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ORIGINAL RESEARCH |
From the 1 Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
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ABSTRACT |
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METHODS: Women who were infected with HIV from January 1, 1998, to January 8, 2004, and who had a 1-hour and 3-hour glucola test were identified. Medical records were reviewed to obtain demographic characteristics and obstetric and laboratory data. Drug regimens at the time of glucola testing were determined. Human immunodeficiency virus–infected women were then matched 1:3 to HIV-noninfected gravidas by race, age, and year of delivery.
RESULTS: One hundred seventy-one HIV-infected women had glucola results available. Twelve percent had an abnormal 1-hour glucola result and 3% had an abnormal 3-hour result. This was similar to the HIV-noninfected population. Forty-five percent of the HIV-infected cohort was on a protease inhibitor at the time of glucola testing. Protease inhibitor exposure had no effect on glucola test results. HIV infection itself also did not increase abnormal glucola test results.
CONCLUSION: Glucose intolerance in this obstetric population was not associated with the diagnosis of HIV or with the use of protease inhibitors. Protease inhibitors should continue to be an option for the treatment of HIV in pregnancy.
LEVEL OF EVIDENCE: II-2
We sought to determine if protease inhibitor use was associated with increased glucose intolerance in our population of HIV-infected pregnant women. We hypothesized that protease inhibitors would not alter 1-hour and 3-hour glucola results in HIV-infected women. In addition, non–HIV-infected gravidas were used as controls to contrast glucose screening in these two populations.
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MATERIALS AND METHODS |
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All women enrolled for prenatal care during the study period were routinely tested for gestational diabetes at 24 to 28 weeks, unless they had an indication for immediate testing, or at first prenatal care visit thereafter. Screening for gestational diabetes was performed after ingestion of 50 g of a commercially available glucose solution followed 1 hour later by measurement of serum glucose. A serum glucose of 140 mg/dL or greater was considered abnormal. Women with abnormal 1-hour glucola results received a 3-hour 100-g oral glucose tolerance test after an overnight fast. Results of the 100-g glucose tolerance tests were interpreted according to the National Diabetes Data Group.12 Normal values for fasting and 1, 2, and 3 hours after the 100-g glucola were defined as 105, 190, 165, and 145 mg/dL, respectively. If 2 or more values were at or higher than those cutoffs, then the 3-hour glucola result was considered to be abnormal and the patient was classified as a gestational diabetic.
Using our computerized medical records system, we gathered the 1-hour and 3-hour glucola test results for each HIV-infected pregnant patient who had a first prenatal visit between January 1, 1998, and January 8, 2004. If a patient had multiple eligible deliveries, we only reported the glucola results for the most recent pregnancy. Drug regimens for each patient at the time of glucola testing were determined using the HIV database. The HIV-infected women were matched to HIV-negative gravidas in a ratio of 3 control women to 1 HIV-infected woman. These control women were randomly selected from the general population by matching for age, race, and year of delivery. Body mass index (BMI) was calculated for both cases and controls.
Statistical comparisons were made with 
2 for categorical data and t test for continuous data. A P value of .05 or less was considered statistically significant. Approval for this study was obtained from the Institutional Review Board of the University of Texas at Southwestern Medical School.
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RESULTS |
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Medication usage in the HIV-infected women varied over the study period as protease inhibitors became more widely used. Seventy-seven (45%) of the women were on a regimen containing protease inhibitors during their pregnancy. Sixty-five women (38%) were on zidovudine with or without 3TC, 24 (14%) received no therapy, and 5 (3%) were on another nonnucleoside reverse transcriptase inhibitor combined with a nucleoside reverse transcriptase inhibitor. Because protease inhibitors have been associated with glucose intolerance, the women exposed to protease inhibitors were compared with those receiving another regimen or no medication.
A comparison of the demographic and pregnancy characteristics of the protease-inhibitor–exposed women and the nonexposed HIV-infected women is found in Table 1. More women not exposed to protease inhibitors were nulliparous when compared with women exposed to protease inhibitors (27% versus 12%, P = .025). Nonexposed women also had a greater mean estimated gestational age at first visit (14.9 ± 8.6 versus 11.8 ± 6.4, P = .004). Age and race were not different between populations, and BMI did not differ in the two groups.
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Table 1 also details the social and HIV-related data of the two groups. Protease-inhibitor–exposed women were more likely to have a prepregnancy diagnosis of HIV (74% versus 47%, P < .001), whereas there were no significant differences between groups in regard to an acquired immunodeficiency syndrome diagnosis or use of tobacco products, alcohol, or intravenous drugs.
Twenty-one women (12%) in the HIV-infected cohort had an abnormal 1-hour glucola screen result. Of these, 8 women were exposed to protease inhibitors. There was no significant increase in abnormal 1-hour glucola screen results with protease inhibitor exposure (12% versus 16%, P = .65). Five women (3%) in the HIV-infected cohort had an abnormal 3-hour screen result. Of these, 4 women were exposed to protease inhibitors, which was not significant (P = .26). Protease inhibitor exposure was not associated with an increased risk of pregnancy-associated hyperglycemia.
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DISCUSSION |
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The relationship between protease inhibitors and impaired glucose tolerance has not been well-defined. Reports of diabetes and hyperglycemia in HIV patients receiving protease inhibitors first appeared in 1997, shortly after they were introduced onto the market (Visnegarwala et al [letter]; Eastone et al [letter]). Since then, studies have continued to document a possible relationship between protease inhibitors and insulin resistance, particularly in conjunction with impaired lipid metabolism, hyperlipidemia, and peripheral lipodystrophy. One study evaluating possible mechanisms for the deterioration of glucose tolerance with protease inhibitors found that it may occur in two ways: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue, and 2) impairment of the ability of the ß-cell to compensate.17
Newer evidence suggests that HIV infection itself and perhaps nucleoside reverse transcriptase inhibitor therapy play a role in the development of insulin resistance, independent of the effect of protease inhibitors. HIV and nucleoside reverse transcriptase inhibitors may be associated with lipodystrophy manifested as truncal obesity and peripheral fat loss, respectively. However, it is unclear whether or not this lipodystrophy contributes to insulin resistance.6
The effect of protease inhibitors on glucose tolerance during pregnancy is controversial. Until 2004 there were only 2 small studies with opposing results. One study retrospectively compared the impact of highly active antiretroviral therapy with protease inhibitors on 41 HIV-infected pregnant patients with 23 HIV-infected pregnant patients receiving only zidovudine. It concluded that highly active antiretroviral therapy and protease inhibitor therapy was associated with an increased rate of impaired glucose tolerance in pregnancy and impaired fetal growth.18 The other study prospectively evaluated 41 HIV-infected pregnant women, 14 of whom were taking protease inhibitors and 27 of whom were not. They found that the use of protease inhibitors did not significantly increase the risk of an elevated glucola result, nor was the mean glucola result increased in the women taking protease inhibitors.19
In the last 2 years, the results from 2 large multicenter trials have been published.20,21 Both address gestational diabetes in relation to antiviral therapy; specifically type and duration of antiretroviral therapy use. The Pediatric AIDS Clinical Trial Group (PACTG) 316 trial results reported an association between protease inhibitor use and gestational diabetes, specifically with long-term antiviral use.20 However, the Women and Infants Transmission Study, reported in 2005, did not find an association between protease inhibitor use and gestational diabetes.21 However, the length of protease inhibitor exposure before pregnancy was not collected in this study. The varying findings in the above four studies may also be explained by differences in patient population and methods of diagnosis of gestational diabetes along with BMI differences which were not analyzed. The strength of this study is that it is a single-center study with a stable population, BMI data available, and a uniform method of diabetes detection.
This study has a number of limitations that should be mentioned. First of all, we did not have results for all HIV-infected patients; perhaps those who declined GTT or presented too late would have been more likely to have elevated results. Secondly, we did not look at period of protease inhibitor exposure. It is possible that those with elevated results had been exposed for shorter or longer periods. In addition, we did not look at neonatal outcomes; we do not know what impact protease inhibitor use in our population had on neonatal hypoglycemia or fetal growth. We did not look at the effect of individual protease inhibitors on the glucola test results, although the majority of women exposed to protease inhibitors were treated with Nelfinavir. Finally, the numbers are limited because this is a single center. To show a halving of the rate of abnormal 1-hour glucola testing, a sample size of 199 in each arm would be required for an 80% power.
Our current study of 171 women validates the conclusion that protease inhibitor use does not significantly impair glucose tolerance during pregnancy in our HIV-infected patients. Although protease inhibitors probably do affect glucose intolerance to a degree over time, clinically significant glucose intolerance in pregnancy, determined by abnormal glucola test results, was not substantiated in this study. The continuation of protease inhibitors or the addition of protease inhibitors as a part of combination therapy during pregnancy should be considered in this light, and current treatment recommendations for both the treatment of maternal HIV infection and prevention of perinatal transmission should be followed.
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Footnotes |
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doi:10.1097/01.AOG.0000207657.94360.78
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REFERENCES |
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2. Lumpkin MM. Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of HIV. Rockville (MD): FDA Public Health Advisory; 1997.
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17. Woerle JH, Mariuz PR, Meyer C, Reichman RC, Popa EM, Doston JM, et al. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 2003;52:918–25.
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21. Tuomala RE, Watts DH, Li D, Vajaranant M, Pitt J, Hammill H, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr 2005;38:449–73.[Medline]
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