Recommendations for those on the Frontline Against Hepatitis C
Jules Levin*, Joseph Bick*, M.D., and Elizabeth Stubblefield*
The management of Hepatitis C infection (Hepatitis C Virus) was the subject of an expert "consensus panel" discussion at the National Institutes of Health this past June. From the discussions at the meeting, guidelines for testing, treating and preventing Hepatitis C Virus were developed and are now posted on the internet (www.consensus.nih.gov). Hepatitis C Virus prevention in prison is also the subject of a special issue of the Morbidity and Mortality Weekly Report, to be published later this year. Events at the consensus meeting and aspects of the two publications that concern correctional health providers are reviewed in this HEPP Report.
There are six known Hepatitis C Virus genotypes. Patients with genotype 2 or 3 are two to three times more likely to achieve a sustained viral response to treatment than those with genotype 1. The duration of combination therapy with pegylated IFN who are not co-infected and do not have genotype 1 is usually 24 weeks, while co-infected patients and those with genotype 1 are usually treated for at least 48 weeks (See HEPPigram, page 6).
THE ROLE OF LIVER BIOPSY
The NIH consensus panel emphasized the role of liver biopsy in the management of Hepatitis C Virus. Biopsies grade the severity of disease and stage the degree of fibrosis and permanent architectural damage in a patient. Radiological testing such as ultrasound cannot indicate the stage of disease except in the setting of advanced cirrhosis. Measuring ALT also does not reliably assess the stage of liver disease, particularly in HIV-infected patients. While the majority of Hepatitis C Virus patients with consistently normal ALT have early Hepatitis C Virus disease, 22% may have more advanced disease.16 Because patients with genotypes 2 and 3 respond so well to treatment, there was some debate about the need for biopsy prior to treatment in those patients (See HEPPigram, page 6). In addition, among HIV-infected patients, a higher percentage of patients with normal ALT may have moderate or more severe liver disease. Therefore, some experts suggest that patients with consistently normal ALT be treated no differently than patients with consistently abnormal ALTs.16
In addition to more accurate staging of disease, biopsies also confirm the Hepatitis C Virus diagnosis, exclude alternative diagnoses, predict responsiveness to treatment, and provide a baseline for future comparison.17 The biopsy can provide extremely useful information, but lack of access to liver biopsy should not exclude appropriately selected patients from having access to Hepatitis C Virus treatment.
TREATMENT OF HEPATITIS C
The therapy of chronic hepatitis C has evolved steadily since alpha IFN was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen for most patients appears to be a 24- or 48-week course of the combination of pegylated IFN and RBV.
The development of pegylated IFN (peg IFN) and the use of peg IFN in combination with RBV (combination therapy) are important advancements in the treatment of Hepatitis C Virus that were emphasized during the NIH conference (see HEPP News, April 2002). Two forms of peg IFN have been developed and studied in large clinical trials: peg IFN alfa-2a (Pegasys: Hoffman La Roche, Nutley, NJ) and peg IFN alfa-2b (Pegintron: Schering-Plough Corp., Kenilworth, NJ).
Combination therapy leads to rapid improvements in serum ALT levels and disappearance of detectable Hepatitis C Virus RNA (end of treatment response) in up to 70% of monoinfected patients. For patients with genotype 2 or 3, response rates in studies are 75-90%. For patients with genotype 1, response rates are 30-46%. Preliminary data from ongoing studies suggest that HIV-coinfected patients will have lower response rates. Success depends on several factors including genotype, viral load, and stage of disease. For patients who maintain negative Hepatitis C Virus RNA for 24 weeks after stopping Hepatitis C Virus therapy, results from several studies show 98% remain Hepatitis C Virus RNA negative (sustained response). Small studies following patients for up to 11 years show well over 90% of those who achieve a sustained response remain Hepatitis C Virus RNA negative. In some patients who were Hepatitis C Virus RNA negative, Hepatitis C Virus could no longer be found in the liver. Unlike the situation with HIV, the Hepatitis C Virus virus cannot integrate into the host genome, and therefore eradication of the virus is possible. At the NIH consensus panel, Dr. Jay H. Hoofnagle pronounced Hepatitis C Virus "curable".18 Indeed, since the last consensus panel on Hepatitis C Virus convened in 1997, the availability of highly effective combination therapy that can eradicate Hepatitis C Virus infection has lead many experts to consider treatment where previously they might not have treated. In order to evaluate the clinical outcomes and survival, however, studies of long-term follow-up for these patients and coinfected patients is necessary.
SPECIAL CONSIDERATIONS FOR HIV/Hepatitis C Virus CO-INFECTION
All HIV-infected persons should be screened for Hepatitis C Virus. The 2002 NIH consensus panelists recommended that studies are needed to determine the best strategies for treating Hepatitis C Virus and HIV co-infected patients. Co-infected patients may have an accelerated course of Hepatitis C Virus disease. As a result, some clinicians believe that early treatment of Hepatitis C Virus is indicated in those who are HIV infected. Thus far, studies of co-infected individuals have enrolled mainly patients with "stable" (usually defined as CD4 counts >300 and HIV viral loads <5000) HIV infection and well-compensated liver disease. Preliminary studies suggest that combination (IFN/RBV) therapy is more efficacious than IFN monotherapy in those who are co-infected.19
Small studies done several years ago reported that Hepatitis C Virus and HIV-co-infected patients responded to therapy just as well as mono-infected patients.20 More recently, better designed studies suggest the response rate in co-infected patients is likely to be lower than in those who are not HIV-infected. This reduced response may be attributed to the impairment HIV causes to the immune system and/or higher therapy discontinuation rates due to drug side effects and toxicities. Although it has not yet been well researched, patients co-infected with HIV may require 48 weeks therapy or longer regardless of whether they have genotype 1 or 2. Speaking at the NIH Consensus Conference, Dr. David Thomas of Hopkins suggested that the "balance has shifted" in favor of treatment of HIV-infected patients, even though larger studies will be needed to determine the rate of progression of Hepatitis C Virus in these patients, the duration of therapy that may be required and their overall response to treatment (See Figure 3). When asked by a Consensus Conference audience member what CD4 cutoff should be used to exclude patients from treatment, Dr. Thomas could not define one. He went on to say that good control of HIV infection was essential if Hepatitis C Virus were to be treated, but otherwise he could see no contraindication to treatment of HIV-infected patients.21
An additional concern is that co-infected patients may experience more side effects and adverse events, such as anemia and leukopenia. These side effects can make adherence to therapy more challenging.
A high percentage of co-infected patients are African-Americans and greater than 90% have genotype 1. Patients with genotype 1 have a lower rate of response to therapy. One study showed that African-Americans with genotype 1 experienced lower response rates than Caucasians with genotype 1, suggesting that factors other than genotype may also be responsible.23 These factors have not been well defined, and merit further research.
Side effects of therapy can include fatigue, irritability, emotional distress, weight loss, and depression. Adverse laboratory events can include anemia, leukopenia, and thrombocytopenia. More uncommonly, therapy can cause autoimmune disease (particularly thyroid disease), and suicidal ideation or attempts. For these reasons, close follow-up of patients on therapy is essential. Ideally, patients should be seen weekly for the first four weeks after initiation of therapy. After the first month, patients who are doing well can be seen less often i.e. every four weeks. It is important for prisoners to be able to inform the clinician of all side effects they experience so that effective interventions can be initiated. Support services are needed to guide patients through the process of starting and maintaining therapy.
OUTCOMES OF THERAPY
For those without cirrhosis, achieving a sustained response to therapy should prevent progression to decompensated liver disease or cancer. Experts believe that a sustained response to therapy among people with cirrhosis should also prevent progression, but studies are still inconclusive.15 Several studies previously conducted provide evidence that IFN use in patients with cirrhosis and non-responders can slow or reverse disease progression.24 These results indicate that patients with cirrhosis who achieve a sustained viral response have a good chance of stopping and perhaps reversing disease progression. Further study, however, is necessary.
Hepatitis C Virus Epidemiology
It has been estimated that 1-2% of the general population (2.9 to 5.8 million people) in the United States has been exposed to HCV1, with 75% to 85% developing chronic Hepatitis C Virus infection. The behavior that puts people most at risk for exposure to Hepatitis C Virus is intravenous drug use (IDU). Other risks include use of shared injection equipment including cotton filters and "cookers,"2 unprotected sex with an Hepatitis C Virus-infected partner (3%-13% lifetime risk), and receipt of blood products prior to 1988. Prevalence rates in certain high-risk groups are as high as 90% (Figure 1). Since so many of the behaviors that put people at risk for developing Hepatitis C Virus infection also put them at risk for incarceration (ie IDU), it should not be surprising that Hepatitis C Virus is common in the correctional setting.