Treatment with an
antiretroviral regimen based on a protease inhibitor magnifies any underlying genetic
susceptibility to diabetes for women living with HIV, investigators report in the
online edition of AIDS. In
non-African American women, treatment with two nucleoside reverse transcriptase
inhibitors (NRTIs) and a protease inhibitor significantly increased the
diabetes risk associated with five genes. Protease inhibitor-based therapy
increased the diabetes risk associated with one gene (or allele) by a factor of two.
European-derived diabetes mellitus risk alleles was associated with
substantially increased risk of diabetes mellitus among non-African American
HIV-infected women treated with cART [combination antiretroviral therapy],
containing at least three components from the NRTI and protease inhibitor
classes,” comment the authors. “Whereas these variants are associated with a
modest 10-35% increased risk of diabetes mellitus among White and Hispanic
general populations, the magnitude of increased risk was 60-170% per risk allele
among HIV-infected non-African American women taking these cART regimens.”
The investigators believe
their findings support “more personalized approaches to HIV treatment” that
take into account the underlying genetic risk of diabetes.
Type 2-diabetes is
an increasingly important cause of serious illness among people living with HIV.
Antiretroviral treatment, especially therapy based on a protease inhibitor, has
consistently been associated with increased incidence of diabetes.
In the general
non-African American population, certain genes have been shown to increase the
risk of type-2 diabetes by between 20-70%. Investigators from the Women's Interagency HIV Study (WIHS) wanted to see if antiretroviral therapy magnified the
diabetes risk associated with these genes.
designed a study involving 969 women living with HIV who received care after 1995.
None had diabetes at baseline. Data on the incidence of type-2 diabetes and use
of antiretroviral treatment were collected. The women were screened for the
presence of 14 genes associated with elevated diabetes risk. The investigators
analysed the association between HIV treatment type, genetic profile and
susceptibility to diabetes varies according to ethnicity. Therefore
analyses were performed separately for non-African American women (white,
Hispanic, Asian and others) and African American women.
population consisted of 378 non-African American women and 591 African American women.
Forty-nine women in each ethnic group developed type-2
Nine of the fourteen
genes were associated with risk of incident type-2 diabetes. There was
statistical heterogeneity across these genes (p < 0.05).
One gene (TCF7L2
rs7903146) was associated with a reduced
risk of diabetes for women taking two NRTIs and a non-nucleoside reverse
transcriptase inhibitor (NNRTI).
Five genes were
significantly associated with incident type-2 diabetes for women taking two or
more NRTIs and a protease inhibitor.
rs1470579 gene was especially associated with elevated diabetes risk. For women
taking two NRTI/protease inhibitor therapy, each additional copy of the gene
increased the risk of diabetes more than two-fold (HR = 2.46; 95% CI,
1.08-5.53). The gene was also associated with an increased risk of diabetes for
those treated with three NRTIs, with or without an NNRTI (HR = 2.67 per alle;
95% CI, 1.67-4.31).
The other genes
associated with elevated diabetes risk for women taking two NRTIs and a
protease inhibitor were:
only applied to women of non-African American descent. For African American
women, the JAZF rs864745 allele was modestly protective against diabetes for those
taking two NRTIs with an NNRTI as well as individuals who were not receiving
combination antiretroviral therapy. No other relationships between genetic
profile, antiretroviral therapy and diabetes risk were present for African
suggest the NNRTI-based regimen may be preferred for non-African Americans with
genetic predisposition for diabetes mellitus, given that the alternative
regimen of two NRTIs and one or more protease inhibitors substantially
increases the diabetes mellitus risk in those with an underlying genetic
predisposition,” conclude the authors.