Treatment with d4T and/or ddI, a low CD4 cell count, female gender and possibly ethnicity are risk factors for increased lactate levels and lactic acidosis, potentially dangerous side-effects of antiretroviral therapy, according to an international study published in the November 30th edition of AIDS.
Several recent studies have shown that patients receiving fixed-dose antiretroviral therapy that includes d4T are at increased risk of developing lactic acidosis and the drug is no longer recommended in WHO guidelines because of this. All the other risk factors identified by the study as risk factors for the side-effect also occur more frequently in resource-limited settings.
Evidence has been accumulating since the mid-1990s that some NRTI drugs can damage the mitochondria in cells, leading to the development of a number of side-effects including fat wasting, peripheral neuropathy and lactic acidosis.
Lactic acidosis is an uncommon, but potentially life-threatening antiretroviral side-effect, and up to 60% of patients who develop it dying as a result.
Although all NRTI drugs have been implicated with increases in lactate levels, studies have consistently shown that therapy with the so-called ‘d’ drugs (dideoxynucleosides), particularly d4T (stavudine, Zerit), are associated with the development of lactic acidosis.
Access to antiretroviral therapy in resource-limited settings is expanding rapidly, but such treatment programmes are reliant upon NRTIs, particularly the thymadine analogues AZT and d4T. These two drugs have been associated with a greater risk of side-effects than abacavir and tenofovir, which are now cornerstones of antiretroviral therapy in richer countries. Because of cost they are not currently a viable option in poorer countries.
It is therefore important to identify the risk-factors for lactic acidosis in resource-limited settings. Therefore investigators designed a multi-centre, international, case-controlled study to identify the risk-factors for severe elevations in lactate levels and lactic acidosis in patients treated with antiretroviral drugs.
The study was retrospective and included patients diagnosed with elevated lactate levels or lactic acidosis between 1997 and 2004. Two randomly selected controls were matched with each case.
Patients were diagnosed with lactic acidosis if they had arterial blood pH below 7.35, blood bicarbonate below 20 mmol/l and blood lactate levels above the reference range in the treatment centre. Patients with elevated lactate levels were also included in the investigators’ analysis if they had blood lactate levels above 5 mmol/l in two consecutive tests.
A total of 110 cases (49 of whom had lactic acidosis) were included in the investigators’ analysis. These patients were matched with 220 controls.
The cases were significantly older than the controls (42 years vs. 36 years, p = 0.01), and were more likely to be non-white (42% vs. 31%, p = 0.03).
CD4 cell counts were significantly lower in cases than controls (median, 248 cells/mm3 vs. 400 cells/mm3, p
Cases were much more likely than controls to have side-effects linked to mitochondrial toxicity (odds ratio [OR], 5.87; 95% CI, 3.14 – 10.98).
The investigators then looked at the antiretroviral drugs the cases and controls were receiving. They found that d4T was being taken by 70% of cases and that 61% of cases were receiving ddI therapy. The corresponding figures for controls were 40% and 28%.
The risk of severely elevated lactate levels or lactic acidosis appeared to diminish with the duration of ddI therapy (OR for patients receiving therapy for under twelve months, 9.26; for patients receiving over 24 months of therapy, 2.28).
In multivariate analysis, which controlled for baseline CD4 cell count, the investigators found that severely elevated lactate levels or lactic acidosis were associated with age over 40 years (OR, 2.6; 95% CI, 1.08 – 6.29), female gender (OR, 5.97; 95% CI, 1.92 – 18.5), low current CD4 cell count (CD4 cell count below 200 cells/mm3, OR, 7.58; below 100 cells/mm3, OR, 8.11), and, compared to therapy with AZT/3TC, treatment with d4T/ddI (OR 19.87, 95%CI 4.49-87.91), d4T (OR .14, 95%CI 1.03-16.68) or ddI (OR 5.24, 95%CI 1.24-22.19).
“In conclusion, exposure to dideoxynucleosides was strongly associated with the likelihood of developing hyperlactataemia/lactic acidosis. The impact of such an adverse effect may be much more important in resource-limited countries, not only because of the frequent use of such drugs but also because other risk factors independently associated with hyperlactataemia/lactic acidosis are also more frequent”, write the investigators.
Lactic Acidosis International Study Group. Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy. AIDS 21: 2455 – 2464, 2007.