News Story #18342

By Louise Lazear

Evolving lab methods provide more tools in the fight against hepatitis

Viral hepatitis is a disease that impacts human health on a worldwide basis. In the U.S., initiatives in prevention, detection and treatment have helped to moderate some of its more ravaging effects. However, public health officials, clinicians and scientists continue to grapple with issues regarding identification of risk groups, screening and testing recommendations, post exposure management, and treatment and counseling of infected individuals. Perhaps the greatest concern is the potentially astronomical burden on healthcare and the impact on society in general as the estimated

3 million Americans chronically infected with HCV progress with their disease. While heightened public awareness remains key, developments in diagnostic markers, new therapies and the potential for new vaccines are helping to strengthen our armament against this formidable adversary.

Viral hepatitis is known to be caused by at least five different viruses: HAV, HBV, HCV, HDV, and HEV. Symptoms range from none to mild abdominal discomfort to severe vomiting, diarrhea, and jaundice. In some cases, patients spontaneously clear the virus, while others experience chronic conditions with significant morbidity and mortality. Currently, serological evaluation and liver biopsy are the recommended means for diagnosis of viral hepatitis infection and extent of damage to the liver.

HAV and HEV are transmitted via the fecal/oral route, and do not cause chronic infection. HBV, HCV and HDV are bloodborne viruses that can produce chronic infection which in many cases remain asymptomatic until extensive injury occurs, leading to liver failure or hepatocarcinoma. Incidence and prevalence varies by virus type: HAV occurs most frequently, followed by HBV and HCV. It is believed that HDV infection occurs only with HBV, and an estimated four percent of persons with HBV are co-infected with HDV. HEV is rare in the U.S., but can occur in high rates in developing countries where the virus may be endemic. HAV and HBV can both be prevented with vaccination.

HAV, historically known as infectious hepatitis, is transmitted via oral contact with feces, or with food, water or objects contaminated with the feces of an infected person. Without inactivation by heat (at least 180 degrees for one minute) or use of bleach to disinfect surfaces, HAV can remain stable for months. In rare occasions, HAV is known to have been transmitted in blood from donors during the viremic phase of infection. The causative RNA agent is a 27 nm picornavirus, which may produce symptomatic or asymptomatic infection after an incubation period of 15 to 50 days. During infection, HAV resides in the liver, is excreted in bile, and eventually shed via stool. Diagnosis of acute HAV infection requires serological detection of IgM antibody to capsid proteins of HAV (IgM anti-HAV), which are detectable five to 10 days prior to symptom onset, and for up to six months post infection. IgG anti-HAV can be detected in early infection, and remains detectable over the course of the patient’s lifetime, indicating lifelong immunity. Nucleic acid testing (NAT) determination of HAV RNA in the feces and blood of infected individuals is less commonly performed.

The incidence of HAV infection appears to be erratic and not tied to other types of viral hepatitis. During epidemics, up to 35,000 cases per year have been reported in the U.S. HAV infection is one of the most frequently reported diseases that can be prevented with vaccination. According to data from NHANES III (National Health and Nutrition Examination Survey III), prevalence of HAV infection increases with age, household crowding and poverty levels. Over the period 1991 through 1998, 63 percent of acute cases of hepatitis were caused by HAV. In addition, an estimated 100 persons each year die from liver failure as a result of the disease.

Those at risk for infection include household contacts of infected persons, sex contacts of infected persons, persons living in areas with consistently high rates of HAV incidence, male/male sex participants, and injected and non-injected drug users. While an estimated one-third of Americans exhibit immunity to HAV, vaccination against the virus remains the best protection. The CDC recommends vaccination for persons older than two years in the following risk categories: those traveling to areas with increased rates of HAV infection, male/male sex participants, injected and non-injected drug users, persons with clotting factor disorders and/or chronic liver disease, and children living in regions of the U.S. with high rates of HAV infection. In May 2001, the FDA licensed a combined vaccine against HAV and HBV for use in persons 18 or older. Called Twinrix, the vaccine combines the antigenic components used in separate vaccines for HAV and HBV since 1995 and 1989, respectively.

HBV is a bloodborne agent that can cause chronic liver disease leading to death in 15 to 20 percent of chronically infected persons. Twenty-eight percent of acute hepatitis cases over the period 1991-1998 were caused by HBV. It is estimated that 1.25 million people in the U.S. are chronically infected, and that 20 to 30 percent of these acquired infection during childhood. Up to 90 percent of women who are carriers can transmit the virus to their infants. However, due to screening pregnant women for HBV and newborn vaccination programs, the number of new infections per year has declined from an average of about 450,000 in the 1980s to approximately 80,000 in 1999. While prevalence has remained at 5 percent over the last 20 years, HBV is responsible for about 5,000 deaths per year. Worldwide, chronic HBV infection has risen to the primary cause of cirrhosis and hepatocellular carcinoma.

HBV is transmitted via blood and body fluids from infected persons. Risk groups include persons with multiple sex partners or with diagnosis of an STD, male/male sex participants, sex contacts of infected persons, injected drug users, household contacts of infected persons, infants born to infected mothers, infants and children of immigrants from areas with high rates of HBV, healthcare and public safety workers, and hemodialysis patients. Prevention primarily involves routine HBV vaccination of persons up to 18 years of age, and vaccination of risk groups of all ages. Other prevention programs are aimed at pregnant woman/new mother screening, newborn vaccination, and targeting high-risk groups via education and vaccination programs.

While the routine vaccination of children and screening of pregnant women have reduced the rate of new cases, targeting adults in the high-risk group remains a public health challenge. In 1992 and in March of this year, the CDC published recommendations regarding vaccination with regard to the changing epidemiology of the disease. “At the time of our previous publication, which reported data through 1988, the incidence of acute hepatitis B had basically remained fairly stable despite the availability of vaccine beginning in 1982,” said Miriam Alter, Ph.D., of the division of viral hepatitis at the CDC. “The primary reason was that our vaccination strategy at that time was focused on high-risk groups of adults, who are very difficult to reach with vaccination programs. Using that information, we went forward with a national program to incorporate hepatitis B into routine childhood vaccination. That has been very successful. In our publication this past March, which includes data through 1998, we’ve experienced a dramatic decline in the rate of new cases. The biggest percent reduction was in adolescents. Unfortunately, we still continue to have problems vaccinating adults, especially those who have high-risk sexual and drug use practices.”

According to Alter, the new data prompted the CDC to strengthen implementation of the recommendations already in place. “While eventually routine vaccination of children and adolescents will eliminate transmission, in order to hasten progress to that point we need to strengthen our vaccination efforts for older adolescents and adults,” she said. The CDC recently released materials to help STD and HIV/AIDS clinics incorporate HBV vaccination into their counseling and treatment programs.

HBV is diagnosed via a panel of markers that include determination of the presence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), antibody to HBe antigen (anti-HBeAb), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs), IgM antibody to hepatitis B core antigen, and HBV DNA. As use of these markers become more common, clinicians are discovering new information about disease progression. Recently, researchers in the U.S. have detected occult HBV infection in persons that are HBV DNA positive, but HBsAg negative. Additionally, physicians in Taipei have found that HBeAg along with HBsAg may be useful predictive markers for the development of hepatocarcinoma in HBV-infected individuals.

In routine screening, patients are evaluated for the presence of HBsAg. If positive, additional testing is performed to determine if viral replication is ongoing. This is done to assess treatment options. “A positive HBsAg tells you that a person is infected. The next question is whether they have active growth of the virus, or replication, “ said hepatology specialist Victor J. Navarro, M.D., medical director of liver transplantation at Thomas Jefferson University Hospital in Philadelphia. “Two tests are used to do that. The first is HBeAg. When positive, it suggests that the virus is actively replicating. The other test we often ask for is HBV DNA, which is also positive when there is active replication. There are times when the HBV DNA is positive, but the e antigen is negative. This occurs when someone is infected with a hepatitis precore mutant. In this case, HBV is present and growing, but doesn’t generate the e antigen due to a genetic mutation. It doesn’t mean necessarily that the virus is more aggressive or that the person will be any sicker,” he explained.

According to Navarro, 95 percent of people infected with HBV clear the virus. The remaining 5 percent remain chronically infected. Of those, some are candidates for therapy. Both viral load and active replication impact treatment response. “People with high viral loads are less likely to respond to treatment. The best candidates for therapy are patients with elevated liver enzymes, but relatively low levels of virus. This indicates vigorous immune activation against the virus, and the treatment augments the immune response and thus its efficacy,” he added. Both quantitative branched-chain DNA and PCR can be used to assess for viral load. “A higher viral load indicates that the patient has active replication. The problem with PCR is that it is overly sensitive…. The branched DNA assay is less sensitive. It’s lower limit of detection is somewhat higher, and when positive, we are a bit more sure that clinically significant replication is occurring,” he explained.

After diagnosis, patients are typically evaluated for liver disease, and when appropriate undergo a rigorous regimen of alpha interferon or lamivudine therapy. Treatment endpoint is to stop viral replication, rather than elimination of the virus. According to Navarro, interferon-based treatment typically results in a sustained response in about 30 to 40 percent of patients. However, lamivudine produces a response rate of approximately 20 percent, and also has an appreciable rate of resistance development. End-stage disease may result in liver transplantation. HBV infection can recur after transplantation. However, researchers have found that treatment with both hepatitis B immune globulin and lamivudine significantly increases HBV-free survival rates in post-transplant patients with prior infection.

While strides in public awareness and vaccination programs have helped in the fight against HAV and HBV, HCV can be characterized as a silent killer with little or no opposition. NHANES III data demonstrate that about 1.8 percent of Americans, close to 4 million people, have been infected with HCV, and as many as 75 to 80 percent go on to develop chronic infection. It is estimated that 20 to 50 percent of infected individuals are at risk of developing cirrhosis and hepatocellular carcinoma. The course of the disease spans decades, and many, if not most infected individuals are unaware of its presence. According to the CDC, HCV is the leading cause of known liver disease in our country and accounts for an estimated 8,000 to 10,000 deaths annually. HCV is the primary reason for liver transplantation in the U.S.

While the number of new infections per year has decreased from an average of 240,000 in the 1980s to approximately 40,000 in 1998, public health officials remain concerned about the impact of past incidence of infection on the future burden of HCV-associated complications. According to researchers at the CDC, projections indicate that while HCV prevalence has declined, the number of persons infected for more than 20 years could increase substantially before peaking in 2015. In addition, if the rate of new cases does not increase into the future, people born between 1945 and 1960 will be at highest lifetime risk of acquiring the disease.

HCV is a single-strand RNA virus classified in the family Flaviviridae. Six genotypes and more than 90 subtypes have been identified. This high degree of heterogeneity may account for difficulties in vaccine development and poor therapeutic response. About 70 to 75 percent of HCV infection in the U.S. is attributable to genotype 1, which is associated with a poorer prognosis. The major route of transmission is through parenteral contact with blood or blood products from infected individuals. Routine blood donor screening for HCV began in 1990, and with the advent of more assays in 1992, the risk of transmission from transfusion has been reduced to less than one for every 100,000 products infused. The most common source of new infection in the U.S. is injected drug use, although many people with no known exposure to blood or history of drug use have become infected with the virus. According to the CDC, sources of infection include: injected drug use (60 percent); sexual transmission (15 percent); transfusion (10 percent, before screening initiatives); and occupational exposure (4 percent). About 10 percent of cases are of unknown origin.

Risk groups for HCV include injected drug users, recipients of clotting factors made before 1987, hemodialysis patients, recipients of blood and/or organ transplants prior to 1992, occupational blood exposure, birth to an infected mother, those with an infected sex partner, and those having multiple heterosexual partners. According to the CDC, HCV testing is routinely recommended for persons ever having injected drugs, those who received clotting factors made before 1987, those who received blood products and/or organs before July 1992, long-term hemodialysis patients, persons with elevated liver enzymes, healthcare workers after exposure, and children born to HCV-positive women.

Several assays are used to diagnosis and monitor HCV infection. Initial evaluation includes detection of antibody to HCV (anti-HCV) with an immunoassay. Positive results indicate past or present infection, but cannot distinguish between acute, chronic, or resolved states. Because the anti-HCV immunoassay alone has a low positive predictive value in low risk patients, the CDC recommends that all positive results undergo supplemental assay, typically recombinant immunoblot assay (RIBA). An anti-HCV positive person is defined as both immunoassay positive and supplemental assay positive. In some cases, especially in high-risk patients, immunoassay positivity alone is enough to confirm diagnosis.

Persistent HCV infection in anti-HCV positive patients should be confirmed with a (qualitative) PCR HCV RNA assay. The current FDA approved qualitative PCR HCV RNA assay has a lower limit of detection of 50 IU/ml. Recently, a transcription-mediated amplification assay with an even lower detection limit has been developed. A single positive qualitative HCV RNA assay confirms active replication, but a single negative result does not mean that the patient is not viremic. Once a patient has a confirmed positive result, repeated qualitative HCV RNA assays are not routinely required in the management of untreated patients.

There is little correlation between viral load and disease progression. However, quantitative measurement of HCV RNA using quantitative PCR or branched-chain DNA assays assists in evaluation of response to antiviral treatment. Patients may also be monitored with serial ALT measurements, and some may go on to biopsy to detect fibrotic changes in the liver.

Because of cost issues and lack of guidelines, many laboratories do not perform confirmatory testing of anti-HCV positive samples. The CDC is in the process of addressing these issues, and new recommendations are slated to be available at the end of the year. “The problem is there is no regulation regarding confirmatory testing of the EIA for HCV,” said Alter. “Therefore, like any other screening test, it can result in false positives. We are developing guidelines for labs to use to implement a standard algorithm for confirming antibody results. It is not intended as a medical management tool, but rather a laboratory tool to ensure that when antibody results are reported out, they can be consistently interpreted.”

To determine these guidelines, the CDC compared the average signal to cut-off (s/co) ratio of EIA against RIBA results across a diverse set of populations, and noted a correlation between the two assays: individuals with an EIA s/co ratio of 3.8 or greater were 95% or more likely to be RIBA positive. If s/co was less than 3.8, the chances of that individual being a RIBA positive were low, at about 10% or less.

According to Alter, the CDC is proposing that the laboratory may report out an EIA as positive if the s/co ratio is 3.8 or greater. At s/co ratios less than 3.8, an automatic reflex to confirmatory testing is recommended. Issues regarding the appropriate reflex testing are yet to be resolved. “We prefer that it be RIBA, because that confirms antibody. Some labs may choose to do HCV RNA testing. But if the HCV RNA is negative, they must perform the RIBA anyway. The other issue is that the same sample that is handled for routine serology cannot be used for nucleic acid testing. … From a practical point of view, it would be easier to do supplemental antibody testing,” she explained. Implications for adopting this new standard not only address cost issues, but public health issues as well. “A lot of public health surveillance systems are based on laboratory reports to initially identify the number of positives in their community. If we can’t rely on the report as representing a true positive, it makes it very difficult to use this data as a basis for surveillance.”

While all patients with chronic HCV are potential candidates for antiviral therapy, those at increased risk for cirrhosis are usually targeted for treatment. Both viral load over time and genotype can predict treatment response moving forward. Quantitative RT-PCR and branched chain DNA assays are used to determine viral load, and several methodologies are available to determine the genotype. “Quantitative PCR determines viral load which allows us to predict the value of treatment,” said Navarro. “Genotyping is important because people with genotype 1 require a year of treatment. Fifty percent of these patients will clear the virus entirely. Genotypes 2 and 3 require only six months of treatment, and these patients are able to entirely clear the virus 80% of the time,” he added. Treatment for HCV involves combination PEG-interferon and ribavirin therapy. Considered the gold standard in treatment, these drugs can in some cases reduce the level of virus in the blood to undetectable levels. Recently, researchers in France demonstrated a marked decrease in the progression of fibrosis in patients receiving high doses of ribavirin with PEG-interferon, and further discovered that 49 percent of these patients experienced cirrhosis reversal. The side effects of treatment make compliance a serious issue, and add to the value of both primary and secondary prevention measures.

Currently, HCV prevention is focused on identification and testing of at risk persons to determine infection status. In addition, the CDC recommends that HCV-positive individuals undergo medical evaluation and management, and counseling to prevent further liver damage and to prevent transmission to others. Development of a vaccine for HCV is underway, despite the monumental challenge of targeting a virus with such a high mutation rate, along with the lack of a reliable culture system for propagation of HCV in the research laboratory. Researchers at Johns Hopkins recently discovered that humans may be able to acquire immunity to HCV, similar to a process found while studying chimpanzees. This research adds to an increasing body of evidence suggesting both the potential and the need for vaccine development.

Until that time and beyond, it is likely that the number of new assays available to the clinical laboratorian for detection and management of viral hepatitis will continue to grow. And as HCV infectivity reaches its peak a decade from now, demands on the laboratory will likely increase as well.

Louise Lazear is a freelance writer based in Charlotte, N.C.

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Caring for those who care for us: preventing, diagnosing and managing hepatitis infection among healthcare workers

In the U.S., OSHA estimates that close to 5.6 million workers in healthcare and related occupations are at risk for exposure to bloodborne pathogens. About 80 percent of blood contacts occur due to sharps injuries, and many of these are unreported. While everyone strives to practice the highest level of safety to protect both workers and patients in healthcare settings, accidents do happen: OSHA estimates that healthcare workers sustain between 600,000 to 800,000 injuries involving contaminated sharps per year. Most of these injuries occur within the nursing profession, and studies indicate that as many as 33 percent of these are related to the disposal process. Concern for exposure to infectious materials in other occupational settings, including firefighters, police, EMTs and other first responders, remains a large issue for public health professionals. Despite a growing body of regulations and guidelines to protect workers in all settings, vigilance and knowledge are paramount to keeping oneself out of harm’s way.

More than 20 pathogens are known to be transmitted through small amounts of blood, including HIV, hepatitis B and C, syphilis and malaria. The risk of infection after occupational exposure varies with the agent involved, the type of exposure, the amount of blood involved and the amount of agent in the patient’s blood. While most exposure occurs with sharps injuries, workers can also become infected through contact with the eye, nose, mouth and skin.

In order to address risk of infection due to bloodborne infectious agents, in 1991 OSHA issued a standard regulating occupational exposure to these pathogens, including HIV, HBV and HCV. The standard provides guidance for healthcare worker safety, reporting and access to both preventive and post exposure management. Due primarily to technical advancements in employee protection, in 2000 Congress passed the Needlestick Safety and Prevention Act which directed OSHA to revise the standard to clarify the need for employers to implement select safer needle devices as they become available, and to maintain a master log of injuries related to contaminated sharps. The CDC estimates that between 62 and 88 percent of sharps injuries could be eliminated with the use of safer devices, including sharps with built-in safety features that limit the risk of injury, and the use of needleless systems to both collect bodily fluids and deliver medication. According to the AHA, the cost of follow-up for high-risk exposure in cases where no infection occurs is almost $3000 per needlestick injury, escalating to $1 million or more in cases of serious infections. According to a recent article in Michigan Nurse, the difference in cost between the new safe needle and standard devices is about 28 cents.

Despite the introduction of hepatitis B vaccine in 1992, infection due to occupational exposure to the virus remains a concern among workers and public health officials alike. Although there has been a 90 percent decrease in the number of estimated cases of occupational infections, the CDC reports that approximately 800 workers annually become infected after exposure to the virus. However, those who have received hepatitis B vaccine and have developed and maintained immunity are at little or no risk for infection. Risk of infection in unvaccinated persons ranges from six to 30 percent, and is dependent upon the degree of contact with infected blood and the HBeAg status of the individual. In addition, individuals who are both HBeAg and HBsAg positive have a greater likelihood of transmitting HBV. Although percutaneous injuries are the most efficient method of transmitting HBV, studies of outbreaks have shown that many infections could come from contact of non-intact skin or mucous membranes to infected blood or body fluids. It has been demonstrated that HBV can remain active in dried blood on environmental surfaces for at least one week.

Since recommendations for healthcare worker vaccination for HBV came into effect, the rate of infection among this population has decreased dramatically. Prior to 2001, about 100 million people in the U.S. received the vaccine. The most common side effects include pain at the injection site and mild fever. However, vaccine-induced antibodies to HBV gradually decline over time, and up to 60 percent of individuals having an initial response will lose detectable antibodies over the course of 12 years. In addition, some individuals do not undergo seroconversion after completion of the three-dose series. Currently, there are no recommendations for post-vaccination antibody testing to confirm immunity. Additionally, the need for booster doses to maintain immunity is an ongoing debate within the medical community.

Treatment for exposure to HBV includes both vaccine and hepatitis B immune globulin, and should begin within 24 hours and no later than seven days post exposure. Treatment is dependent upon the hepatitis B surface antigen status of the source individual, whether the worker had been vaccinated and if the vaccine provided immunity. However, healthcare workers are not traditionally tested post-vaccination to confirm immunity status. “The testing of healthcare workers for protective immunity is somewhat controversial”, said Stanley Geyer, M.D., chairman of the department of pathology and laboratory medicine at Western Pennsylvania Hospital in Pittsburgh. “The reason is that the response rate to vaccination is 99 percent. Some people feel that it is not worth testing 100 people to find one non-responder.” Geyer and his associates have evaluated a new assay for anti-HBs on the Ortho-Clinical Diagnostics Vitros ECi Immunodiagnostic System. “What Ortho has done, which is unique among laboratory manufacturers, is to compare their antibody readout with the known World Health Organization (WHO) standard, which states that 10 mIU/ml of antibody concentration is said to represent positive immune response. They have also chosen to create an indeterminate range for results between .5 and 1.19. In our laboratory, we retest these individuals, and if results remain indeterminate, we recommend that that employee or patient be retested over time.”

Having a standardized assay for anti-HBs has helped enhance quality and has introduced automation for hepatitis testing in Geyer’s lab. It has also helped in developing testing algorithms for immunity to HBV. “There is a phenomenon in our laboratory where people have some markers that are positive for hepatitis B, so I know that they have been exposed. They may have HBsAg, or they may have antibody to hepatitis B core antigen, but they don’t have anti-HBs. We continue to test these people until we are convinced they have, or won’t undergo seroconversion. Having a sensitive assay that correlates with a known standard helps us to define what the cut-off is, and what the clinical significance is,” Geyer added.

Unlike HBV, there is no vaccine to provide immunity against HCV. Fortunately, HCV is not transmitted efficiently from occupational exposure to blood. Studies of hospital-based workers reveal that one percent of these individuals have evidence of HCV infection. Transmission rarely occurs by mucousal exposure to blood, and unlike HBV, it is thought that the risk of infection through environmental contamination is very low. The average incidence of seroconversion due to needlestick injury is about 1.8 percent. However, in the only study using PCR to measure HCV RNA post exposure, seroconversion rates were as high as ten percent.

There are no recommended treatments to prevent HCV infection after exposure. However, the CDC recommends that the source be tested for anti-HCV, and if positive, the worker should be tested for anti-HCV and ALT at baseline and at four to six months. All anti-HCV immunoassay positive results should undergo confirmatory testing with RIBA. For earlier diagnosis, the CDC recommends testing for HCV RNA at four to six weeks post exposure. Additionally, HCV positive workers are recommended to undergo medical evaluation and management. Because of the low risk of infection and transmission, there are no recommendations for specific precautions for healthcare workers exposed to HCV.

Heightened public awareness of the possibility of HCV infection among first responders has prompted much concern within the public health community. Recently, the CDC summarized the results of five studies from 1991 to 2000 that sought to determine the prevalence of HCV in specific groups of firefighters, EMTs and paramedics in selected locations. While stating that these professionals were at risk for infection, the CDC found that the risk for acquiring infection was extremely low, and that HCV infection was related to non-occupational factors. Despite the fact that these studies could not entirely exclude the possibility that some individuals acquired HCV from occupational exposure, the CDC does not recommend routine testing of this or any group with such low prevalence, unless they have an increased risk for infection due to other factors. However, testing for HCV is recommended for postexposure management.

Healthcare workers love their profession, and understand the risks and rewards of their positions. New tools that provide testing for infectious disease may one day change the way we monitor our immunity and infectivity status in both workers and patients. Notwithstanding the critical efforts to protect these professionals from bloodborne and other pathogens, practicing vigilance and safety remains the best form of defense against acquiring disease while on the job.

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The rising challenge of managing hepatitis infection among people living with HIV

As life expectancies improve for people with HIV/AIDS, hepatitis viruses are emerging as an increasing threat to life and wellness in those who may be co-infected. Better HIV antiretroviral therapies and prophylaxis of opportunistic infection are now allowing people to live long enough with HIV to manifest problems associated with hepatitis infection. Because hepatitis shares many risk factors with HIV, prevention measures to avoid hepatitis infection are particularly important in an already immunosuppressed, HIV-infected population. And, accurate diagnosis of hepatitis is critical to the effective care and management of co-infected patients.

According to the Centers for Disease Control and Prevention (CDC), approximately one quarter of people infected with HIV are also infected with HCV. Among injection drug users, co-infection may be as high as 90 percent.

When a person is identified with HIV, it is important to assess risk and immune status for both hepatitis B and hepatitis A, and to administer appropriate vaccination. More than two-thirds of those vaccinated develop antibody responses. The CDC notes that prevaccination screening for antibodies against hepatitis A and hepatitis B in this high-prevalence population is appropriate and cost-effective. Postvaccination testing is recommended only for hepatitis B.

There is evidence that the serological response rate for vaccination may be poor in individuals with low CD4+ T cell counts, so intervention should ideally take place before CD4 cell counts fall. Initiating treatment before CD4 counts fall is important to managing HCV co-infection as well.

Hepatitis C-related liver disease, in particular, is emerging as one of the most important factors affecting mortality and morbidity in co-infected patients. While the influence of HCV on the long-term natural history of HIV is less than certain from our current knowledge, HIV-HCV co-infection has been associated with higher titers of HCV and more rapid progression to liver disease. “From a practical standpoint, the big killer in a subset of patients is HCV. There is a significant group of co-infected individuals where hepatitis C seems to progress in natural history more rapidly, and they are dying of cirrhosis more rapidly than those not co-infected with HIV,” said Eugene Schiff, M.D., professor of medicine, chief of the Division of Hepatology, and director of the Center for Liver Diseases at the University of Miami. “The reason for this HCV progression is not clear, but for a doctor who is managing co-infected individuals, hepatitis C is becoming a major problem as far as life expectancy.”

Managing HCV in HIV co-infected individuals is challenging. “Ideally, you would begin treatment for HCV before a CD4 count drops and before highly active antiretroviral therapy (HAART) is required for HIV. Once a person is on antiviral therapy for HIV, and then the antivirals for HCV are added, the therapies become very difficult to tolerate, both physically and psychologically,” said Schiff. “If you can initiate HCV treatment while CD4 counts and immune status remain good, treating a co-infected individual will be like treating someone not infected with HIV.” Combination therapy of PEG-interferon and ribavirin would be initiated.

With HCV the aim of treatment is a cure, and determining the genotype of the C virus at the initiation of treatment helps a clinician establish targets for length of treatment. The aim is to treat people whose chance of remission is high, and to avoid the side effects and expense of treatment in people who have little chance of clearing the virus. HCV RNA levels are established at baseline and minimally at three months, and if they drop sufficiently (by 2 or more logs) or become negative, there is indication that response will be achieved and therapy should be continued. If levels do not drop sufficiently, according to Schiff, the treatment strategy should be aimed at curtailing or slowing liver fibrosis. A physician may consider long term PEG-interferon alone (up to five years) while waiting for new antiviral medication to be available.

HCV RNA quantitation is an important diagnostic tool in the management of co-infected individuals, helping a physician and patient determine whether therapy is having enough impact to warrant withstanding the side effects, and expense, of treatment. IVD manufacturers have improved quantitative HCV RNA testing sensitivity, simplicity and turnaround time, but the expense and extra handling requirements for molecular testing remain.

A new development in the marketplace anticipated by physicians and laboratorians is the total HCV core antigen test. “We know from studies that total HCV core antigen levels parallel RNA levels both in time from infection and in magnitude. The limitation of the total HCV core antigen test is in its sensitivity, but it offers a rapid turnaround time, and is much less expensive than PCR. It can therefore be performed more frequently, and is a good test to put in a panel when ordering acute or chronic viral hepatitis tests,” said Schiff. “The total HCV core antigen test would go into a panel to tell you if there is virus present in the early period following exposure. And while managing treatment for those with known infection, total HCV core antigen tests can be followed, and once the total HCV core antigen becomes negative, more sensitive assays can be used to determine if the virus has truly cleared. Because the expense of the total HCV core antigen test is lower, it gives greater opportunity for testing at more frequent intervals to show whether a patient is responding to treatment. The assay can be ordered from the same sample as the other hepatitis tests, turnaround time is faster, and results all come back at the same time. For the primary care doctor especially, this is a real advantage.”

Alongside the role of the physician in the management of disease in co-infected individuals is a crucial role for laboratorians, physician’s assistants, nurses and counselors, as each can help to guide a person through treatment, and repeat the critical messages about the prevention of further disease.

Irene Fried is a freelance writer based in Raleigh, N.C.