HIV and AIDS Articles by Topic - A to Z  

Lactic Acidosis in HAART-treated Women in Botswana, Africa

By Ronald Baker, PhD

Nucleoside reverse transcriptase inhibitors (NRTIs) are routinely used as "backbone" drugs in HAART regimens worldwide, and generally are considered safe and effective. NRTI-based antiretroviral regimens, especially combinations containing d4T (stavudine; Zerit) and ddI (didanosine; Videx), play an increasingly large role in resource-poor countries, such as those in southern Africa, due to their ease of use and lower cost compared with regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs).

Unfortunately, in addition to their benefits as components of effective HAART, d4T and ddI also have been associated with the development of various manifestations of mitochondrial toxicity, including lactic acidosis, myopathy (muscle damage), pancreatitis, peripheral neuropathy, and lipoatrophy (fat wasting [1]. For this reason, U.S. HIV treatment guidelines no longer recommend the d4T/ddI combination for people starting antiretroviral therapy for the first time.

The most serious of these toxicities are lactic acidosis and pancreatitis, which may be life-threatening. Mortality rates of up to 80% have been reported in patients on HAART with plasma lactate concentrations >10.0 mmol/L [2].

Researchers with the Botswana-Harvard School of Public Health AIDS Initiative Partnership in Gaborone, Botswana enrolled 658 HIV positive adults (69% women) in the Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study, a large ongoing randomized clinical trial that closely examined the participants for antiretroviral-associated toxicities.

Results of the Tshepo trial, in which patients have completed almost 2 years of follow up, appear in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes (September 13, 2007).

Results

• Of the 650 subjects who initiated therapy with NRTI-based HAART, 2.0% developed moderate to severe symptomatic hyperlactatemia (elevated blood lactate).

• 7 patients (1.0%), all of whom were women, were diagnosed with lactic acidosis.

• Female sex (P = 0.008) and being overweight (BMI >25) (P = 0.001) were predictors of the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis.

• Older age (> 40 years) showed a statistical trend (P = 0.053) as an additional predictor for the development of hyperlactatemia.

• Exposure to d4T and/or ddI for 6 or more months was not predictive of hyperlactatemia (P = 0.102).

• Patients diagnosed with lactic acidosis had a mean BMI of 32.38 at the time of toxicity and had been receiving HAART for a mean of 12.1 months.

• 4 of the 7 patients with lactic acidosis (57%) died of lactic acidosis and/or hemorrhagic pancreatitis.

• These 4 patients also had a diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of death.

Based on their findings, the study authors concluded that rates of lactic acidosis "appear to be higher" in southern Africa compared with rates observed elsewhere.

In addition, they noted that risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis "appear to be multifactorial but include female gender and a body mass index greater than 25."

Additional studies are ongoing to evaluate the participants for other possible risk factors, such as host genetic differences, wrote the authors.

Discussion

The authors emphasized that the data from the Tshepo trial showed unusually high rates of lactic acidosis (1.0%) among adults on HAART, and they pointed out that similar results have been seen patients from Khayelitsha, South Africa [3]. These facts suggested to the authors that, "adults in southern Africa may be at greater risk for potentially serious complications of NRTI-based ART."

As stated earlier, the Tshepo study data demonstrate that being female and overweight "are predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis." Furthermore, patients older than 40 years also may be at higher risk for these serious and life-threatening toxicities.

"Because all of our patients who died as a result of lactic acidosis also had clinical or laboratory evidence of hemorrhagic pancreatitis, it will be important for more detailed studies to be performed to determine whether these are actually primary pancreatitis cases with the secondary development of lactic acidosis," wrote the authors.

Because female sex and higher BMI appear to be risk factors for lactic acidosis, this situation will need to be carefully monitored in countries with large antiretroviral treatment programs in which large numbers of patients are placed on HAART regimens containing d4T [4].

"Our data also suggest that policymakers in Africa may need to reconsider certain NRTI-based first-line HAART regimens containing d4T," according to the authors. They suggested offering at-risk women NRTIs that produce less mitochondrial toxicity, such as 3TC (lamivudine; Epivir, emtricitabine (Emtriva), abacavir (Ziagen) , or tenofovir (Viread). "These NRTIs have been shown to be well tolerated, and less likely to cause severe mitochondrial toxicity," they noted [5].

10/16/07

Source
CW Wester, OA Okezie, AM Thomas, and others. Higher-Than-Expected Rates of Lactic Acidosis among HAART-Treated Women in Botswana: Preliminary Results from a Large Randomized Clinical Trial. Journal of Acquired Immune Deficiency Syndromes (Epub ahead of print September 13, 2007).

References

1. A Carr and DA Cooper. Adverse effects of antiretroviral therapy. Lancet 356: 1423-1430. 2000.

2. V Falco, D Rodriguez, E Ribera, snd others. Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 21 cases and review of the literature. Clinical Infectious Diseases 34: 838-846. 2002.

3. A Boulle, G Van Cutsem, D Coetzee, and others. Regimen durability and tolerability to 36-month duration on ART in Khayelitsha, South Africa 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO. 2006. Abstract 66.

4. AS Muula, TJ Ngulube, S Siziya, and others. Gender distribution of adult patients on highly active antiretroviral treatment (HAART) in Southern Africa: a systematic review. BMC Public Health. www.biomedcentral.com. Accessed August 21, 2007.

5. JE Gallant, S Staszewski, AL Pozniak, and others. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naïve patients: a 3-year randomized trial. Journal of the American Medical Association 292: 191-201. 2004.