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Mitochondrial Toxicity of Ribavirin and HAART Correlates with Virological Response of HCV in HIV/HCV Co-infected Patients
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics and is on the speaker's bureau for GSK and Cubist.
Synopsis: Sixty-four patients with HIV/HCV coinfection being treated with pegylated interferon alpha (IFN) plus ribavirin (RBV) were evaluated for mitochondrial toxicity (MT). Patients receiving concomitant HAART showed greater increases in lactate levels than those not receiving HAART, and lactate levels were correlated with RBV dose. While pancreatitis and hepatic steatosis were more common in patients concomitantly receiving HAART plus IFN/RBV, those patients demonstrating evidence of MT achieved higher rates of sustained virologic response (SVR) than did patients without evidence of MT.
Source: Reiber T, et al. Mitochondrial toxicity is associated with virological response in patients with HIV and hepatitis C virus coinfection treated with ribavirin and highly active antiretroviral therapy. Clin Infect Dis. 2010;202:156-160.
Data for 64 HIV/HCV co-infected patients treated in a prospective study of pegylated IFN alpha + RBV were analyzed. IFN was administered at 180 mcg SQ/week and RBV was dosed at 800 mg daily for patients with HCV genotype 2 or 3 and 1,000-1,200 mg/day for the first 12 weeks in patients with genotype 1 or 4, then reduced to 800 mg/day until completion of therapy. In addition to standard laboratory studies, venous lactate and various pancreatic enzymes were measured during the course of the trial. MT toxicity also was assessed by liver biopsy, which was performed at baseline and six months following cessation of therapy by presence or absence of hepatic steatosis.
Adverse events were significantly more common in the 48 patients who received concomitant HAART vs. the 16 patients who did not receive HAART: hyperlactemia 25% vs. 12%, pancreatic enzyme elevation 38% vs. 12%, hepatic steatosis after therapy 52% vs. 17%, LDH elevation 27% vs. 12%, and hemolytic anemia 13% vs. 0%. These toxicities were most strikingly seen in the 34 HAART-treated patients who received high-dose RBV.
SVR was achieved in 56% of patients who received HAART and in 31% of those who did not receive HAART. SVR was achieved in 73% of patients with MT vs. 44% of patients without an MT event.
A large proportion of the patients receiving care at the HIV clinic I direct in San Jose, CA, are coinfected with HCV. While all of our clinicians attentively diagnose and treat (when appropriate) these patients with IFN+RBV, frankly only a small proportion of these patients actually complete the course of therapy, and an even smaller proportion achieve SVR. (Data from the APRICOT study show only a 29% SVR rate in HIV/HCV patients with HCV genotype 1 infection; consistent with our clinical experience.) I also have been impressed that IFN+RBV therapy is a tough regimen for many of our patients to take. In addition to the commonly recognized adverse effects of RBV-related anemia, IFN-related neutropenia, and depression, I have been impressed by how many of our patients just look and feel sick during their time on IFN+RBV, often appearing to age years in just a few months.
Data from this study suggest that the cumulative toxicities of IFN+RBV and HAART are largely related to mitochondrial toxicity (most likely due to the additive effects of nucleoside/nucleotide analogue antiretroviral RT inhibitors plus the nucleoside analogue RBV). Perhaps the "silver lining" from this study is that it appears that the presence of mitochondrial toxicity in these co-infected patients actually correlates with SVR. Sharing this information with patients might help give them hope to "hang in there," at least through 12 weeks of therapy, at which point the presence or absence of HCV RNA by a sensitive qualitative assay can help guide whether or not continued IFN+RBV therapy has a good chance of producing SVR. Of course, we desperately need more effective and less toxic small-molecule inhibitors of HCV. However, in the next few years, it appears that even these candidate agents (for example, the HCV protease inhibitor, teleprevir) need to be given in combination with IFN+RBV.