By Liz Highleyman

Mitochondrial toxicity, or damage to energy-producing structures within cells, has been linked to antiretroviral therapy. Some studies have implicated the "D-drug" nucleoside reverse transcriptase inhibitors (NRTIs) stavudine (d4T; Zerit) and didanosine (ddI; Videx), while other blame the thymidine analogs d4T and zidovudine (AZT; Retrovir).

Mitochondrial toxicity may lead to various manifestations, potentially including lactic acidosis, lipoatrophy (fat loss) in the face and limbs, and a type of liver toxicity characterized by an enlarged fatty liver (hepatomegaly with steatosis).

Drug-induced liver mitochondrial toxicity is a particular concern for HIV positive individuals with hepatitis C virus (HCV) coinfection. People with pre-existing liver damage are less able to tolerate hepatotoxic drugs, and some studies suggest that drug-induced hepatotoxicity might contribute to the high rate of liver-related death in HIV-HCV coinfected patients.

As described in a research letter in the June 19, 2008 issue of AIDS, investigators from British Columbia, Canada, conducted a prospective cohort study looking at liver biopsies to assess mitochondrial damage in HIV-HCV coinfected individuals on or off HAART.

The study included 23 coinfected men, 14 of whom were on stable combination antiretroviral therapy for more than 6 months, and 9 of whom were off HAART for more than 6 months. At the time of liver biopsy, all were naive to anti-HCV therapy, had no serious liver disease, and had no opportunistic infections within the past month.

Two ultrasound-guided liver biopsy samples were obtained from each participant between 2003 and 2006. The researchers performed electron microscopic ultrastructural analysis of the liver tissue samples, and assessed mitochondrial DNA and RNA, and gene expression levels.

The study authors initially hypothesized that coinfected individuals currently receiving HAART would show greater liver mitochondrial damage than those not on HAART. Instead, they found that while hepatocytes (liver cells) tended to be larger in patients on HAART compared with those off HAART (P = 0.05), mitochondrial volume, cristae density, lipid volume, and mitochondrial DNA and RNA levels were similar in the antiretroviral treated and untreated groups.

In conclusion, the investigators wrote, "this study provided no evidence that patients coinfected with HIV and HCV show increased liver mitochondrial damage if on concomitant HAART."

In their discussion, they noted that prior findings of HAART-related mitochondrial toxicity may have been due to the specific drugs used. The majority of HAART-treated patients in the current study were not taking D-drugs, which have largely fallen out of favor - at least in industrialized countries -- due to their side effects; only 2 participants were on stavudine, and none was on didanosine or the older, discontinued zalcitabine (ddC; Hivid).

"These results suggest that HAART with predominantly non-D-drug-containing regimen[s] may not be a reason to delay or avoid the start of HCV antiviral therapy in coinfected individuals," the authors continued. "This is especially true as liver disease progression and not drug-induced hepatotoxicity is the most common cause of mortality in this population."

7/25/08

Reference
M Matsukura, F Chu, M Au, and others. Liver ultrastructural morphology and mitochondrial DNA levels in HIV/hepatitis C virus coinfection: no evidence of mitochondrial damage with highly active antiretroviral therapy [Research Letters]. AIDS 22(10): 1226-1229. June 19, 2008. (Abstract)