Successful Treatment of Chronic Hepatitis C Reduces the Risk of Antiretroviral-related Liver Toxicity in HIV-HCV Coinfected Patients

Liver toxicity has emerged as a primary cause of morbidity and mortality in HIV positive patients. Most of the antiretroviral drugs currently in use may cause elevated levels of the liver enzymes ALT and AST. Coinfection with hepatitis C virus (HCV) is common in HIV patients, due to the similarities in viral transmission routes, and increases the risk for drug-related hepatotoxicity 3-fold.

In the current issue of the Journal of Infectious Diseases (September 1, 2007), researchers at Hospital Carlos III in Madrid and the HIV Unit at Hospital San Millán in Logroño, Spain, report results of a retrospective study that analyzed the incidence of severe elevations in liver enzyme  levels during antiretroviral therapy in a group of HIV-HCV coinfected patients after their completion of a full course of interferon-based therapy [1]. Following are the summary results of this Spanish study.

The extent of liver fibrosis in HIV-infected patients with chronic hepatitis C seems to be an important determinant of the risk of hepatotoxic events during anti-HIV therapy, and patients with HIV-HCV coinfection experience accelerated progression of liver fibrosis.

Therapy with pegylated interferon plus ribavirin may clear HCV infection in about 50% of patients, and most patients experiencing HCV eradication show liver histology improvements and have an improved clinical prognosis. Yet it remains unclear whether a sustained virological response (SVR) following interferon-based therapy will improve hepatic tolerance of anti-HIV drugs in HIV-HCV coinfected patients.

The investigators first identified all HIV-HCV coinfected patients at 2 large HIV clinics in Madrid and selected 32 who were exposed to antiretroviral therapy for the current study; 66% were men and the mean age was 38 years. They then recorded hepatic events according to the achievement of SVR and assessed the presence of advanced liver fibrosis.

Patients were offered liver fibrosis staging between September 2004 and 2006. Patients with hepatitis B or other liver diseases were excluded. Patients with alcohol abuse (defined as daily consumption >50 grams for >2 years) were interviewed regularly.

Results

·         Overall, 33% of patients achieved SVR.

·         40% had advanced liver fibrosis after interferon-based therapy.

·         49 episodes of liver toxicity occurred during a mean of 35 months of follow-up (9.7% per year) after interferon therapy.

·         The yearly incidence of hepatic events was greater in patients who did not achieve SVR than in those who did (12.9%  vs 3.1%; P < .001).

·         The incidence of hepatic events was also greater in patients with advanced liver fibrosis than in those without (14.4% vs. 7.6%; P = .003).

·         Drugs involved in hepatic events were:

o        dideoxynucleoside analogues (namely, didanosine [Videx] and stavudine [Zerit]): 40%;

o        nevirapine (Viramune): 30%;

o        efavirenz (Sustiva): 11%;

o        protease inhibitors (PIs): 8%.

·         Lack of SVR and the use of dideoxynucleosides were independent predictors of hepatotoxicity after interferon therapy.

·         Conversely, regimens containing PIs or efavirenz were associated with a decreased risk of hepatic events.

Conclusion and Discussion

Based on these findings, the study authors concluded, “Sustained HCV clearance after interferon-based therapy reduces the risk of liver toxicity during antiretroviral therapy, which should further encourage the treatment of chronic hepatitis C in HIV-coinfected patients.”

“In this population, prescription of PIs or efavirenz decreases and use of dideoxynucleoside analogues increases the risk of hepatotoxicity,” they added.

These study results showed that the risk of antiretroviral-associated hepatic events in HIV-HCV coinfected patients who had eliminated HCV after a course of anti-HCV therapy was significantly diminished, compared with that in patients who did not clear the virus (9.3% vs. 37.5%).

The authors wrote, “In our study, patients with hepatic events were more frequently receiving dideoxynucleoside analogues or nevirapine.” Prior studies have also noted the potential of these drugs to cause liver toxicity. “However, in our series,^” wrote the authors, “only the use of dideoxynucleosides remained associated with hepatotoxicity in the multivariate analysis.” 

The current study found -- similar to previous reports -- that triple-nucleoside regimens not containing dideoxynucleoside analogues, efavirenz, or PIs resulted in a diminished risk of antiretroviral-related hepatic events.

The authors concluded, “Successful treatment of chronic hepatitis C, besides preventing the development of end-stage liver disease, may reduce the risk of subsequent liver toxicity during antiretroviral therapy in HIV-HCV coinfected patients. This fact represents a further argument for prioritizing the treatment of chronic hepatitis C in this population.”

Editorial by Curtis Cooper, MD

In an editorial that accompanies the present article [2], Dr. Curtis Cooper of the University of Ottawa Hospital wrote, “I generally favor addressing HIV infection first and then turning my attention to concurrent HCV infection.” Dr. Cooper noted that for patients who present late in their disease with low CD4 T-cell counts and HIV-related opportunistic infections, “[the Spanish researchers’] findings are not applicable; such patients will need to receive HIV antiretroviral therapy first and take their chances with liver toxicity.”

He added, however, that some HIV-HCV coinfected patients present sooner, and that for these individuals, “the possibility of reducing the incidence of antiretroviral-related liver toxicity by first eliminating HCV infection is very relevant.”

Dr. Cooper concluded, “Given the relative pros and cons, it seems premature to delay highly active antiretroviral therapy, when recommended by current treatment guidelines, without additional study of this strategy in these gray-zone patients [who present late in their disease with low CD4 T-cell counts].”

Department of Infectious Diseases, Hospital Carlos III, Madrid, and HIV Unit, Hospital San Millán, Logroño, Spain.

References                 

1. P Labarga, V Soriano, M E Vispo, and others. Hepatotoxicity of Antiretroviral Drugs Is Reduced after Successful Treatment of Chronic Hepatitis C in HIV-Infected Patients. Journal of Infectious Diseases 196(5): 670-676. September 1, 2007.

2. C L Cooper. De-"Liver"-ing HIV/Hepatitis C Virus–Coinfected Patients from Antiretroviral Hepatotoxicity (Editorial). Journal of Infectious Diseases 196(5): 656-658. September 1, 2007.