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Can Science Meet the Challenges of the HCV Pandemic?

New Treatment Options for Chronic Hepatitis C

July 1998

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Three percent of the world’s population may be infected with hepatitis C -- 170 million people -- a number larger than all but a handful of the planet's nation-states. The World Health Organization (WHO) published that global estimate of hepatitis C virus prevalence in March of 19971 and updated it in November of that year.2 (See Table 1 for a listing of prevalence by nation.)

Up to 85 percent of those infected with the hepatitis C virus (HCV) are projected to develop chronic HCV infection. They are at risk for developing cirrhosis of the liver, liver failure, and hepatocellular carcinoma as the slow moving disease works its quiet progress. The overwhelming majority of those infected, 90 percent, cannot afford treatment and there is no effective vaccine against HCV.3

In the US, the estimates of HCV infection are no less staggering. According to the Centers for Disease Control and Prevention (CDC), four million Americans may be infected with HCV -- four times the estimated incidence of HIV.3 "Probably 3.5 of the four million [HCV-infected] people [in the US] have no idea that they are infected," says David L. Thomas, MD, a hepatitis researcher at Johns Hopkins University in Baltimore. In the US, HCV has become the leading reason for liver transplants, and between 8000 and 10,000 Americans die each year from HCV-related illnesses3 compared to 34,947 deaths from AIDS-related illness in 1966.4 According to the National Institutes of Health (NIH), the mortality figures may triple by the year 2010, as the consequences of the slowly developing infection become more apparent.3 Hepatitis C may already have the potential to kill more Americans than HIV.

Clinicians and scientists have been searching to improve the long-term efficacy of alpha interferon monotherapy which until recently had been the only approved therapy for chronic hepatitis C. The US Food and Drug Administration’s (FDA) recent approval of the first combination therapy for chronic hepatitis C may have a profound effect upon the lives of hundreds of thousands of people living with this disease.

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Studies conducted by the NIH in the 1980s suggested the potential benefit of interferon alfa-2b in patients with what then was labeled chronic non-A and non-B hepatitis.5, 6 A series of randomized, double blind, placebo controlled trials confirmed the efficacy of the agent in normalization of serum alanine aminotransferase (ALT) and histological improvement in necroinflammatory liver lesions.7, 8, 9, 10

Based on these studies, the FDA in 1991 approved interferon alfa-2b for the treatment of chronic non-A and non-B hepatitis (subsequently termed hepatitis C after HCV was identified in 1989) at a dose of 3 million units (MIU) subcutaneously three times weekly (tiw) for 6 months.

Approximately 50 percent of patients on this regimen sustain a normalization of ALT and histological benefit. Levels of viremia often are reduced in these patients. Complete eradication of the HCV RNA from serum, peripheral blood mononuclear cells, and the liver has been reported, but is rare for patients receiving monotherapy.11

Approximately 70 to 80 percent of patients who experience a normalization of serum ALT levels on this regimen will later relapse. This occurs within a few months to a year. Only 10 to 20 percent of the treated patients have a sustained response lasting at least three years.12

Some types of patients fare better than others. These include younger patients, those with lower body weight, people who abstain from alcohol, and women who have had a shorter duration of infection, and those who have low HCV virologic counts.13, 14, 15 Some studies suggest that initial treatment regimens of 12 to 18 months may increase the sustained response rate.16, 17 For those who fail therapy, one option has been to rechallenge with the same dosage regimen for 3 to 12 months. However this salvage therapy regimen has not proven to be very effective.18

Some physicians believe that the current dosage regimen of interferon alpha monotherapy is suboptimal and choose to increase both frequency and dose size, which anecdotally has been able to substantially increase the number of patients who clear HCV (refer to the interview with Jerry Powell, MD, on page 31 of this issue of the Journal). Clinical trials are now underway to confirm the benefits of such dosing alternatives and, if the results prove successful, a modification of the current label indication may be warranted.


Can lessons in pathogenesis and therapeutics learned from HIV apply to HCV?

In his plenary address to more than 1000 delegates at the hepatitis C conference in Monte Carlo last January, David Ho, MD, detailed some of the lessons from HIV research that may be applicable to HCV. Ho called the delegates' attention to the importance of the level of viremia in predicting the rate of HIV disease progression, since it reflects the level of virus production by infected cells.

Ho went on to point out the kinetics of viral clearance during HIV treatment reveal secondary compartments of infection. These secondary compartments remain reservoirs of infection leading to relapse unless treatment is sufficiently aggressive in both amount and duration to eliminate virus from all infected compartments.

Ho reminded the delegates that the inability to detect virus in the blood does not mean that all infectious virus has been eliminated. Very large numbers of viral particles, 10 to 100 billion, are produced each day, thus creating many opportunities for variants (mutants) to develop. This means that by using a single-agent approach, drug-resistant forms will likely arise and predominate.

Ho also predicted that the most reasonable approach to achieving a durable remission or cure will be to treat aggressively to reduce the number of proliferating particles, using combinations of drugs to create a condition in which the numbers of particles and the rate of mutation are not adequate to generate the mutations required to achieve resistance to the combination regimen.


Another approach to achieve a greater sustained response to therapy is to add another agent to interferon alpha. The combination of interferon alfa-2b and ribavirin has been used in approximately 25,000 HCV-infected patients worldwide in clinical trials and expanded access programs. Ribavirin is a synthetic nucleoside analogue with a broad spectrum antiviral activity. An aerosol powder form of the drug has been FDA-approved for short-term treatment of infants with respiratory illness. Ribavirin is manufactured by ICN Pharmaceuticals. However, Schering-Plough, which also manufactures interferon alfa-2b, has an exclusive global marketing contract for the oral version of the drug with the exception of the European Union.

Schering-Plough applied for FDA approval of their combination of interferon alfa-2b and ribavirin for patients with chronic HCV infection who had relapsed after interferon alpha monotherapy. The pharmaceutical manufacturer submitted safety and efficacy data on two nearly identical controlled double-blind clinical trials, (one in the US and the second in the European Union and Pacific nations) involving a combined total of 345 patients with chronic HCV infection who had received previous treatment with the standard dosage of interferon alpha therapy and who relapsed after achieving an initial response. Relapse patients were identified as patients who had normal ALT values within one year following the end of the most recent course of therapy.

HCV plasma RNA was measured by PCR and a blinded reading of all liver biopsies was conducted by a single hepatologist using the Knodell Histology Activity Index. All patients in the two trials were randomized to receive subcutaneous injections of 3 MIU tiw and daily oral ribavirin (1000 mg for those under 75 kg and 1200 mg for those above 75 kg in body weight) or a matched placebo for 24 weeks of treatment. The principal endpoint of the trials was sustained virologic remission 24 weeks after conclusion of therapy.

At six months post treatment, 79 of the 173 patients (45.7 percent) who received the interferon alfa-2b and ribavirin had an undetectable virus level compared to 8 of the 172 patients (4.7 percent) who received the interferon alfa-2b and placebo. Patient tolerance of the combination therapy was good with only 6 percent of the patients treated with the combination therapy discontinuing therapy due to adverse events versus 3 percent of patients treated with the interferon alfa-2b and placebo. The results in the pair of trials were virtually identical. In the US study, 43 percent of the ribavirin arm and 4 percent of the placebo arm had a sustained loss of HCV RNA. The figures for the international study were 48 percent and 5 percent, respectively.

The sponsor obtained and examined pre- and post-treatment liver biopsies in 277 patients. In the American study, 62.2 percent in the combination arm and 42.2 percent in the interferon arm showed an improvement of 2 or greater on the Knodell Histology Activity Index. The international study mirrored these results with 63.8 and 42.5 percent, respectively. At the FDA advisory meeting on May 4, 1990, Schering-Plough presenter Jan Albrecht, MD, noted that these figures include all treated patients. "When you look at histologic improvement relative to response at the end of 24 weeks of treatment, as measured loss of HCV RNA, we find that of the patients who responded, 83 percent had improvements in liver biopsy." The mean change from baseline in the responder was 4 on the Knodell scale. "This is a very large increase."

"HCV RNA and genotype were important predictors of response," Albrecht said. However, the combination performed better than interferon alone across all virus loads and all genotypes. "In the genotype 1 patients, who we consider the most difficult to treat, we have a 44 percent response. And in those very difficult to treat patients, genotype 1 with a viral load greater than two million copies/ml, there is a 24 percent response."

It remains unclear whether the difficulty in treating genotype 1 is because of something inherent to the quasi species or because infection occurred earlier and the virus had become more entrenched.

Tan Nguyen, MD, PhD, the clinical reviewer of the submission for the FDA, concluded that patients who show a response earlier have a better chance of having a sustained suppression of HCV. Those patients who did not clear the virus by week 12 are unlikely to do so by week 48, regardless of the treatment regimen.

The Schering-Plough safety database for the combination is 1182 patients, plus reports from expanded access. The known side effects of the two drugs are combined "without any exacerbation between the two," said Albrecht. Patients in the combination arm tended to have more severe side effects and were more likely to use dose reduction to combat them. However, there were no new or unanticipated side effects among the 25,000 who have taken the drugs in combination.

The US trial reported more psychiatric events related to interferon than did the international trial. FDA clinical reviewer Russell Fleischer, PA-C, MPH, said the "phenomenon has been observed in other international trials." It may reflect clinical differences within the populations or cultural ones as to what patients report and physicians observe.

Ribavirin is mutagenic, so contraception must be practiced by all parties during therapy and an ensuing six-month wash-out period. There are currently no data on HCV’s ability to mutate resistance to ribavirin. The drug accumulates in the body over time, which opens the possibility of an initial loading dosage and then a lower sustaining dose. Dose reduction trials are underway.

Ribavirin’s principal adverse reaction is hemolysis, which is mild, dose- dependent, and returns to baseline within four weeks of cessation of the drug. Other mild side effects may include fatigue, insomnia, and nausea.

After a careful review of the NDA data, the FDA advisory committee unanimously recommended approval of the submission. On June 3, 1998, the FDA approved Schering-Plough’s combination of interferon alfa-2b (Intron A) injection and ribavirin capsules (Rebetol) for the treatment of chronic HCV in patients with compensated liver disease who had relapsed following interferon alpha monotherapy. The company is marketing the combination only as a package under the trade name Rebetron.



Rebetron Information
REBETRON™ - a combination of REBETOL™ (Ribavirin, USP) Capsules and INTRON® A (Interferon alfa-2b, recombinant) - is for the treatment of chronic hepatitis C in patients who have relapsed following alpha interferon therapy. REBETRON is marketed by Schering-Plough Corporation.
Dosage
    The recommended dosage of Rebetron combination therapy is 3 MIU of Interon A injected subcutaneously three times per week and 1,000-1,200 mg of Rebetol capsules administered orally in a divided daily (morning and evening) dose for 24 weeks. Patients weighing 75 kg (165 pounds) or less should receive l,000 mg of Rebetol daily, while patients weighing more than 75 kg should receive 1,200 mg of Rebetol daily.

Adverse Experiences
    Rebetron combination therapy is associated with significant risk of abnormal fetal development. Women of childbearing potential should not begin therapy until a report of negative pregnancy test has been obtained.

    The most common adverse experiences associated with Rebetron combination therapy are flu-like symptoms, such as headache, fatigue, mylagia, and fever, which appear to decrease in severity as treatment continues.

    Psychiatric disorders have been reported during Rebetron combination therapy, both inpatients with a previous psychiatric history and in patients with no psychiatric history. These adverse events include depression, which may be severe, and rare cases of suicide ideation and suicidal attempt.


Schering-Plough announced on May 18, 1998, results of two combination trials in 1744 treatment-naive patients. The dosing regimen and end points were the same as in the salvage trials above. The combination arm showed 33 percent clearing HCV after 24 weeks of therapy and 41 percent clearing the virus after 48 weeks. This compared to 6 and 16 percent clearance, respectively, by those receiving interferon plus placebo.

On June 16, 1998, Schering-Plough filed a supplemental New Drug Application to the FDA seeking to extend Rebetron’s label indication to include treatment-naive patients with chronic HCV infection and requested priority review status for the application.

Schering-Plough’s licensing agreement with ICN gives Schering-Plough exclusive rights to market oral ribavirin for hepatitis C in all major world markets, except in the European Union, where both companies have the right to market oral ribavirin for hepatitis C. Schering-Plough has filed two Health Registration Dossiers (HRD) with the European Agency for the Evaluation of Medicinal Products (EMEA); one for the combination therapy with the same indication that has been approved by the FDA, the other for oral ribavirin capsules which ICN plans to market under the brand name Virasole.

The FDA approval, and Schering-Plough’s decision to market the products only as a package, raises some interesting issues. As detailed in Table 2, the FDA has already approved three interferon products for treating hepatitis C. In addition to the Schering-Plough product, Hoffman-La Roche markets interferon alfa-2a (trade name Roferon A), and Amgen has alfacon-1 (trade name Infergen) for essentially the same use.

Since ribavirin is not an effective monotherapy for treating HCV infection, the rules of the game would apparently preclude its submission to the FDA for approval as monotherapy.

The practical effect of the Schering-Plough/ICN marketing arrangement gives Schering-Plough a virtual monopoly on HCV combination therapy. The marketing agreement essentially shuts out Hoffman-La Roche and Amgen from the global combination therapy market for HCV disease.

Development of new anti-HCV drugs is progressing. However it may be several years before effective new agents are available. Other drugs being tested as interferon therapy combinations such as ursodeoxycholic acid have not as yet generated substantive data.19 There was some initial interest in corticosteroids because of their effectiveness in reducing serum ALT levels in some patients, but this benefit was clouded by increased viremia levels.20

Evaluating drugs for clinical benefits in treating hepatitis C is "problematic because of the long latency period," says Diane Murphy, MD, director for antiviral drugs at the FDA’s Center for Drug Review. The agency has come to accept suppression of plasma HCV RNA and normal ALT levels as surrogate markers of therapeutic trials. The critical measurement points in protocol designs are baseline, end of treatment, and a sustained response six months after termination of therapy.

The crystalline structure of HCV has been delineated, and several pharmaceutical companies are using it to reverse-engineer helicase and protease inhibitor drugs, much as they did with the protease inhibitors for HIV. The HCV protease is asymmetric, and it may be hard to create a blocking compound for the site. But at least two companies already have lead compounds in development. Still, with even the most successful fast-track development process, it is likely to take years before a product is market-ready.

Thymosin is under development by SciClone Pharmaceuticals, San Mateo, California. It is an immune modulator that does not act directly on HCV but enhances the body’s production of interferon and interleukin. It is used in China to treat hepatitis B and is available through some buyers’ clubs in the United States. Oral dosing of interferon is in clinical trials for hepatitis B, and the results may be applicable to HCV.

Oral dosing would eliminate the need for injections, ease administration, and perhaps significantly reduce the side effects of the drug as well as opening the door to opportunities to distribute an oral interferon in less industrialized countries heaviest hit by the hepatitis C pandemic. However some researchers believe that oral administration of interferon alpha is impractical.

The historic lack of more effective therapies for hepatitis C has sparked wider interest in natural or alternative therapies. As with most of these products there are scant clinical data to justify safety and efficacy. Anecdotally alternative treatments claim to improve liver function, and modulate immune responses.

There are claims that dandelion and artichoke encourage the flow of bile from the liver; licorice root (glycyrrhizin) quells inflammatory processes; milk thistle (silymarin) promotes liver regeneration; and that many of the natural therapies are antioxidants. Unfortunately they may be the only option the patient can afford or the local medical system can provide.

"Seventy percent of the (HCV) patients in this town are taking milk thistle," says New York University professor of medicine, Douglas Dieterich, MD, "but how do you know if the stuff they are taking is the same as in Minnesota or California?"

The major challenge to science will be the development of an inexpensive and effective oral formulation of anti-HCV drugs that can be widely distributed to the millions of people in less-industrialized nations who have chronic hepatitis C and no access to current approved therapies. The challenge of developing a low-cost effective vaccine against HCV infection is also critical to protect the hundreds of millions of people throughout the world who are in risk of contracting HCV.3


Sexual Transmission of Hepatitis C?

The lack of definitive data on risk factors for the sexual transmission of HCV presents a serious challenge to responsible people with hepatitis C, as well as to physicians and other healthcare professionals who counsel them.

Two studies from Japan and Taiwan indicated that long-term cohabitation may be a risk factor. The Japanese study identified 154 viremic HCV index patients and found that 27 percent of the patients’ spouses remained HCV uninfected (as determined by PCR) and 83 percent infected with HCV of identifiable genotypes of their indexed spouses. None of the study subject spouses who were married less than ten years became infected. This led the authors to conclude that the risk of infection increases with the duration of the marriage.21 The Taiwan study demonstrated a spousal HCV infection rate of 28 percent bases on a second generation ELISA test for anti-HCV. What surprised investigators was that 54 percent of the parents of the indexed patients also tested positive.22

Another Japanese study provided conflicting data. The study analyzed vertical and horizontal HCV transmission data ion an isolated island where hepatitis C is endemic. Of the 53 children with HCV-positive mothers, only 3 tested positive for HCV. In 17 of 234 couples only 17 of both spouses tested HCV-positive. In 11 pairs of spouses in whom the HCV genotype was determined, only half had a similar genotype.23

A US study recruited subjects from a STD clinic. Ninety-five percent of the subjects were African American. None of the subjects were IV drug users. A multivariate analysis showed no difference in the increase of the rate of HCV, HIV, or HBV infection in multiple lifetime sex partners. Among couples, women whose sex partners were anti-HCV positive were 3.7 times more likely to have anti-HCV than females whose sex-partners were anti-HCV negative. For men, anti-HCV positivity had no relation to the anti-HCV status of their partners. This led the authors to conclude that male-to-female HCV transmission was more efficient.24

After a review of the data on risks of sexual transmission of HCV, the NIH Consensus Statement Conference on Hepatitis C concluded that the data reviewed indicated some increase in sexual transmission with anal intercourse, sex during menstrual cycles, and years of cohabitation or marriage. The assumption was that the risk of sexual transmission is low. However, the lack of definitive data could not permit making recommendations, either pro or con, on universal precautions.3










Table 1.
Hepatitis C virus infection prevalence in 1997
Country/AreaHCV prevalence (%)Country/AreaHCV prevalence (%)
Algeria*0.18Luxembourg*0.50
Angola*1.00Madagascar3.30
Argentina*0.56Malaysia3.00
Australia0.31Mauritius*2.10
Austria*0.21Mexico0.74
Bangladesh*2.40Micronesia (Federated States of)1.50
Belarus*1.44Mongolia10.70
Belgium0.87Morocco1.10
Belize1.07Mozambique2.06
Benin*1.50Nepal*0.33
Bhutan*1.30Netherlands0.10
Bolivia16.30New Zealand0.33
Botswana*0.00Nicaragua0.57
Brazil2.60Niger2.50
Bulgaria1.11Nigeria1.40
Burundi11.10Norway*0.09
Cambodia*4.00Oman*0.90
Cameroon12.50Pakistan2.40
Canada*0.15Palestinian Self-Rule Areas5.20
Central African Republic*4.50Panama*0.10
Chad4.80Papua New Guinea7.00
Chile*0.96Paraguay*0.28
China4.07Peru*0.00
China (Province of Taiwan)1.60Philippines*3.60
Colombia1.00Poland1.40
Costa Rica*0.30Portugal*0.46
Croatia*1.40Puerto Rico1.90
Cuba0.80Qatar*2.80
Cyprus*0.10Republic of Korea1.70
Czech Republic0.24Republic of Moldova*4.90
Democratic Republic of the Congo (former Zaire)6.40Réunion*0.80
Denmark*0.25Romania4.50
Dominican Republic*2.40Russian Federation2.00
Ecuador*0.70Rwanda*17.00
Egypt18.10Saudi Arabia1.80
El Salvador*0.18Senegal*2.90
Ethiopia0.84Seychelles*0.77
Finland*0.02Singapore0.54
France1.15Slovakia0.39
French Guiana*1.50Solomon Islands*0.90
Gabon6.50Somalia0.97
Germany0.12South Africa1.70
Ghana5.40Spain0.74
Greece1.51Sudan3.20
Grenada*1.12Suriname*5.50
Guadeloupe*0.80Swaziland*1.54
Guatemala*0.67Sweden0.003
Guinea*10.70Switzerland0.24
Haiti*2.00Thailand5.60
Honduras*0.09Togo*3.30
Hong Kong Special Administrative Region of China0.50Trinidad and Tobago*4.90
Hungary0.98Tunisia*0.40
Iceland*0.06Turkey1.50
India1.85Uganda1.17
Indonesia2.10Ukraine*1.20
Iraq*0.50United Arab Emirates*0.83
Ireland0.10United Kingdom 0.02
Israel0.44United Republic of Tanzania*72.2
Italy0.48United States of America1.80
Jamaica*0.33Uruguay*0.47
Japan2.30Vanuatu*0.90
Jordan*2.10Venezuela0.94
Kenya0.90Viet Nam6.10
Kiribati*4.80Yemen2.60
Kuwait3.30Zambia*0.00
Libyan Arab Jamahiriya7.90Zimbabwe*0.22



Table 2.
Hepatitis C Facts
Clinical Sequelae of Hepatitis C
Resolved acute infection5-15%
Chronic infection
 - Normal ALT
 - Elevated ALT
10-30%
70-90%
Consequences of Chronic Hepatitis C Infection
Progressive liver injury
  - Fibrosis, cirrhosis
Hepatocellular carcinoma
Extrahepatic disease
- Essential mixed cryoglobulinemia   - Membranoproliferative glomerulonephritis
- Porphyria cutanea tarda   - Lichen planus
Natural History of Chronic Hepatitis C
Liver DiseaseYears (average)*
Chronic hepatitis10-20
Cirrhosis20-30
Hepatocellular carcinoma>30
* Interval from infection to liver disease
FDA-Approved Drugs for the Treatment of Hepatitis C†
Generic name Trade name Usual dose
Interferon alfa-2b Intron® A 3 MIU tiw
Interferon alfa-2a Roferon®-A 3 MIU tiw
Alfacon-1 Infergen® 9 µg tiw
Interferon alfa-2b/ribavirin
Interferon alfa-2b
Ribivarin†
RebetronTM
Intron® A
Rebetol
3 MIU of Interon A injected subcutaneously tiw and 1,000-1,200 mg of Rebetol capsules administered orally in a divided daily (morning and evening) dose for 24 weeks. Patients weighing 75 kg (165 pounds) or less should receive l,000 mg of Rebetol daily, while patients weighing more than 75 kg should receive 1,200 mg of Rebetol daily.
Assessment of Efficacy of Interferon Therapy
Category Measurement Result
Biochemical ALT1 Normal
Virological HCV RNA1 Undectable
Histological Liver Biopsy2 Improved
Symptoms QOL scales2 Improved
1 Used routinely in clinical practice
2 Used in clinical research trials
Data adapted from the American Digestive Health Association and the American Liver Foundation.
† Additional data on Rebetron added by the Journal


Bob Roehr is a medical writer based in Washington, DC (e-mail: bobroehr@aol.com).


References

1. World Health Organization. Hepatitis C: global prevalence. Weekly Epidemiological Record. No. 10, 1997, pp65-72

2. World Health Organization. Hepatitis C: global prevalence. Weekly Epidemiological Record. No. 46, pp341-348

3. National Institutes of Health: National Institutes of Health Consensus Development Statement Online: Management of Hepatitis C. 1997 March 24-26 [cites 1998, April 27]; 15:in press.

4. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report. Vol.9, No.2

5. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha- interferon. N Engl J Med 1986;315:1575-8

6. Di Bisceglie AM, Martin P, Kassiandes C, Lisker-Melman M, Murray L, Waggoner J, et al. Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo controlled trial. N Engl J Med 1989;321: 1506-10

7. Davis GL, Barlart LA, Schiff ER, Lindsay K, Bodenheimer HC, Jr., Perrillo RP, et al. Treatment of chronic hepatitis C with recombinant interferon alfa: a multicenter randomized controlled trial. N Eng J Med 1989; 321:1501-6

8. Marcellin P, Boyer N, Giostra E, Degott C, Courouce AM, Degos F, et al. Recombinant human alpha-Interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology 1991;13:601-3

9. Saracco G, Rosina F, Torrani-Cerenzia MR, Lattore V, Chiandussi L, Gallo V, et al. A randomized controlled trial of Interferon alfa-2b as therapy for chronic non-A, non-B hepatitis. J Hepatol 1990;11(suppl 1):843-9

10. Causse X, Godinot H, Chevallier M Chossegros P, Zoulim F, Ouzan D, et al. Comparison of 1 or 3 MU of interferon alfa-2b and placebo in patients with chronic non-A, non-B hepatitis Gastroenterology 1991;101: 497-502

11. Romeo R, Pol S, Berthelot P, Brechot C: Eradication of hepatitis C virus RNA after alpha-interferon therapy. Ann Intern Med 121:276-277, 1994

12. Sakamoto N, Enomoto N, Kurosaki M, et al: Comparison of the hypervariable region of hepatitis C virus genomes in plasma and liver. J Med Virol 46:7-11, 1995

13. Nousbaum J-P, Pol S, Nalpas B, et al: Hepatitis C virus type 1b (II) infection in France and Italy. Ann Intern Med 122:161-168

14. Okazaki T, Yoshihara h, Suzuki K, et al: Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol 29:1039-1043, 1994

15. Hayashi J, Ohmiya M, Kishihara Y, et al: A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C. AM J Gastroenterol 89:2151-2156, 1994

16. Kasahara A, Hayashi N, Hiramatsu N, et al: Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: A multicenter randomized control trial. Hepatology 21:291-297, 1995

17. Poynard T, Bedossa P, Chevallier M, et al: A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non- B hepatitis. N Eng J Med 332:1457-1462, 1995

18. Marcellin P, Pouteau M, Martinot-Peignoux M, et al: Lack of benefit of escalating dosage of interferon alfa in patients with chronic hepatitis C. Gastroenterology 109:156-165, 1995

19. Boucher E, Jouanolle H, Andre P, et al: Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: Results from a controlled randomized trail in 80 patients. Hepatology 21:322-327, 1995

20. Margrin S, Craxi A, Fabiano C, et al; Hepatitis C viremia in chronic liver disease: Relationship to interferon-alpha or cortico-steroid treatment. Hepatology 16:273-279, 1994

21. Akahane Y, Kojima M, Sugai Y et al. Hepatitis C virus infection in spouses of patients with type C chronic liver disease. Ann Intern Med 1994; 120:749-52

22. Chang TT, Liou TC, Young KC et al. Intrafamillial transmission of hepatitis C virus: The important role of in apparent transmission. J Med Virol 1994 42:91-6

23. Nakashima K, Ikematsu H, Hayashi J et all. Intrafamilial transmission of hepatitis C virus: among the population of an endemic area of Japan. JAMA 1995; 274: 1459-61

24. Thomas DL, Zenilman JM, Alter HJ et al. Sexual transmission of hepatitis C among patients attending sexually transmitted diseases clinic in Baltimore; an analysis of 309 sex partners. J Infect Dis 1995: 171:768-75


©1998, Medical Publications Corporation

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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