Frequency and seriousness of lactic acidosis mean that d4T should not be used in first-line therapy, say Ugandan researchers

An eighth of antiretroviral-treated patients at an HIV clinic in Uganda, who developed lactic acidosis as a side-effect of their HIV treatment, died because of the complication, doctors report in the August 15^th edition of Clinical Infectious Diseases.

The physicians, from Mulago Hospital in Kampala, highlight several problems diagnosing and managing lactic acidosis in resource limited settings. These include a lack of laboratory facilities, the unavailability of supportive therapy, and the prohibitive expense of alternative antiretroviral drugs which do not cause lactic acidosis.

Because of the prevalence and seriousness of lactic acidosis, the investigators recommend that d4T (stavudine, Zerit), a drug widely used in fixed-dose anti-HIV therapy in Africa and particularly associated with lactic acidosis, should no longer be used in first-line therapy.

The prognosis of HIV-positive individuals in Uganda has improved considerably since potent antiretroviral therapy became more widely available due to initiatives including the Multicountry AIDS Program and the President’s Emergency Plan for AIDS Relief (PEPFAR).

First-line anti-HIV therapy in Uganda consists of AZT (zidovudine, Retrovir) or d4T plus 3TC (lamivudine, Epivir) with either nevirapine (Viramune) or efavirenz (Sustiva). Lactic acidosis is a serious side-effect of anti-HIV drugs in the nucleoside reverse transcriptase inhibitor (NRTI) class, particularly ddI and d4T, and to a lesser extent, AZT. It is thought that the side-effect is caused by the drugs’ mitochondrial toxicity.

Lactic acidosis has been well described in patients receiving potent anti-HIV therapy in industrialised countries, but there are limited data about the side-effect in Africa. One study from South Africa found a high incidence of lactic acidosis (19 cases per 1,000 individuals) amongst patients receiving first-line therapy, and the most widely fixed-dose treatment used in Africa contains d4T, a drug known to involve a risk of mitochondrial toxicity and lactic acidosis.

Investigators therefore outlined 24 cases of lactic acidosis amongst the 3745 patients receiving antiretroviral therapy at their clinic between October 2005 and October 2006. All the patients were receiving d4T. The median duration of HIV therapy before the development of lactic acidosis was thirteen months. The patients’ median age was 36 years, and 83% were female. Baseline CD4 cell count before the initiation of fixed-dose antiretroviral therapy was 104 cells/mm³.

Non-specific symptoms that can be suggestive of lactic acidosis were present in all 24 patients. Symptoms included abdominal pain, weight loss, vomiting, and fatigue. Other symptoms suggestive of mitochondrial toxicity were also widely reported, with 20 patients having peripheral neuropathy and four severe lipoatrophy of the face or lower extremities. Median serum lactate level at the time lactic acidosis was diagnosed was 6.61 mmol/l. Abdominal sonography showed that seven patients had a fatty liver.

All the patients stopped anti-HIV therapy and were provided with B vitamin supplements. Five patients were admitted to hospital for supportive care consisting of intravenous fluids. Unfortunately, five patients died. Of the remaining 19 patients, eleven switched anti-HIV therapy, three to a nucleoside-sparing regimen including Kaletra, six to AZT, one to abacavir, and one to tenofovir. The remaining eight patients are waiting for the normalisation of their lactate levels and the availability of alternative drugs before recommencing anti-HIV therapy.

The investigators believe that the actual incidence of lactic acidosis in their clinic is probably much higher. They note that the symptoms are generally non-specific and can be mistaken for malaria or gastroenteritis.

Laboratory facilities to monitor lactate levels were not available to the authors, and patients had to be referred to a private facility for lactate testing. Unfortunately, a number of patients did not have the $7 for the test.

Treatment for lactic acidosis involves the withdrawal of antiretroviral therapy, but as HIV therapy is only initiated in resource-limited settings when an individual is already seriously ill because of HIV, or at a significant risk of this occurring, this can involve very real risks for a patient’s health.

Supportive therapy for lactic acidosis, such as riboflavin, is unavailable in Uganda, and alternative nucleoside/nucleotide drugs that do not cause mitochondrial toxicity – abacavir and tenofovir – are prohibitively expensive. Although nucleoside-side sparing regimes that include a protease inhibitor are a possible option, they have the disadvantage of high pill-burden and the use of important treatment options that need to be reserved for second-line therapy.

“Symptomatic hyperlactatemia is an important and potentially fatal complication of antiretroviral therapy in African patients, and it is associated with a high mortality in otherwise stable patients who are receiving long-term antiretroviral therapy”, write the investigators.

They conclude that doctors and patients need a “high index of suspicion” about the side-effect, laboratory facilities need to be affordable, abacavir and tenofovir should be available in treatment access programmes, and “free antiretroviral therapy programs should also consider excluding stavudine as a drug of choice in first-line regimens.”