Protease inhibitor therapy increases underlying genetic risk of diabetes for women with HIV

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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.

“Carrying known 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.



A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.


A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

heterogeneous or heterogeneity

Diverse in character or content. For example, the ‘heterogeneity’ of clinical trials means that they, and their results, are so diverse that comparisons or firm conclusions are difficult.

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.

They therefore 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 diabetes incidence.

Genetic 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.

The study population consisted of 378 non-African American women and 591 African American women. Forty-nine women in each ethnic group developed type-2 diabetes.  

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.

The IGF2BP2 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:

  • CDKAL1 rs7754840
  • CDKN2A/B rs564398
  • CDKN2A/B rs10811661
  • FTO rs8050136

These findings 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 American women.

“Our results 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.


Frasco MA et al. Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in the Women’s Interagency HIV Study. AIDS 28, online edition. DOI: 10.1097/QAD.0000000000000366, 2014.