Standards of Care and Standards of Screening for High Glucose With HIV

How often do U.S. clinicians meet American Diabetes Association (ADA) treatment goals in HIV-positive people with diabetes? At two big urban HIV centers in Chicago¹ and New York,² HIV providers hit glycemic goals in one half to three quarters of patients -- depending on the hemoglobin A1c (HbA1c) target -- close to rates reported in the general population (Table 1).

But only about half of diabetic HIV patients in these cohorts met ADA blood pressure goals, and only one third nailed triglyceride targets. Clinicians at both sites admitted they may have overestimated proportions of on-target patients because they eliminated people with fewer visits or hemoglobin A1c measurements. And neither survey looked at how rigorously clinicians screen HIV patients for high glucose, insulin resistance, or diabetes -- or how well they manage prediabetes.

Keen attention to glucose abnormalities and their control in people with HIV assumes growing importance as these complications loom larger in HIV populations. From the mid-1990s to the mid-2000s, U.S. hospital admissions for diabetes rose 2.2-fold in people with HIV compared with 1.4-fold in HIV-negative people.³ Although studies disagree on whether HIV infection independently boosts chances of diabetes, this chronic disease clearly adds to myocardial infarction risk in people with HIV⁴˒⁵ and can cause or contribute to kidney disease, liver disease, stroke, cognitive decline, and other HIV-linked maladies.

Meeting Metabolic Treatment Targets (or Not)

The retrospective diabetes-control studies took place at Chicago's CORE Center¹ and New York's Weill Cornell Medical College,² where HIV clinics care for thousands of patients yearly in a uniform, multidisciplinary manner and staffs have logged countless hours of experience caring for people with HIV. High proportions of HIV/diabetes patients at both centers were black or Hispanic, average age topped 50 years, and mean body mass index verged on the obesity threshold (Table 1). All study participants were adults with diabetes established by standard measures. Almost all took antiretrovirals and most had an undetectable viral load (Table 1).

Both research teams calculated proportions of HIV diabetes patients who met two 2008 ADA goals for HbA1c -- below 7% or below 8%. (Current ADA guidelines suggest HbA1c goals ranging from below 6.5% to below 8%, depending on patient traits and risk of diabetes treatment side effects.⁶ Normal HbA1c lies below 5.7%.⁷)

For the general population, HbA1c is the main test used to manage and study diabetes.⁷ It measures attachment of glucose to hemoglobin in red blood cells. Because red cells live about 3 months, HbA1c determines a person's average blood glucose over the past few weeks to 3 months -- an advantage over the glucose snapshot with fasting glucose assays. Whether a person has fasted for 24 hours or just gobbled six glazed donuts has no impact on HbA1c-measured glucose, whereas a straight measure of glucose in blood requires fasting. Studies reviewed below indicate that HbA1c underestimates blood glucose in people with HIV. (See "Screening for high glucose" below for HbA1c use in people with HIV.) U.S. experts are divided on using HbA1c as a way to test HIV patients for diabetes.⁸⁻¹⁰

Proportions of HIV-positive diabetes patients who reached HbA1c targets proved similar in the two studies -- 54% in Chicago¹ and 57% in New York² below 7%; 72% in Chicago and 78% in New York under 8% (Table 1). Chicago did better in getting diabetes patients to hit a blood pressure goal below 130/80 mm Hg -- 56% versus 42% in New York. Chicago also had a much higher proportion of patients on target for HDL cholesterol (51% versus 32%), while both clinics struggled to guide patients toward a triglyceride tally below 150 mg/dL (39% and 31%). The New York group noted that only 47% of their patients had eye exams for retinopathy, and only 19% got screened for microalbuminuria.

Both research teams observed that HbA1c goal attainment in their HIV patients with diabetes mirrors or exceeds findings in the general population.¹˒² Both teams also suggested their results may exceed those in broader U.S. HIV populations because they included only people with two or more clinic visits in 1 year (and thus possibly represented a more engaged population) and because both centers provide multidisciplinary teams with deep HIV experience.

Regardless of such variables, reaching a treatment goal in about half of patients might well be deemed failure. It is, for example, when the endpoint is proportion of patients with an undetectable HIV load. The Chicago and New York clinicians offer colleagues several suggestions for improving diabetes care in people with HIV (Table 2).

Managing Prediabetes and Diabetes in People With HIV

ADA experts outline treatment of high glucose in the general population,⁶ and those regularly updated guidelines form the basis for HIV-specific advice from the Health Resources and Services Administration (HRSA).⁸ As with treatment of other comorbidities in people with HIV, treatment of diabetes can be complicated by the retrovirus, by certain antiretrovirals, and by conditions frequently seen in HIV populations.

The goal of diabetes therapy in HIV-positive people, HRSA advises,⁸ is to keep HbA1c below 7% while avoiding hypoglycemia. Hypoglycemia is more common with insulin therapy than with most oral antidiabetics, HRSA says.

In a recent review of diabetes and HIV, Anne Monroe and Todd Brown from Johns Hopkins University and Marshall Glesby from Weill Cornell Medical College offered some pointers on setting treatment targets with HbA1c, suggesting that the goal "may need to be more stringent" in people with HIV than in the general population because HbA1c underestimate glucose levels in HIV populations (see next section).¹⁰ Reaching glycemic targets may reduce vascular complications of diabetes, research indicates, but "more intensive glucose control" has its downside -- a higher risk of severe hypoglycemia and death. The Hopkins-Cornell team suggested "tighter control (HbA1c 6.0% to 6.5%) is more appropriate for younger, healthier patients, whereas looser control (HbA1c 7.5% to 8.0%) may be more appropriate for older patients with multiple comorbidities who are prone to hypoglycemia."¹⁰

HRSA guidelines say metformin remains the drug of choice for high glucose in overweight people, but prescribers should avoid it in people with lipoatrophy, which metformin can worsen.⁸ Some sulfonylureas should be avoided in people with creatinine clearance below 50 mL/min, and thiazolidinediones (the glitazones) should not be given to people with "significant liver disease." Studies disagree on whether rosiglitazone boosts myocardial infarction risk. But both rosiglitazone and pioglitazone have been linked to congestive heart failure (CHF) and should not be used in people with CHF.⁸

HRSA guidelines add this advice for managing HIV-positive people with high glucose:

• Treat abnormal lipids and hypertension.

• Cut cardiovascular risk through lifestyle modification (exercise, weight loss, smoking cessation, moderate alcohol intake).

• Measure urine microalbumin and creatinine.

• Schedule a yearly retinal exam.

• Perform an annual foot exam.

• Start 75 to 162 mg of aspirin daily in people with macrovascular disease or a history of vascular events.

• Consider daily aspirin for people with higher coronary heart disease risk.

Can aggressive management of diabetes and its comorbidities prolong life? Yes, indeed, according to a 13-year randomized trial of 160 people in Denmark with type 2 diabetes and persistent microalbuminuria.¹¹ Steno-2 Study investigators randomized them to standard care or to "intensified, target-driven therapy" including behavior modification, antiplatelet therapy, blood pressure management, cholesterol management, and diabetes/glucose management. After an average 7.8 years of treatment and 5.5 years of further observation, people in the intensive-care arm had almost a 50% lower risk of death, a 60% lower risk of cardiovascular death, and a 60% lower risk of cardiovascular events. The intensive regimen had few major side effects.

Monroe, Glesby, and Brown offer a concise review of diabetes treatment, covering initial management, switching antiretroviral regimens, diet, exercise, metformin, second-line treatments, sulfonylureas, thiazolidinediones (glitazones), insulin, incretins, and other agents.¹⁰

Screening for High Glucose: Where Does HbA1c Fit In?

Given the high morbidity and mortality of diabetes mellitus -- and difficulties reaching glucose targets in people with HIV (Table 1) -- spotting poorly controlled blood sugar early has become a keystone of HIV care. HIV Medicine Association (HIVMA) experts recommend screening everyone with HIV every 6 to 12 months by measuring fasting blood glucose and/or HbA1c.⁹ They advise screening before antiretroviral therapy begins and 1 to 3 months after starting or changing regimens. Fasting blood glucose between 100 and 125 mg/dL indicates prediabetes, and anything higher signals diabetes (Figure 1). An HbA1c below 5.7% is normal, 5.7% to 6.5% means prediabetes, and anything higher indicates diabetes.

An oral glucose tolerance test (OGTT) may also be used to screen for glucose abnormalities (normal less than 140 mg/dL, prediabetes 140 to 199 mg/dL, diabetes 200 mg/dL or higher).⁸ A random glucose at or above 200 mg/dL in people with symptoms of hyperglycemia (thirst and frequent urination) also indicates diabetes.⁸ HRSA guidelines note that the role of the OGTT in HIV-positive people is "uncertain," but it may be appropriate for people with multiple risk factors.⁸ In the general population OGTT is, however, the preferred test for pregnant women, the ADA says.⁶ Patients must eat normally in the 3 days before an OGTT and fast 8 hours before the test, which takes up to 3 hours.

ADA guidelines counsel that any test indicating diabetes should be repeated to rule out laboratory error, "unless the diagnosis is clear on clinical grounds," such as classic symptoms of hyperglycemia or hyperglycemic crisis.¹³ When two of these three tests (fasting glucose, HbA1c, or OGTT) disagree, repeat the test with a result above the diagnostic cut point and make the diagnosis based on the confirmatory test.

For HIV-positive people diagnosed with diabetes, HRSA recommends HbA1c monitoring every 3 months in people with an elevated value and every 3 to 6 months in those "with stable and adequate glucose control"⁸ (Table 3). The goal should be a value below 7%. But using and interpreting HbA1c to screen for diabetes in HIV patients is more problematic, and guideline advice is inconsistent. HIVMA says HbA1c (or fasting glucose) "may be used to screen for glucose intolerance and diabetes" in people with HIV,⁹ while HRSA cautions that the test remains unvalidated for screening in HIV-positive people⁸ and Monroe, Glesby, and Brown advise against using HbA1c to screen for diabetes.¹⁰

Comparison of HbA1c and fasting glucose in HIV-positive and HIV-negative at-risk men in the Multicenter AIDS Cohort Study (MACS) found that HbA1c underestimates blood glucose in men with HIV.¹⁴ The analysis involved 1357 HIV-positive men and 1500 HIV-negative men seen at a median of 11 visits over 13 years. The MACS team used the relationship between HbA1c and fasting glucose in HIV-negative men to determine expected HbA1c in HIV-positive men.

When blood glucose stood at 125 mg/dL, HbA1c values lay a median 0.21% lower in men with versus without HIV.¹⁴ This difference widened at higher glucose levels. Nearly two thirds of the HIV group (63%) had at least one visit with clinically significant HbA1c discordance (defined as an observed/expected HbA1c at or below -0.5%). The investigators found that discordance was independently associated with four variables:

1. CD4 count below 500 cells/mm³

2. Use of a protease inhibitor, a nonnucleoside, or zidovudine

3. High mean corpuscular volume

4. Abnormal corpuscular hemoglobin

Other research indicates that use of abacavir boosts chances of HbA1c inaccuracy.¹⁵

Summarizing this largest comparison of HbA1c in people with and without HIV, the MACS researchers concluded that "HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to underdiagnosis and to under-treatment of established diabetes mellitus."¹⁴

Four previous studies in more than 500 men and women with HIV also found that HbA1c underestimates blood glucose.¹⁵⁻¹⁸ Women's Interagency HIV Study (WIHS) investigators have observed that, besides high mean corpuscular volume and anemia, factors that can contribute to HbA1c inaccuracy are chronic alcoholism and acute blood loss.¹⁹ On the other hand, they noted, African Americans have higher HbA1c values than whites with similar glucose concentrations.²⁰ At the same time, the WIHS team found that using fasting blood glucose plus HbA1c to screen for diabetes enhances diagnostic accuracy compared with fasting blood glucose alone in an analysis of 150 HIV-positive women and 550 HIV-negative women.¹⁹

Clinical investigators at a large New York City hospital calculated the sensitivity and specificity of HbA1c in identifying new diabetes in 395 antiretroviral-treated people with HIV.²¹ (Sensitivity is the ability of a test to identify people who have a disease; specificity is the ability of that test to classify people who do not have the disease as negative.) A fasting blood glucose at or above 126 mg/dL determined that 22 people had newly diagnosed diabetes. At a cutoff of 6.5%, HbA1c had a sensitivity of only 40.9% but a specificity of 97.5% in identifying fasting glucose-determined incident diabetes. When the researchers set the HbA1c cutoff at 5.8% (indicating prediabetes), sensitivity improved to 88.8% while specificity dropped to 77.5%. This finding encouraged the HIVMA to suggest using a 5.8% threshold for people with HIV.⁹

Studying 352 adults with or at risk for HIV infection in the Bronx, New York, researchers found that fasting blood glucose alone identified 52% of people with new hyperglycemia (prediabetes or diabetes determined by two fasting measures a median of 18.6 months apart).²² OGTT alone identified 33% of cases of new hyperglycemia, while fasting blood glucose plus OGTT identified 15%. In other words, relying solely on fasting blood glucose to screen for hyperglycemia misses one third of new cases in a group with or at risk of HIV. The HIV-positive and negative groups in this study both had a median age of 50.

What should HIV clinicians make of these knotty glucose monitoring findings? Colleen Hadigan and Sarah Kattakuzhy, HIV metabolic experts at the National Institutes of Health, suggest that, "for practical purposes, most investigators conclude that fasting blood glucose and HbA1c are the diagnostic tests of choice, and that there is not enough evidence in the HIV population to recommend for or against either strategy."²³

In contrast, HIV/diabetes mavens Anne Monroe, Marshall Glesby, and Todd Brown flatly say "we do not recommend using HbA1c for screening."¹⁰ They recommend fasting plasma glucose or the oral glucose tolerance test to diagnose diabetes in people with a shortened red-cell lifespan, such as pregnant women or people with hemolytic anemia. Monroe and colleagues add that discordant HbA1c results are more likely in people with a lower CD4 count, those taking nucleosides (especially abacavir), and those with higher mean corpuscular volume.

Because mean corpuscular volume predicted discordance between HbA1c and blood glucose, the MACS investigators believe clinicians should be "particularly cautious" in using HbA1c to diagnose or manage diabetes in people with a mean corpuscular volume at or above 95 fL.¹⁴ In such people, they found, odds of discordant HbA1c readings were 4- to 15-fold higher than in people with mean corpuscular volume below 95 fL. They also suggested that using complete blood counts to identify people with mean corpuscular hemoglobin above 31 pg "might serve as an alert that HbA1c levels need to be interpreted with caution."¹⁴

In the four HIV subgroups with high risk of HbA1c/blood glucose discordance (numbered list above), the MACS team suggested using direct measures of glycemia -- fasting blood glucose or OGTT -- to diagnose diabetes and, for people with diabetes, "to consider a lower HbA1c level treatment target in order to prevent long-term diabetes complications."¹⁴

References

1. Adeyemi O, Vibhakar S, Max B. Are we meeting the American Diabetes Association goals for HIV-infected patients with diabetes mellitus? Clin Infect Dis. 2009;49:799-802.

2. Satlin MJ, Hoover DR, Glesby MJ. Glycemic control in HIV-infected patients with diabetes mellitus and rates of meeting American Diabetes Association management guidelines. AIDS Patient Care STDS. 2011;25:5-12.

3. Kourtis AP, Bansil P, Kahn HS, Posner SF, Jamieson DJ. Diabetes trends in hospitalized HIV-infected persons in the United States, 1994-2004. Curr HIV Res. 2009;7:481-486.

4. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356: 1723-1735.

5. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with HIV disease. J Clin Endocrinol Metab. 2007;92:2506-2512.

6. American Diabetes Association. Executive Summary: Standards of medical care in diabetes -- 2014.

7. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The A1C test and diabetes.

8. U.S. Department of Health and Human Services Health Resources and Services Administration. Guide for HIV/AIDS clinical care. April 2014.

9. Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:e1-e34.

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

11. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591.

12. American Diabetes Association. Diagnosing diabetes and learning about prediabetes.

13. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; 37(Suppl1):S81-S90.

14. 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.

15. Kim PS, Woods C, Georgoff P, et al. A1C underestimates glycemia in HIV infection. Diabetes Care. 2009;32:1591-1593.

16. Diop ME, Bastard JP, Meunier N, et al. Inappropriately low glycated hemoglobin values and hemolysis in HIV-infected patients. AIDS Res Hum Retroviruses. 2006;22:1242-1247.

17. Glesby MJ, Hoover DR, Shi Q, et al. Glycated haemoglobin in diabetic women with and without HIV infection: data from the Women's Interagency HIV Study. Antivir Ther. 2010;15:571-577.

18. Polgreen PM, Putz D, Stapleton JT. Inaccurate glycosylated hemoglobin A1C measurements in human immunodeficiency virus-positive patients with diabetes mellitus. Clin Infect Dis. 2003;37:e53-e56.

19. Tien PC, Schneider MF, Cox C, et al. Association of HIV infection with incident diabetes mellitus: impact of using hemoglobin A1C as a criterion for diabetes. J Acquir Immune Defic Syndr. 2012;61:334-340.

20. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann Intern Med. 2010;152:770-777.

21. Eckhardt BJ, Holzman RS, Kwan CK, Baghdadi J, Aberg JA. Glycated hemoglobin A(1c) as screening for diabetes mellitus in HIVinfected individuals. AIDS Patient Care STDS. 2012;26:197-201.

22. Polsky S, Floris-Moore M, Schoenbaum EE, et al. Incident hyperglycaemia among older adults with or at-risk for HIV infection. Antivir Ther. 2011;16:181-188.

23. Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism in the setting of human immunodeficiency virus. Endocrinol Metab Clin North Am. 2014;43:685-696.