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Interferon/ribavirin Decreases Liver Enzyme Levels and May Enable Re-initiation of Antiretroviral Therapy in HIV-HCV Coinfected Patients with HAART-related Liver Injury

By Ronald Baker, PhD

HIV positive patients who are coinfected with hepatitis C virus (HCV) are at increased risk for drug-induced liver injury (DILI) compared with patients with HIV monoinfection. The mechanisms responsible for this association are unknown.

It is important to understand the interaction between HIV and HCV, due to the fact that approximately 30% of all HIV positive individuals worldwide are co-infected with HCV.

Recurrent drug injury limits antiretroviral therapy options for HIV patients and leads to loss of HIV viral suppression and immunological decline. In addition, symptomatic hepatotoxicity (drug-induced liver toxicity) is associated with significantly greater morbidity and mortality compared with asymptomatic elevations of aminotransferases (ALT, AST). Patients who have symptomatic drug-related liver injury may develop liver failure and die.

In the current study, published in the November 15, 2007 issue of Clinical Infectious Diseases, researchers hypothesized that interferon would induce biochemical improvement through its anti-inflammatory properties and thereby make it safe to re-introduce antiretroviral therapy in patients with DILI.

Patients with symptomatic DILI were referred to the study investigators for evaluation; liver biopsy was performed for all patients, except 1 who had clinical cirrhosis.

Results

  • 7 of 12 enrolled patients had recurrent DILI.

  • All 12 patients with AIDS and Grade 3-4 hepatotoxicity were treated with interferon plus ribavirin.

  • The mean baseline CD4 cell counts was 124 cells/mm3 and the mean HIV RNA level was 115,369 copies/mL.

  • Liver biopsies showed significant necroinflammation and fibrosis.

  • 3 patients continued to receive antiretroviral therapy when they began treatment with interferon plus ribavirin; 9 re-initiated antiretroviral therapy within an average of 12 weeks after HCV treatment initiation.

  • All 12 patients achieved significant improvement in aminotransferase levels and continued to receive antiretroviral therapy during a mean follow-up period of 26.5 months.

  • All 12 experienced subsequent HIV suppression and immunological reconstitution (mean CD4 cell count increase of 251 cells/mm3).

  • However, only 1 individual had sustained HCV suppression after completion of treatment with interferon plus ribavirin.

Based on these findings, the study authors concluded, “In patients with symptomatic drug-induced liver injury, treatment with interferon/ribavirin led to decreases in aminotransferase levels, which enabled the re-initiation of antiretroviral therapy.”

They also noted, “The beneficial effects of interferon-based therapy may be modulated through the suppression of proinflammatory cytokines, even in virologic nonresponders.”

Finally, they stated, “Herein, we propose a novel mechanism for DILI, whereby HCV- and HIV-associated inflammatory mediators induce liver injury synergistically.”

Discussion

Symptomatic DILI can lead to discontinuation of antiretroviral therapy, with consequent immunological compromise, according to the authors. “This was clearly evident in this case series, where several of our patients had absolute CD4 T cell counts < 200 cells/mm3 at the time of referral.”

Anti-HCV therapy resulted in significant decreases in aminotransferase levels, which allowed for the re-introduction of anti-HIV treatment, resulting in significant improvements in HIV-related parameters.

HCV treatment guidelines differ in their recommendations with regard to the CD4 cell threshold that should be used to initiate hepatitis C therapy. Some experts recommend treatment only if the CD4 cell count is greater than 350 cells/mm3; others suggest that there is no absolute threshold below which anti-HCV is contraindicated. 

The study authors argued that individuals with symptomatic drug-associated hepatotoxicity and underlying liver disease should be considered for HCV treatment, regardless of CD4 cell count, “when recurrent DILI is thwarting efforts to maintain a patient on life-saving antiretroviral therapy.”

However, they emphasized that symptomatic drug injury [from antiretroviral therapy] can be life-threatening, regardless of the presence or absence of immunosuppression. “Continuation of antiretroviral therapy treatment in this clinical circumstance can be devastating,” they declared.

“Because of our concerns regarding the presence of symptomatic hepatotoxicity, we prioritized the treatment of HCV infection over HIV infection, despite the presence of advanced immunosuppression,” wrote the authors.

The researchers had already discussed and accepted the probability that the study patients would not achieve eradication of HCV. Instead, their goal for patients was to once again make it safe to re-introduce anti-HIV therapy.

“In conclusion,” wrote the authors, “we have shown that treatment with interferon and ribavirin can facilitate the reintroduction of antiretroviral therapy in patients with symptomatic hepatotoxicity, even when virologic suppression of HCV is not achieved. We propose that chronic viral hepatitis may directly increase the risk of DILI by altering the hepatic microenvironment through induction of inflammation and proinflammatory cytokines, such as TNF-alpha.”

Finally, they suggested that antiretroviral therapy should never be withheld because of concerns about potential DILI, “because the vast majority of patients tolerate treatment with HAART safely.” They added that, “The small subset of HIV-HCV coinfected patients who do develop symptomatic drug toxicity often have multiple cofactors that contribute to host susceptibility to liver injury.”

Lemuel Shattuck Hospital, Tufts University School of Medicine, Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, and Boston Medical Center, Boston, MA.

10/23/07

Reference
BH McGovern, C Birch, MT Zaman, and others. Managing Symptomatic Drug-induced Liver Injury in HIV/Hepatitis C Virus-coinfected Patients: A Role for Interferon. Clinical Infectious Diseases 45(10): 1386-1392. November 15, 2007.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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