An American study to be published in the December 15th edition of Clinical Infectious Diseases (now available on-line) found that HIV-positive individuals treated with HAART have elevated levels of a key marker for oxidant stress.
Oxidant stress refers to the generation of free radicals in the body that damage cells and tissue. Oxidant stress is thought to play a key role in diseases such as diabetes, and the normal human aging process.
Although anti-HIV drugs have been linked with metabolic complications, it was not known if HAART increased oxidant stress.
To answer this question, investigators from Vanderbilt University in Tennessee measured levels of F2 isoprostanes (F2IsoP), a key marker for oxidant stress in 120 HIV-positive individuals receiving primary care in 2002.
Investigators gathered information on the particular anti-HIV drugs and HAART regimens used by the patients in the study to see if any particular medicines or treatment combinations were associated with increased oxidant stress. The Vanderbilt researchers also monitored viral load and blood lipids.
The mean age of the study participants was 41 years, 20% were female, 34% African-American, and 3% were Hispanic. A little under three-quarters of patients were taking anti-HIV therapy, the most commonly prescribed regimens being AZT, 3TC and abacavir (18%), AZT, 3TC and efavirenz (15%), and AZT, 3TC and nelfinavir (9%).
Plasma F2 IsoP concentrations were greater than the upper limit of normal in 28 individuals (23% of the study sample), of whom 25 (89%) were taking anti-HIV therapy.
In univariate analysis, a viral load below 10,000 copies/mL (p=0.009), and the use of efavirenz (p=0.06) were significantly associated with greater concentrations of the key oxidant stress marker. When the investigators restricted their analysis to include only the individuals who were taking anti-HIV drugs, there remained a trend toward higher F2 IsoP concentrations in individuals receiving efavirenz. Amongst patients not taking HAART there was no correlation between F2 IsoP concentrations and viral loads. Smoking was not associated with elevated F2 IsoP levels.
The investigators further explored the effects of HAART on oxidant stress by looking at F2 IsoP concentrations in patients with a viral load below 400 copies/mL and comparing these concentrations with patients who were not taking anti-HIV therapy. There was a trend (p=0.053) for patients with a viral load below 400 copies/mL to have higher F2 IsoP concentrations, and F2 concentrations exceeded normal levels in 38% of patients with a viral load below 400 copies/mL, but in only 10% of patients who were not on anti-HIV therapy.
In multivariate analysis the investigators found an independent association with viral load (p=0.03) and the use of efavirenz (p=0.049).
Although the investigators found that patients taking HAART were significantly more likely to have elevated blood lipids by multivariate analysis(p2 IsoP concentrations in univariate analysis. It was not possible to include these variables in the multivariate analysis because measurements were missing in almost half the patients.
”These findings suggest that therapeutic control of HIV…replication by antiretroviral medications is associated with increased oxidant stress in many patients and that oxidant stress is not increased in patients with uncontrolled viral replication”, write the investigators.
Given the number involved in the study, the investigators suggest that their findings should be treated with caution, particularly the association between efavirenz use and increased risk of oxidant stress.
The investigators suggest that further research is needed to determine the extent to which oxidant stress is a component of immune reconstitution
To determine the role of uncontrolled HIV viral replication on oxidant stress, the investigators recommend that a clinical trial is conducted which compares F2 IsoP concentrations in HIV-positive patients who are not taking HAART with HIV-negative age and sex matched controls.
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Hulgan T et al. Oxidant stress is increased during treatment of human immunodeficiency virus infection. Clinical Infectious Diseases 37 (on-line edition), 2003.