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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

     
          

Hepatitis C in Corrections: Testing, Treatment and Co-infection

William M. Cassidy*, MD, Louisiana State University Health Services Center
David Guidry**, Louisianna State University
Courtney E. Colton***, IDCR Managing Editor

http://www.idcronline.org/

Disclosures:
*Consultant: Schering, Roche, InterImmune. Grant/Research Support: Schering, Roche, Merck. Speaker’s Bureau: Schering, Roche, GlaxoSmithKline, Merck
**Nothing to disclose
***Nothing to disclose

Background
With an estimated worldwide prevalence of 2.2%, hepatitis C virus (HCV) is one of the most prevalent chronic viral infections in the world.1 Incarcerated populations have dramatically higher rates of HCV infection than non-incarcerated populations. Approximately 2.0% of the United States (US) non-incarcerated population has been infected with HCV; 1.3% are chronically infected. In contrast, seroprevalence studies have found HCV infection rates ranging between 16-43%2,3,4 among incarcerated populations; 12-35% of inmates have chronic infection.

HCV is a viral infection transmitted primarily through blood and blood products. Approximately 75% of acutely infected patients will develop chronic infection, and 20% of those with chronic infection develop cirrhosis within 20 years.6 While there is no vaccine for HCV, effective strategies for preventing transmission exist.5 Additionally, the current standard-of-care treatment regimen, pegylated interferon (PEG IFN) alfa plus ribavirin (RBV), has demonstrated higher sustained virologic response (SVR) rates, defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment and six months later, compared to standard interferon. PEG IFN alfa plus RBV is safe and efficacious in both HCV mono-infected7 and HIV/HCV co-infected patients.

Because nearly one-third of all HCV-infected persons pass through correctional facilities each year8, and will eventually return to the communities from whence they came, providing HCV screening, testing, treatment and prevention education (including education regarding re-infection and basic primary prevention for those who do not test HCV-infected) within corrections could have important public health implications. Testing and, when appropriate, treating HCV-infected inmates could reduce disease transmission in the communities to which inmates return.

    

Testing
Currently, the United States Task Force for Preventive Services recommendations caution against routinely screening patients for HCV infection,9 as screening tests have low positive predictive values (PPV) if the prevalence of the disease in the population being screened is less than 10%. Those recommendations do not apply to drug-using populations. The most efficient means of HCV transmission is through injection drug use; estimates of HCV prevalence for injection drug users (IDUs) are as high as 90% in some regions.10 Since a large number of inmates have previously or currently inject drugs and because approximately one-third of HCV-infected persons pass through corrections every year, most experts recommend that prison inmates be screened for HCV infection.11

Accordingly, Centers for Disease Control and Prevention (CDC) recommendations regarding HCV screening in correctional settings includes the following statements: (1) All inmates should be questioned regarding risk factors for HCV infection during entry medical examinations, and those with risk factors should be tested for HCV; (2) The sensitivity of risk factor-based screening should periodically be determined by seroprevalence surveys, in combination with ascertainment of demographic and risk factor information. Serologic testing of expanded groups of inmates or all inmates is recommended when: (2a) self-reported history of risk factors alone identifies <75% of anti-HCV positive inmates or (2b) the prevalence of risk factors for HCV infection, including injection drug use, is known to be high (>75%), and a high prevalence (>20%) of HCV infection exists among inmates who deny risk factors.5

Persons who received a blood or organ transplant prior to 1992 should also be tested.4 Although transmission from exposure to an infected sexual partner is less efficient, any individual who has had multiple sexual partners or who believes one of his or her partners is HCV-infected, should be tested. Lastly, persons with unexplained elevations of aminotransferase levels, those who have ever been on hemodialysis, and those with HIV infection, should all be tested for HCV infection.2

Laboratory Diagnosis of HCV
Eighty percent of individuals with acute HCV infection are asymptomatic.12 Identification of HCV infection is accomplished by initially testing for antibodies to HCV (anti-HCV.) To prevent false-positive results, testing should include an antibody screening assay, followed by confirmatory testing of positive results with a more specific assay (Table 1.) Because a positive test result for anti-HCV does not distinguish between acute and chronic infection, HCV RNA testing should be performed in individuals who test positive for anti-HCV. Chronic infection is defined as the presence of HCV RNA for a minimum of six months.13

HCV Genotypes
There are six different HCV genotypes. Because HCV genotype is the strongest predictor of response to treatment,14 genotype should be determined in all HCV-infected persons prior to treatment. Studies indicate that individuals infected with HCV genotype 1 are the least likely to achieve a SVR, while those infected with genotypes 2 and 3 are much more likely to achieve a SVR.1 It should be noted that 95% of HCV-infected African Americans are infected with genotype 1, while only 65% of non-African Americans are infected with genotype 1.15 Two tests, which are not FDA-approved, are currently available for HCV genotyping. These include the Trugene HCV 5'NC Genotyping Kit (Visible Genetics) and the Inno LiPA HCV II (Innogenetics.) These tests fail to identify HCV genotype in less than 3% of HCV-infected persons, and may display a mixed genotype in 1%-4% of HCV-infected persons.2

Liver Biopsy
Various protocols exist in a number of correctional systems to determine who should receive a liver biopsy and tehse are not consistent among different state department of corrections. This point is important if liver biopsy is considered a prerequisite for treatment, because those who do not qualify for biopsy would not be considered candidates for treatment. The following criteria have all been used to determine who should receive a liver biopsy: (1) two elevated ALT levels greater than two times the upper limit of normal, at least three months apart; (2) one ALT level greater than two times the upper limit of normal; (3) one ALT level greater than 1.5 times the upper limit of normal; (4) any ALT elevation at any time (but not persistently normal ALT); (5) all HCV-infected persons. The California DOC offers liver biopsy to all HCV-infected persons 45 or older, regardless of ALT levels, while those younger than 45 must have elevated ALT levels. It should be noted that the available literature does not clearly lend support to any particular criteria as listed, and that decisions in individual cases should be guided by the totality of the clinical picture for each patient.

Liver biopsy results reveal information regarding the extent of fibrosis (staging) and degree of hepatic inflammation (grading), thus helping the patient and provider decide on the course, and urgency, of therapy.16 Various scoring systems for defining staging and grading have been developed. The components of two of these scoring systems are shown in Table 2.

More-than-portal fibrosis on liver biopsy (Metavir score of >2 or an Ishak score of >3) is an important predictor of future progression of liver disease and the need for HCV treatment.11 Scoring is usually provided in the pathology laboratory report.

Non-invasive tests, including the FibroSURE test and aspartate aminotransferase to platelet radio index (APRI), may be alternatives to liver biopsy. Both tests are limited in that they poorly differentiate between stages 1 and 2 fibrosis. Often this represents the cutoff wherein many protocols determine whether patients will or will not receive interferon/RBV therapy. Therefore, non-invasive tests are only helpful when severe liver damage or cirrhosis is the expected finding.

Because of decreased SVR rates in HCV genotype 1-infected patients, many clinicians obtain a liver biopsy for these patients to guide treatment recommendations. HCV genotype 2- and 3-infected patients have a higher likelihood of achieving a SVR and so some advocate treating all such patients, regardless of liver disease severity, and without liver biopsy. Current AASLD recommendations state that a liver biopsy should be performed, regardless of ALT levels, and for all genotypes, when the results will influence whether treatment is recommended. A biopsy is not required to initiate therapy.7

Treatment
The current standard-of-care treatment regimen for HCV mono-infection and HIV/HCV co-infection is PEG IFN alfa plus RBV.10 The two FDA-approved PEG IFN products; PEG IFN alfa-2a (Pegasys®, Hoffman-La Roche) and PEG IFN alfa-2b (Peg-Intron®, Schering-Plough Corporation) have demonstrated similar indicators of both treatment response and adverse events, but further studies are needed to compare the efficacy of the two products.6,10

If, at 12 weeks of treatment, the early virologic response (EVR) indicates that there has not been a 2 log decline in HCV RNA relative to baseline HCV RNA, the patient is unlikely to achieve a SVR and treatment should be discontinued.17

Treatment is not recommended for individuals under certain circumstances (Table 3.)

All HCV-infected patients should receive hepatitis A virus (HAV) and HBV vaccinations if they are non-immune (see this months IDCR-o-gram.)

    

Drug Side Effects
Side effects of PEG IFN alfa may include neutropenia, thrombocytopenia, depression, hypothyroidism, irritability, concentration and/or memory disturbances, fatigue, headaches, nausea, vomiting, weight loss, insomnia, and flu-like symptoms.18

Side effects of RBV may include hemolytic anemia, fatigue, and rash. Pregnant women should not be prescribed RBV, as it can result in birth defects. During treatment and for six months post-treatment, men and women should use contraception methods to avoid pregnancy.11 RBV is contraindicated in patients on dialysis and in patients who have severely elevated creatinine clearance.

All adverse effects tend to decrease in severity after the initial few weeks of treatment, and may be managed with antidepressants, growth factors (i.e. epoetin, granulocyte colony-stimulating factor), and analgesics.10

Treatment Failure
Individuals who fail to achieve a SVR after initial treatment may be able to achieve a SVR with a re-treatment regimen of PEG IFN plus RBV. A SVR is typically achieved in 25%-40% and 10% of patients who failed to respond to interferon alfa monotherapy and interferon alfa plus RBV, respectively.19 AASLD guidelines state that "retreatment with PEG IFN plus RBV should be considered for non-responders or relapsers who have significant fibrosis or cirrhosis and who have undergone previous regimens of treatment using non-pegylated IFN. Retreatment with PEG IFN plus RBV with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of PEG IFN plus RBV, even if a different type of PEG IFN is administered."11

Normal ALT Levels
The Federal Bureau of Prisons (FBOP) protocol currently states that the management of HCV-infected inmates should be restricted to those inmates with an ALT level greater than or equal to two times the upper limit of normal.20 However, in a given patient, ALT levels may fluctuate. Additionally, when other laboratory abnormalities exist (i.e. low platelet count) further evaluation and/or treatment are indicated. Current controversy exists regarding whether patients, in whom all biochemical markers of liver injury are normal and in whom ALT levels are normal on multiple occasions, should be treated.

The 2002 National Institutes of Health (NIH) consensus conference statement on management of HCV-infected patients with persistently normal ALT levels stated, "Approximately 30% of patients with chronic HCV infection have normal ALT levels…Although most of these patients have mild disease, histologically, some may progress to advanced fibrosis and cirrhosis."21

A recent study evaluated the efficacy and safety of antiviral therapy for chronic HCV-infected patients with persistently normal ALT levels. Patients with at least three normal ALT values over an 18 month period were randomized to receive one of the following: PEG IFN alfa-2a 180 mg/wk plus RBV 800mg/day for 24 weeks, the same combination for 48 weeks, or no treatment. All patients were monitored for 72 weeks. An SVR was achieved by 30% and 52% of the patients treated for 24 and 48 weeks, respectively. No patient achieved a SVR in the untreated group. HCV genotype 1-infected patients achieved SVR rates of 13% and 40% with 24 and 48 weeks of treatment, respectively. HCV genotype 2- or 3-infected patients achieved SVR rates of 72% and 78% with 24 and 48 weeks of treatment, respectively. While there are no current recommendations regarding whether to treat patients with normal ALT levels, study authors concluded that the efficacy and safety of PEG IFN alfa-2a plus RBV for chronic HCV-infected patients with normal ALT levels is similar to that in patients with elevated ALT levels.22

HIV/HCV Co-Infection
Among HIV-infected individuals living in the US, nearly 30% are co-infected with HCV.vi HCV is common in HIV-infected individuals because of the shared routes of transmission of the two diseases. While HCV infection often takes 20 to 30 years to progress to cirrhosis, the course of HCV is accelerated in the presence of HIV.vi Aggressive treatment of HIV/HCV co-infected individuals is warranted, given the potential for increased immunosuppression and decreased response to antiretroviral therapy (ART.)

In the AIDS Pegasys Ribavirin Co-Infection Trial (APRICOT) involving HIV/HCV co-infected patients, 40% and 62% of HCV genotype 1- and HCV genotype 2- or 3-infected patients, respectively, achieved a SVR. These are the highest SVR rates among co-infected patients in any reported study thus far.23 It should be noted that all participants in this study had well controlled HIV; viral load averaged 50 µg/ml and CD4 count averaged 500 cells/ml. In co-infected patients, the duration of HCV therapy is increased from 24 to 48 weeks for genotype 2- and 3-infected patients. Because of a high relapse rate for genotype 1-infected patients, extending HCV therapy from 48 to 72 weeks may improve therapy outcomes. For more information on co-infection, please refer to the case study in this month's issue.

Why Treat?
Treatment of chronic HCV infection has been shown to be cost-effective. In a recent study, a Markov model of disease progression was constructed to determine if the gain in SVR achieved with PEG IFN alfa-2a plus RBV would be worth the incremental cost. In the model, cohorts of patients received PEG IFN alfa-2a plus RBV for 48 weeks (genotype 1, genotype non-1 with fibrosis) or 24 weeks (genotype non-1 without fibrosis.) The model predicted that in HCV genotype 1-infected patients, PEG IFN alfa-2a plus RBV would increase life-years (LY) by .78 years and quality adjusted life years by (QALY)i by .67 years, compared with interferon alfa-2b plus RBV. The associated cost per LY and QALY gained would be $11,952 and $13,804, respectively. In HCV genotype non-1-infected patients, PEG IFN alfa-2a plus RBV would increase LY and QALY by 1.17 and 1.01 years, respectively, compared with interferon alfa-2b plus RBV; the associated cost per LY and QALY gained would be $4,132 and $4,772, respectively. The study authors concluded that PEG IFN alfa-2a plus RBV for the treatment of naďve adults with chronic HCV infection, regardless of HCV genotype, is cost-effective; halting the progression of disease and avoiding costly future morbidities largely offset costs associated with treatment.24 Other studies have arrived at similar conclusions.25

The correctional environment, with its high HCV prevalence rates among inmates, provides an opportunity to diagnose and treat populations at the highest risk of HCV infection. Because no formal national guidelines for the treatment of HCV within corrections exist, most guidelines are system-specific. Research on the implementation of cost-effective HCV screening, testing, and treatment among the incarcerated population is essential.

iEditor's Note:
QALY: A year of life adjusted for its quality or its value. A year in perfect health is considered equal to 1.0 QALY. The value of a year in ill health would be discounted.

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