Douglas G. Fish, MD
HIV and Hepatitis C: Expert Commentary
Approximately 15% to 30% of people with HIV are estimated to be co-infected with hepatitis C virus (HCV) in the United States, and up to 90% of those with HIV secondary to injection drug use are co-infected.1,2 Chronic liver disease from co-infection, including cirrhosis and hepatocellular carcinoma, leads to significant morbidity and mortality.
Most patients who are co-infected with hepatitis C are diagnosed with chronic disease. This is diagnosed when the hepatitis C antibody is reactive and subsequent viral load (RNA) testing is positive. Acute hepatitis C is less common and can be associated with spontaneous clearance. Estimates of spontaneous clearance rates are lower, however, among persons with HIV than in those who are mono-infected.3 Rates of perinatal transmission of hepatitis C are approximately 20% for HIV-infected mothers co-infected with hepatitis C, considerably more than for HCV mono-infected mothers.4
Substantial progress has been made in the treatment of hepatitis C, and more patients are having sustained virologic responses (SVRs) with combination weekly pegylated interferon and twice-daily oral ribavirin therapy. Most of these patients with SVR are thought to be cured of their hepatitis C. Clinical trials involving co-infected patients have informed treatment guidelines, including those of the New York State Department of Health AIDS Institute.5
Pegylated interferon and ribavirin have greatly improved treatment responses, especially for persons with HCV genotypes 2 and 3. Updated recommendations in these guidelines (see the following sections of this document) include annual HCV antibody testing for persons with continued high-risk behaviors, such as injection drug use and multiple sexual partners; quantitative viral load testing to confirm a reactive HCV antibody result on enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassay (EIA); and consultation with a mental health professional when prescribing anti-HCV therapy for persons with mental health disorders. A section on baseline assessment has been added (Section 8: Hepatitis C Treatment and Treatment Monitoring), along with a table on treatment recommendations based on liver biopsy results (Table 4) and updates on algorithms for the diagnosis of hepatitis C (Figure 1) and for guiding therapeutic decisions on the basis of HCV RNA responses to treatment (Figure 2).
In summary, we should now be looking for reasons to treat our HIV/HCV co-infected patients, as opposed to looking for reasons not to treat. The therapeutic pipeline for newer anti-HCV therapies -- such as telaprevir, an oral protease inhibitor -- is rich, and these therapies will have to be studied in co-infected populations for safety, tolerability, efficacy, and pharmacokinetic interactions with available antiretroviral medications.
• Hepatitis A Virus
• Hepatitis B Virus
• Hepatitis C Virus
1.Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients co-infected with human immunodeficiency virus: A cross-sectional analysis of the U.S. Adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831-837.
2.Centers for Disease Control and Prevention. Recommendations for the prevention and control of hepatitis C virus (HCV) infection and HCV related disease. MMWR Recomm Rep. 1998;47(RR-19):1-39.
3.Piasecki BA, Lewis JD, Reddy KR, et al. Influence of alcohol use, race, and viral co-infections on spontaneous HCV clearance in a U.S. veteran population. Hepatology. 2004;40:892-899.
4.National Institutes of Health. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1-46.
5.Medical Care Criteria Committee. Hepatitis C. New York State Department of Health AIDS Institute. Available at: http://www.hivguidelines.org/clinical-guidelines/ Accessed October 27, 2010.
Hepatitis C Virus: Guideline for Care
Editor's Note: This guideline was prepared and published by the New York State Department of Health AIDS Institute HIV Clinical Guidelines Program. It has been republished here. Please note that recommendations are assigned an evidence-based rating and use the rating scheme developed by the Department of Health and Human Services.
What's New in the Latest Update (May 2010)
Significant revisions [to this guideline] include the following:
• An annual HCV antibody test is now recommended for HIV-infected patients who have continued high-risk behaviors but are seronegative for HCV; such individuals include:
◦ Injection drug users
◦ Men who have sex with men (MSM) and don't use barrier protection
◦ Anyone with multiple sexual partners
• Quantitative HCV RNA viral load testing is now recommended for HIV-infected patients:
◦ To confirm a reactive HCV ELISA antibody screen
◦ To exclude HCV infection in those who are seronegative for HCV but have risk factors for HCV exposure and unexplained liver disease, including increased serum liver enzymes
• A table has been added that lists the tests for measuring HCV RNA (see Table 1)
• Figure 1. HCV Testing Algorithm for HIV-Infected Patients has been updated
• Assessment for anti-HCV therapy is now recommended for HIV-infected patients with acute HCV infection (see Section 6: Deciding Whether to Treat HCV in HIV-Infected Patients)
• Sections on assessment of mental health disorders and alcohol and substance use have been added (see Section 5: Evaluation and Initial Management of Confirmed Hepatitis C Infection)
• A new section has been added on ongoing evaluation of patients when anti-HCV therapy is deferred (see Section 7: Ongoing Evaluation of Patients in Whom Anti-HCV Treatment Is Deferred)
• A new section has been added that outlines baseline assessments and counseling at initiation of therapy (see Section 8: Hepatitis C Treatment and Treatment Monitoring)
• Consultation with a psychiatrist is now recommended when prescribing anti-HCV therapy for HIV-infected patients with mental health disorders
• Figure 2. Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients has been updated and now recommends determining whether or not to continue anti-HCV treatment after week 12 by assessing for virologic response according to quantitative HCV RNA
• A table has been added that outlines strategies for managing side effects of anti-HCV therapy (see Table 7)
Hepatitis C virus (HCV) is a common cause of death from liver disease among the HIV-infected population. Approximately 15% to 30% of people with HIV are estimated to be co-infected with HCV in the United States. The rate is much higher among patients infected with HIV through injection drug use (approximately 70% to 90%) or individuals with hemophilia who received factor concentrates before 1987. Data collected from the ACTG A5001 cohort demonstrate that HIV/HCV co-infected patients visit the emergency department more frequently, are hospitalized more often, and have longer hospital stays than HIV mono-infected patients. Other studies have established HCV-related end-stage liver disease as a leading cause of in-hospital mortality among HIV-infected patients.[5-7]
Therapy for HCV has become increasingly successful. However, anti-HCV therapy is complex, particularly in the presence of HIV, and requires many treatment considerations, as well as careful monitoring.
The similar routes of exposure for HIV and HCV place patients with either infection at risk for HIV/HCV co-infection.
Natural History of Hepatitis C Virus
HCV and HIV are both RNA viruses but belong to different viral families (Flaviviridae and Retroviridae, respectively) and have very different life cycles. Like HIV, HCV mutates frequently, establishing a genetically diverse population of viral quasi-species within each infected host. This genetic diversity is at least partly responsible for the ability of HCV to evade the body’s immune defenses and establish chronic infection. Unlike HIV, HCV RNA replicates in the cytoplasm of its host cell, the hepatocyte. This mode of genetic replication prevents incorporation of the HCV genome into the hepatocyte, enabling possible clearance of HCV from plasma and eradication of infection.
Acute HCV Infection
Acute HCV disease is often asymptomatic, with 25% to 35% of HCV mono-infected patients developing only mild constitutional symptoms or jaundice. Symptoms may be even milder or occur less frequently in HIV-infected patients. This lower incidence of symptomatic presentation in HIV-infected patients has been attributed in part to a weaker immune response compared with HCV mono-infected patients. Patients who experience symptoms, which are suggestive of a stronger immune response, have demonstrated better clinical outcomes in comparison with patients who are asymptomatic during acute HCV infection.
The acute phase is defined as the first 6 months of HCV infection. During this time, serum alanine aminotransferase (ALT) levels frequently rise, fluctuate, and fall again, which indicates recovery from the acute phase. Estimates of spontaneous HCV clearance without treatment are 15% to 45% in non-HIV-infected adults and 11.5% in HIV-infected adults. Likelihood of HCV clearance among HIV-infected individuals is diminished in patients with lower CD4 cell counts, especially CD4 <200 cells/mm3. Treatment of acute HCV infection in HIV-infected adults is supported by a 60% to 70% SVR rate.
Chronic HCV Infection
Chronic infection arises in individuals who do not clear the virus during acute infection. Two thirds of patients with chronic infection develop persistent or fluctuating serum ALT elevations, which are indicative of active liver inflammation. Because serum ALT levels may normalize intermittently, a single normal serum ALT level does not indicate that liver damage is absent. In contrast to many other liver diseases, the degree of ALT elevation in HCV-infected individuals frequently fails to correlate with the degree of liver inflammation observed on liver biopsy.
Up to 30% of patients with either HCV mono-infection or HIV/HCV co-infection may have persistently normal liver chemistries but still have significant liver disease.
Histologic Damage in Chronic HCV Infection. Chronic HCV infection can cause inflammatory infiltration, particularly of the portal tracts, as well as both focal and bridging necrosis and fibrosis. Typically, chronic HCV infection results in a lymphocyte-predominant inflammatory infiltrate in the portal tracts and periportal regions of the liver. Inflammation may activate hepatic stellate cells to produce collagen. This, in turn, leads to the deposition of fibrous tissue first in the portal tracts and then in periportal regions. In more advanced stages of fibrosis, bridging fibrosis between portal tracts is present, and, in more advanced cirrhosis, fibrotic nodules are also present.
Cirrhosis and Hepatocellular Carcinoma in HCV Infection. Approximately 10% to 15% of patients with HCV infection will progress to cirrhosis after 20 years of infection. After development of cirrhosis from HCV, hepatocellular carcinoma (HCC) occurs at an estimated rate of 0% to 3% per year. The incidence of HCC from any cause of cirrhosis in the United States increased from 1.6 per 100,000 in 1975 to 4.9 per 100,000 in 2005; among black men, the incidence was 7.0 per 100,000 in 2005.
Progression to cirrhosis occurs more quickly in men, in patients who use alcohol, in those who acquire HCV after 40 years of age, and in HIV/HCV co-infected patients.
HCV Genotypes. HCV exists in 6 known genotypes and over 50 genotypic subtypes. Approximately 70% of patients with HCV in the United States are infected with genotypes 1 and 4, with genotypic subtype 1a being more common than subtype 1b. Ninety-one percent of HCV-infected non-Hispanic blacks were infected with genotype 1 in the third National Health and Nutrition Examination Survey (NHANES III). Although there are no known differences in clinical course among the various genotypes and subtypes, genotypes 1 and 4 are known to have a poorer response to interferon-based therapy than genotypes 2 and 3.
Routes of Transmission of Hepatitis C Virus
Parenteral Transmission. Parenteral transmission is the primary route for HCV infection. Injection drug use accounts for at least 60% of all new infections in the United States. In some populations of injecting drug users, >80% have been infected with HCV; however, lower prevalence has been found in other populations, particularly among young users. Patients should be advised to avoid sharing any injection or drug preparation equipment. Although HCV transmission may be reduced through cleansing shared syringes with bleach and water between uses, HCV can also be transmitted through the use of other equipment, including cookers (metal bottle caps), water for dissolving drugs and rinsing syringes, cotton for filtering the solution, and tourniquets.
The risk for HCV infection from injury with an HCV-contaminated needle is 1.8%. For information regarding management of occupational exposure to HCV, refer to HIV Prophylaxis Following Occupational Exposure .
Sexual Transmission. The efficiency of sexual transmission of HCV is much lower than HIV or other sexually transmitted viruses. However, isolated outbreaks of permucosal HCV transmission have been reported among HIV-infected MSM.[18-23] In the setting of the following risk factors, HCV transmission was increased among HIV-infected MSM compared with non-HIV-infected MSM: sharing drugs via anal or intranasal routes; unprotected anal intercourse and anal/oral (“rimming”) or anal/hand contact (“fisting”); and the presence of other sexually transmitted infections (STIs).
Among non-HIV-infected, monogamous, heterosexual couples who are discordant for HCV, the risk for sexual HCV transmission is estimated to be 0% to 0.6% annually. Limited data suggest that the presence of HIV does not increase the risk for sexual HCV transmission amount heterosexual couples. Some studies have shown that long-term, monogamous partners of HCV-infected individuals (>10 years) have slightly higher rates of HCV infection than the general population; however, the rate remains low (1.5%).[25,26]
Guidelines indicating that barrier protection may not be necessary between HCV-discordant sexual partners apply only in the setting of HCV mono-infection and do not apply in the setting of HIV/HCV co-infection.
Perinatal Transmission. Maternal-fetal transmission of HCV in mono-infected women with detectable HCV RNA at delivery is approximately 4% to 7%. However, HIV co-infection increases the risk for perinatal transmission to 20%.
Nonsexual Household Transmission. Nonsexual household transmission is rare in the United States, although it has been known to occur, probably through inadvertent exposure to blood or infectious body fluids.