Can Science Meet the Challenges of the HCV Pandemic?
New Treatment Options for Chronic Hepatitis C
Three percent of the worlds 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 Administrations (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.
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.
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 HCVs 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.
Ribavirins 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-Ploughs 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.
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 Rebetrons label indication to include treatment-naive patients with chronic HCV infection and requested priority review status for the application.
Schering-Ploughs 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-Ploughs 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 FDAs 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 bodys 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
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4. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report. Vol.9, No.2
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This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication Journal of the International Association of Physicians in AIDS Care.