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Background: Adherence and retention concerns raise questions about the effectiveness and cost-effectiveness of oral HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM)., Methods: Using an adolescent-focused simulation model, we compared annual HIV screening alone with tenofovir disoproxil fumarate/emtricitabine-based oral PrEP with every 3-month HIV screening in YMSM (aged 15-24) at increased risk of HIV. Data derived from published sources included: age-stratified HIV incidence/100 person-years (PY) on- or off-PrEP (0.6-10.1 or 0.4-6.4), PrEP retention at 6 years (28%), transmissions by HIV RNA level (0.0-78.4/100PY) and annual costs of antiretroviral therapy ($32 000-69 000), HIV care ($3100-34 600), and PrEP program/generic drug ($900/360). Outcomes included transmissions (percent of cohort infected), quality-adjusted life-years (QALYs), costs ($), and incremental cost-effectiveness ratios ($/QALY). We explored the sensitivity of findings to variation in HIV incidence and drug prices., Results: Compared with annual screening alone, PrEP would increase QALYs (9.58 to 9.67), reduce new infections (37% to 30%), and decrease costs (by $5000) over 10 years. PrEP would remain cost-saving for HIV incidence off-PrEP ≥5.1/100PY or annual PrEP price ≤$1200. Over a lifetime horizon, PrEP would be cost-saving for HIV incidence off-PrEP ≥1.0/100PY, across all retention assumptions examined. PrEP would not be cost-effective at HIV incidence ≤0.1/100PY, regardless of drug price, due to programmatic costs., Conclusions: In US YMSM at increased risk of HIV, generic oral PrEP and every-3-month screening would be cost-saving compared with annual screening alone, even with high discontinuation and low adherence, over a range of HIV incidences., Competing Interests: Potential conflicts of interest. M. C. W. reports consulting fees from Quadrant Health Economics for health economics consulting unrelated to the content of this manuscript. R. J. L. reports personal consulting fees from Gilead Sciences and Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Human immunodeficiency virus-seronegative men aged 15-22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15-19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113)., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence., Methods: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews., Results: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits., Conclusion: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.

We examined associations of 25-hydroxy vitamin D (25-OHD), tenofovir disoproxil fumarate (TDF), and bone toxicity. We studied TDF/emtricitabine (FTC) HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM). Bone toxicity was predefined using bone mineral density/content change from baseline to week 48. Baseline serum 25-OHD was dichotomized as <20 ng/mL (insufficient/deficient) versus ≥20 (sufficient), and week 48 dried blood spot tenofovir diphosphate (TFV-DP) as >700 fmol/punch (protective against HIV acquisition) versus ≤700. Associations were examined by univariate and multivariable logistic regression, reporting crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs). Of 101 enrolled, 69 had complete bone assessments and 25-OHD; of these, 59 had week 48 TFV-DP data. Median (Q1-Q3) age was 20 (18-21) years; 54% were black/African American. In univariate analysis, participants with baseline 25-OHD <20 ng/mL (OR = 5.4; 95% CI = 1.9-16.5) and blacks (OR = 4.9; 95% CI = 1.7-15.2) had greater odds of bone toxicity than those with 25-OHD ≥20 or other races. TFV-DP was not associated with bone toxicity (OR = 1.6; 95% CI = 0.5-5.5). In multivariable analysis, compared with those with 25-OHD ≥20 and TFV-DP ≤700, those with 25-OHD ≥20 and TFV-DP >700 (OR = 11.5; 95% CI = 1.4-169.6), 25-OHD <20 and TFV-DP ≤700 (OR = 19.4; 95% CI = 3.0-228.7), and 25-OHD <20 and TFV-DP >700 (OR = 32.3; 95% CI = 3.3-653.6) had greater odds of bone toxicity after adjusting for race. In multivariable models, 25-OHD insufficiency, protective TFV-DP concentrations, and black race were significantly associated with bone toxicity after 48 weeks of TDF/FTC PrEP in YMSM. Clinical Trials Registration: NCT01769469.

Background: Young men who have sex with men (YMSM) experience disparities in HIV acquisition more than any other group. Daily oral pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine has been shown to effectively prevent HIV transmission in YMSM; however, recent studies suggest that young Black men who have sex with men experience subprotective levels of tenofovir diphosphate more frequently than other groups., Setting: Combined data from Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 110/113, 2 open-label PrEP studies that provided PrEP and evidence-based behavioral interventions to YMSM aged 15-22 years., Methods: Bivariate and logistic regression analyses were used to examine sociodemographic and behavioral factors associated with protective tenofovir diphosphate levels (defined as ≥700 fmol/punch) in ATN 110/113 data., Results: In bivariate analysis, self-identified Black participants, residential displacement due to sexual orientation, low perceived risk, and stigma with the medication were associated with subprotective levels. Hispanic ethnicity was associated with protective levels. In the final models, Black males were less likely to have subprotective levels than non-Black males at 4, 8, and 12 weeks. Self-reported displacement due to sexual orientation was associated with subprotective levels, whereas older age was as associated with protective levels., Conclusions: These findings highlight how future behavioral research and biomedical prevention efforts in YMSM will need to address PrEP disparities that may occur in young Black men who have sex with men, perception of risk, and lack of key supportive housing during this period that may be critical factors that contribute to HIV acquisition.

Tobacco has been associated with worse HIV disease progression in adult samples of people living with HIV; however, studies have yet to examine these effects in youth living with HIV (YLWH). This study examined the association between tobacco smoking behaviors and sustained viral suppression among a sample of 820 YLWH who were recruited through the Adolescent Medicine Trials Network for HIV Interventions. Participants completed a cross-sectional survey and then staff abstracted viral suppression data from medical records for up to 26 weeks prior to enrollment. Overall, 20.4% of youth reported daily or almost daily tobacco use. In multivariable analyses, older age and daily or almost daily tobacco smoking, and ART adherence remained statistically significant in predicting sustained viral suppression over the study period. These findings underscore the need for tobacco screening and interventions in HIV care settings in order to identify youth in need of additional smoking cessation services.

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., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tenofovir disoproxil fumarate (TDF) increases serum parathyroid hormone (PTH) and 1,25 dihydroxy vitamin D (1,25-(OH) 2 D), and decreases bone mineral density (BMD). Optimal treatment of TDF-associated BMD loss requires an understanding of the primary cause of these abnormalities., Methods: Secondary review of data from two studies of TDF use in youth, comparing the relationship of PTH, 25-hydroxy vitamin D (25-OHD) and 1,25-(OH) 2 D in three groups with varying exposures to TDF: youth without HIV enrolled in a trial of TDF/emtricitabine (FTC) for HIV pre-exposure prophylaxis (PrEP) at baseline (no TDF exposure) and after 12 weeks of TDF (short-term TDF exposure); and youth with HIV treated with TDF-containing combination antiretroviral therapy (cART) for at least 6 months at study entry (long-term TDF exposure). Relationships were evaluated by correlation analyses., Results: Participants ranged in age from 17 to 24 years and >50% were Black/African American. In persons not treated with TDF, PTH had the physiologically appropriate negative correlation with 25-OHD (r=-0.3504, P=0.004). Correlations between PTH and 25-OHD in groups treated with TDF were weaker or absent. With longer term TDF treatment in persons with HIV, 25-OHD and 1,25-(OH) 2 D had the positive correlation similar to that found in vitamin D deficiency., Conclusions: TDF changes the relationship of 25-OHD to PTH, suggesting that in persons using TDF for PrEP or cART, a higher than usual target for serum 25-OHD concentration might be needed to reduce PTH and optimize bone health., Clinical Trials Registration: NCT01751646 (ATN 109) and NCT01769469 (ATN 117).

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.

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., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

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.

New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Introduction: Adolescents and young adults aged <25 are a key population in the HIV epidemic, with very high HIV incidence rates in many geographic settings and a large number who have limited access to prevention services. Thus, any biomedical HIV prevention approach should prepare licensure and implementation strategies for young populations. Oral pre-exposure prophylaxis (PrEP) is the first antiretroviral-based prevention intervention with proven efficacy across many settings and populations, and regulatory and policy approvals at global and national levels are occurring rapidly. We discuss available data from studies in the United States and South Africa on the use of oral PrEP for HIV prevention in adolescent minors, along with some of the implementation challenges., Discussion: Ongoing studies in the United States and South Africa among youth under the age of 18 should provide the safety data needed by the end of 2016 to contribute to licensure of Truvada as daily PrEP in adolescents. The challenges of completing these studies as well as foreseeable broader challenges highlighted by this work are presented. Adherence to daily PrEP is a greater challenge for younger populations, and poor adherence was associated with decreased efficacy in all PrEP trials. Individual-level barriers include limited familiarity with antiretroviral-based prevention, stigma, product storage, and social support. Structural challenges include healthcare financing for PrEP, clinician acceptability and comfort with PrEP delivery, and the limited youth-friendly health services available. These challenges are discussed in the context of the work done to date in the United States and South Africa, but will likely be magnified in the setting of limited resources in many other countries that are heavily impacted by HIV., Conclusions: Adolescent populations are particularly vulnerable to HIV, and oral PrEP in these populations is likely to have an impact on population-level HIV incidence. The challenges of disseminating an HIV biomedical prevention tool requiring daily usage in adolescents are formidable, but addressing these issues and starting dialogues will lay the groundwork for the many other HIV prevention tools now being developed and tested., Competing Interests: None.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18-24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 <350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.

Background: Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited., Design: Adolescent Trials Network 061 examined changes over 48 weeks of cART in T-cell subsets and markers of T-cell and macrophage activation in subjects with pre-therapy CD4 > 350 cells/mm. All subjects had optimal viral suppression from weeks 24 through 48., Methods: Subjects (n = 48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls., Results: Significant increases over 48 weeks were noted in all CD4 populations, including total, naive, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA), whereas numbers of CM and EM RO CD8 cells declined significantly. By week 48, CD4 naive cells were similar to controls, whereas CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls., Conclusions: In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However, CD8 T-cell and macrophage activation persists at higher levels than uninfected controls.

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.

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.).

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.

Background: The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial., Methods: HIV-positive and high-risk HIV-negative female adolescents were enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) longitudinal cohort study. At each semi-annual clinical visit, cervical lavage samples were tested for 30 HPV types. Type-specific and carcinogenic risk-specific HPV prevalence and incidence were compared in 373 eligible participants: 146 HIV-negative female adolescents with a median follow-up of 721.5 [IQR: 483-1301] days and 227 HIV-positive female adolescents. Of the 227 HIV-positive participants, a fixed set (n = 100) were examined both before and after HAART initiation; 70 were examined only before HAART initiation; and 57 were examined only after HAART initiation, with overall median follow-up of 271 [IQR: 86.5-473] and 427.25 [IQR: 200-871] days respectively for before and after HAART initiation., Results: Of the 373 eligible participants, 262 (70%) were infected with at least one type of HPV at baseline, and 78 of the remaining 111 (70%) became infected with at least one type of HPV by the end of the study. Overall, the incidence and prevalence of HPV types 58, 53/66, 68/70, and 31/33/35 were much higher than the established carcinogenic and HPV vaccine types 16 and 18, especially in HIV-positive females both before and after HAART initiation. Baseline prevalence for individual high-risk HPV types ranged, depending on type, from 0.7-10%, 1-17%, and 1-18% in the HIV-negative group, the HIV-positive before HAART initiation group, and the HIV-positive after HAART initiation group, respectively. Likewise, the incidence ranged, depending on HPV type, from 0.64-9.83 cases/100 PY, 3.00-12.80 cases/100 PY, and 1.49-17.05 cases/100 PY in the three groups, respectively. The patterns of each HPV type infection, clearance, and persistence did not differ considerably before or after the introduction of HAART and were clearly independent of CD4+ change within the short post-HAART follow-up period., Conclusions: HAART did not immediately affect the incidence of type-specific HPV infections within a short-period follow-up; however, future studies are warranted in larger populations to evaluate HAART's impact over longer periods.

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV.

The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects > or =18 to <25 years old receiving (> or =28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), concentration at 24 h postdose (C(24)), and total apparent oral clearance (CL/F) values were 35,971 ng x hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC(0-24), C(max), C(24), and CL/F values were 2,762 ng.hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < or = 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C(max) and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

This study examined the prevalence of primary human immunodeficiency type 1 (HIV-1) drug resistance among recently infected youth in the United States. Of the 55 subjects studied, major mutations conferring HIV drug resistance were present in 10 (18%). Eight (15%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations, with the majority (6) having the K103N mutation; 2 (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; and 2 (4%) had protease inhibitor (PI) mutations. Phenotypic drug resistance was present in 12 (22%) subjects: 10 (18%) for NNRTIs, 2 (4%) for NRTIs, and 3 (5.5%) for PIs. The prevalence of primary HIV-1 drug resistance, particularly to NNRTIs, in this group of recently infected youth was high.

Adherence to highly active antiretroviral therapy (HAART) was investigated among HIV-infected adolescents recruited from 13 US cities into the REACH (Reaching for Excellence in Adolescent Care and Health) project, the first large-scale disease progression study of HIV-positive adolescents infected through sexual behaviour or injection drug use. Of 161 subjects, 7% could not correctly identify all their prescribed medications; 11% could identify them but reported never taking at least one medication. The majority (83%) reported taking all of their medications at least some of the time, but only 50% of these subjects reported full adherence. Therefore, only 41% of the sample reported full adherence. A strong association was found between adherence and reduced viral load. A CD4 level of > or = 500 cells/mm3 was also associated with adherence. Higher levels of depression were significantly associated with decreased adherence, and a trend was found for an association between number of medications prescribed and adherence. Strict adherence to HAART is critical for sustained suppression of viral replication allowing for immune recovery and reducing the risk of the selection of antiviral resistance. Adherence appears to be a serious problem among HIV-positive adolescents. Better education, intervention to relieve depression, and efforts to improve ease of medication use are essential.