Background:  Perinatal HIV infection has been reported to be associated with mitochondrial dysfunction, both in association with disease progression and in response to ART. Partly due to the absence of a specific diagnostic algorithm, mitochondrial dysfunction has not been widely studied in children with HIV infection. Studies conducted to date have included a small number of HIV-infected children.

Methods:  Participants were enrolled in the Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C between 1993 and 2004. We used 2 clinical case definitions of mitochondrial dysfunction:  the Enquête Perinatale Francaise (EPF) criteria developed for HIV-uninfected children perinatally exposed to both HIV infection and ART, and the Mitochondrial Disease Classification (MDC), developed to identify children in the general population with respiratory chain disorders. Applicable MedDRA terms were assigned for each clinical definition. Persistence of conditions for 6 months was required, and laboratory abnormalities were graded using the National Institutes of Health Division of AIDS 2004 toxicity tables for adverse events. Associations between recent single and dual NRTI use and possible mitochondrial dysfunction were estimated using multiple logistic regression.

Results:  Of 2931 perinatally infected children, 982 (34.4%) met the case definition of mitochondrial dysfunction by one or both classifications, and 135 of the cases (13.7%) died. Of the MDC cases, 80% were incident, compared with 64% of the EPF cases. Overall concordance for mitochondrial dysfunction case identification between the EPF and MDC was 86.3%, of which 10.8% met both criteria, and 75.5% met neither. The mortality rate varied between mitochondrial dysfunction case definition subgroups and was highest among incident cases meeting both criteria (22.1%) vs 14.9% of incident mitochondrial dysfunction cases overall. Exposure to stavudine (d4T) was most strongly associated with mitochondrial dysfunction in the adjusted analyses using both case definitions (EPF OR 2.74; 95%CI 1.97 to 3.82; MDC OR 2.78; 95%CI 2.07 to 3.73). Of NRTI combinations, lamivudine (3TC)/d4T, d4T/didanosine (ddI), and zidovudine (ZDV)/3TC had adjusted odds ratios >1.5.

Conclusions:  These results are consistent with previous studies associating NRTI with presumptive mitochondrial dysfunction. Additional studies are needed to determine potential mechanisms for these findings and to confirm that these clinical signs are indeed related to mitochondrial abnormalities.