Over one year of 3TC use associated with increased risk of diabetes for HIV-positive women

Cumulative nucleoside reverse transcriptase inhibitor (NRTI) use, particularly 3TC (lamivudine, Epivir) is associated with an increased risk of type 2 diabetes in HIV-positive women, according to a US study published in the August 28^th edition of AIDS.

The investigators speculate that “NRTI-induced mitochondrial dysfunction” could be contributing to the development of diabetes. By contrast, neither protease inhibitor treatment, nor treatment with non-nucleoside reverse transcriptase inhibitors use (NNRTIs) were associated with the development of diabetes mellitus.

Diabetes mellitus has been a concern for HIV-infected individuals since reports emerged implicating protease inhibitors in the development of glucose intolerance and insulin resistance.

Studies demonstrating an association between antiretroviral treatment and the development of heart disease have intensified the need to clarify the relationship between anti-HIV therapy and diabetes mellitus as diabetes is a primary risk factor for cardiovascular illness.

Earlier studies looking at the association between antiretroviral therapy and diabetes mellitus have been limited by the small number of cases reported, their reliance on self-report, or the lack of an HIV-negative comparator group.

Investigators from the prospective Women’s Interagency HIV Study (WIHS), which includes HIV-positive women and women with a risk of HIV infection, followed 2,088 women for five and a half years to determine the incidence of diabetes mellitus and its association with anti-HIV therapy.

The study included 1,524 HIV-positive women and 564 HIV-negative women. At three-monthly intervals between 2000 and 2006 they had their fasting glucose monitored and the HIV-infected women provided information on the use of antiretroviral drugs.

Women with fasting glucose above 1.26mg/l, or who were prescribed diabetes medication, were classified as having incident diabetes mellitus. Body measurements were taken at baseline and throughout the study, and before entry to the study, the women were questioned about the presence of traditional risk-factors for diabetes.

HIV-positive and HIV-negative women were well-matched on entry to the study, although HIV-positive women were significantly older (39 versus 34 years, p 2 versus 28 kg/m², p = 0.001), a lower median hip size (99cm versus 102cm, p

Median fasting glucose was 830mg/l, and was the same in HIV-positive and -negative women. During follow-up, a total of 152 incident cases of diabetes mellitus were diagnosed, 116 of which were in women with HIV.

Compared with the diabetes mellitus incidence rate in HIV-negative women (1.96 per 100 person-years), HIV-positive women not taking anti-HIV therapy had a lower incidence rate of 1.53 per 100 person-years. The incidence rate was higher for women taking one or two drug anti-HIV treatment (3.40 per 100 person-years). For women taking protease inhibitor-containing anti-HIV therapy, the incident rate was 2.5 per 100 person years, and for women taking potent anti-HIV therapy that did not include a protease inhibitor, the incidence rate was 2.89 per 100 person years.

In adjusted statistical analysis, none of the associations between treatment group and diabetes mellitus were significant.

However, the investigators found that longer cumulative exposure to NRTI drugs was associated with an increased risk of diabetes mellitus compared to no NRTI use (relative hazard [RH], 1.81; 95% CI, 0.83 – 3.93 for zero to three years of NRTI treatment with a RH of 2.64; 95% CI, 1.11 – 6.32, for over three years of NRTI exposure).

Neither cumulative exposure to protease inhibitors, nor cumulative exposure to NNRTIs was found to be associated with the development of diabetes mellitus.

In further analysis, of the four most commonly used NRTIs (AZT, abacavir, d4T and 3TC), only cumulative exposure to 3TC was found to be significantly associated with an increased risk of diabetes mellitus (over one year of 3TC exposure, adjusted RH, 2.81; 95% CI, 1.33 – 5.95).

“We conclude that cumulative exposure to NRTI, but not PI or NNRTI, was associated with increased diabetes mellitus incidence”, write the investigators. They add, “NRTI remain the backbone of effective antiretroviral therapy, and so regular monitoring of fasting glucose levels in HIV-infected patients is warranted. Study of the biological mechanisms by which NRTI might induce disorders in glucose metabolism is a priority.”