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Background: Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development. Methods: We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates. Results: The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (-330T and -166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw * 04 and DQB1 * 05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P Conclusions: Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae.

Background: Antioxidant nutrient deficiencies may hasten the progression of HIV disease by impairing antioxidant defenses. Objective: The objective of the study was to determine whether HIV infection is associated with poor selenium status and low antioxidant protection by glutathione and glutathione peroxidase (GPX). Design: In a cross-sectional study of 365 HIV-positive and HIV-negative adolescents and young adults, we examined the relation of plasma selenium, whole-blood glutathione, and whole-blood GPX to HIV status, disease severity, immune activation, and oxidative damage. Results: Selenium deficiency (plasma selenium Conclusions: Subjects had adequate selenium status, although HIV-related immune activation was associated with lower plasma selenium concentrations. GPX activity appears to have been induced by the oxidative stress associated with HIV infection and use of antiretroviral therapy. Thus, young, well-nourished subjects can mount a compensatory antioxidant response to HIV infection. KEY WORDS Glutathione, glutathione peroxidase, selenium, oxidative stress, HIV

Background: Vitamin D status affects immune function and thus may affect the progress of HIV infection. Objectives: Our goals were to assess vitamin D intake and status in subjects with HIV infection and in matched control subjects and to determine whether HIV infection was associated with vitamin D insufficiency. Design: Plasma 25-hydroxyvitamin D [25(OH)DI concentrations and vitamin D intake were measured in a cross-sectional study of members of the Reaching for Excellence in Adolescent Health (REACH) cohort. Results: The subjects were aged 14-23 y; 74% were female, and 72% were black. Mean (+ or -]SE) vitamin D intake from food was 30% greater (P = 0.023) in HIV-positive subjects (295 [+ or -] 18 IU/d; n = 237) than in HIV-negative subjects (227 [+ or -] 26 IU/d; n = 121). The prevalence of vitamin D supplement use was 29% (104 of 358 subjects) and did not differ significantly by HIV status (P = 0.87). Mean plasma 25(OH)D did not differ significantly (P = 0.62) between the HIV-positive (20.3 [+ or -] 1.1 nmol/L; n = 238) and HIV-negative (19.3 [+ or -] 1.7 nmol/L; n = 121) subjects, nor was HIV status a significant predictor of plasma 25(OH)D when multiple regression analysis was used to adjust for other variables. The prevalence of vitamin D insufficiency [plasma 25(OH)D [less than or equal to] 37.5 nmol/LI in the subjects was 87% (312 of 359 subjects). Conclusions: HIV infection did not influence vitamin D status. The prevalence of vitamin D insufficiency in both HIV-positive and HIV-negative REACH subjects was high, perhaps because these disadvantaged, largely urban youth have limited sun exposure. KEY WORDS Vitamin D, HIV infection, dietary intake, adolescents, race

Background: Oxidative stress during H1V infection may impair immune function, cause more rapid disease progression, and increase requirements for dietary antioxidants such as vitamins C and E. Objectives: The study had 2 principal objectives. The first wets to ascertain whether HIV infection and immune activation were associated with lower plasma concentrations of ascorbate, urate, and [alpha]- and [gamma]-tocopherols and with total antioxidant status (TAS). The second objective was to ascertain whether these antioxidants were associated with protection against oxidative damage. Design: This was a cross-sectional study involving 241 HIV-positive and 115 HIV-negative subjects aged 14-23 y. Subjects were primarily female (76%) and African American (70%), and 21% were Hispanic. Results: Plasma ascorbate was significantly lower, but [gamma]-tocopherol and TAS were significantly higher in subjects with HIV infection when the analysis was adjusted for dietary intake and sex. Plasma [alpha]-tocopherol did not differ significantly by HIV status, Plasma [gamma]-tocopherol also was higher in subjects with oxidative damage than in those without such damage. More than 90% of subjects had adequate plasma concentrations for both ascorbate and [alpha]-tocopherol, although [alpha]-tocopherol concentrations were lower than expected on the basis of third National Health and Nutrition Examination Survey data. Conclusions: Low plasma ascorbate concentrations in HIV-positive subjects suggest that vitamin C requirements are significantly higher in those with HIV infection. Plasma tocopherol concentrations were not depressed by HIV infection and may be maintained by compensatory mechanisms such as the activity of [alpha]-tocopherol transfer protein. KEY WORDS Antioxidants. [alpha]-tocopherol, [gamma]-tocopherol. ascorbate, oxidative damage

Scedosporium inflatum is a newly identified pathogenic member of the dematiaceous (dark olive, grey or black) fungi. It differs from other members of the genus by its colonial morphology and the distinct character of its spore-bearing structures. Colonies are flat, spreading, olive-gray to black in color, and wooly textured. Other morphological characteristics and distinctions are described. Eleven case reports of S. inflatum infection are detailed and include clinical course, therapeutic intervention attempted, and outcome. They are believed to be the first reported cases of infection by this organism. Eight cases followed invasive S. inflatum infection and three cases followed colonization by the fungus, without firm evidence of invasiveness. Ten patients suffered penetrating trauma or underwent surgery prior to infection. A predisposition for fungal involvement of cartilage and joint areas was demonstrated. Infection in the case of an immunosuppressed patient had a fatal outcome. Resistance to amphotericin and other high potency antifungal agents was observed and some patients recovered without antifungal treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

The aims of this study were to: 1) determine prevalence of anogenital and oral HPV, 2) determine concordance between HPV at anal, perianal, scrotal/penile, and oral sites; and 3) describe factors associated with anogenital HPV types targeted by the 9-valent vaccine. Data were collected from 2012 to 2015 among men who have sex with men 18–26 years of age enrolled in a vaccine trial (N = 145). Penile/scrotal, perianal, anal, and oral samples were tested for 61 HPV types. Logistic regression was used to identify factors associated with types in the 9-valent vaccine. Participants’ mean age was 23.0 years, 55.2% were African-American, and 26.2% were Hispanic; 93% had anal, 40% penile, and 6% oral HPV. Among those with anogenital infection, 18% had HPV16. Concordance was low between anogenital and oral sites. Factors independently associated with a 9-valent vaccine-type HPV were: race (African-American vs. White, OR=2.67, 95% CI=1.11–6.42), current smoking (yes vs. no, OR=2.37, 95% CI=1.03–5.48), and number of recent receptive anal sex partners (2+ vs. 0, OR=3.47, 95% CI=1.16–10.4). Most MSM were not infected with HPV16 or HPV18, suggesting that they may still benefit from HPV vaccination, but anogenital HPV was very common, highlighting the importance of vaccinating men before sexual initiation.

Background and Objectives: In adolescents and young adults, multiple studies have identified sexual activity and behaviors as significant risk factors for acquiring both human cytomegalovirus (HCMV) and hepatitis B virus (HBV). However, there are no reports on the prevalence or risk factors for infection of these viruses and hepatitis C virus (HCV) in an adolescent population with sexually acquired HIV. Goals: To examine the seroprevalence and risk factors of HBV, HCV, and HCMV infection in a population of HIV-infected male and female adolescents and in an age- and risk behavior-matched HIV-uninfected cohort. Study Design: A cross-sectional analysis of HBV, HCV, and HCMV infections in a cohort of HIV-infected and HIV-uninfected adolescents. Results: Adolescent males infected with HIV were more likely to have evidence of HBV and HCMV infection than HIV-uninfected males (23.7% versus 0%, respectively, for HBV, P = 0.008; 79.7% versus 50%, respectively, for HCMV, P = 0.004). HIV-infected females were more likely to have evidence of HCMV infection (78.5% versus 61.4%, P = 0.003) than HIV-uninfected females. No significant difference was found for HBV infection in the two groups of females. The rate of HCV infection (1.6%) was too small to make comparisons between the groups. To determine whether the differences in infection rates for HBV and HCMV could be explained by factors other than HIV status, a variety of possible risk factors were examined using univariate and multivariate analyses. A significant risk factor for HBV and HCMV infections for males was a homosexual or bisexual orientation. For females, a risk factor for HBV infection was having more than 10 lifetime sexual partners; for HCMV infection, HIV infection was the only risk factor. In addition, in the HIV-infected cohort, 15% of females and 36% of males who were seropositive for HBV had evidence of active HBV infection. Conclusions: These results emphasize the need for continued development of primary and secondary prevention programs and clinical screening and treatment for HBV and HCMV in adolescents., HIV-infected teenagers are at risk of hepatitis B and cytomegalovirus infection. In men, homosexuality or bisexuality was a risk factor for both infections. In women, having more than 10 lifetime sexual partners was a risk factor for hepatitis B and HIV infection was a risk factor for cytomegalovirus infection

Context: Data suggest that in adults, human papillomavirus (HPV) infections and their sequalae, squamous intraepithelial lesions (SILs), occur more commonly among human immunodeficiency (HIV)-infected women because of the HIV-associated [CD.sup.+] T-cell immunosuppression. Since adolescents are more likely to be early in the course of HIV and HPV infections, the study of both infections in this age group may help elucidate their initial relationship. Objective: To examine the prevalence of and risks for cervical HPV infection and SILs by HIV status in a population of adolescent girls. Participants: Subjects recruited at each of the 16 different US sites participating in a national study of HIV infection in adolescents. Main Outcome Measures: Cervical HPV DNA findings using polymerase chain reaction detection techniques and Papanicolaou smear from baseline visits. Infection with HPV was categorized into low- (rarely associated with cancer) and high- (commonly associated with cancers) risk types. Results: Of 133 HIV-infected girls, 103 (77.4%) compared with 30 (54.5%) of 55 noninfected girls were positive for HPV (relative risk [RR], 1.4; 95% confidence interval ICI], 1.1-1.8). The risk was for high-risk (RR, 1.8; 95% CI, 1.2-2.7) but not low-risk (RR, 1.2; 95% CI, 0.4-3.9) HPV types. Among the girls with HPV infection, 21 (70.0%) of the non-HIV-infected girls had normal cytologic findings compared with only 29 (29.9%) of the HIV-infected girls (P [is less than] .001). Multivariate analysis showed that HIV status was a significant risk for HPV infection (odds ratio [OR], 3.3; 95% CI, 1.6-6.7) and SIL (OR, 4.7; 95% CI, 1.8-14.8), but CD4 cell count and viral load were not associated with infection or squamous intraepithelial lesions. Only 9 girls had a [CD.sup.+] T-cell count of less than 0.2 cell x [10.sup.9]/L. Conclusions: High prevalence of HPV infection in both groups underscores the risky sexual behavior in this adolescent cohort. Rates of HPV infection and SILs were higher among HIV-infected girls, despite similar sexual risk behaviors and the relatively healthy state of our HIV-infected group. Infection with HIV may enhance HPV proliferation through mechanisms other than CD4 immunosuppression, particularly early in the course of HIV infection. Arch Pediatr Adolesc Med. 2000;154:12 7-134, HIV infection in adolescent girls may enhance active human papillomavirus (HPV) proliferation and the presence of HPV-associated squamous intrepithelial lesions (SILs), even early in the course of HIV infection. HPV has been established as a necessary component in the development of squamous cell cervical cancers. Of 197 adolescent girls tested, the incidence of HPV was 56% among those who were HIV positive and 31% among those who were not infected with the HIV virus. The high prevalence of HPV-associated SILs in the HIV-infected girls suggests that the host immune response may play a significant role in the development of HPV-associated cancers.

Background Tenofovir disoproxil fumarate (TDF) increases serum parathyroid hormone (PTH) and 1,25 dihydroxy vitamin D (1,25-(OH)2D), 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)2D 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)2D 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).

ObjectivesThis study sought to examine the prevalence of STIs and whether substance use frequency and/or problematic use—specifically alcohol, marijuana and other drugs—was associated with having an STI diagnosis among youth living with HIV (YLWH)MethodsA sample of 823 YLWH were recruited at 14 adolescent HIV clinics through the Adolescent Medicine Trials Network for HIV Interventions. Study staff abstracted STI data from medical records for up to 26 weeks prior to participants’ completing a cross-sectional survey including the ASSIST (Alcohol, Smoking and Substance Involvement Screening Test), which measures substance use frequency and consequences.ResultsAlmost one-third of youth had been diagnosed with an STI (30.5%) at the time of their baseline assessment. In multivariable analyses, those who engaged in weekly or greater marijuana use (adjusted OR (AOR)=10.66, 95% CI: 4.39 to 25.87, P<0.001) had an increased odds of being diagnosed with an STI. Additionally, youth who met alcohol use criteria for moderate (AOR=5.23, 95% CI: 2.50 to 10.93, P<0.001) and high risk (AOR=6.53, 95% CI: 1.20 to 35.68, P<0.05) alcohol use had an increased odds of being diagnosed with an STI compared with low-risk alcohol users.ConclusionsStudy findings underscore the need to investigate the role of greater frequency of marijuana use and problematic alcohol use in STI incidence among YLWH. Given the associations between both substance use frequency and problematic use in STI diagnoses among YLWH seen in HIV care settings, clinicians should use validated substance use screening tools which capture both frequencies and consequences in order to identify YLWH who may need further evaluation and treatment.

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

IMPORTANCE: Youths aged 13 to 24 years old living with human immunodeficiency virus (HIV) are less likely than adults to receive the health and prevention benefits of HIV treatments, with only a small proportion having achieved sustained viral suppression. These age-related disparities in HIV continuum of care are owing in part to the unique developmental issues of adolescents and young adults as well as the complexity and fragmentation of HIV care and related services. This article summarizes a national, multiagency, and multilevel approach to HIV care for newly diagnosed youths designed to bridge some of these fragmentations by addressing National HIV/AIDS Strategy goals for people living with HIV. DESIGN, SETTING, AND PARTICIPANTS: Three federal agencies developed memoranda of understanding to sequentially implement 3 protocols addressing key National HIV/AIDS Strategy goals. The goals were addressed in the Adolescent Trials Network, with protocols implemented in 12 to 15 sites across the United States. Outcome data were collected from recently diagnosed youth referred to the program. MAIN OUTCOMES AND MEASURES: Cross-agency collaboration, youth-friendly linkage to care services, community mobilization to address structural barriers to care, cooperation among services, proportion of all men who have sex with men who tested, and rates of linkage to prevention services. RESULTS: The program addressed National HIV/AIDS Strategy goals 2 through 4 including steps within each goal. A total of 3986 HIV-positive youths were referred for care, with more than 75% linked to care within 6 weeks of referral, with almost 90% of those youths engaged in subsequent HIV care. Community mobilization efforts implemented and completed structural change objectives to address local barriers to care. Age and racial/ethnic group disparities were addressed through targeted training for culturally competent, youth-friendly care, and intensive motivational interviewing training. CONCLUSIONS AND RELEVANCE: A national program to address the National HIV/AIDS Strategy specifically for youths can improve coordination of federal resources as well as implement best-practice models that are adapted to decrease service fragmentation and systemic barriers at local jurisdictions.

IMPORTANCE: Most human immunodeficiency virus (HIV)–infected youths are unaware of their serostatus (approximately 60%) and therefore not linked to HIV medical or prevention services. The need to identify promising and scalable approaches to promote uptake of HIV testing among youths at risk is critical. OBJECTIVE: To evaluate a multisite HIV testing program designed to encourage localized HIV testing programs focused on self-identified sexual minority males and to link youths to appropriate prevention services after receipt of their test results. DESIGN, SETTING, AND PARTICIPANTS: Testing strategies were evaluated using an observational design during a 9-month period (June 1, 2015, through February 28, 2016). Testing strategies were implemented by 12 adolescent medicine HIV primary care programs and included targeted testing, universal testing, or a combination. Data were collected from local youth at high risk of HIV infection and, specifically, sexual minority males of color. MAIN OUTCOMES AND MEASURES: Proportion of sexual minority males and sexual minority males of color tested, proportion of previously undiagnosed HIV-positive youths identified, and rates of linkage to prevention services. RESULTS: A total of 3301 youths underwent HIV testing. Overall, 35 (3.6%) of those who underwent universal testing in primary care clinical settings, such as emergency departments and community health centers, were sexual minority males (35 [3.6%] were males of color) compared with 236 (46.7%) (201 [39.8%] were males of color) who were tested through targeted testing and 693 (37.8%) (503 [27.4%] were males of color) through combination efforts. Identification of new HIV-positive cases varied by strategy: 1 (0.1%) via universal testing, 39 (2.1%) through combination testing, and 16 (3.2%) through targeted testing. However, when targeted tests were separated from universal testing results for sites using a combined strategy, the rate of newly identified HIV-positive cases identified through universal testing decreased to 1 (0.1%). Rates of new HIV-positive cases identified through targeted testing increased to 49 (6.3%). Youths who tested through targeted testing (416 [85.1%]) were more likely to link successfully to local HIV prevention services, including preexposure prophylaxis, compared with those who underwent universal testing (328 [34.1%]). CONCLUSIONS AND RELEVANCE: The findings suggest that community-based targeted approaches to HIV testing are more effective than universal screening for reaching young sexual minority males (especially males of color), identifying previously undiagnosed HIV-positive youths, and linking HIV-negative youths to relevant prevention services. Targeted, community-based HIV testing strategies hold promise as a scalable and effective means to identify high-risk youths who are unaware of their HIV status.

ABSTRACTNew 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.)

IMPORTANCE: Human immunodeficiency virus (HIV) diagnoses continue to increase among young men who have sex with men (YMSM). Many YMSM living with HIV engage in sexual risk behaviors, and those who have a detectable viral load can transmit HIV to sex partners. Understanding factors that are related to sexual risk taking among virologically detectable (VL+) YMSM can inform prevention and treatment efforts. OBJECTIVES: To describe differences between virologically suppressed (VL−) and VL+ YMSM living with HIV and to identify correlates of condomless anal intercourse (CAI) and serodiscordant CAI among VL+ YMSM. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional survey conducted from December 1, 2009, through June 30, 2012, we studied 991 HIV-infected YMSM 15 to 26 years of age at 20 adolescent HIV clinics in the United States. Data analysis was conducted December 1, 2013, through July 31, 2015. MAIN OUTCOMES AND MEASURES: Demographic, behavioral, and psychosocial assessments obtained using audio computer-assisted self-interviews. Viral load information was obtained via blood draw or medical record abstraction. RESULTS: Of the 991 participants, 688 (69.4%) were VL+ and 458 (46.2%) reported CAI, with 310 (31.3%) reporting serodiscordant CAI in the past 3 months. The VL+ YMSM were more likely than the VL− YMSM to report CAI (detectable, 266 [54.7%]; suppressed, 91 [44.4%]; P = .01) and serodiscordant CAI (detectable, 187 [34.9%]; suppressed, 57 [25.0%]; P &lt; .01). Multivariable analyses indicated that among VL+ YMSM, those reporting problematic substance use were more likely to report CAI (adjusted odds ratio [AOR], 1.46; 95% CI, 1.02-2.10) and serodiscordant CAI (AOR, 1.45; 95% CI, 1.06-1.99). Black VL+ YMSM were less likely to report CAI (AOR, 0.63; 95% CI, 0.44-0.90) or serodiscordant CAI (AOR, 0.66; 95% CI, 0.46-0.94) compared with other VL+ YMSM. In addition, VL+ YMSM who disclosed their HIV status to sex partners were more likely to report CAI compared with nondisclosing YMSM (AOR, 1.35; 95% CI, 1.01-1.81). Transgender participants were less likely to report CAI than cisgender participants (AOR, 0.35; 95% CI, 0.14-0.85). Last, VL+ YMSM who reported currently being employed were less likely to report serodiscordant CAI than those who were unemployed (AOR, 0.74; 95% CI, 0.55-0.99). CONCLUSIONS AND RELEVANCE: Targeted multilevel interventions are needed to reduce HIV transmission risk behaviors among YMSM living with HIV, particularly among those who are VL+.

To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection.

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.

ABSTRACTTenofovir 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.IMPORTANCE(The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.)

Multiple studies have shown excellent response rates after hepatitis B immunization in youth; however, one previous study conducted in urban youth demonstrated poor responses.

ABSTRACTThe 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 ≥18 to <25 years old receiving (≥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 (AUC0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng·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 AUC0-24, Cmax, C24, and CL/Fvalues 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/Ffor 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≤ 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 Cmaxand 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/Fbecause 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.

The responses to HAART in HIV-infected adolescents infected through risk behaviors are not well defined. PACTG 381 collected intensive immunologic and virologic data on youth naive to or with minimal exposure to antiretroviral therapy who began HAART. Subjects were evaluated according to their weeks 16–24 virologic response. Comparisons with a cohort of HIV-uninfected adolescents from the REACH cohort were performed. Cox proportional hazards models were used to identify baseline and week 24 predictors of virologic failure. Only 69 of 120 subjects (58%) achieved virologic suppression by weeks 16–24, whereas 55 of 69 (80%) demonstrated control to week 60. Higher CD4+ naive T cells (CD4+/62L+/RA+: hazard ratio [HR], 2.13; p = 0.018), higher CD8+ activated T cells (CD8+/CD38+/DR+: HR, 1.40, p = 0.028 per 100 cells/mm3) and higher CD8+ naive T cells (CD8+/62L+/RA+: HR, 1.72; p = 0.005) at weeks 16–24 in subjects with early viral success were predictive of subsequent failure. By week 60, total CD4+ T cells remained significantly lower than in uninfected controls. Adolescents beginning HAART achieve moderate rates of viral suppression by weeks 16–24. In those who do achieve early virologic control, suppression to week 60 is high although total CD4+ T cells remain significantly lower than in uninfected controls. Several T cell markers were predictive of subsequent virologic failure in subjects achieving short-term success. Further study is warranted to determine whether these predictors provide any benefit to clinical management.

The purpose of this study was to evaluate predictors of HIV-1 disease progression in a cohort of predominantly female and minority adolescents who had acquired their HIV-1 infections through sexual risk behaviors. Subjects were identified from the REACH cohort who were not on antiretroviral therapy for at least 1 year and whose baseline CD4+ T cells were >300 cells/mm3. Biomedical and demographic characteristics of the subjects at the start of the study period were evaluated as predictors of CD4+ T cell loss in univariate and multivariate models. Two-thirds of the 99 subjects meeting the selection criteria were female and 87% were black or Hispanic similar to the REACH cohort as a whole. Higher absolute CD8+ CD38+ T cell counts at the start of the assessment period were associated with a greater rate of loss of CD4+ T cells. HIV-1 RNA viral load was among other potential predictors of HIV-1 disease progression that had no association with the rate of CD4+ T cell loss in this cohort. This study extends the observed association of higher CD8+ CD38+ T cells numbers being predictive of HIV-1 disease progression into predominantly female, minority youth.

African-Americans (AFAM) and Hispanics (HIS) represent only 13% and 12% of the U.S. population but 54% and 19%, respectively, of annually incident HIV-1 infections in the United States. The 88 patients in the current study were from U.S. racial or ethnic minority groups (72% African-American, 17% Hispanic), female (85%), and adolescent (mean age 20 years). Their HLA allele distributions were distinct from patterns in U.S. whites. Overall, HIV-1-specific T cell responses were observed in 91% of participants: 75% recognized peptides in Gag, 67% Pol, 57% Nef, and 41% Env. The patients recognized 87 (36%) of 244 Gag, Pol, Env, or Nef peptides tested. Similar to what has been seen in white cohorts, epitope-rich peptide clusters were identified within conserved functional domains in Gag matrix, Gag capsid, Pol reverse transcriptase, and Nef. Peptides representing variable regions from within the B subtype or with more changes from the B subtype consensus sequence were less likely to stimulate a positive T cell response. A small percentage (17%) of unique T cell responses was found in this cohort that displayed no previously known T cell epitopes. Dominant responses generally overlapped with epitope-rich regions in HIV-1 described previously for whites, although many of these peptides were likely restricted by HLA class I alleles not previously associated with these epitopes. Hence host genetic variation among different racial groups may have less impact on the utility of candidate HIV-1 vaccines than previously suspected.

Our objective was to determine whether treatment-naive HIV-infected adolescents manifest abnormalities in thymus function and peripheral T cell repertoire, and to assess relationships of these immunologic characteristics with each other, with plasma HIV virus load, and T cell surface markers. TCR Vβ repertoire was determined by CDR3 length spectratyping in purified CD4+ and CD8+ T cells of high-risk, HIV-negative adolescents and of treatment-naive, HIV-infected adolescents. Thymus function was investigated by the simultaneous examination of T cell receptor excision circles (TRECs) in the CD4+ and CD8+ T cell subsets. HIV-infected adolescents exhibited significantly greater perturbations in their TCR Vβ repertoire in comparison with HIV-negative subjects. Perturbations in the CD8+ T cell compartment were more profound in comparison with CD4+ T cells. The CD4+ TCR Vβ perturbations were negatively correlated with the total and phenotypically naive CD4+ T cells, and with CD4+ TRECs. CD8+ TRECs, although not correlated with CD8+ TCR Vβ perturbations, showed negative correlation with memory and activated CD8+ T cells. Interestingly, TRECs in CD4+ and CD8+ T cells were not significantly different between HIV-infected and uninfected adolescents. The TCR Vβ repertoire in adolescents is profoundly perturbed even in early stages of HIV infection, when total CD4+ cell counts in most subjects are within normal limits. The correlative analyses demonstrating negative association of CD4+ cell TRECs with CD4+ TCR Vβ perturbations and of CD8+ TRECs with CD8+ cell activation markers provide evidence of the intense activation of the central and peripheral immune compartments in this study population.

This report examines the relationship between substance use, psychosocial stressors, and natural killer (NK) cell enumeration and function in HIV-infected and high-risk uninfected adolescents. We studied the association of demographic characteristics; self-report measures of alcohol, tobacco, and marijuana use; and self-report measures of psychosocial stressors (depressive symptoms, anxiety) with three immune outcomes: NK (CD3-CD16+CD56+) absolute counts, lytic units per peripheral blood mononuclear cells (PBMCs), and lytic units per NK cell. In addition, we determined the association of HIV disease stage, antiretroviral therapy (ART), CD4+ T-cell count, and viral load with these outcomes in the subset of HIV-infected adolescents. Methods: This cross-sectional analysis reports on data collected during a longitudinal observational study of adolescents (the REACH Study). A cross-sectional analysis was performed with data from the first visit for each subject that met criteria for concurrent (within 3 days) assessment of NK number and function, substance use, and psychosocial data. The data set represented 501 subjects. Analyses were performed separately for the HIV-seropositive and seronegative adolescents. In the HIV-seronegative population, there were no significant predictors of NK cell count and only female gender was significantly associated with CD3-CD16+CD56+ NK lytic units per PBMC. Analysis of the HIV-seronegative cohort also showed that black race was significantly associated with higher lytic units per NK cell. Results: In HIV-seropositive adolescents, we observed an association of female gender with lower NK cell number and lytic units per PBMC, but not with lytic units per NK cells. Current use of one or two antiretroviral drugs was predictive of lower NK numbers. This drug effect was also noted in the functional assay per PBMC but not per NK cell. Increasing worry scores and no marijuana use over the past 3 months were associated with lower functional NK measures per PBMC in HIV-seropositive youth. Laboratory-confirmed recent marijuana use was highly predictive of increased lytic activity calculated per NK cell. These effects were not observed in similar analyses of data from HIV-seronegative adolescents. Depressive symptoms, assessed with an epidemiologic screening tool, were not found to be predictive of NK cell number or function in either the HIV-seronegative or the HIV-seropositive subset. These findings document associations between substance abuse, psychosocial variables, and NK numbers and function in adolescents.

ABSTRACTThe roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1- to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4+-T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4+-T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4+-T-cell counts of 534 and 499 cells/mm3, respectively. Only 8.1% of subjects had CD4+-T-cell counts below 200 cells/mm3, and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4+-T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.

ABSTRACTCircular DNA molecules known as T-cell receptor rearrangement excision circles (TREC) arise during T-cell development and are present in cells that have recently emigrated from the thymus. In cross-sectional studies, the number of peripheral blood lymphocytes bearing TREC decreases with age, consistent with an anatomically demonstrated loss of thymic epithelial tissue. TREC numbers increase following hematopoietic stem cell transplantation and during therapy for human immunodeficiency virus (HIV) infection. Quantitation of TREC has therefore been proposed as a parameter of thymic activity. In this study, we used real-time PCR to quantify TREC in peripheral blood samples obtained longitudinally from HIV-seronegative adolescents. TREC values in peripheral blood T cells were very stable throughout adolescence, once thought to be a time of rapid involution of the thymus. In addition, in a cross-sectional analysis, we examined TREC values in a cohort of HIV-positive adolescents and found evidence of ongoing thymopoiesis in perinatally infected individuals, despite lifelong infection. These data demonstrate the utility of TREC assessment in adolescents and that HIV infection does not uniformly result in accelerated thymic involution in childhood.

Proliferation within T lymphocyte subsets of HIV-infected adolescents was quantified by detection of Ki-67, a nuclear antigen found in cells in late G1, S, or G2 phases of the cell cycle. Median percentages and absolute counts of Ki-67+ cells for all subsets tested (CD4 naive and memory, CD8 naive and memory) were significantly higher for HIV-infected adolescents compared to uninfected controls. CD8 naive cells of HIV-infected adolescents had the greatest increase in rate of proliferation and number of proliferating cells compared to uninfected controls. In HIV-infected adolescents, the percentage and absolute number of proliferating CD4 naive cells were considerably lower than corresponding values for the other subsets. CD4 percent correlated inversely with Ki-67 expression in CD4 memory, CD8 naive, and CD8 memory cells, while Ki-67 expression in CD4 and CD8 memory cells correlated directly with average CD38 molecules/CD8 cell and absolute number of CD8/CD38/HLA-DR cells, consistent with T cell activation. These results indicate that in adolescents, HIV infection is associated with increased proliferation within CD4 and CD8 naive and memory subsets. Proliferation within the CD8 naive subset was higher than that observed previously for HIV-infected adults, suggesting that adolescents have a greater ability to regenerate and/or expand CD8 naive cells. CD4 naive cells of HIV-infected adolescents had a low rate of proliferation, and the total number of CD4 naive cells was low, suggesting that regeneration and/or peripheral expansion are limited and may contribute to the reduced size of this subset. The Ki-67 assay provided new and useful information on in vivo lymphocyte proliferation in HIV-infected adolescents.

ABSTRACTFlow cytometry analysis of lymphocyte subset markers was performed for a group of sexually active, human immunodeficiency virus (HIV)-negative adolescents over a 2-year period to establish normative data. Data were collected in the REACH Project (Reaching for Excellence in Adolescent Care and Health), a multicenter, longitudinal study of HIV-positive and high-risk HIV-negative adolescents. Two- and three-color flow cytometry data were collected every 6 months for these subjects. We determined the effects of gender, race, and age on the following lymphocyte subset markers: total CD4+cells, CD4+nai¨ve cells, CD4+memory cells, all CD8+cells, CD8+nai¨ve cells, CD8+memory cells, CD16+natural killer cells, and CD19+B cells. Gender was the demographic characteristic most frequently associated with differences in lymphocyte subset measures. Females had higher total CD4+cell and CD4+memory cells counts and lower CD16+cell counts than males. Age was associated with higher CD4+memory cell counts as well as higher CD8+memory cell counts. For CD19+cells, there was an interaction between age and gender, with males having significantly lower CD19+cell counts with increasing age, whereas there was no age effect for females. Race and/or ethnicity was associated with differences in total CD8+cell counts and CD8+memory cell counts, although both of these associations involved an interaction with gender.

In HIV-1-infected individuals, plasma viral RNA concentration as well as preservation of CD8+ naive T cells can vary by age. Host genetic factors previously shown to mediate HIV-1 pathogenesis in adults and children may operate differently in HIV-1-infected adolescents. Our PCR-based haplotyping of genetic variants at the loci encoding CC (β) chemokine receptor 2 (CCR2) and CCR5 revealed nine haplotypes (designated A through G*2) in 179 seronegative and 228 seropositive adolescent participants from the Reaching for Excellence in Adolescent Care and Health (REACH) Study of the Adolescent Medicine and HIV/AIDS Research Network. The influence of CCR2-CCR5 haplotypes and genotypes on plasma HIV-1 RNA level was assessed in 207 AIDS-free seropositive individuals (mostly African-American females) who either did not receive therapy or had discontinued therapy for 6-12 months during initial follow-up between 1996 and 1999. The CCR2-64I-coding haplotype F*2 and the infrequent CCR5 Δ32-bearing haplotype G*2 had negligible impact on HIV-1 RNA level (p > 0.83) and CD4+ T cell counts (p > 0.30). In contrast, nine carriers of the E/E genotype had significantly higher (p = 0.007) plasma HIV-1 RNA level and slightly reduced CD4+ cell counts (p = 0.15) compared with those not carrying E/E or F*2 or G*2. The effect of E/E on HIV-1 RNA was stronger (p < 0.001) in a multivariable model adjusted for F*2 or G*2 (p = 0.45), race (p = 0.23), gender (p = 0.002), age (p = 0.26), and history of antiretroviral therapy (p < 0.001). Thus, among the major CCR2-CCR5 haplotypes/genotypes in chronically infected and predominantly African-American adolescents, only the E/E genotype appeared to influence early host-virus equilibration.

The REACH Project (Reaching for Excellence in Adolescent Care and Health) of the Adolescent Medicine HIV/AIDS Research Network was designed as a study of an adolescent cohort composed of HIV-1-infected and-uninfected subjects. The goal of the analysis presented was to examine the relationship of CD4+ T cell counts and HIV-1 plasma viral loads in adolescents. The CD4+ T cell counts of 84 HIV+ subjects who were 13 to 19 years of age were measured at the clinical sites, using ACTG standardized techniques. HIV-1 viral loads in frozen plasma were determined by the NASBA/NucliSens assay at a central laboratory. Past and current treatment with antiretroviral drugs was determined by medical record abstraction and interview data. The slope of the line generated by regressing log10 HIV-1 RNA (copies/ml) versus CD4+ T cell counts of REACH subjects who are antiretroviral drug naive was negative and significantly different than zero. A negative association has also been reported for antiretroviral drug-naive, adult males in the Pittsburgh Men's Study, a component of MACS (Pitt-MACS) (Mellors J, et al .: Science 1996;272:1167). These data show that in adolescents, as in adults, HIV-1 RNA concentrations are correlated with corresponding absolute CD4+ T cell count. The slopes of the lines generated with data from each cohort were different (p = 0.003). In addition to age, there are sex and racial differences in the makeup of the two cohorts. Any or all of these differences may affect the slopes of the lines.

Clinical resistance to many therapies for malaria is a rapidly evolving problem in most endemic areas, particularly, Southeast Asia. Recent studies have suggested linkages between the mdr-like genes ofPlasmodium falciparumand resistance to quinoline containing compounds. Other studies have found an association between allelic polymorphisms in the DHFR gene and antifol resistance in these parasites. The purpose of this study was to further examine these associations in recent isolates from Cambodia. DNA sequences and gene copy number of thepfmdr1and the DHFR-TS gene in 10 Cambodian isolates were analyzed and correlated with the drug sensitivity pattern. No new intragenic alleles were detected in thepfmdr1gene by a full-length DNA sequence analysis of the L-14/Cambodia clone. The allelic variations seen inpfmdr1in these isolates did not correlate with chloroquine resistance as previously reported. The full-length sequence of the DHFR domain of the DHFR-TS gene revealed three or four point mutations in each Cambodian isolate. The latter findings may be correlated with high-level resistance to the antifolate drugs as has been previously described. None of the Cambodian isolates presented gene amplification in eitherpfmdr1or DHFR-TS genes.