We determined the relationship between HIV infection and other risk factors for prevalent diabetes in one of the largest prospective cohorts of HIV infected persons and HIV uninfected controls and founnd that HIV infection per se
was not associated with a higher risk of DM. In fact, the risk of DM at baseline was lower in the HIV infected (OR 0.84, 95% CI 0.72-0.97) compared with HIV uninfected persons. Most of this difference was driven by the differnce in the group with lowest BMI suggesting a role of improving health status leading to a higher risk. This observation is further strengthened by the association of higher CD4+ lymphocyte counts with an increased risk of diabetes. There were many differences in the prevalence of risk factors for DM in the HIV infected and uninfected persons. HIV infected persons were younger and had a lower BMI, which decreases the risk for DM, but were more likely to be racial minorities and had a higher prevalence of HCV, which increases risk. Even after adjusting for these risk factors, HIV was associated with a lower risk of DM. We believe that the net risk of DM is determined by a complex interplay of individual factors, with the traditional risk factors dominating the profile leading to an overall lower risk in HIV infected persons. Lower prevalence and risk in the HIV infected group may also reflect a referral/diagnostic bias, with more people in the general medicine clinics seeking care for evaluation and treatment of DM. Another possibile mechanism is the differential level of immune activation and inflammatory response in HIV infected and uninfected persons. While HIV infected persons may have higher levels of high sensitivity C-reactive protein levels, those with HCV/HIV coinfection have lower levels than uninfected persons.19, 20
How these interact in a given patient to determine the net risk of diabetes require further study.
We found that HCV infection is associated with a higher risk of DM in the HIV infected group, and demonstrated a similar trend in the uninfected group in multivariable analysis (although this trend did not reach statistical significance, the effect size was similar). This confirms the suggestion from some previous studies that HCV affects the risk of DM in a complex manner, and such risk is influenced significantly by other more traditional risk factors.10, 21
In our analysis, the risk conferred by HCV is not altered by the presence of liver damage as measured by elevated alanine and aspartate aminotransferase levels. (data not shown) Whether HCV and HIV act synergistically at a cellular level or through other factors to increase the risk of DM is not known. Insulin resistance and higher levels of inflammatory cytokines are also seen in patients with chronic HCV (but not with HCV/HIV coinfection as referenced in the previous paragraph), and may be one common pathway leading to a higher risk of DM.22-25
We found that use of CART was associated with a significantly higher risk of DM in the HIV infected group. This is essentially a confirmation of multiple previous studies that have demonstrated induction of insulin resistance and a higher risk of DM with the use of CART. The precise role of each class, or each drug in the CART regimens is extremely difficult to determine since such therapy is always used in combination, and often changes in individual subjects. We studied the role of CART in several different ways, including cumulative exposure, current exposure and past exposure for each class (as a part of CART) as well as CART itself. The results were generally consistent indicating a higher risk of DM with use of NRTI and NNRTI. However, the association with PI use was not significant in the multivaraible model. Mitochondrial toxicity associated with nucleoside reverse transcriptase inhibitors (e.g. stavudine, zidovudine and didanosine), 26-29
likely plays a role in the risk associated with NRTI class of drugs. Since PIs are almost never used alone, it is possible that the risk being attributed to NRTIs is at least partly due to the use of PIs. It is notable that the mean duration of NRTI use was nearly twice that of PI use, and duration of NNRTI use was significantly less than duration of NRTI or PI use. In addition, it is also possible that patients with higher risk for DM or with existent DM are more likely to be treated with a NNRTI containing regimen instead of a PI containing regimen. The risk of DM due to each class of drugs may be related to a cumulative dose effect, and individual class exposure cannot currently be separated from concurrent use of a second or third class of the CART regimen.
Our finding of a lower risk of DM associated with increasing alcohol use and drug use is intriguing. Increasing quantity/frequency of alcohol use was associated with increasing protection except in HIV infected persons who consumed > 60 drinks per month. Increasing alcohol use is associated with increasing liver damage, and may be expected to increase the risk of diabetes. We conducted separate analyses including liver damage (defined as alanine or aspartate aminotransferase levels > 5 times upper limit of normal) with and without HCV in the models and found no significant association with liver damage. It is also plausible that increased alcohol consumption and drug abuse or dependence may lead to poor nutrition and lower BMI which may indirectly dilute the association with DM. However, we found no significant association between quantity and frequency of alcohol use and BMI. Another possibility is that people with alcohol and drug abuse may not seek medical care and the opportunity to diagnose DM may have been missed. We did find that non-drinkers were older, while moderate to heavy drinkers were more likely to be younger. These data suggest that while some of the decreased association with alcohol is due to the alcohol consuming population being younger, there are other likely mechanisms that modulate this effect.
There are many strengths of our study. This study was conducted in a large, prospective cohort of HV infected persons and appropriate controls. VACS has validated measures of alcohol and drug abuse, as well as well defined algorithms for identifying comorbidities. We use multiple sources of data (surveys, electronic medical records, national data) to ensure as complete and accurate data collection as possible. However, certain limitations should also be noted. Most important, we analyzed prevalent diabetes, not incident diabetes. While we find a negative association between HIV infection and diabetes at baseline, it is entirely possible that incidence rates may be very different. Data on BMI and laboratory data were gathered in the course of routine clinical care. There are few women included in this analysis. Little is known about alcohol consumption patterns among women infected with HIV. Family history of DM is an important risk factor and was not determined in our study. Most of our study subjects were enrolled between 2002-2004. With the approval of newer antiretrovirals and updated recommendations about initial regimens, it is possible that the risk associated with CART may have changes. Finally, it has been argued that the veterans in care are a non-representative sample for the US population in general. However, with the exception of this gender difference, HIV infected veterans are similar to many other HIV infected persons, being more likely to be people of color, having contracted HIV via injection drug use or heterosexual exposure, and to be of lower socioeconomic status.2
According to the National Institutes of Health, the estimated prevalence of diagnosed and undiagnosed DM among people age 20 or older is 11.2% in men and 10.2% in women. (http://diabetes.niddk.nih.gov/DM/PUBS/statistics/
, accessed February 20, 2009) Prevalence of DM is 9.8% among non-Hispanic whites and 14.7% among non-Hispanic blacks. Since only 2.5% of the HIV infecteed and 7.9% of the HIV uninfected subjects in our study were women, readers are cautioned to interpret any gender differences in our study with caution.
In conclusion, we found that HIV itself is not associated with a higher risk of DM. In fact, after adjusting for traditional risk factors, HIV is actually associated with a lower risk. A return to a more healthy state with increasing BMI and CD4+ lymphocyte counts was associated with a higher risk of diabetes. However, the magnitude of association with the traditional risk factors varies between HIV infected and uninfected persons. Further studies are warranted to understand the mechanisms behind our observations.