Liver Toxicity, Ritonavir, and Hepatitis C: New Data Published
On January 5 JAMA (the Journal of the American Medical Association) published a study by Johns Hopkins researchers, who reviewed charts of 298 patients who were beginning antiretroviral treatment.1 The major findings were (1) that persons with chronic viral hepatitis (usually hepatitis C, in this study) can be treated safely with protease inhibitors, and (2) that ritonavir was much more likely to cause liver problems than the other protease inhibitors (a result which differs from that of some other studies, for reasons which are not known).The main purposes of this study were to determine how frequently liver toxicity occurs, particularly in patients who already had chronic hepatitis C or B. Data is needed because "the actual incidence of drug-induced hepatotoxicity and role of chronic viral hepatitis are poorly understood since anecdotal reports generally omit the number of exposed persons and may focus attention on exceptional cases or high-risk populations. Conversely, clinical trials are frequently restricted to persons at low risk for adverse events. Also, clinical trials underrepresent minority groups, women, and injection drug users, and may exclude those with chronic HCV or HBV infection."1 (This study's population was almost 75% African American, 24% white, and 2% other races, reflecting the population receiving HIV treatment at Johns Hopkins; no statistically significant racial differences in liver toxicity were found.) Severe liver toxicity was defined as grade 3 or 4 laboratory abnormalities of liver function tests (either AST or ALT), based on a definition used by the AIDS Clinical Trials Group (ACTG).
Results and Conclusions
The major results of this study were:
Patients with chronic viral hepatitis can be treated safely with antiretrovirals, if precautions are taken. These patients had almost 3.7 times the risk of severe liver toxicity as those without hepatitis B or C infection; however, 88% of them did not have significant liver toxicity. In the 12% who did, medications were stopped in most cases, and there were no deaths due to liver problems.
Ritonavir (NorvirŪ) use was associated with a much higher rate of severe liver toxicity in this study than other treatments--30% of the patients, compared to about 6% for all the other protease inhibitors used, and for nucleoside-only treatments. Some other studies have found much lower rates of comparable liver toxicity for ritonavir, while finding rates comparable to the new Johns Hopkins study for other antiretroviral treatments. (The Johns Hopkins cohort had a high rate of patients who also had hepatitis C--about 50%--which might seem to be an explanation. However, a surprising finding is that those with hepatitis C who were treated with ritonavir were no more likely to develop severe liver toxicity than those with hepatitis C who were treated with other antiretrovirals. There were too few cases of hepatitis B in this study to make similar comparisons.)
No one knows why the risk of liver toxicity with ritonavir was much higher in this study than other studies.
Johns Hopkins Medical Institution summarized the results in a January 4 press release:
"Some doctors have been reluctant to use protease inhibitors, so they have prescribed other medications that are either harder to take or less effective, says Sulkowski [the lead author]. This study shows that liver toxicity is fairly high with these drugs and that ritonavir is more toxic than others. These drugs, however, can be used safely if liver enzyme levels are monitored closely.
"The study also shows that reluctance in prescribing protease inhibitors may do more harm than good. If you were to exclude every patient with hepatitis C from getting these medications, you would be denying treatment to many of those who would benefit from the drugs, said Sulkowski."
Abbott's Response
Abbott Laboratories, the maker of ritonavir, issued a statement, which includes the following:
"Abbott has been monitoring and reporting results of abnormalities in liver function tests associated with Norvir use to regulatory authorities and to the medical community throughout the product's history. Our data of more than 900 patients in three controlled clinical studies demonstrated the overall incidence of severe hepatotoxicity with Norvir, using similar criteria as the JAMA article, is consistently in the range of 5 - 10 percent. In addition, we have observed in these studies that this incidence is increased in patients with underlying liver disease, such as HCV or HBV, and proactively notified the FDA in November 1996, which resulted in labeling reflecting these observations."
For More Information
For the abstract of the Johns Hopkins article, and a link to the full text see:http://jama.ama-assn.org/
The Johns Hopkins press release for January 4 is at: http://www.hopkinsmedicine.org/
Abbott's information about ritonavir, including the official labeling, is at http://www.rxabbott.com/norvir/5_7_2_important_information.cfm
References
1. Sulkowski MS, Thomas DL, Chaisson RE, and Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. January 5, 2000; volume 283, number 1, pages 74-80.
