How does liver fibrosis affect the risk of liver toxicity for people with hepatitis C and HIV coinfection who are taking a cocktail of medications for HIV treatment? That's a question that doctors in Madrid, Spain wanted answered. Their study appears in the February 15 issue of the journal Clinical Infectious Diseases.1

HAART Regimens for HIV
For people infected with both hepatitis C and HIV—the virus that causes AIDS—doctors typically prescribe a combination of antiretroviral drugs to suppress HIV, with the aim of avoiding viral resistance to any one drug. This combination of medications is known as HAART (Highly Active Antiretroviral Therapy). While HAART does not suppress the virus completely, it has reduced the numbers of deaths due to HIV.²

The medications used to treat HIV currently fall into two classes:

• Reverse transcriptase (RT) inhibitors—These work by interfering with an enzyme called reverse transcriptase that HIV needs to make copies of itself. There are two types of RT inhibitors, including nucleoside/nucleotide drugs that provide faulty DNA building blocks, halting the genetic chain that the virus uses to replicate, and non-nucleoside RT inhibitors that bind reverse transcriptase so that the virus cannot use this enzyme.
• Protease inhibitors—These medications interfere with the protease enzyme that HIV uses to produce infectious viral particles.2

It's been suggested that people with hepatitis C who take HAART as a therapy for HIV face a higher risk of developing liver toxicity compared to those without HCV.³ HIV has emerged as a chronic disease since the development of HAART, requiring doctors to prescribe more medications for longer periods of time, wrote Lidia Aranzabal, MD, in the department of Infectious Diseases at Hospital Ramon y Cajal in Madrid, and her fellow researchers. "Therefore, it is not surprising that HAART-associated toxicity, especially liver toxicity, has perhaps become one of the limitations to treatment," the researchers wrote.

Thus, medical experts have suggested that drugs like protease inhibitors should be initiated only after a patient has been successfully treated for hepatitis C.⁴

Questions Still Unanswered
But does the risk of liver toxicity depend on the type of HAART medicines a patient takes? And is the condition of his or her liver play a role? The researchers cite other studies that have suggested that HAART drugs called nonnucleoside reverse-transcriptase inhibitors tend to increase the risk of this type of toxicity.

But information about the incidence of liver toxicity in this context is "controversial", the study authors pointed out.

In their prospective study, Aranzabal's team enrolled 107 patients diagnosed with both hepatitis C and HIV. Each patient underwent a liver biopsy to determine the level of their fibrosis progression, then were followed for a total of 2 years. All patients had been previously prescribed HAART.

Fibrosis is a condition of the liver as a result of hepatitis C. It's manifested as scarring in the liver that can lead to cirrhosis, which in turn can lead to end-stage liver disease and hepatocellular carcinoma. It's estimated that approximately 10 to 15 percent of people develop cirrhosis about 20 years after initial infection.⁵

Correlating Fibrosis Stage with Drug Toxicity
Patients' fibrosis was graded according to a classification scale, ranging from F0 (no fibrosis) to F5 (advanced fibrosis). Aranzabal and her team then measured liver toxicity by determining levels of 2 liver enzymes in the bloodstream: aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The higher the levels of these enzymes, the more likely a particular patient suffered liver toxicity. (ALT and AST are released by the liver into the bloodstream when it's damaged; thus, higher blood levels of these enzymes are an indication of liver disease).

The researchers compared the stage of fibrosis in each patient with the incidence of liver toxicity caused by taking HAART medications They found that 25 percent had liver toxicity which occurred, on average, approximately 6 months after beginning HAART therapy. Half of those with toxicity exhibited symptoms.

"The incidence was greater for patients with stage F3 or F4 fibrosis than for those with stage F1 or F2 fibrosis," wrote Aranzabal's group. They found that 38 percent of those with the later stages of fibrosis had hepatic toxicity compared to just 15 percent with earlier stages of fibrosis. The risk for patients with advanced fibrosis was nearly 3 times what it was for those with early-stage liver fibrosis, Aranzabal's group wrote.

High levels of liver enzymes were also associated with toxicity risk from the medications, but only in those with early-stage fibrosis. The duration of HCV infection, duration of HAART medication, AIDS diagnosis, levels of hepatitis C virus, HCV genotype, and immune system cell count had no effect on a person's risk of liver toxicity, they said.

The Impact of Certain HAART Medications
The investigators then examined the risk of toxicity based on the type of HIV medication that each patient was taking. Of 86 patients receiving nonnucleoside reverse-transcriptase inhibitors (NNRTIs), 11 developed toxicity. (The patients had either been prescribed nevirapine or efavirenz).

In those with early stage fibrosis, the rates of toxicity were generally the same, no matter which NNRTI an individual was taking. But there was a greater incidence of toxicity for those taking NNRTIs with advanced fibrosis, the researchers found, compared to those with advanced fibrosis not taking NNRTIs.

"Our study shows that the risk of hepatotoxicity for HIV and HCV-coinfected patients undergoing treatment depends on the stage of liver fibrosis," Aranzabal and her team concluded.
 
Further, for those taking NNRTIs, the extent of liver damage may be the most important factor to determine a patient's risk of liver toxicity from HAART, they added. "Therefore, this group should be monitored more closely if a decision to initiate treatment with drugs from this class is made."

1. Aranzabal L, Casado JL, Moya J et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis 2005 Feb 15;40(4):588-93.
2. National Institute of Allergy and Infectious Diseases. National Institutes of Health (NIH). Treatment of HIV Infection. Available at: http://www.niaid.nih.gov/factsheets/treat-hiv.htm. Accessed February 9, 2005.
3. Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 2004 Jan 20;170(2):229-38.
4. Dieterich DT. Hepatitis C virus and immunodeficiency virus: clinical issues in coinfection. Am J Med 1999 Dec 27;107(6B):79S-84S.
5. National Institutes of Health (NIH). Consensus Development Conference Statement. Management of Hepatitis C: 2002. 2002 Jun 10-12. Available at: http://consensus.nih.gov/cons/116/091202116cdc_statement.htm. Accessed February 10, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.