Diabetes in people with HIV over 50 linked to old ARVs

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People with HIV over the age of 50 are more likely to have developed type 2 diabetes if they started antiretroviral treatment before 1999 or had a longer exposure to older antiretroviral drugs such as stavudine (d4T) or first-generation protease inhibitors such as nelfinavir or indinavir, according to a study of people receiving HIV care in British Columbia, Canada.

The onset of diabetes was much less likely in people aged 50 and over who started treatment from 2010 onwards, or who started treatment at a higher CD4 cell count, according to the study led by Silvia A Guillemi at the department of family practice, faculty of medicine, University of British Columbia, Vancouver, British Columbia, and the Clinical Education and Training Programme, British Columbia Centre for Excellence in HIV/AIDS.

The findings are likely to provide reassurance that modern HIV treatment carries little risk of promoting the development of diabetes in people with HIV.

Diabetes mellitus, or type 2 diabetes, develops as a consequence of failures in the body’s ability to handle glucose. Production of insulin, the hormone which regulates glucose levels, may decline or cells may stop responding to insulin. When this happens glucose stays in the blood and is not taken up by cells for use as fuel. Over time, a high level of glucose in the blood leads to damage to small blood vessels, causing kidney damage, cardiovascular disease, lower limb damage and loss of sight.

Type 2 diabetes is more common in people who are obese and becomes more common with age. People with HIV are more likely to be diagnosed with type 2 diabetes but it is unclear to what extent HIV-related factors lead to a higher incidence of diabetes in people with HIV.

To investigate this question researchers at the St Paul’s Hospital, Vancouver, the University of British Columbia and the British Columbia Centre for Excellence in HIV/AIDS analysed the incidence of type 2 diabetes in people living with HIV who started treatment at St Paul’s Hospital up until July 31 2015. The cohort was predominantly male (89%) and white (83%) with a high prevalence of hepatitis C co-infection (43%) and Aids-defining illness during the follow-up period (31%).

Patients were classified as having developed type 2 diabetes if at any time they had a blood sugar measurement above 11.1 mmol/L, or HbA1C > 6.5%, or had been prescribed antidiabetic medication or been recorded as diagnosed with diabetes.
Out of 1065 people who were aged 50 or over in July 2015, 235 people developed diabetes during an average of 13 years of follow-up. This represents an incidence rate of 1.61 new cases per 100 person-years of follow-up, 39% higher than the observed rate in the Canadian general population.

The study found no significant difference in the risk of developing diabetes by age at HIV diagnosis or age at treatment initiation, nor was developing diabetes associated with having hepatitis C virus antibodies or with injecting drug use. Sex, weight, or latest body mass index were not associated with the risk of developing diabetes.

In a further analysis restricted to people who had pre-treatment viral load measurements available (N = 1065), the development of diabetes was associated with several HIV-related factors including lower CD4 cell nadir, lower CD4 cell count at antiretroviral therapy (ART) initiation and ART initiation in the period 1997-2004. People who started treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were less likely to develop diabetes (p = 0.003).

After controlling for other factors in a multivariable analysis, people who started treatment in the period 1997-2004 were almost 50 times more likely to develop diabetes compared to people who started treatment between 2005 and 2009 (adjusted odds ratio 48.9, 95% confidence interval 21.32-112.17).

In univariate analysis the duration of treatment with each of stavudine (d4T), zidovudine (AZT), lopinavir, indinavir and nelfinavir was associated with an increased risk of developing diabetes. In the case of stavudine, each 10% increase in time on the drug was associated with 39% increase in the risk of diabetes (OR 1.39, 1.27-1.53) while for nelfinavir, the risk increased by 63% for each 10% increase in time on the drug (OR 1.63, 1.19-2.24).

On average, people who developed diabetes spent 21% of their time on treatment taking a regimen that contained stavudine, whereas those who did not develop diabetes were exposed to the drug for 7% of the time they had taken antiretroviral treatment (p < 0.001). There were similarly pronounced differences in the duration of drug exposure between those who developed diabetes and those who did not develop diabetes for the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine and zidovudine, and for the protease inhibitors indinavir, nelfinavir and lopinavir. People who developed diabetes had significantly less exposure to the newer antiretrovirals tenofovir, atazanavir and darunavir compared to those who did not, reinforcing the authors’ conclusion that diabetes in people with HIV is chiefly a consequence of first-generation antiretroviral treatment.

The effect of some protease inhibitors and NRTIs on the development of insulin resistance is well-established, say the authors, who report that the incidence of diabetes began to drop sharply after 2000, with only two diagnoses of diabetes in the entire clinic population between 2010 and 2015. This change coincides with the replacement of indinavir, nelfinavir and stavudine by NNRTIs and by the nucleotide analogue tenofovir in first-line antiretroviral treatment.

The authors say that it is important to monitor for type 2 diabetes in people with HIV, but stress that “the incidence of diabetes mellitus is likely to decline in PLWH (people living with HIV) who initiated ART more recently with the use of newer ART agents.”

Abstract
Objective: We sought to determine the incidence and factors associated with development of diabetes mellitus (DM) in older HIV-infected individuals.
Research design and methods: We analyzed data from people living with HIV (PLWH) ≥50 years of age enrolled in a large urban HIV outpatient clinic in Vancouver, British Columbia. Patients were categorized as having DM if they had random blood sugar ≥11.1 mmol/L, fasting blood sugar ≥7 mmol/L, HbA1C ≥6.5%, antidiabetic medication use during the follow-up period, or medical chart review confirming diagnosis of DM. We estimated the probability of developing DM, adjusting for demographic and clinical factors, using a logistic regression model.
Results: Among 1065 PLWH followed for a median of 13 years (25th and 75th percentile (Q1–Q3): 9-18), the incidence of DM was 1.61/100 person-years follow-up. In the analysis of factors associated with new-onset DM (n=703), 88% were male, 38% had a history of injection drug use, 43% were hepatitis C coinfected, and median body mass index was 24 kg/m2 (Q1–Q3: 21–27). Median age at antiretroviral therapy (ART) initiation was 48 years (Q1–Q3: 43–53) and at DM diagnosis was 55 years (Q1–Q3: 50–61). Patients who started ART in 1997–1999 and had a longer exposure to older ART were at the highest risk of developing DM.
Conclusions: Among PLWH aged ≥50 years, the incidence of DM was 1.39 times higher than men in the general Canadian population of similar age. ART initiated in the early years of the epidemic and exposure to older ART appeared to be the main drivers of the development of DM.

Authors
Faizal Samad, Marianne Harris, Cathy M Puskas, Monica Ye, Jason Chia, Sarah Chacko, Gregory P Bondy, Viviane D Lima, Julio SG Montaner, Silvia A Guillemi

Aidsmap material
BMJ Open Diabetes Research & Care abstract


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