By Debra Johnson, NP, PA-C, Samantha Cohen, PA-C, and Maurizio Bonacini, MD

Epidemiologic data indicate that worldwide, about 40 million individuals now are infected with HIV, about 370 million are infected with hepatitis B virus (HBV) and about 180 million are infected with hepatitis C virus (HCV).

Hepatitis is the term used to describe a nonspecific inflammation of the liver. The causes of hepatitis are many, such as drug- or alcohol-induced, viral, parasitic, infiltrative or nonspecific hepatitis. The route of transmission varies according to the underlying cause of hepatitis. The initial clinical presentation of the acute phase of hepatitis, regardless of the underlying cause, may range from asymptomatic to severe fatigue, jaundice, nausea, vomiting and diarrhea.

All patients whose laboratory values are monitored will have increases in their transaminases, which in some cases can be quite impressive, with aspartame transaminase (AST) and alanine transaminase (ALT) ranging into the thousands.

Patients who are co-infected with human immunodeficiency virus (HIV) can complicate the course of hepatitis, and in fact the drugs used to treat HIV infection may actually increase the risk of drug-induced hepatitis.

This article will provide information about the pathophysiology, specific causes, sequelae and treatments that are available commercially or in current clinical trials for hepatitis A virus (HAV), HBV, HCV, hepatitis D (HDV), hepatitis E (HEV), hepatitis G (HGV) and drug-induced hepatitis, including alcohol and antiretroviral therapy.

Several studies have shown hepatitis and HIV infection transmission may occur simultaneously, and that patients who present with acute hepatitis should be screened for acute HIV infection. HIV is a virus that is transmitted through body-fluid contact.1-2 The virus infects the macrophages, monocytes and the CD4 T-cells, causing a diminishment in the overall number and function of the cells that are responsible for immune response to infection. Many times in persons living with HIV (PWHIV), a co-infection with hepatitis may increase morbidity and mortality. People co-infected with HIV and viral hepatitis are more likely to develop chronic hepatitis progressing into liver failure or have an increased risk of developing hepatic carcinoma. Several published reports have noted the increase in poor outcome for PWHIV who are co-infected with HBV or HCV.3-5

Pathophysiology Review

The liver is located in the right upper quadrant of the abdomen, underneath the ribs. When the liver is enlarged (hepatomegaly) it can protrude below the rib cage and may be readily to palpation and tender. The liver is considered part of the digestive system and plays an important role as a detoxifier, by processing potentially harmful agents into safe chemicals. The liver is also responsible for glucose metabolism and manufactures and controls the release of bile, an important enzyme that breaks down fats and starches, the sources of cellular energy. The liver is capable of regeneration to a degree and can continue to function despite considerable damage.

Hepatitis can be diagnosed after blood is obtained and shows an elevation in transaminases (ALT and AST). Normal values for transaminases may vary from laboratory to laboratory but should remain less than 60 IU/L. Elevation in transaminases does not render a diagnosis and only indicates that inflammation is present. To determine a diagnosis, liver biopsies must be performed. Since a liver biopsy may be difficult to obtain and is associated with morbidity or mortality, most acute hepatitis is a presumptive diagnosis based on clinical indicators and laboratory markers.

Hepatitis A

HAV is transmitted through oral-fecal contact. Acute HAV usually has an acute phase that lasts from four to six weeks with or without jaundice, fatigue and hepatomegaly. During this time, HAV IgM will be detectable (acute phase) but will be replaced by IgG. During this acute phase, individuals with a co-infection of HIV may have a considerable drop in T-cell counts that will rebound in six to 12 weeks after acute infection. HAV is generally cleared from the body after six weeks. It may take several months to fully recover from an acute episode of HAV. In general, an acute infection with HAV will not produce any sequelae, however a co-infection with HIV may lead to permanent liver damage and an increase in HIV viral replication.6-7

The impact on HIV-infected patients may include disruption of their antiretroviral therapy, increases in viral replication and a sometimes dramatic decrease in CD4 T-cell counts. In some patients who acquire acute HAV infections, CD4 T-cells will decrease low enough (below 200 cells/mm3) that the patient may be reclassified as having AIDS. However, generally, the CD4 T-cells will rebound back to baseline once the patient has completed the acute phase. Viral replication will also return to baseline once the patient is able to resume antiretroviral therapy.

Treatment for HAV is usually supportive care with rest and discontinuation of drug therapy until the acute phase is completed, at which time therapies may be restarted. Maintaining hydration, bed rest, no contact sports and good nutrition are all essential for a complete recovery.

During 1995, a vaccination for HAV became available and should be considered as preventive therapy in patients with chronic terminal infections such as HIV infection and who are not HAV IgG-positive at the time of their diagnosis. This may prevent potential infections for those individuals who may be immunocompromised. The cost of the vaccination varies, and in some facilities that have research studies, or in the states that have the AIDS Drug Assistance Program (ADAP), the HAV vaccine may be free to HIV-infected patients.

Hepatitis B

HBV infection remains a considerable health problem worldwide and a significant cause of liver disease and liver cancer in humans.8 HBV is readily transmitted via parenteral and sexual routes, and as such, it is commonly found in individuals who are co-infected with HIV-1. For an immunocompromised host, a frequent outcome of HBV is the development of a chronic carrier state that does not spontaneously resolve over time. Approximately 20% of patients are unable to clear the virus, and the infection may continue to develop, leading to hepatomegaly, cirrhosis and/or primary hepatocellular carcinoma.9

All blood and body fluids are considered to be potentially infectious. In infected patients, HBV particles have been found in saliva, semen and cervical secretions; thus, it is considered to be potentially transmitted by percutaneous and nonpercutaneous (usually sexual) routes.

Common modes of transmission include accidental puncture of the skin with an infected needle, blood splashed in the eye or sharing of unsterilized needles. Other modes include exposure to instruments while receiving tattoos, ear piercing or acupuncture, as well as sharing razors or toothbrushes. Aerosolized blood in the vicinity of centrifuges and dental drills may also play a role in transmission.10

HBV can present in any age group, with certain population groups considered to be at high risk for HBV infection, including Alaskan Eskimos, Pacific Islanders and infants born to women who are first-generation immigrants from endemic regions. The usual incubation period is 28 to 160 days. Patients may present with insidious symptoms such as arthralgias, rash, nausea, vomiting and, less commonly, jaundice.

The laboratory diagnosis is made via HBsAg, which will be positive or reactive. It represents both a current and chronic infection and is presumed to be infectious. The Anti-HBc-positive will also be positive during a current and chronic infection with HBV. It may also represent a past infection, but is not diagnostic for an acute infection unless the patient is also positive for anti-HBc IgM. A laboratory anti-HBs that is positive indicates immunity. If HBcAb is positive, there is natural immunity; if negative, the patient will need vaccination.

HBV DNA is currently the most accurate test to assess current disease and infectivity. It will not be present if the person is HBV negative or has had the vaccination series. Patients who have not cleared HBV from their blood within six months are considered chronic carriers of hepatitis B and will need to be monitored on a regular basis. These patients should be vaccinated with HAV if they are HAV antibody-negative to protect the liver from further potential damage.

Currently, there are few pharmacologic solutions for individuals co-infected with HIV and HBV. Several previous clinical studies have assessed the efficacy of other medications such as lamivudine (3TC, Epivir), famcyclovir (Famvir) and adefovir (Preveon) with significantly promising results. Clinically, patients may be continued on lamivudine after a vRNA rebound indicating virologic failure to lamivudine with the hopes that the patient who is co-infected may still benefit from lamivudine. Available data suggest that lamivudine shows promise as an effective treatment for chronic HBV. Serum HBV DNA by liquid hybridization decreased in all patients and was undetectable at the end of the treatment in seven of 12 (58%, 25 mg), 13 of 14 (93%, 100 mg), and 14 of 16 (88%, 300 mg) patients with decreases in abnormal ALT.11-12 Most of the data that are available addressing chronic HBV response with lamivudine have been gathered in HIV-negative patients. Little data are available in patients who are co-infected with human immunodeficiency virus (HIV) and chronic HBV.

Several reports have found early resistance to lamivudine in non-HIV infected patients. Data from a study done on immunocompromised adults with chronic HBV showed a high incidence of lamivudine resistance, which may have implications for the concept of long-term virus-suppressive therapy of chronic HBV by lamivudine monotherapy.13

Although adefovir was not approved for use as an antiretroviral by the Food and Drug Administration, it has been shown to have activity against HBV along with its daughter compound, tenofovir, which may become available this year.

Prevention is still the most desirable, and it is suggested that all patients have a baseline HBV screening done as a new patient and receive the vaccine, which consists of a series of three injections. The initial injection is at baseline, then a second in one month and the third six months after the initial injection. At five-years postvaccination, approximately 80% of people remain anti-HBs positive. In the HIV-infected individual, this number has been shown to fall to response levels of only 30% to 50%.

Hepatitis C

Hepatitis C is considered to be the most common cause of chronic liver disease, with more than 70% of those patients with acute HCV not able to clear the virus. Initially called non-A, non-B hepatitis, it was first identified in the 1970s, and it has only been in the last several years that we could test for the presence of HCV through the use of polymerase chain reaction RNA testing. More than 3 million people are now chronically infected with HCV throughout the world. The Centers for Disease Control and Prevention estimate that 12,000 people die of hepatitis C-related causes each year and this is expected to increase to 38,000 per year by 2010. Hepatitis C is currently the most common cause of liver transplantation, and reinfection of the transplanted liver appears to occur at a high rate. All individuals diagnosed with HCV should be considered potentially infectious. Unlike hepatitis A and B, previous exposure does not confer immunity.

Women usually fair better than men; individuals who acquire HCV after the age of 40 tend to have a poor prognosis.14 People who respond to alpha-interferon quickly do better, and those with a HCV vRNA of greater than 2 x 106 tend to have a worse prognosis. Patients who receive alpha-interferon therapy have a 50% response, and at one year on therapy their response rate doubles. The addition of ribavirin increases the chance of response to alpha interferon. PEGylated alpha-interferon is a new formulation that keeps drug in the serum longer, has markedly improved response, especially in those patients with cirrhosis.15-16

Epidemiologic studies have shown that risk factors include people who are non-Hispanic African-Americans, body piercing, homemade tattoos and sharing a common device to snort cocaine such as a rolled-up bill or straw. Ten percent of individuals who are HCV-positive have no identifiable history of exposure. Other routes of transmission include use of common razors, needles, toothbrushes, nail clippers, acupuncture needles or blood transfusion before 1983. It still remains unclear whether contact with semen, vaginal fluids or saliva can transmit the virus. HCV now accounts for 90% of transfusion-related causes of hepatitis.

A co-infection in a PWHIV with both HCV and HBV increases morbidity and mortality significantly.17 These viruses commonly occur together because they share the same routes of transmission. The immunosuppression caused by HIV appears to accelerate the course of HCV and HBV. Usually less than 15% of patients will recover after the acute phase of infection; cirrhosis of the liver will generally occur in 25% of those infected over a 20- to 39-year period. End-stage liver disease resulting in death will occur in approximately 19%, and 20% to 30% will develop hepatic carcinoma. It has been hypothesized that the decreased response of the CD4 cells can be implicated in the lack of immune response and excretion of the circulating HCV.

The incubation period is seven to eight weeks. The disease can be deceptive because even those with normal liver enzymes can be infected and transmit HCV. Most people are asymptomatic and do not present with jaundice. If symptoms are present, they tend to be mild and may include flu-like illness, fatigue, nausea, anorexia, fever, abdominal pain or dark urine. Due to the subclinical nature of this disease, it is suggested that routine testing for HCV should be done in patients who present with symptoms that defy other diagnoses, as well as those who are immunocompromised.

Before PCR testing became available, the only test available was the detection of anti-HCV antibodies. Positive anti-HCV does not distinguish between acute or chronic states of disease. It is 95% sensitive to the presence of chronic HCV. We now know that many patients, especially those who are immunocompromised, may not have the antibodies present for HCV and must be diagnosed by HCV PCR RNA. Most people who test positive for HCV are considered to be chronic carriers of the disease. The genetic diversity of this virus allows it to escape immune surveillance and increase the rate of chronic infection. Anti-HCV may be absent in the first four to eight weeks of infection.

At the National Institutes of Health Conference in 1997, which focused on the management of HCV, it was specifically stated that patients with HIV and HCV may have an accelerated course of disease. Therefore those patients with stable HIV infection and clinical status should be considered for treatment of HCV. Guidelines for treatment include age of less than 55, persistently elevated enzyme levels (greater than 1.5-fold increase in ALT and AST), positive HCV in the serum and signs of inflammation on liver biopsy. Several studies have evaluated the use of alpha-interferon subcutaneously without a significant improvement in the patients' disease status. Ribavirin, a drug first approved to treat respiratory syncytial virus, has shown promising activity against a broad spectrum of viruses. When used as a single agent, it decreases serum ALT levels, but sustained response is rarely if ever achieved. Several new clinic trials using alpha-interferon and ribavirin show more promise.

Initially, 50% to 60% of patients respond will respond; however, 80% to 90% will relapse within six months to one year after treatment has stopped. Side effects include flu-like symptoms such as headaches, nausea, vomiting, anorexia, diarrhea, depression, fatigue and thinning of hair. Labs may show a decrease in platelets and white blood cell counts.

Several studies are also investigating the efficacy of amantadine, which is also used to treat influenza. Some reports claim HCV-RNA clearance at month three of treatment. Studies are now testing the response to triple therapy using interferon, ribavirin and amantadine. Studies are also beginning using a different mechanism of attack against HCV, blocking the viral kinetics. These are PEGylated forms of interferon, which appear to require less medication with subsequently less side effects. Currently, there is no vaccine available for hepatitis C.

As clinicians, we must weigh the quality of life of our patients who suffer from side effects with the estimated benefits of an as yet unproven therapy. Hepatitis C may progress gradually to hepatocellular carcinoma over 10 to 40 years. Although increased ALT and AST reveal ongoing liver damage, they do not reliably predict the severity of liver injury. In patients with consistently elevated liver enzymes, right upper quadrant ultrasound and possibly a liver biopsy should be done to assess the severity of disease.

Hepatitis D

HDV has been reported in the last several years as a viral hepatitis that appears to usually be transmitted with HCV and HIV through parenteral or sexual contact. HDV shares the same type of patient and can be found in Western Europe and North America.18 Chronic HDV infection is usually associated with severe histological changes in the liver and a rapidly progressive course that can lead to cirrhosis, liver failure and death.19 The high morbidity and mortality of chronic HDV justifies the use of antiviral therapy with interferon to modify the natural course of the disease. Co-infection with HDV appears to suppress HCV replication; however, the prognosis is poor.20

Hepatitis E

Hepatitis E (HEV) appears to be less common, with only a few cases reported in Europe. Furthermore, limited data available do not support the sexual transmission of HEV.21 Moreover, HIV-infected homosexual men do not appear to be at greater risk of HEV hepatitis than HIV-negative patients.22 Until further prospective studies focusing on HEV are conducted, current recommendations do not support serological testing, and it is not in the best interest of the HIV population.

Hepatitis G

HGV, also known as GB virus C, is prevalent but is not known to be associated with any chronic disease. Infection with HGV may affect the risk for AIDS in HIV-infected persons. HGV has just been recently recognized; therefore little data are currently available about its potential pathologic implications.23

Drug-Induced Hepatitis

Several drugs are known to cause hepatitis such as isoniazid, nevirapine, many of the protease inhibitors, fluconazole, Bactrim, rifampin, testosterone, estrogen, Dilantin, products that contain oil bases such as vitamin A or E, and alcohol. Patients infected with HIV take at least three different types of antiretrovirals, all of which can lead to drug-induced hepatitis.

The nucleoside reverse transcriptase inhibitor class of antiretrovirals, especially zidovudine (AZT) can advance to steatosis, which may be more common in women, advancing to hepatic failure. Death occurs rarely. Monitoring transaminases monthly at the start of antiretrovirals is considered standard of care. Once the liver transaminases are stable, transaminases should be monitored every two to four months.

Increased incidence of indinavir nephrolithiasis in patients with hepatitis B or C virus infection currently receiving indinavir (Crixivan) has been reported.24 Caution and vigilant monitoring should be taken in those patients with underlying viral hepatitis and the prescribing of antiretroviral therapy.

Differential Diagnosis

The most common cause of chronic hepatitis is viral. However, there are other entities that need to be ruled out. Other causes, such as Wilson's disease, steatohepatitis, autoimmune hepatitis and alpha-antitrypsin deficiency need to be excluded in the presence of negative viral hepatitis serologies and should be considered in the differential when hepatitis is suspected. Serologically, all of these disorders may have very similar presentations. They may all present with elevated enzymes and chronic inflammation on biopsy. Most can be ruled out based on physical exam–for example, Keyser-Fleisher rings in the eyes–or ruled out based on specific lab findings, such as ceruloplasmin or alpha-antitrypsin levels. When all viral etiologies and zebras are excluded, the next step would be to evaluate for chemical or drug induced injury.

Almost every known drug has at one time or another been implicated as a cause of liver damage. The liver is so susceptible to injury because of function of processing the chemicals and drugs, which enter the bloodstream. Damage to the liver can depend on whether the ingested drug is an inducer or suppressor of the P-450 mechanism along with concomitant medications that are given. This mechanism allows unstable toxins to be produced and cause damage to the hepatocytes. This can present a challenge for providers who treat HIV-positive patients.

When first evaluating an increase in liver enzymes in patients with negative hepatitis serologies, it is important to consider every chemical that is ingested, whether it is a prescribed medication or an herbal or vitamin and mineral supplement. No chemical is too trivial to be considered.

Most liver injury occurs within days to weeks after ingestion. It can take many months between toxic buildup occurs and lab tests first appear abnormal. Usually the removal of the offending chemical can lead to rapid improvement. Once it has been removed the enzymes will return to normal and no other specific therapy is needed.

Treatment

Treatment for a drug-induced hepatitis is to discontinue the offending agent; however, at times that can be difficult to do. This is especially true with patients who are taking antiretroviral agents with undetectable viral RNA, or patients who are currently receiving anti-tuberculosis treatment. The clinically acceptable limit in laboratory analysis of transaminases is five times the upper limit of normal, and many clinicians will choose to continue therapy and monitor laboratory values closely before stopping medications. Many times, transaminases will return to baseline without ever obtaining a diagnosis of the cause of hepatitis. However, great care must be used with close monitoring of liver function tests, because there have been reports of fatal drug induced hepatitis.

In patients with a history of hepatitis B or C it is not uncommon to observe waxing and waning of transaminases, and in some PWHIV, transaminases can continue to remain slightly evaluated above two times the upper limit of normal. In these patients, the primary provider may decide to continue antiretroviral therapy and monitor laboratory markers closely. This decision would be based on the concern that the stopping and starting of antiretroviral therapy may lead to development of resistant HIV to the current medications.

Interferon may decrease viremia, but current data on the use of three times a week interferon along with ribavirin are not impressive. Anorexia, weight loss and wasting are a common side effect with the use of interferon and may not prove to be a long-term effective treatment. However, the use of interferon has been shown to improve the outcome of patients infected with viral hepatitis. Additional data are needed from ongoing clinical trials, which include once a week PEGylated interferon.

Prevention is Best

Hepatitis can be a direct result of a co-infection with a virus or the drugs that may be required to treat HIV infection. Prompt evaluation of an increase in liver enzymes with consideration being given to HIV testing can lead to a diagnosis and appropriate further evaluation, which may include discontinuation of the offending drug and close follow-up. HIV infection alters the course of viral hepatitis infections, increasing carriage states and viral replication. Interestingly, the effect is the opposite in terms of liver disease. Milder liver injury is seen in patients with chronic hepatitis B who become severely immunosuppressed, despite extremely high levels of HBV viremia. In contrast, rapidly progressive liver disease seems to occur in HIV-infected patients with chronic hepatitis C and hepatitis D while HCV/HDV viremia rises as the CD4 T-cell count fails. Liver disease can be aggressive with cirrhosis, liver failure and hepatic carcinoma. In the case of viral hepatitis, consideration should be given to the use of interferon in the setting of a clinical trial or under the direction of a hepatologist experienced with co-infection of HIV until more information becomes available. Preliminary results from current clinical trials using the combination of interferon (PEGylated) plus ribavirin for the treatment of HCV and HDV look very promising for both rates of sustained response and safety.

Prevention is still the best intervention. The use of abstention or condoms and not sharing drug paraphernalia to decrease the risk of hepatitis B and C has been shown to be effective. Good hand washing is an important first-line prevention to protect transmission of most viruses. Hepatitis vaccinations should be considered for individuals who may be at high risk. Little information is available about other causes of hepatitis, and ongoing studies are needed to evaluate effective treatment for those individuals who are already infected with chronic disease. a

Debra Johnson is a clinical instructor at the University of Southern California in Los Angeles and an investigator with the University's clinical trials unit, as well as a PA at the Rand Schrader HIV Clinic in Los Angeles. She is on the ADVANCE for Physician Assistants editorial advisory board. Samantha Cohen is an HIV specialist at Los Angeles County/University of Southern California Medical Center. She also serves as a co-investigator on multiple ACTG studies. Maurizio Bonacini is a physician in AIDS medicine in Los Angeles.

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