Avoid d4T say investigators after finding high incidence of lactic acidosis in Botswana

Approximately 1% of individuals starting antiretroviral therapy in Botswana developed the potentially fatal side-effect, lactic acidosis according to the results of a study published in the November 1^st edition of the Journal of Acquired Immune Deficiency Syndromes. Such an incidence of lactic acidosis is significantly higher than that seen in industrialised countries, although consistent with other studies looking at the side-effect in sub-Saharan Africa, one of which was conducted in Uganda and the results reported on aidsmap.com.

The World Health Organization has recommended that d4T should be avoid in first-line therapy because of the risk of side-effects. WHO also set out guidance for reductions in d4T dose to help avoid toxicities in instances when the drug is used.

In the current studu investigators found that use of d4T (stavudine, Zerit) and ddI (didanosine, Videx) were associated with the development of the side-effect and that women were at particular risk, especially if they were overweight, or aged over 40 years.

Antiretroviral therapy is becoming increasingly available in resource-limited countries. The rollout of anti-HIV treatment is reliant upon generic, fixed-dose combinations that include two NRTIs and an NNRTI. One of the drugs favoured for first-line fixed-dose treatment is d4T. This drug has a potent anti-HIV effect and its formulation and cost make it attractive for inclusion in fixed-dose generic therapy.

But the drug can cause mitochondrial toxicity, producing side-effects including peripheral neuropathy, lipodystrophy and lactic acidosis; a side-effect which has also been associated with ddI.

Lactic acidosis is a very serious side-effect and increased plasma lactate concentrations above 10.0mmol/l have been associated with an 80% mortality rate.

Increased lactate levels have been observed in 20%-60% of antiretroviral-treated patients receving drugs known to cause mitochondrial toxictiy with between 0.1% and 0.4% if individuals developing symptomatic lactic acidosis.

Studies have shown that women, particularly if they are pregnant, have an increased risk of lactic acidosis. Other risk factors include, as stated above, treatment with d4T or ddI, a low CD4 cell count and poor creatinine clearance.

Botswana commenced an antiretroviral treatment programme in 2002. First-line therapy consists of AZT (zidovudine, Retrovir) with 3TC (lamivudine, Epivir) with either efavirenz (Sustiva) or nevirapine (Viramune). Second-line treatment consists of d4T and ddI with ritonavir-boosted lopinavir.

The Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study enrolled 650 adults between 2002 and 2004 who started anti-HIV therapy on one of six regimens. Investigators reported on the incidence of treatment-limiting side-effects, particularly lactic acidosis in these patients.

Patients were followed for a median of 90 weeks, and by the end of November 2005, 124 patients (19%) had had to change treatment because of side-effects. The overall incidence of treatment-modifying side-effects was 11 per 100 person-years of follow-up. Seven (6%) of the patients changing treatment because of toxicities did so because of lactic acidosis.

A total of 59 patients had their lactate levels screened to monitor for lactic acidosis. Of these individuals, 19 had plasma lactate levels above 4.40mmol/ml, or twice the upper limit of normal. Symptoms of lactic acidosis were present in 15 of these patients; eight were diagnosed with moderate-to-severe hyperlactemea and seven were diagnosed with lactic acidosis.

These 15 patients were all women and had been taking antiretroviral therapy for a mean of ten month. Symptoms were present for a mean of 31 days. Six died, and five of the deaths were attributed to antiretroviral therapy (four to lactic acidosis and one to liver failure).

The seven patients diagnosed as having lactic acidosis had a mean age of 43 years. Mean serum lactate level was 9.60mmol/l, median CD4 cell count was 234 cells/mm³ and mean body mass index (BMI) at the time lactic acidosis was diagnosed was 32. All the women were taking an antiretroviral regimen that included d4T and/or ddI. Four of the women also had a diagnosis of pancreatitis and four were diagnosed with peripheral neuropathy.

Factors associated with moderate-to-severe increases in serum lactate or lactic acidosis were female gender (p = 0.0078) and being over-weight (a BMI above 25, p = 0.018). Age over 40 years was of borderline significance (p = 0.051).

“Preliminary data from the Tshepo study document higher-than-expected rates of lactic acidosis among HAART-treated adults in Botswana”, write the investigators. They add, “our data…suggest that policymakers in Africa may need to reconsider certain NRTI-based first-line HAART regimens containing d4T. Until additional information is available, one may consider initiating at-risk females on NRTIs that have been shown to exhibit less mitochondrial toxicity, such as lamivudine (or emtricitabine), abacavir or tenofovir.”