By Liz Highleyman

Studies have shown that as a class, nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicity, or damage to small energy-producing structures within cells. Mitochondrial toxicty can lead to various symptoms and conditions, including lactic acidosis, lipoatrophy (fat loss in the limbs and face), peripheral neuropathy, and possibly pancreatitis and liver damage.

Since various NRTIs differ in terms of the type and severity of adverse effects resulting from mitochondrial toxicity, French researchers conducted a study to assess the association between use of specific NRTIs, changes in mitochondrial DNA (mtDNA) levels, and clinical symptoms. The study included participants from the randomized ALBI-ANRS 070 clinical trial testing antiretroviral therapy in treatment-naive HIV positive patients.

Mitochondrial DNA levels in peripheral blood mononuclear cells (PBMCs) were measured at baseline and after 6 and 12 months. Symptoms of lipodystrophy -- of which lipoatrophy is one manifestation -- were assessed after 30 months using a standardized questionnaire.

Results

• Overall, mean mtDNA level decreased significantly, from 5847 copies/cell at baseline to 3176 copies/cell at month 12 (P < 0.0001).

• Among 37 patients receiving AZT (zidovudine; Retrovir) plus 3TC (lamivudine; Epivir), the mean mtDNA levels were 6098, 6807, and 3725 copies/cell at baseline, month 6, and month 12, respectively.

• Among 40 subjects receiving d4T (stavudine; Zerit) plus ddI (didanosine; Videx), the mean mtDNA levels were 5616, 5731, and 2648 copies/cell, respectively.

• The proportion of subjects in the lowest quartile of mtDNA levels (< 1421 copies/cell) at month 12 was much higher in the group with lipodystrophy (n = 18) compared to the group without lipodystrophy (n = 28) (44% vs 7%, respectively; P = 0.008).

• After 12 months, a larger reduction in mtDNA levels from baseline was observed in patients in the d4T plus ddI arm.

• A low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy.

Conclusion

In conclusion, the authors wrote, measurement of mitochondrial DNA "may be of value for the early prevention of lipodystrophy in treated HIV-infected patients."

Since the toxicities of d4T and ddI have become more apparent and less toxic alternatives have become available, the combination of d4T plus ddI is no longer considered a preferred NRTI background for individuals starting antiretroviral therapy for the first time.

02/16/07

Reference
G Chene, B Amellal, G Pedrono, and others. Changes in the Peripheral Blood mtDNA Levels in Naive Patients Treated by Different Nucleoside Reverse Transcriptase Inhibitor Combinations and Their Association with Subsequent Lipodystrophy. AIDS Research & Human Retroviruses 23(1): 54-61. January 2007.