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Diabetes risk, screening, and monitoring in people with HIV.

An interview with Todd T. Brown, MD, PhD

Associate Professor of Medicine and Epidemiology Division of Endocrinology, Diabetes & Metabolism Johns Hopkins University Baltimore, Maryland

Is HIV a diabetes risk factor?

Mascolini: Many HIV populations have high frequencies of classic diabetes risk factors, but is HIV itself a risk factor?

Brown: This is a controversial question: different cohorts have different results. Some cohorts like the MACS found a clear increase in the prevalence and incidence of diabetes in HIV-infected people compared with uninfected controls. (1) This has also been seen in the Women's Interagency HIV Study (WIHS) (2) and in several other cohorts. But other cohorts such as the Veterans Aging Cohort Study (VACS) have seen quite the opposite--that HIV-infected patients in the VA system have a lower incidence of diabetes than veterans without HIV. (3) So I think the impact of HIV on diabetes risk is probably population-dependent.

What we're seeing with HIV and diabetes is similar to what we see for other comorbidities: HIV disease itself may have some impact, antiretroviral therapy may have an impact, and traditional risk factors for the comorbidity are also critically important. We can look at each of those factors in turn.

For HIV disease itself, we know that HIV is associated with chronic inflammation. Even patients who have undetectable viral loads have residual inflammation that's thought to lead to comorbidities, and diabetes is one of them. We showed in the AIDS Clinical Trials Group that TNF receptor levels 48 weeks after antiretroviral initiation, when people had a suppressed viral load, were associated with incident diabetes. (4) From that perspective, HIV is probably an independent risk factor for diabetes.

The next category is the effect of antiretrovirals. Antiretrovirals have changed quite a bit since the introduction of highly active antiretroviral therapy (HAART): In general the medications have become a lot more metabolically friendly, and this improvement definitely includes effects on glucose metabolism. In the late 1990s, soon after widespread uptake of HAART, research showed that early protease inhibitors (PIs) had a marked effect on glucose metabolism. PIs have gotten better over the course of the past 15-plus years, and currently used PIs have relatively modest effects on glycemia. Thymidine nucleoside analogs, particularly stavudine, were also associated with abnormal glucose metabolism, not only through direct effects, but also indirectly by inducing lipoatrophy, which in turn is associated with insulin resistance and diabetes onset.

Probably the biggest drivers of diabetes in HIV populations are traditional risk factors--mainly increased adiposity and obesity. We're seeing high rates of obesity in HIV populations, just as we are in the general population, and this is the biggest driver of the diabetes epidemic in the United States. The other major factor of course is age. The HIV population is getting older, and age is a major diabetes risk factor.

Other reasons why HIV patients may have an increased risk of diabetes are other infections: Hepatitis C infection is associated with abnormal glucose metabolism, and this may contribute to diabetes in HIV/HCV-coinfected patients. Concomitant medications may also play a role. Steroids have a huge effect on glucose metabolism, and for patients taking medications that interfere

with steroid metabolism--such as ritonavir and cobicistat--this may be a particular problem. Also, some HIV patients take atypical antipsychotics, which can increase diabetes risk by increasing weight and also through an independent effect on glucose metabolism.

The bottom line is that HIV patients can have several diabetes risk factors that HIV-uninfected patients don't have, so they may be at higher risk for diabetes.

Mascolini: What's going on in your own patient population in terms of diabetes incidence? Have you seen any change over the past decade or since the introduction of combination antiretroviral therapy?

Brown: It's a little tricky to tease this apart because we saw overall exponentially increased rates of diabetes in the general population during this time. I think diabetes incidence may have decreased slightly in HIV patients during the HAART era as the medications got better, and a cohort study in France showed this quite nicely. (7) But because as a population we're getting fatter, overall diabetes rates are very high, not only in HIV populations but in the general population. Perhaps the specific impact of antiretroviral therapy on diabetes incidence has decreased over this time, but the overall rates of diabetes have actually increased, probably because of increased adiposity.

Impact of newer antiretrovirals

Mascolini: Older antiretrovirals like d4T and indinavir were linked to glucose abnormalities. Among antiretrovirals often prescribed today, do any pose a risk of dysregulated glucose?

Brown: Glucose metabolism and adiposity generally get worse after antiretroviral initiation. This effect is probably driven by the fat increase many people have after starting antiretroviral therapy. One outstanding question is whether this is a return-to-health phenomenon that is part and parcel of getting better from HIV, or whether it is a maladaptive response and whether the proportion of fat versus lean mass is abnormal in people who start antiretroviral therapy. But I don't think there are big differences between individual current antiretrovirals in terms of their effects on glucose metabolism.

ACTG A5257 was a study of HIV-infected treatment-naive patients initiating either ritonavir-boosted atazanavir, boosted darunavir, or raltegravir with tenofovir/emtricitabine. (8) In the A5260 substudy of A5257, we looked at the effects of these three regimens on glucose metabolism and adiposity, (9) and these results will be detailed at CROI in an oral presentation.

Mascolini: When you talk with primary HIV providers, do they seem to have a good understanding of how current antiretrovirals affect glucose or insulin?

Brown: I think there's an overemphasis on the effects of specific antiretrovirals on glucose metabolism. As we already discussed, some first-generation antiretrovirals had an important effect on glucose metabolism, but the agents used today generally don't. That's not to say there aren't some patients whose blood sugars become quite deranged while they're taking certain current antiretrovirals, probably for genetic reasons. But I think there's an overemphasis in the HIV community on how much currently prescribed antiretrovirals affect glucose metabolism.

Advice on screening HIV patients for diabetes

Mascolini: In your group at Hopkins, what's the protocol for glucose screening and follow-up for a person with newly diagnosed HIV?

Brown: The HIV guidelines in place right now suggest that we should get some measure of glucose metabolism and screen for diabetes at the time of HIV diagnosis, after 3 to 6 months of antiretroviral therapy, and yearly thereafter. These guidelines were written earlier in the HAART era, when we were seeing a large effect of antiretroviral therapy on glucose metabolism. Today this recommendation might be a little bit of overkill. However, the tests to screen for diabetes are relatively benign and relatively low in cost, so it probably does make sense to get these fasting tests when you're getting fasting lipids, for example.

The American Diabetes Association recommends diagnosing diabetes with one of four tests: (1) a fasting glucose, with 126 mg/dL or higher indicating diabetes, (2) a 2-hour 75-g oral glucose tolerance test, with 200 mg/dL or greater considered diabetes, (3) a random glucose with symptoms of diabetes--polyuria and polydipsia--and a diagnostic cutoff of 200 mg/dL or higher, or (4) hemoglobin Alc (HbAlc), which came online in 2010.

Hemoglobin Alc has some advantages over the other tests in that it needs no special preparation--patients don't have to fast before the test or swallow a glucose solution. Also, instead of giving you a one-point-in-time look at glucose, which can bounce around a little bit, it gives you an integrated view over 3 months, which is the life of the red blood cell: The test calculates glucose by measuring its attachment to a hemoglobin moiety in red blood cells. Because of these advantages, hemoglobin A1c is quite attractive.

The caveat is that the hemoglobin Alc may underestimate glycemia in HIV patients. (10) The effect of this underestimation is somewhere between 0.2 to 0.5 hemoglobin A1c percentage points. A hemoglobin A1c of 6.5% in an HIV patient may be equivalent to an HbA1c of about 7.0% in an HIV-uninfected patient. This makes the use of hemoglobin A1c for the diagnosis of diabetes a little bit tricky in HIV-positive patients. It could potentially lead to the underdiagnosis of diabetes in people with HIV. For that reason I generally recommend that we stick to the fasting glucose tests for screening.

The reasons behind this hemoglobin A1c discordance in people with HIV aren't entirely clear. HIV patients may have a low-grade hemolysis that causes increased red blood cell turnover and an artificial lowering of hemoglobin A1c--that is, a disconnect between glycosylation of the hemoglobin molecule and what the actual blood glucose is.

One very strong risk factor for hemoglobin A1c/ glycemia discordance that has been seen in multiple studies, including our work in the MACS, (10) is a high mean corpuscular volume (MCV). The higher the MCV is over 90 or so, the greater the hemoglobin A1c/glycemia discordance. This is useful clinically since MCV is routinely measured on a complete blood count (CBC). In my practice, if I see an MCV in the high 90s or over 100 in an HIV-infected patient, I know not to trust the HbA1c too much. The reasons underlying this association are unclear, but we hypothesize that these larger red cells are taken out of circulation more quickly than normal-size cells.

Mascolini: Does hemoglobin A1c have a role in monitoring patients once they start treatment for high blood glucose?

Brown: I do follow the A1c in HIV patients because it is a critical measure. One of the important developments in the diabetes world over the past few years is the individualization of the hemoglobin A1c goal. We used to shoot for a hemoglobin A1c less than 7.0% in everyone.

Now the recommendation is to take a more individualized approach. For people at potentially higher risk for hypoglycemia or with comorbidities, the recommendation is to relax the hemoglobin A1c target to between 7 and 7.5, and in some cases up to 8. For younger people who don't have comorbidities, you might push them a little bit harder to reach a lower Alc target. For an HIV patient, I take that individualized approach and might push them a little bit harder, knowing that their hemoglobin Alc may be an underestimate of their real glycemia.

Referral and antiretroviral interactions

Mascolini: Are there glucose-related clinical developments in HIV patients that should prompt HIV clinicians to refer those patients to an endocrinologist?

Brown: Referral really depends on how comfortable the provider is in dealing with diabetes. As an endocrinologist, I see patients with the full gamut of severity of diabetes. Some physicians get me involved after a patient has tried one drug, for example, metformin, and they clearly need additional drugs. Other providers will get me involved when two drugs have failed. Others will call me in when a patient has diabetes complications that make overall care complicated. Others will get me involved when the consideration of insulin is on the table.

So it depends on the provider's comfort level and infrastructure in dealing with diabetes. It is a resource-intensive disease, and oftentimes endocrinologists might be better equipped in terms of having certified diabetes educators and nutritionists available to help care for these patients.

Mascolini: Are there any other clinical issues related to HIV and diabetes that you'd like to bring to the attention of HIV clinicians?

Brown: One important issue with all comorbidities is the potential interaction between antiretrovirals and drugs used to treat the comorbidities. In the diabetes world we've been fortunate in that many of the drugs used to treat diabetes can be used without a problem in HIV-infected patients regardless of what antiretrovirals they're taking.

There are a few notable exceptions. Some of the new DPP-4 inhibitors--the gliptin class of hypoglycemics--can interact with antiretrovirals. Saxagliptin, for example, is a substrate for CYP3A4, so it should probably be avoided in HIV-infected patients taking a CYP3A4 inhibitor like ritonavir or cobicistat. (5)

The other interaction that can affect many HIV patients with diabetes is the interaction between metformin and the integrase inhibitor dolutegravir. (6) Depending on the dose of dolutegravir, metformin concentrations can increase by 50% to 100%. So I generally go with metformin dose reductions in those patients. That's an important interaction that clinicians should know as more and more patients start integrase inhibitor-based regimens.

Tips from this interview on diabetes management in people with HIV

* The impact of HIV itself on diabetes risk remains controversial, but there is no question that HIV populations carry a heavy burden of traditional diabetes risk factors.

* The hemoglobin A1c test underestimates blood glucose in people with HIV. A hemoglobin A1c of 6.5% in an HIV patient may be equivalent to 7.0% in an HIV-uninfected patient, so this test should probably not be used to screen for diabetes in people with HIV.

* Hemoglobin A1c targets for diabetes treatment should probably be individualized, with more stringent targets (6.0% to 6.5%) for younger people without comorbidities, and looser targets (7.0% to 8.0%) for older people with comorbidities and thus a higher risk of hypoglycemia.

* High mean corpuscular volume (MCV) is a strong predictor of hemoglobin A1c/glycemia discordance. If I see an MCV in the high 90s or over 100 in an HIV-infected patient,

I know not to trust the HbA1c too much.

* The dose of saxagliptin, an oral hypoglycemic agent, may need to be lowered to 2.5 mg when given with a potent CYP3A4 inhibitor. (5)

* The HIV integrase inhibitor dolutegravir increases metformin plasma exposure and may necessitate downward dose adjustment of metformin. (6)

* Whether an HIV patient with diabetes should be referred to an endocrinologist depends on the provider's comfort level in managing diabetes. Bear in mind that specialists have an array of resources that can improve diabetes management, like certified diabetes educators and nutritionists.

Making diet and exercise part of the glucose-control plan


Diagnosing and Managing Diabetes in HIV-Infected Patients: Current Concepts

Anne K. Monroe. [1] Marshall J. Glesby, [2] and Todd T. Brown [2]

A recently published review by Todd Brown and colleagues offers guidance on integrating diet and exercise into a glucose-control plan for people with HIV:

* "Referral to a registered dietician for medical nutrition therapy is recommended for all patients with diabetes mellitus, as even modest weight loss (as little as 2 kg) can have an impact on glycemic control.

* "Calorie guidelines for weight loss are (1) 1200-1500 calories/day for women or 1500-1800 calories/day for men; (2) an energy deficit of 500 or 750 calories per day, based on the individual; or (3) an evidence-based diet that restricts a certain food type (eg, high-carbohydrate foods) to create an energy deficit.

* "Dietary recommendations for patients with DM include monitoring carbohydrate intake, limiting consumption of sugar-sweetened beverages, and following a Mediterranean-style diet.

* "A patient-friendly diet guide is available at (

* "Aerobic exercise is recommended for at least 150 minutes a week, spread out over at least 3 days per week, along with strength training twice a week.

* "An exercise partner, use of a pedometer with a target (eg, 10 000 steps/day), or individualized counseling with exercise prescription" may encourage people to exercise.

* "Linking patients with community- or workplace-based programs may increase exercise uptake."

The article also analyzes the impact of antiretrovirals and statins on diabetes risk, individualized management of diabetes, drug therapy for diabetes, comprehensive cardiovascular risk reduction, and other issues.

Monroe AK, Glesby MJ, Brown TT. Diagnosing and managing diabetes in HIV-infected patients: current concepts. Clin Infect Dis. 2015; 60:453-462.


(1.) Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the Multicenter AIDS Cohort Study. Arch Intern Med. 2005; 165:1179-1184.

(2.) Justman JE, Benning L, Danoff A, et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr. 2003; 32:298-302.

(3.) Butt AA, McGinnis K, Rodriguez-Barradas MC, et al. HIV infection and the risk of diabetes mellitus. AIDS. 2009; 23:1227-1234.

(4.) Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care. 2010; 33:2244-2249.

(5.) Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW. Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin Pharmacol. 2011; 3:13-25.

(6.) Zong J, Borland J, Jerva F, Wynne B, Choukour M, Song I. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc. 2014; 17(4 Suppl 3):19584.

(7.) Capeau J, Bouteloup V, Katlama C, et al. Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment. AIDS. 2012; 26:303-314.

(8.) Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014; 161:461-471.

(9.) Impact of antiretroviral therapy on metabolic, skeletal, and cardiovascular parameters. NCT00851799.

(10.) Slama L, Palella FJ Jr, Abraham AG, et al. Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters. J Antimicrob Chemother. 2014; 69:3360-3367.
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Title Annotation:Perspectives
Author:Mascolini, Mark
Publication:Research Initiative/Treatment Action!
Article Type:Clinical report
Geographic Code:1USA
Date:Jan 1, 2015
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