on the use of alcohol.

Fattovich and colleagues from Italy found no statistically significant difference in the development of HCC or in mortality in HCV cirrhotic patients treated with IFN or in controls (Fattovich 1997). In this retrospective cohort study, 329 patients with cirrhosis were followed for a mean period of five years. The yearly incidence of HCC was 2.3% for the untreated controls and 1.0% for the 193 IFN-treated patients. After adjustment for clinical and serologic differences at baseline, the five-year estimated probability of HCC was 2.1% and 2.7% in the IFN and control patients, respectively. There was, however, a reduction in the complications of cirrhosis in the IFN-responding patients.

Shiffman and colleagues followed 53 patients without virologic response to IFN to determine if long-term IFN treatment improved their liver histology (Shiffman 1999). After failing a six-month course of IFN, 27 were randomized to continue IFN for 24 months while 26 went off therapy and were observed. After 30 months of treatment, 80% of 27 patients had histologic improvement with a fibrosis score decline from 2.5 to 1.7 (P<0.03). Of the 26 patients who went off therapy, 30% had a worsening of hepatic histology and an increase in mean fibrosis score of 2.2 to 2.4 (P<0.01). Interferon does appear to offer histologic improvement even to those who do not respond virologically to IFN. Yet, after two years of being off therapy, less than one-third had a worsening in hepatic histology. Unless we know for certain that improvement in hepatic histology accords real, clinically meaningful benefit (i.e., survival), it is difficult to recommend continued, long-term use of IFN with its pronounced toxicity profile. The decision must ultimately rest with the patient.


HCV Treatment of Selected Patients and Populations

Race as a Prognostic Factor? HCV-infected African Americans and Their Response to IFN

There is a certain amount of controversy about an apparently poorer response to IFN among HCV-infected African Americans than among HCV-infected individuals of other races. In many IFN studies, African Americans have fared poorly on IFN treatment, both as monotherapy and in combination with RBV (Reddy 1999). In the absence of treatment, natural history data suggest that African Americans have less cirrhosis than whites. In a recently presented HCV natural history study of African Americans, Wiley and colleagues documented that after three decades of HCV exposure, 18% of African Americans had cirrhosis compared to 31% of matched non-African-American HCV patients (P = 0.04) (Wiley 2000).

Reddy and colleagues, in concert with Amgen's Consensus Interferon (CIFN) Study Group, reviewed results from a 1997 study which randomized 470 patients to receive CIFN (9 micrograms tiw) or IFN alfa-2b (3 MU tiw) (Tong 1997). Specific differences in response rates according to race were analyzed (Reddy 1999). Baseline and treatment results are summarized on the next page:


Baseline, Biochemical, and Virological Results in Four Racial Groups on CIFN
FeatureWhite AmericansAfrican AmericansHispanic AmericansAsian AmericansP
N=380404010
Baseline Features
  Sex (male)74%63%70%10%NS
  Mean ALT (U/L)132116118117NS
  Cirrhosis12%5%20%10%NS
  Median HCV RNA3 million3.6 million1.9 million1.4 millionNS
  Genotype 166%88%69%40%0.004+
Biochemical Response
  ETR44%13%25%40%0.04+
  SR22%8%10%3%0.04+
Virologic Response
  ETR33%5%28%40%0.04+
  SR12%2%10%30%0.07+
+ = African American compared to white patients
(Reddy 1999)


The median viral load decrease by week 24 on therapy was 2.5 logs in white patients (range: 3.0 to 0.012 million copies/mL) compared to 0.5 logs in the African-American patients (P = 0.014). Nonetheless, for the virologic SR rate -- the primary endpoint of the parent study -- it is important to articulate here that only a non-significant trend was noted in differences between all African-American and all white patients (P = 0.07).

As with other IFN studies, baseline HCV RNA levels (P = 0.0002) and genotype (P = 0.0004) were predictive of a response to therapy. It initially appeared that the higher rate of genotype 1 in African Americans (35 of 40 had genotype 1) was responsible for the difference in response rates. There was a significant difference in EOT response rates in genotype 1 white and African-American patients (22% vs. 6%, respectively; P = 0.038). This difference, however, disappeared in the SR rates (six months after treatment), as 7% in whites compared to 3% in African Americans achieved SR (P = 0.369). When controlling for genotype and HCV RNA in a logistic multiple regression analysis, neither race nor gender was a statistically significant factor associated with a virologic SR. There were also no significant differences in adverse events between races.

Initial differences in HCV treatment response rates between Whites and Blacks were also observed in the two large U.S. and international randomized combination IFN/RBV studies (McHutchinson 1998; Poynard 1998). McHutchinson and colleagues recently presented a retrospective subset analysis of the two studies to determine reasons for differences in response rates between Whites and Blacks3. Only 53 out of the total 1,744 patients were black. The SR rates by race are detailed in the tables below:


Virological SR Rates in Four Racial Groups from the U.S. & International IFN/RBV Randomized Controlled Trials
Treatment
Arms
White
(N = 1,600)
Black
(N = 53)
Hispanic
(N = 32)
Asian
(N = 27)
P
Combined434/1,600 (27%)6/53 (11%)5/32 (16%)12/27 (44%)0.01
IFN/RBV346/925 (37%)6/28 (21%)4/15 (27%)11/20 (53%)
IFN88/675 (13%)0/25 (0%)0/12 (0%)1/7 (14%)


Baseline Differences between Whites and Blacks
Baseline FeaturesWhiteBlacksP
Genotype 165%96%<0.0001
Median Age42 years45 years0.0006
Median Weight79 kg90 kg<0.0001
HAI Score7.17.80.03


No other baseline differences, such as HCV RNA-level or ALT, were observed. There were no differences in the treatment adherence rate (as measured by pill and vial count) between Whites and Blacks.

After controlling for genotype, there was no difference in the SR rate between Whites and Blacks (P = 0.24). Similar to the findings by Reddy and colleagues, however, there was a significant difference (after controlling for genotype) between the groups in median viral load decreases by week 24 on therapy. According to McHutchinson, "These observations suggest that there may be inherent host differences among racial groups" (McHutchinson 1999).

Results from both studies are intriguing. These results were from post-hoc subset analyses, and the disproportionate number of Blacks/African Americans to Whites (83 vs. 1,980) makes it difficult to draw accurate conclusions. There appears to be something different in the way Blacks/African Americans with HCV, compared to Whites, respond to IFN. The answer cannot be that Blacks/African Americans are ubiquitously unresponsive to the antiviral effects of IFN. We know this because Blacks/African Americans with HBV have been shown to actually have a better response to IFN than Whites with HBV. Lau and colleagues demonstrated this fact in their long-term follow-up of HBV patients treated with IFN monotherapy (Lau 1997). It may be the genetic make-up of the HCV virus in Blacks/African Americans that is responsible for the poor response to IFN. Further prospective randomized studies (and, of course, better HCV therapies) are needed to understand this racial difference. I agree wholeheartedly with K. Rajender Reddy's concluding remarks on this issue:

The clinical finding of a low response rate to alfa interferon among African- American patients further supports the urgent need for better therapies of this disease and stresses the importance of evaluating new therapies in all categories of patients. Hepatitis C is reported to be 2 to 3 times more common among African Americans than among non-Hispanic whites. For that reason, African Americans should make up a sizeable proportion of patients enrolled in trials of antiviral therapy of this disease. (Reddy 1999).


Patients with Acute HCV

Approximately 15% to 20% of individuals with acute HCV will completely recover from infection (MJ Alter 1992; Shakil 1995; Villano 1999). Because of the high rate of chronicity, IFN has been studied to determine if immediate treatment can arrest development of HCV before it becomes chronic. Numerous IFN monotherapy treatment studies in patients with acute HCV infection (mostly from blood transfusions) have been conducted since 1989. Drawing conclusions from these studies has been difficult for at least four reasons: 1) different doses, administration methods (IV vs. SC), and duration (4, 6, 12, 24 weeks) of IFN were used; 2) only a few studies were randomized and controlled; 3) different response criteria (biochemical and/or virologic) were examined; and 4) small sample size (the average study had ~30 patients) (Esteban 1999).

The most common regimen tested has been 3 MU of IFN for 12 weeks. Poynard and colleagues conducted a meta-analysis and identified four randomized controlled trials that used 3 MU for 12 weeks (Poynard 1996).

The 1997 NIH Consensus Panel did not discuss the treatment of patients with acute HCV infection in much detail. Only two sentences were written:

Data suggest a benefit from interferon treatment with higher clearance of HCV RNA in patients with acute hepatitis C. In light of these findings, interferon treatment of patients with acute hepatitis C could be recommended. (NIH Consensus Panel 1997)

Just mentioning that treatment "could be recommended" gives treating physicians little guidance. We may never fully know the most efficacious way to treat (dose, schedule, duration) these patients. According to Juan Ignacio Esteban,

Available data are, however, too limited to give definite guidelines as to the optimal dose, duration and timing, and given the practical eradication of transfusion-associated hepatitis C, it is unlikely that further large controlled trials will ever be conducted to clarify these issues. (Esteban 1999)


HCV Patients with Persistently Normal ALT Levels

Approximately 25% of chronic HCV patients have persistently normal ALT levels, and most have no symptoms related to liver disease (Marcellin 1999). Neither the 1999 EASL or 1997 NIH Consensus Panel recommends treatment for HCV patients with persistently normal ALT levels outside a clinical trial (EASL 1999; NIH Consensus Panel 1997). It is recommended that they be monitored every four to six months.

While median HCV RNA levels do not differ between chronic HCV patients with normal and abnormal ALT levels, individuals with persistently normal ALT levels more often have a milder degree of histologic abnormalities. In an analysis of 16 published studies totaling 447 patients with persistently normal ALT levels, Marcellin found: 24% with normal liver of non-specific changes; 54% with chronic persistent hepatitis; 21% with chronic active hepatitis; and only 0.8% with cirrhosis (Marcellin 1999).

IFN monotherapy studies in this population have similar methodological limitations as acute HCV treatment trials. In Marcellin's analysis, only one published study included untreated controls and one reported on liver histology. Silverman and colleagues found none of the IFN- treated patients achieved a virologic SR or documented change in liver histology one year after therapy (Silverman 1997). Sangiovanni and colleagues randomized 31 HCV patients with persistently normal ALT levels to receive either IFN (3 MU tiw) for six months or no treatment (Sangiovanni 1998). At the end of treatment, no difference was seen virologically; 15 of 16 IFN-treated patients and 14 of 15 controls, respectively, were still HCV RNA-detectable. ALT levels flared up in ten IFN patients and only one control (62% vs. 7%; P< 0.005). It is because of these ALT flare-ups on IFN and the lack of virologic control that IFN is not recommended for the treatment of HCV patients with persistently normal ALTs. Many combination IFN/RBV studies in this population are ongoing, yet none has been published.


HCV Patients with Cirrhosis

The 1997 NIH Consensus Panel and 1999 EASL Consensus Statement both state that HCV patients with clinically decompensated cirrhosis (those with jaundice, ascites, variceal hemorrhage [bleeding from abnormal blood vessels in the esophagus] or hepatic encephalopathy) should not be treated with standard therapy but should be considered for liver transplantation (NIH Consensus Panel 1997; EASL 1999). For patients with compensated cirrhosis, the NIDDK says that therapy "can be offered," and EASL says that they "may be treated." Neither appears convinced by data (mostly Japanese) indicating that IFN reduces the risk of HCC or improves survival. (See "Experimental Treatments" for a discussion of treatment in cirrhotics.)


Children and the Elderly with HCV

A vast majority of IFN and IFN/RBV studies have excluded individuals with HCV under the age of 18 and over the age of 60; thus, there are scant and incomplete data with which to make recommendations on treating children and the elderly.

Smaller studies employing standard dose IFN in children with HCV have shown that response rates are similar to those seen in adults (Ruiz-Moreno 1992; Balistreri 1995). Neither the NIDDK or EASL makes a firm recommendation to treat or not to treat children except to say that: 1) long-term effects of IFN in children (e.g., growth) are unknown; and 2) if children are treated, it should be with IFN monotherapy because the pediatric dose and safety profile of ribavirin in children has not been established (NIDDK 2000; EASL 1999). Nonetheless, in a New England Journal of Medicine review article, Jay Hoofnagle makes the case that IFN treatment in children with HCV might be beneficial:

In view of the findings that adult patients without cirrhosis had better long-term responses than those with cirrhosis, it seems appropriate to treat children with chronic hepatitis C even if symptoms are absent and histologic features of the liver suggest mild disease, as long as serum aminotransferase concentrations are elevated. (Hoofnagle 1997)

The NIDDK does not recommend treatment for all HCV patients over the age of 60, but suggests they be "managed on an individual basis since the benefit of treatment in these patients has not been well documented and side effects appear worse in older patients" (NIDDK 2000).


HIV/HCV Coinfected Patients

(For a detailed discussion, see "HIV/HCV Coinfection".)
The 1997 NIH Consensus Panel, NIDDK, and EASL state that HIV/HCV coinfected patients either "should" or "may" be treated as long as they have established control of their HIV infection (NIH Consensus Panel 1997; EASL 1999; NIDDK 2000). The NIDDK correctly points out that in coinfected patients with minimal immunosuppression (>400 CD4 cells/mL), responses to IFN monotherapy are similar in frequency to those HCV patients not infected with HIV (NIDDK 2000). Almost all U.S. and international hepatologists interviewed for this report say that they first have coinfected patients begin potent HIV antiretroviral therapy (an HIV protease inhibitor or a non-nucleoside reverse transcriptase inhibitor plus two nucleoside reverse transcriptase inhibitors) to control their HIV, and subsequently treat them for HCV as they would their HIV-negative patients.

There is, however, incomplete data on coinfected patients treated with IFN. All coinfected patients were excluded from every study discussed in this chapter. Most treatment studies conducted in coinfected patients over the past eight years have been non-randomized pilot/safety trials using different response criteria, IFN doses, and treatment durations. The largest IFN coinfection treatment study published to date enrolled a total of 119 patients (90 HIV-positive patients and 29 HIV-negative controls) (Sorriano 1996).

Only a handful of coinfection studies using IFN/RBV combination therapy have been conducted. They have been small safety studies and mostly presented as conference abstracts. Weisz and colleagues from New York conducted a small, 21-patient coinfection study to determine if combination therapy with IFN and RBV was safe and more effective than IFN monotherapy in HIV-positive individuals with HCV. The results looked promising for those in the combination group; however, it is unclear whether combination therapy was better than IFN alone in this study because patients were unevenly randomized into the two treatment arms. What can be said about the combination of IFN and RBV is that it appears safe in people with HIV who are also on potent antiretroviral therapy. The side effects, such as depression, flu-like symptoms and anemia were no more prominent in the combination therapy group than in the IFN monotherapy group.


Conclusion

Less than 50% of individuals with HCV on treatment today are able to clear their HCV virus. The ability to clear virus on IFN and RBV varies according to genotype and baseline HCV RNA level (viral load): those with low HCV RNA (< 2 million copies/mL) and genotype non-1 have an ~65% chance of a virologic sustained response (SR), while those with high baseline HCV RNA and genotype 1 achieve only an ~27% chance of a virologic SR.

Further research is needed to better understand the clinical significance of a long-term virologic response and its impact on liver disease progression, hepatocellular carcinoma and mortality. For some HCV patients, combination therapy may be a "cure," but for the vast majority, more effective and less toxic therapies are needed.


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  1. Patients who weighed <75 kg were administered 1,000 mg/day and those >75 kg received 1,200 mg/day.
  2. The number of patients with genotypes 4, 5, and 6 were too small to measure separately so they are lumped with genotype 1 patients in this analysis.
  3. The printed abstract uses the term Black (upper-case) to describe African-Americans and others of non-white, Hispanic or Asian race. The term Caucasian is used instead of white. In accordance with the abstract, I will use the term Black (upper-case) and Caucasian.
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