Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. Methods: This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). Results: Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). Conclusions: For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. Clinical Trials Registration: NCT01751646.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

BACKGROUND: The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS: This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS: At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS: In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION: NCT00490412.

Effect of intensive glycemic therapy on erectile function in men with type 1 diabetes.

PURPOSE: We determined whether intensive glycemic therapy reduces the risk of erectile dysfunction in men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial. MATERIALS AND METHODS: The Diabetes Control and Complications Trial randomized 761 men with type 1 diabetes to intensive or conventional glycemic therapy at 28 sites between 1983 and 1989, of whom 366 had diabetes for 1 to 5 years and no microvascular complications (primary prevention cohort), and 395 had diabetes for 1 to 15 years with nonproliferative retinopathy or microalbuminuria (secondary intervention cohort). Subjects were treated until 1993, and followed in the Epidemiology of Diabetes Interventions and Complications study. In 2003 we conducted an ancillary study using a validated assessment of erectile dysfunction in 571 men (80% participation rate), 291 in the primary cohort and 280 in the secondary cohort. RESULTS: Of the participants 23% reported erectile dysfunction. The prevalence was significantly lower in the intensive vs conventional treatment group in the secondary cohort (12.8% vs 30.8%, p = 0.001) but not in the primary cohort (17% vs 20.3%, p = 0.49). The risk of erectile dysfunction in primary and secondary cohorts was directly associated with mean HbA1c during the Diabetes Control and Complications Trial, and Epidemiology of Diabetes Interventions and Complications combined. Age, peripheral neuropathy and lower urinary tract symptoms were other risk factors. CONCLUSIONS: A period of intensive therapy significantly reduced the prevalence of erectile dysfunction 10 years later among those men in the secondary intervention cohort but not in the primary prevention cohort. Higher HbA1c was significantly associated with risk in both cohorts. These findings provide further support for early implementation of intensive insulin therapy in young men with type 1 diabetes.

Urinary incontinence among women with type 1 diabetes--how common is it?

PURPOSE: We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS: We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS: Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS: Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted.

Sexual dysfunction and symptom impact in men with long-standing type 1 diabetes in the DCCT/EDIC cohort.

INTRODUCTION: Male sexual dysfunction is a common complication of diabetes (DM), but the relative impact of erectile dysfunction (ED), orgasmic dysfunction (OD), and/or decreased libido (DL) on global sexual bother has not been assessed. AIM: To assess the relationship between ED, OD, and DL and overall sexual satisfaction in men with type 1 DM, and determine which form of dysfunction causes the most bother. METHODS: The study cohort consisted of 713 men with type 1 DM who completed the Diabetes Control and Complication Trial and then participated in the follow-up Epidemiology of Diabetes Interventions and Complications Study. In year 10 of EDIC, 583 (83%) completed a validated instrument assessing ED, OD, and DL and the bother these conditions cause. Statistical tests determined the concordance of function and bother in each domain, and the impact of each domain on overall sexual satisfaction. MAIN OUTCOME MEASURES: Patient-reported outcomes using responses to individual items of the International Index of Erectile Function (IIEF). RESULTS: ED was present in 34%, OD in 20%, and DL in 55%. When correlated with overall sexual satisfaction, ED had the highest weighted kappa (0.84, 95% confidence interval [CI] = 0.80-0.87), while OD (0.57, 95% CI = 0.51-0.63) and DL (0.55, 95%CI = 0.48-0.62) were considerably lower. Furthermore, the single item assessing confidence in getting and keeping an erection had the strongest correlation with overall sexual bother as well as specific erectile bother. CONCLUSIONS: ED, OD, and DL are highly prevalent in men with long-standing type I diabetes. All three sexual dysfunctions cause bother in men with DM, but ED causes more general sexual bother and likely has a greater overall impact on quality of life. Our data underscore the importance of asking men with DM about their sexual function and point to the need for further research to investigate disorders of orgasm and desire.

An HIV Preexposure Prophylaxis Demonstration Project and Safety Study for Young MSM.

BACKGROUND: Young men who have sex with men (YMSM) are a key population for implementation of preexposure prophylaxis (PrEP) interventions. This open-label study examined adherence to PrEP and assessed sexual behavior among a diverse sample of YMSM in 12 US cities. METHODS: Eligible participants were 18- to 22-year-old HIV-uninfected MSM who reported HIV transmission risk behavior in the previous 6 months. Participants were provided daily tenofovir disoproxil fumarate/emtricitabine (Truvada). Study visits occurred at baseline, monthly through week 12, and then quarterly through week 48. Dried blood spots were serially collected for the quantification of tenofovir diphosphate (TFV-DP). RESULTS: Between March and September 2013, 2186 individuals were approached and 400 were found to be preliminarily eligible. Of those 400, 277 were scheduled for an in-person screening visit and 200 were enrolled (mean age = 20.2; 54.5% black, 26.5% Latino). Diagnosis of sexually transmitted infections, including urethral and rectal chlamydial/gonococcal infection and syphilis, at baseline was 22% and remained high across visits. At week 4, 56% of participants had TFV-DP levels consistent with ≥4 pills per week. By week 48, 34% of participants had TFV-DP levels consistent with ≥4 pills per week, with a noticeable drop-off occurring at week 24. Four HIV seroconversions occurred on study (3.29/100 person-years). Condomless sex was reported by >80% of participants, and condomless anal sex with last partner was associated with higher TFV-DP levels. CONCLUSIONS: Acceptability of PrEP was high, and most participants achieved protective drug levels during monthly visits. As visit frequency decreased, so did adherence. YMSM in the United States may need PrEP access in youth-friendly settings with tailored adherence support and potentially augmented visit schedules.

Safety and Feasibility of Antiretroviral Preexposure Prophylaxis for Adolescent Men Who Have Sex With Men Aged 15 to 17 Years in the United States.

Importance: Adolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults. Objective: To examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM). Design, Setting, and Participants: Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP. Exposures: All participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks. Main Outcomes and Measures: The main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC. Results: Among 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively. Conclusions and Relevance: Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence. Trial Registration: clinicaltrials.gov Identifier: NCT01769456.

Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youths treated with tenofovir disoproxil fumarate.

BACKGROUND: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF. METHODS: A randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group. RESULTS: At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035). CONCLUSIONS: These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.

The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men.

BACKGROUND: This study examined the feasibility of a combination prevention intervention for young men who have sex with men (YMSM), an anticipated target population for HIV preexposure prophylaxis (PrEP). METHODS: Project PrEPare, a pilot study using a randomized 3-arm design, compared an efficacious behavioral HIV prevention intervention (Many Men, Many Voices-3 MV) alone, 3 MV combined with PrEP (tenofovir/emtricitabine), and 3 MV combined with placebo. Eligible participants were 18- to 22-year-old HIV-uninfected men who reported unprotected anal intercourse in the past year. Participants were screened for preliminary eligibility at youth venues and community organizations and were also referred through social networks. Laboratory screening determined final eligibility. Behavioral and biomedical data were collected at baseline and every 4 weeks thereafter for 24 weeks. RESULTS: Sixty-eight youth (mean age = 19.97 years; 53% African American, 40% Latino) were enrolled; 58 were randomized. Self-reported medication adherence averaged 62% (range, 43%-83%), whereas rates of detectable tenofovir in plasma of participants in the emtricitabine/tenofovir disoproxil fumarate arm ranged from 63.2% (week 4) to 20% (week 24). There were 5 ≥ grade 2 adverse events possibly/probably related to the study medication. Sexual risk behavior declined from baseline to week 24 in all study arms. CONCLUSIONS: The feasibility of enrolling at-risk youth, particularly young men who have sex with men of color, into Project PrEPare has been demonstrated. The acceptability of the group intervention along with counseling and testing was high. Self-reported medication adherence and corresponding plasma drug concentrations were low indicating the need for enhanced adherence counseling. Exploration of PrEP use among youth in nonrandomized open label trials is warranted.

Genetic associations with 25-hydroxyvitamin D deficiency in HIV-1-infected youth: fine-mapping for the GC/DBP gene that encodes the vitamin D-binding protein.

Serum 25-hydroxyvitamin D [25(OH)D] is often deficient (<12 ng/ml) or insufficient (<20 ng/ml) in youth living with human immunodeficiency virus type 1 infection (YLH). Based on evidence from multiple genome-wide association studies, we hypothesized that genetic factors associated with 25(OH)D deficiency should be readily detectable in YLH even when controlling for other known factors, including use of the antiretroviral drug efavirenz (EFV). Genotyping by bi-directional sequencing targeted 15 single nucleotide polymorphisms (SNPs) at the GC/DBP locus, with a focus on coding and regulatory variants, as well as those repeatedly reported in the literature. Three intronic SNPs (rs222016, rs222020, and rs222029) in a conserved haplotype block had unequivocal association signals (false discovery rate ≤ 0.006). In particular, the minor allele G for rs222020 was highly unfavorable among 192 YLH (99 African-Americans and 93 others), as gauged by relatively low likelihood for 25(OH)D sufficiency at enrollment (odds ratio = 0.31, p = 9.0 × 10(-4)). In a reduced multivariable model, race, season, latitude, body mass index, exposure to EFV, and rs222020-G were independent factors that collectively accounted for 38% of variance in the log10-transformed 25(OH)D concentration (p < 0.0001). Interaction terms were evident for rs222020-G × season (p < 0.001), latitude × season (especially fall and winter; p < 0.01), and race × EFV use (p = 0.024). Overall, variance in serum 25(OH)D is substantially attributable to multiple factors, but the exact contribution of genetic and non-genetic factors can be obscured by partial overlaps and frequent interactions.

Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection.

CONTEXT: Vitamin D deficiency and insufficiency occur frequently in youth with HIV infection, particularly among those receiving the antiretroviral drug efavirenz. Optimal vitamin D dosing for treatment is unclear. OBJECTIVE: Our objective was to evaluate safety and measure change in 25-hydroxyvitamin D (25-OHD) concentration from baseline to study wk 4 and 12 during treatment with vitamin D(3), 50,000 IU monthly. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized double-blind, placebo-controlled multicenter trial of HIV-infected youth ages 18-24 yr, with viral load below 5000 copies/ml, on stable antiretroviral therapy. INTERVENTION: INTERVENTION included vitamin D(3), 50,000 IU (n = 102), or matching placebo (n = 101) administered in three directly observed oral doses at monthly intervals. RESULTS: At baseline, mean (sd) age was 20.9 (2.0) yr; 37% were female and 52% African-American, and 54% were vitamin D deficient/insufficient (25-OHD < 20 ng/ml), with no randomized group differences. Of evaluable participants vitamin D deficient/insufficient at baseline who were administered vitamin D, 43 of 46 (93%) had sufficient 25-OHD by wk 12. Vitamin D supplementation increased 25-OHD serum concentration from a baseline of 21.9 (13.3) to 35.9 (19.1) ng/ml at wk 12 (P < 0.001) with no change for placebo. Although use of the antiretroviral efavirenz was associated with lower baseline 25-OHD concentration, efavirenz did not diminish the response to vitamin D supplementation. There was no treatment-related toxicity. CONCLUSIONS: Supplementation with vitamin D(3) 50,000 IU monthly for three doses was safe. Increases in 25-OHD occurred in treated participants regardless of antiretroviral regimen.

Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study.

OBJECTIVE: This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m(2) in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC). RESEARCH DESIGN AND METHODS: Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation. RESULTS: A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m(2) (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m(2) (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR. CONCLUSIONS: Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m(2). However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

Comparison of urinary albumin-creatinine ratio and albumin excretion rate in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study.

BACKGROUND AND OBJECTIVES: The objective of this study was to compare random urine albumin-creatinine ratio (ACR) with timed urine albumin excretion rate (AER) in patients with type 1 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 1186 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study provided spot urine specimens concurrent with 4-hour timed urine collections. ACR and AER were compared using Bland-Altman plots, cross-classification of albuminuria status and its change over time, and within-person variability. RESULTS: Despite moderate correlation (r=0.62), ACR levels (mg/g) were lower than AER levels (mg/24 hr). This difference was greatest for men. Gender-specific estimated AER (eAER) values were empirically derived from ACR. Comparing the eAER with measured AER, agreement of prevalent microalbuminuria and macroalbuminuria classification was fair to moderate, and classification of change in albuminuria status over time was different. Intraclass correlations were 0.697 for ACR and 0.803 for AER. Effects of DCCT intensive versus conventional diabetes therapy on urine albumin excretion or classification of albuminuria were similar using the eAER versus measured AER, as were the effects of the previous glycosylated hemoglobin. CONCLUSIONS: Systematic differences exist between urine ACR and AER, related to gender and other determinants of muscle mass. Use of ACR (or eAER) versus AER yields differences in classification of prevalent albuminuria states and changes in albuminuria states over time. These findings support the use of consistent ascertainment methods over time and further efforts to standardize and optimally interpret measurement of urine albumin excretion.

Effect of intensive glycemic control and diabetes complications on lower urinary tract symptoms in men with type 1 diabetes: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

OBJECTIVE: Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS: Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression. RESULTS: Of the 591 men who completed the AUASI questions, nearly 20% (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score >or=8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 EDIC (UroEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS. CONCLUSIONS: These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort.

Risk factors for urinary incontinence among women with type 1 diabetes: findings from the epidemiology of diabetes interventions and complications study.

OBJECTIVES: To determine risk factors for, and long-term effects of, glycemic control on urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study. METHODS: The Diabetes Control and Complications Trial (1982-1993) cohort follow-up, Epidemiology of Diabetes Interventions and Complications trial, began in 1994. In 2004, the female participants (n = 550) completed a self-administered questionnaire on incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Multivariate regression models were used to determine independent predictors of weekly urinary incontinence, both overall and by type. RESULTS: Overall, 38% of women reported any incontinence and 17% reported weekly or greater incontinence. An increasing body mass index (odds ratio 1.1, 95% confidence interval 1.1-1.2) was significantly associated with weekly incontinence, overall and by type. Advancing age and >/=2 urinary tract infections in the previous year were associated with weekly urge incontinence (odds ratio 1.4, 95% confidence interval 1.0-2.0 per 5 years, and odds ratio 4.9, 95% confidence interval 1.8-13.5, respectively). Weaker evidence was seen for increased risk with age for overall weekly incontinence (22% per 5 years, P = .06) and stress incontinence (21% per 5 years, P = .08). CONCLUSIONS: Urinary incontinence is common among women with type 1 diabetes and the risk factors, including advancing age, increased weight, and previous urinary tract infection, are important. Weight reduction and the treatment of urinary tract infections might have the additional benefit of preventing incontinence or reducing its severity.

Sexual dysfunction in women with type 1 diabetes: long-term findings from the DCCT/ EDIC study cohort.

OBJECTIVE: This study aimed to investigate the prevalence and risk factors associated with sexual dysfunction in a well-characterized cohort of women with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study was conducted in women enrolled in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study, a North American study of men and women with type 1 diabetes. At year 10 of the EDIC study, 652 female participants were invited to complete a validated self-report measure of sexual function, standardized history and physical examinations, laboratory testing, and mood assessment. RESULTS: Of the sexually active women with type 1 diabetes in the EDIC study, 35% met criteria for female sexual dysfunction (FSD). Women with FSD reported loss of libido (57%); problems with orgasm (51%), lubrication (47%), and arousal (38%); and pain (21%). Univariate analyses revealed a positive association between FSD and age (P = 0.0041), marital status (P = 0.0016), menopausal status (P = 0.0019), microvasculopathy (P = 0.0092), and depression (P = 0.0022). However, in a multivariate analysis, only depression (P = 0.004) and marital status (P = 0.003) were significant predictors of FSD. CONCLUSIONS: FSD is common in women with type 1 diabetes and affects all aspects of sexual function and satisfaction. Depression is the major predictor of sexual dysfunction in women with type 1 diabetes. These findings suggest that women with type 1 diabetes should be routinely queried about the presence of sexual dysfunction and possible co-association with depression.

Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial--revisited.

OBJECTIVE: The Diabetes Control and Complications Trial (Diabetes 44:968-983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the A1C level. RESEARCH DESIGN AND METHODS: We performed statistical evaluations of these models and additional analyses to assess whether the original analyses were flawed. RESULTS: Statistically, we show that the original results are an artifact of the assumptions of the statistical model used. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ. CONCLUSIONS: A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.

The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the Diabetes Control and Complications Trial.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at improved glucose control markedly reduced the risk of diabetes complications compared with conventional therapy. The principal determinant of risk was the history of glycemia. Recently, McCarter et al. (Diabetes Care 27:1259-1264, 2004) have presented analyses of the publicly available DCCT data using their hemoglobin glycation index (HGI), which is computed as the difference between the observed HbA1c (A1C) and that predicted from the level of blood glucose. In their analyses, the HGI level was a significant predictor of progression of retinopathy and nephropathy in the DCCT, which the authors claimed to support the hypothesis that the biological propensity for glycation, so-called biological variation in glycation, is another mechanism that determines risk of complications. However, we have criticized these analyses and conclusions because, from statistical principles, the glycation index must be positively correlated with the A1C level and thus may simply be a surrogate for A1C. Herein, we present the statistical properties of the glycation index to document its high correlation with A1C. We then replicate the analyses of McCarter et al. using both the HGI and the A1C together. Analyses show conclusively that the glycation index is not an independent risk factor for microvascular complications and that the effect of the glycation index on risk is wholly explained by the associated level of A1C. The HGI should not be used to estimate risk of complications or to guide therapy.