American Foundation for AIDS Research, February 2004
Daniel Raymond

December 2003 — The field of hepatitis C therapy received a welcome boost with the arrival of two new forms of the drug interferon alfa — Schering-Plough’s Peg-Intron and Roche’s Pegasys. A process called pegylation allowed the injectable drugs to be used once a week, instead of the thrice-weekly injections required by standard interferon. Moreover, when combined with ribavirin, the makers of pegylated interferons boasted success rates of over 50% in sustaining undetectable HCV viral load levels, equating to a probable cure. Marketing materials touted “the power of pegylation.”

But cumulative clinical experience and recent reports from the annual meeting of the American Association for the Study of Liver Diseases (AASLD) have shifted from optimism to a more sober recognition of the therapy’s limits and realities. Particularly vexing are questions about the treatment’s effectiveness in people with HIV and in African-Americans; accompanying side effects such as anemia and depression; and the management of people with histories of substance abuse.

HCV coinfection has become an increasing concern for people with HIV. David Nunes of Boston University reported results from an ongoing study on the impact of HIV coinfection on HCV disease (abstract 602). The data revealed more advanced liver disease and liver disease-related deaths in people with HIV compared with those infected with HCV alone. Among 167 coinfected individuals followed for at least one year, eight of fourteen deaths were from liver disease. Only one death was from liver disease among the 111 people infected only with HCV.

These findings parallel those reported in other studies in recent years, which document accelerated liver disease in coinfected people. Since more people are dying of liver disease in the era of antiretroviral therapy, finding effective treatment for coinfected people has become urgent. But preliminary analyses from three large studies of pegylated interferon/ribavirin treatment in people with HIV have not been encouraging. The key measure of treatment success is a sustained virologic response, defined as an undetectable HCV viral load six months after ending therapy. Since many patients who initially respond to treatment later experience viral rebound, sustained virologic response rates are invariably lower than response rates reported in the middle and at the end of therapy. The 24-week results from Adult AIDS Clinical Trial Group’s 5071 study, reported in 2002, showed that 66 participants treated with Peg-Intron/ribavirin had a response rate of 44% halfway through the course of treatment. But experts predict this will translate into a sustained response of around 30%. Even without final results, it is becoming increasingly clear that fewer coinfected people will have sustained responses than persons with HCV alone.

The 48-week data from the French RIBAVIC trial revealed an end-of-treatment response rate of only 37% in volunteers treated with Peg-Intron and ribavirin. RIBAVIC had a high dropout rate, with only 89 of the original 206 participants completing the full course of this treatment, and 23% experiencing significant adverse events. As with A5071, an even lower proportion of the coinfected patients in RIBAVIC will likely have sustained responses, due in part to higher dropout rates and more difficulty tolerating therapy.

The final analyses of these studies will report on data from individuals followed for an additional 24 weeks after they complete 48 weeks of treatment. The results from these studies and from APRICOT — a multicenter trial evaluating Pegasys and ribavirin in coinfected participants — are expected in the spring of 2004. “The 11th Conference on Retroviruses and Opportunistic Infections will be the hot ticket,” predicts Mark Sulkowski of the Johns Hopkins Viral Hepatitis Center.

Treatment by the Numbers
In the meantime, October’s AASLD meeting offered a wealth of research on HCV mono-infection that tempered previous optimism about treatment. A large multicenter study conducted by the Veterans Administration (VA) illustrates some of the current dilemmas for people chronically infected with HCV. Edmund Bini of the VA Medical Center in New York evaluated 4,364 veterans with HCV, 7% of whom were coinfected with HIV (abstract 603). Using the VA’s HCV Treatment Guidelines, only 25% were eligible for treatment, based on clinical criteria and exclusions for substance abuse, psychiatric illness, and other medical conditions. Nearly half of those offered treatment declined, citing side effects and the desire to wait for more effective treatment options.

Norbert Bräu of the Bronx VA Medical Center presented results from another VA study, in which 813 veterans had worse responses to standard interferon and ribavirin than people in previous phase III trials (abstract 1009). Over half of patients stopped treatment early, and the sustained virologic response rate was only 17%. African-Americans had the lowest response rate, a dismal 7%.

African-Americans generally have poorer responses to HCV treatment. Lennox Jeffers of the Miami VA Medical Center presented data on 78 African-Americans and 26 Caucasians who took Pegasys and ribavirin for 48 weeks (abstract 71). All had genotype 1, the strain of HCV considered hardest to treat (people with HCV genotype 2 or 3 only require 24 weeks of treatment). Only 26% of African-Americans had sustained responses, compared with 39% of Caucasians.

The African-American participants were more likely to have higher pretreatment HCV viral loads — associated with a poorer response to therapy. Of participants with high baseline HCV viral loads, only 20% of African-Americans and 25% of Caucasians had sustained responses to treatment. However, William Cassidy from Louisiana State University reported that a greater proportion of African-Americans in the Jeffers study experienced improvement in liver fibrosis after therapy — 25% versus 6% of Caucasians — in an analysis of 69 people who underwent biopsies before and 24 weeks after treatment (abstract 307).

Other analyses of this same study attempted to tease out the source of the differences. Charles Howell from the University of Maryland looked at differences in response by measuring changes in levels of interferon-stimulated genes in African-Americans. He found no overall correlation between gene expression levels and response to treatment (abstract 190). The NIH is conducting a 400-person trial, dubbed VIRAHEP-C, to examine why African-Americans respond differently to treatment than Caucasians, but final results will not be available until 2006. In the meantime, Jeffers recommends studying the effects of treating African-Americans with a higher dose of interferon.

Howell also found no significant differences in adherence to regimens between the groups, defined as taking at least 80% of the original prescribed dose over the duration of treatment (abstract 332). Eighty-six percent of African-Americans and 89% of Caucasians were adherent, with about 80% of each group completing the full course of therapy. However, more African-Americans lowered their Pegasys doses (46% vs 29% in Caucasians), mainly due to neutropenia. This may reflect the lower average neutrophil counts of African-Americans; in this study, African-Americans had lower baseline neutrophil levels, and their levels dropped faster during treatment than did those of Caucasians. Similar proportions in both groups (40%–46%) had to adjust the ribavirin dose, mainly due to anemia.

Managing anemia also poses significant challenges for treating HCV. Ribavirin-induced anemia, diagnosed by a drop in hemoglobin levels, is commonly treated by lowering the dose, which potentially weakens the therapy’s effectiveness. Some clinicians use erythropoietin to treat anemia during ribavirin therapy and allow full ribavirin dosing, but this drug’s impact on treatment outcome is unclear. Lauren Senkbeil from New York-Presbyterian Medical Center studied 50 people treated with Peg-Intron and ribavirin; 16 needed to lower the ribavirin dose for an average of 10 weeks (abstract 1213). Fourteen of these participants were given erythropoietin, all but one of whom resumed taking the original ribavirin dose. Sustained response rates were similar to those who maintained full-dose ribavirin throughout the course of therapy, suggesting a benefit to erythropoietin in managing anemia. But fewer people requiring a reduced Peg-Intron dose had sustained responses, even when prescribed granulocyte colony-stimulating factor in order to resume the original Peg-Intron dose.

Depressing News
Along with anemia, depression is a common side effect of HCV therapy, and can manifest as a symptom of chronic HCV infection itself. Depression is typically ascribed to interferon treatment, although some evidence suggests that ribavirin may also play a role. Several reports documented high rates of depression before and during HCV treatment. A study of 1,500 California Medicaid patients by Jeffrey Markowitz and Elane Gutterman from Health Data Analytics found that about half of patients with diagnosed HCV had been prescribed antidepressants (abstract 981). Importantly, about 85% of these patients were treated for depression before receiving an HCV diagnosis. This group was also more likely to receive interferon treatment following diagnosis. The authors pose two possible scenarios: people prone to depression may also be prone to HCV infection, or HCV itself contributes to depression.

Although not a component of the California Medicaid study, others have looked at the likelihood of treating drepression in people with HCV. Paul Kwo of the Indiana University School of Medicine examined potential differences or biases in the prescribing practices of individual doctors, and has linked antidepressant use and clinical experience with HCV treatment (abstract 1225). He analyzed data from 792 people who took standard interferon and ribavirin. Before starting treatment, 24% of patients were already taking antidepressants, and a significant portion of the remainder received antidepressants throughout the course of therapy. Of the 84 investigators involved in the study, those who had previously treated 100 or more patients for HCV were more likely to prescribe antidepressants during therapy.

Depression can be debilitating and even life threatening; a fairly small but disturbing number of suicides have been reported in HCV treatment studies. Depression may also affect adherence, but its impact on treatment efficacy is unknown. Charles Raison from Emory University in Atlanta followed 102 people undergoing HCV treatment and observed that patients who experience more symptoms of depression during therapy were less likely to have a sustained response to treatment (abstract 344). In contrast, another study by Jennifer Moss at New York-Presbyterian of 55 volunteers receiving Peg-Intron/ribavirin therapy uncovered a link between response to treatment and increased depression (abstract 1206). The authors speculate that both treatment-related depression and virologic response may be biologically interconnected.

Depression may be a particular problem for people coinfected with HIV, suggests Kenneth Sherman of the University of Cincinnati. “We have a study funded by the NIH that examines this issue. My sense is that depression is more common with coinfection, but the data have not yet been fully analyzed,” says Sherman.

Managing depression is also a significant issue for HCV treatment in people with histories of injection drug use, most of whom are infected with HCV. Rates of depression and other kinds of mental illness in this group can run as high as 50%. Marcus Schaefer at Berlin’s Humboldt University treated 11 controls with no history of psychiatric illness and 25 methadone patients with interferon and ribavirin (abstract 333). Fourteen participants on methadone began taking the antidepressant citalopram (Celexa) two weeks before beginning treatment. While the incidence of major depression episodes was relatively high, and similar between the control group and the methadone patients who did not receive citalopram (55% and 64%, respectively), only 14% of methadone patients taking citalopram experienced a major depressive episode.

Another methadone study reported by Stefan Mauss of the Center for HIV and Hepatogastroenterology in Düsseldorf compared HCV treatment outcomes in 50 people on methadone maintenance and a control group of 50 persons with no history of injection drug use or methadone within the last five years or more (abstract 1218). Sustained response rates did not differ significantly between the two groups (39% methadone vs 54% control). A greater number of methadone patients dropped out within the first two months of treatment (11 vs 2 controls), but 50% of those who continued therapy beyond that time had sustained responses, compared with 56% of controls.

Despite favorable response rates and tolerability in pilot studies of HCV therapy for methadone patients, many people with substance abuse histories — particularly current drug users — do not receive treatment for HCV. This issue formed the focus of a November meeting sponsored by the National Institute on Drug Abuse and other federal agencies. Researchers and clinicians presented data and strategies on managing HCV in current and former drug users, emphasizing the low incidence of reinfection with HCV following successful treatment, the relatively good adherence to treatment, and the use of antidepressants to manage psychiatric side effects.

The meeting was partially a response to the history of excluding substance users from HCV treatment. A 1997 NIH-sponsored consensus statement recommended that treatment be withheld until people are abstinent from drugs and alcohol for at least one year, primarily due to concerns about adherence and reinfection from continued injection drug use. In 2002 this recommendation was reversed in a new consensus statement, which recommended that substance users be evaluated on a case-by-case basis, but the meeting’s participants emphasized that clinical practice has not caught up with this change. “In what other disease is the group most likely to be infected the least likely to be treated?” asked Sharon Stancliff of the New York State Department of Health’s AIDS Institute.

In the meantime, the numbers of people undergoing HCV treatment remain relatively flat, at 100,000 per year according to drug company data. Schering-Plough, the manufacturer of Peg-Intron, has seen its market share eroded by competition from Roche’s Pegasys, and will probably see even less profits after the launch of generic ribavirin in the coming months. In response, Schering announced plans for a 2,880-person clinical trial, the IDEAL study, comparing Peg-Intron with Pegasys when each is combined with ribavirin in people with HCV genotype 1. The study will also compare high- and low-dose Peg-Intron, fulfilling a post-marketing commitment made after the FDA approved the drug.

Paging Protease Inhibitors
Regardless of IDEAL’s outcome, many people with HCV will defer treatment until more effective and better-tolerated drugs become available. Such treatments may include the long-awaited HCV protease inhibitors. Unlike interferon and ribavirin, which act through general antiviral and immune-modulating pathways, this new wave of drugs specifically targets HCV. Like HIV protease inhibitors, the drugs attempt to block the HCV serine protease enzyme, which plays a crucial role in viral replication. “The concept of HCV serine protease inhibitors is very exciting,” according to Johns Hopkins’ Sulkowski.

Boehringer Ingelheim developed the first HCV protease inhibitor to enter human studies, BILN 2061, and reported that a two-day course of treatment could reduce HCV viral loads by 100- to 1,000-fold. The company has reportedly halted development of this drug because of toxicities observed at high doses in animals, but other compounds are entering clinical trials. Schering-Plough has an HCV protease inhibitor entering human studies, and Vertex Pharmaceuticals will begin phase I studies of its protease inhibitor, VX-950, in early 2004. Other compounds discussed at the AASLD meeting target other aspects of HCV replication.

At least initially, the new drugs will most likely be added to interferon and ribavirin, since researchers expect that HCV would quickly become resistant to a protease inhibitor used by itself. Even under the most optimistic projections, these new treatments will not be available in the clinic until 2007 at the earliest. For now, researchers continue to work on optimizing treatment outcomes and managing toxicities, while people with chronic HCV face difficult treatment decisions.

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