Todd T. Brown

Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review

Introduction:Prevalence estimates of osteopenia and osteoporosis (reduced bone mineral density; BMD) in HIV-infected patients and the role of antiretroviral therapy (ART) varies in the literature. Methods:We conducted a meta-analytical review of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART-treated versus ART-naive; protease inhibitor (PI)-treated versus PI-untreated. We searched the MEDLINE, PubMed, and EMBASE databases for eligible references between January 1966 and November 2005. Random effects models were used to generate pooled OR estimates and confidence intervals. Results:Of 37 articles identified, 20 met the inclusion criteria. Of the 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis, yielding a pooled OR of 6.4 and 3.7, respectively, compared with HIV-uninfected controls (n = 654) using 11 studies with available data. Compared with ART-naive patients (n = 202, 10 studies), ART-treated individuals (n = 824) had a 2.5-fold increased odds of prevalent reduced BMD. The risk of prevalent osteoporosis (seven studies) was similarly elevated in ART-treated individuals. Compared with non-PI-treated HIV patients (n = 410, 14 studies), PI-treated patients (n = 791) had increased odds of reduced BMD and osteoporosis (12 studies). Few studies adjusted for important covariates such as HIV disease severity or treatment duration. Conclusion:The prevalence of osteoporosis in HIV-infected individuals is more than three times greater compared with HIV-uninfected controls. ART-exposed and PI-exposed individuals had a higher prevalence of reduced BMD and osteoporosis compared with their respective controls. The influence of other disease and treatment variables on these estimates could not be determined.

Fracture Prevalence among Human Immunodeficiency Virus (HIV)-Infected Versus Non-HIV-Infected Patients in a Large U.S. Healthcare System

CONTEXT Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown. OBJECTIVE The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients. DESIGN This was a population-based study. SETTING The study was conducted at a large U.S. health care system. PATIENTS A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared. MAIN OUTCOME MEASURE Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured. RESULTS The overall fracture prevalence was 2.87 vs. 1.77 patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < 0.0001). Among females, the overall fracture prevalence was 2.49 vs. 1.72 per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < 0.0001), vertebral fractures (1.03 vs. 0.49; P < 0.0001), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males. CONCLUSIONS Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients.

Bone Disease in HIV Infection: A Practical Review and Recommendations for HIV Care Providers

Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected subjects. Initiation of antiretroviral therapy is associated with a 2%-6% decrease in BMD over the first 2 years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV-infected post-menopausal women, and all HIV-infected men ⩾50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge.

Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen

Background:Decreased bone mineral density (BMD) has been described in HIV-infected patients initiating antiretroviral therapy (ART), but the contributions of ART and immunologic and/or virologic factors remain unclear. Methods:We compared total BMD changes over 96 weeks in 106 ART-naive HIV-infected subjects who were randomized to receive efavirenz (EFV) + zidovudine/lamivudine (n = 32) or lopinavir/ritonavir (LPV/r) + zidovudine/lamivudine induction (n = 74) for 24-48 weeks followed by LPV/r monotherapy. We also sought to identify factors associated with BMD loss, including markers of systemic inflammation [soluble tumor necrosis factor-α receptors (sTNFR I and II)]. Results:After 96 weeks, the mean percent change from baseline in total BMD was −2.5% (LPV/r) and −2.3% (EFV) (P < 0.01 for within-group changes in either arm; P = 0.86 for between-group differences). No alteration in the rate of BMD change was observed upon simplification to LPV/r monotherapy. Although soluble tumor necrosis factor-α receptor II concentrations at baseline and 24 weeks were at least marginally associated with subsequent changes in BMD (P = 0.06 and P = 0.028, respectively), these associations were no longer significant after adjustment for CD4+ T cell count. Subjects with lower baseline CD4+ T cell count, non-black race, and higher baseline glucose demonstrated a higher risk for >5% decrease in BMD. Conclusions:Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-α activity.

Comparative Effectiveness and Safety of Methods of Insulin Delivery and Glucose Monitoring for Diabetes Mellitus: A Systematic Review and Meta-analysis

BACKGROUND Patients with diabetes mellitus need information about the effectiveness of innovations in insulin delivery and glucose monitoring. PURPOSE To review how intensive insulin therapy (multiple daily injections [MDI] vs. rapid-acting analogue-based continuous subcutaneous insulin infusion [CSII]) or method of monitoring (self-monitoring of blood glucose [SMBG] vs. real-time continuous glucose monitoring [rt-CGM]) affects outcomes in types 1 and 2 diabetes mellitus. DATA SOURCES MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through February 2012 without language restrictions. STUDY SELECTION 33 randomized, controlled trials in children or adults that compared CSII with MDI (n=19), rt-CGM with SMBG (n=10), or sensor-augmented insulin pump use with MDI and SMBG (n=4). DATA EXTRACTION 2 reviewers independently evaluated studies for eligibility and quality and serially abstracted data. DATA SYNTHESIS In randomized, controlled trials, MDI and CSII showed similar effects on hemoglobin A1c (HbA1c) levels and severe hypoglycemia in children or adults with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. In adults with type 1 diabetes mellitus, HbA1c levels decreased more with CSII than with MDI, but 1 study heavily influenced these results. Compared with SMBG, rt-CGM achieved a lower HbA1c level (between-group difference of change, 0.26% [95% CI, 0.33% to 0.19%]) without any difference in severe hypoglycemia. Sensor-augmented insulin pump use decreased HbA1c levels more than MDI and SMBG did in persons with type 1 diabetes mellitus (between-group difference of change, 0.68% [CI, 0.81% to 0.54%]). Little evidence was available on other outcomes. LIMITATION Many studies were small, of short duration, and limited to white persons with type 1 diabetes mellitus. CONCLUSION Continuous subcutaneous insulin infusion and MDI have similar effects on glycemic control and hypoglycemia, except CSII has a favorable effect on glycemic control in adults with type 1 diabetes mellitus. For glycemic control, rt-CGM is superior to SMBG and sensor-augmented insulin pumps are superior to MDI and SMBG without increasing the risk for hypoglycemia. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study

Objective:To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls. Design:Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003. Methods:Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 × 1/[log10(glucose) + log10(insulin)] and fasting hyperinsulinemia (insulin > 15 μU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus. Results:Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02–1.13) and a lower QUICKI (−0.04; 95% CI, −0.07 to −0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2–1.3). Conclusions:Fasting surrogate markers suggest increased insulin resistance in HIV-infected men, which is related to cumulative NRTI exposure.

Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D.

BACKGROUND We aimed to determine whether antiretroviral therapy (ART) initiation with efavirenz (EFV) is associated with decreases in 25-hydroxyvitamin D (25[OH]D) compared with non-EFV regimens. METHODS 25(OH)D was measured from stored plasma samples in 87 ART-naive HIV-positive patients prior to ART initiation with EFV-containing (n=51) or non-EFV-containing (89% with protease inhibitors; n=36) regimens from a single clinic in Cleveland (OH, USA). A repeat measurement was made 6-12 months after ART initiation. The change in 25(OH)D after ART initiation and the prevalence of patients with hypovitaminosis D (< or = 37.5 nmol/l [15 ng/ml]) after ART initiation was compared in those who initiated ART with and without EFV using multivariable linear and modified Poisson regression, respectively. RESULTS Prior to ART initiation, the median (interquartile range [IQR]) 25(OH)D concentration was 52.7 nmol/l (IQR 32.2-72.1), with 33% prevalence of hypovitaminosis D. After 6-12 months of ART, 25(OH)D decreased by a mean +/-se of -12.7 +/-3.7 nmol/l in the EFV group relative to the non-EFV group (P=0.001) after adjustment for baseline 25(OH)D concentration, race and season (non-summer versus summer) at the visit 6-12 months after ART initiation. Similarly, after multivariable adjustment, the risk of hypovitaminosis D after ART initiation was significantly higher in the EFV group compared with the non-EFV group (prevalence ratio 1.8 [95% confidence interval 1.2-2.8]; P=0.007). CONCLUSIONS ART initiation with EFV is associated with significant decreases in 25(OH)D and an increased risk of hypovitaminosis D compared with non-EFV regimens.

Current Concepts in the Diagnosis and Management of Metabolic Complications of HIV Infection and Its Therapy

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Association Between Systemic Inflammation and Incident Diabetes in HIV-Infected Patients After Initiation of Antiretroviral Therapy

OBJECTIVE To determine whether systemic inflammation after initiation of HIV-antiretroviral therapy (ART) is associated with the development of diabetes. RESEARCH DESIGN AND METHODS We conducted a nested case-control study, comparing 55 previously ART-naive individuals who developed diabetes 48 weeks after ART initiation (case subjects) with 55 individuals who did not develop diabetes during a comparable follow-up (control subjects), matched on baseline BMI and race/ethnicity. Stored plasma samples at treatment initiation (week 0) and 1 year later (week 48) were assayed for levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and the soluble receptors of tumor necrosis factor-α (sTNFR1 and sTNFR2). RESULTS Case subjects were older than control subjects (median age 41 vs. 37 years, P = 0.001), but the groups were otherwise comparable. Median levels for all markers, except hs-CRP, decreased from week 0 to week 48. Subjects with higher levels of hs-CRP, sTNFR1, and sTNFR2 at 48 weeks had an increased odds of subsequent diabetes, after adjustment for baseline marker level, age, BMI at week 48, CD4 count at week 48 (< vs. >200 cells/mm3), and indinavir use (all Ptrend ≤ 0.05). After further adjustment for week 48 glucose, effects were attenuated and only sTNFR1 remained significant (odds ratio, highest quartile vs. lowest 23.2 [95% CI 1.28–423], P = 0.03). CONCLUSIONS Inflammatory markers 48 weeks after ART initiation were associated with increased risk of diabetes. These findings suggest that systemic inflammation may contribute to diabetes pathogenesis among HIV-infected patients.

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

Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING 57 sites in the United States and Puerto Rico. PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION The trial was open-label, and ritonavir was not provided. CONCLUSION Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases.