Fortunately, severe hyperlactatemia and lactic acidosis are rare complications of antiretroviral drugs. Although uncommon, with reported incidence rates ranging between 1.3 and 10 episodes per 1000 person-years among patients on antiretroviral therapy, lactic acidosis is a life-threatening complication with a case-fatality rate estimated at around 60% in HIV positive individuals.

Hyperlactatemia and lactic acidosis have been attributed to almost all currently used dideoxynucleosides, a subclass of nucleoside reverse transcriptase inhibitors (NRTIs). The condition is thought to be related to mitochondrial toxicity, or damage to energy-producing structures within cells. Due to changes in the use of different antiretroviral therapies over time, it can be difficult to assess the effect of an individual drug on lactate metabolism and mitochondrial function in vivo.

Nonetheless, almost all studies to date suggest that the dideoxynucleoside NRTIs, in particular d4T (stavudine; Zerit), are associated with severe lactic acidosis. Other dideoxynucleosides commonly used to treat HIV include AZT (zidovudine; Retrovir), ddI (didanosine; Videx) and 3TC (lamivudine; Epivir). Due to sluggish sales and an unfavorable side effect profile (primarily peripheral neuropathy), ddC (zalcitabine; Hivid) was withdrawn from the market in 2006 by its manufacturer, Roche Laboratories.

Given the frequent use of dideoxynucleoside NRTIs in combination HAART regimens, it remains critically important to identify risk factors for adverse events, quantify the risk, and produce evidence-based guidelines for use of these drugs.

The Lactic Acidosis International Study Group conducted a multicenter, international case-control study to identify risk factors for confirmed severe hyperlactatemia and lactic acidosis in HIV patients exposed to antiretroviral therapy. Results were reported in the November 30, 2007 issue of AIDS.

Lactic acidosis was defined as a blood pH < 7.35, bicarbonate < 20 mmol/L, and elevated lactate; hyperlactatemia was defined as 2 consecutive lactate measurements >5 mmol/L.

The study included of 110 cases and 220 controls (2 randomly selected from treated patients by center and calendar year) from centers in 10 countries. The study population included 40 (36.4%) female cases and 40 female controls (18.2%).

The median age was 42 years for cases and 40 for controls. More cases were non-white (41.9%) than controls (31.2%). Case patients, overall, had a shorter duration of exposure to NRTIs.

Results

After adjusting for age, sex, and current CD4 cell count, hyperlactatemia/lactic acidosis remained associated with exposure to ddI in every category of exposure duration, but was most strongly associated with exposure < 12 months.

In a separate multivariable model, apart from exposure to d4T, ddI, or (even more strongly) both, age > 40 years, female sex, and advanced immunosuppression were independently risk factors.

In conclusion the authors wrote, “Hyperlactataemia/lactic acidosis was associated with exposure to dideoxynucleosides, female gender, advanced immunosuppression, and possibly ethnicity. This has important consequences for choice of antiretroviral therapy in resource-limited settings. The association with shorter duration of exposure may support the hypothesis of susceptibility in a small proportion of patients.”

Discussion

The authors concluded that exposure to dideoxynucleoside NRTIs was strongly associated with the likelihood of developing hyperlactatemia/lactic acidosis.

The impact of these adverse effects may have far more profoundly negative consequences in resource-limited countries, not only because of the frequent use of these drugs in these locations due to their low cost and wide availability, but also because people in these countries more often have other risk factors for hyperlactatemia/lactic acidosis.

Women and individuals with advanced HIV disease are at much higher risk of developing serious NRTI-induced mitochondrial dysfunction. “This observation is consistent with the hypothesis of a specific susceptibility to mitochondrial toxicity, where genetic background may or may not lead to subclinical mitochondrial dysfunction and facilitate NRTI-induced mitochondrial damage,” wrote the authors.

They continued, “If so, relatively short exposure to any mitochondrial toxic drug may be enough to induce clinically evident mitochondrial dysfunction.

HIV patients in resource-limited countries often have few options for antiretroviral therapy, and access to laboratory tests for monitoring treatment outcomes and adverse event is scanty.

“Therefore,” the authors concluded, “Further work is needed to examine the risk of these severe complications in African populations, to improve our understanding of susceptibility, and to make antiretroviral agents with lower toxicity available at affordable prices for individuals at high risk of developing toxicity.”

11/30/07

Reference
Lactic Acidosis International Study Group. Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy. AIDS 21(18): 2455-2464. November 30, 2007.