Craig M. Wilson

Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA

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 ≥ 500 cells/mm 3 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.

HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination

Variable immune responses to hepatitis B virus (HBV) infection and recombinant HBV vaccines have been associated with polymorphisms in several genes within the human leukocyte antigen (HLA) complex. Analyses of polymerase chain reaction (PCR)‐based genotyping data from 164 North American adolescents vaccinated with recombinant HBV products confirmed that HLA‐DRB1*07 (relative odds [RO] = 5.18, P < .0001) and human immunodeficiency virus type 1 (HIV‐1) infection (RO = 3.91, P < .001) were both associated with nonresponse to full‐dose vaccination. Further associations were observed with single nucleotide polymorphisms (SNPs) at the IL2 and IL4 loci along with insertion/deletion variants at the IL12B locus (P = .003–.01). Host genetic associations were independent of one another as well as other HLA (A, B, C, and DQB1) and cytokine gene (IL4R, IL6, IL10, and TNF) variants. Statistical adjustments for nongenetic factors (gender, ethnicity, age, HIV‐1 infection, and vaccination protocols) did not substantially alter the strengths of the genetic relationships. The overall distribution pattern of genetic variations was similar between the analyzed vaccinees and additional adolescents (n = 292) from the same cohort. In conclusion, DRB1*07 (or a closely linked allele) and immunoregulatory cytokine gene polymorphisms correlate with variable immune response to recombinant HBV vaccines. (HEPATOLOGY 2004;39:978–988.)

Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa.

Resistance of Plasmodium falciparum to many therapeutic agents is an increasing problem in most endemic areas. The role of the mdr-like gene products of P. falciparum in resistance to quinoline-containing compounds is not clear. The purpose of this study was to further examine the role of pfmdr1 in drug resistance in fresh clinical isolates originating from Africa. Drug susceptibility testing (chloroquine, mefloquine, halofantrine and quinine) and a molecular analysis of pfmdr1 was completed for 51 fresh clinical isolates. A statistical association between the chloroquine sensitivity phenotype and an intragenic allele of pfmdr1 was noted at a position, amino acid 86, which was previously associated with chloroquine resistance. There was little variation in the other intragenic alleles previously associated with chloroquine resistance. No correlation between pfmdr1 intragenic allelic variation and susceptibility to mefloquine, halofantrine or quinine was found. There was no association between gene copy number of pfmdr1 and any drug resistant phenotype in an analysis of selected isolates. This, along with other data, suggests that mefloquine resistance may have arisen by two different mechanisms in African and Southeast Asian isolates. Much more variability in the polyasparaginated region of the pfmdr1 gene was noted in this study than previously reported. In addition, fingerprint analysis using multiplex PCR revealed considerable genetic variability among these isolates.

HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently

The ability of HIV-1-specific CD8+ T cell responses to recognize epitope variants resulting from viral sequence variation in vivo may affect the ease with which HIV-1 can escape T cell control and impact on the rate of disease progression in HIV-1-infected humans. Here, we studied the functional cross-reactivity of CD8 responses to HIV-1 epitopes restricted by HLA class I alleles associated with differential prognosis of infection. We show that the epitope-specific responses exhibiting the most efficient cross-recognition of amino acid-substituted variants were those strongly associated with delayed progression to disease. Not all epitopes restricted by the same HLA class I allele showed similar variant cross-recognition efficiency, consistent with the hypothesis that the reported associations between particular HLA class I alleles and rate of disease progression may be due to the quality of responses to certain “critical” epitopes. Irrespective of their efficiency of functional cross-recognition, CD8+ T cells of all HIV-1 epitope specificities examined showed focused TCR usage. Furthermore, interpatient variability in variant cross-reactivity correlated well with use of different dominant TCR Vβ families, suggesting that flexibility is not conferred by the overall clonal breadth of the response but instead by properties of the dominant TCR(s) used for epitope recognition. A better understanding of the features of T cell responses associated with long-term control of viral replication should facilitate rational vaccine design.

The REACH (Reaching for Excellence in Adolescent Care and Health) project: study design, methods, and population profile

The Reaching for Excellence in Adolescent Care and Health (REACH) Project was designed as an observational study aimed to achieve a better understanding of HIV disease progression and co-morbidity in adolescents in the US. Direct interviews among 242 HIV-infected females and 83 males and 131 high-risk HIV-uninfected females and 40 males aged 12-18 years were conducted to examine the pathogenesis of HIV infection and its spectrum of disease in adolescents. The study also aimed to examine potential immunologic markers in peripheral blood for disease progression specific to adolescents infected with HIV. Results showed that HIV infection predominates among females and youths with poor knowledge on sexual risk behaviors. It was also shown that the seroconversion rate in the homosexual/bisexual male cohort was 7.7/100 person-years while there were no seroconversions among the HIV-uninfected females. Distribution of CD4+ T-cell numbers suggested a progression of the disease among the infected cohorts. Based on the findings the risk behaviors among HIV-infected cohorts demonstrate the need for theory-based development of secondary prevention programs for HIV-positive youth.

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

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

Association between birth outcomes and aflatoxin B1 biomarker blood levels in pregnant women in Kumasi, Ghana

Objective  To investigate the association between birth outcomes and blood levels of aflatoxin B1 (AFB1)‐lysine adduct in pregnant women in Kumasi, Ghana.

Delayed onset of pubertal development in children and adolescents with perinatally acquired HIV infection.

Objective: To examine whether greater severity of HIV infection is associated with delayed initiation of pubertal development among perinatally HIV‐infected children, and to compare sexual maturation of perinatally HIV‐infected children with children in the general US population using the National Health and Nutrition Examination Survey III. Methods: In a prospective cohort study, the authors studied 983 HIV‐infected children aged 6 to 18 years, who had Tanner stage assessed on at least two occasions between 1995 and 2000. Analyses were conducted separately for girls and boys to identify factors associated with onset of puberty or adrenarche (progression beyond Tanner stage 1). Results: Among children who were in Tanner stage 1 at their first assessment, 185 of 413 (45%) girls and 144 of 434 (33%) boys entered puberty during the observation period. In multivariate longitudinal regression analyses adjusted for age, race/ethnicity, time interval between study visits, and other clinical factors, girls with severe immunosuppression (CD4% <15) were significantly less likely to enter adrenarche (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.29‐0.83) and puberty (OR, 0.57; 95% CI, 0.33‐0.96) compared with girls who were not immunosuppressed (CD4% ≥25). For boys, those with severe immunosuppression were significantly less likely to enter adrenarche (OR, 0.52; 95% CI, 0.28‐0.96) and tended to be less likely to begin puberty (OR, 0.69; 95% CI, 0.39‐1.22) compared with boys who were not immunosuppressed. Qualitative comparisons suggested that HIV‐infected children may experience delayed puberty and adrenarche compared with similarly aged children in the general US population. Conclusions: Immunosuppression was associated with delayed pubertal onset in perinatally HIV‐infected children. Further studies of perinatally HIV‐infected and uninfected children are needed to better quantify the delay in pubertal onset and to compare the pace of pubertal maturation.

Host genetic profiles predict virological and immunological control of HIV-1 infection in adolescents

Objective: To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-1-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. Methods: HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1-seropositive adolescents (ages 13–18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of −1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6–12-month interval when no antiretroviral therapy was taken. Results: HLA-B*57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 × 106 cells/l) consistently had more positive (+1 to +2) than negative (−1 to −4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16 000 copies/ml and CD4 cells < 450 × 106 cells/l) or the remainder (n = 134) of the cohort (overall P < 0.0001). Conclusion: A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents.

Immunogenicity and Safety of the Human Papillomavirus 6, 11, 16, 18 Vaccine in HIV-Infected Young Women

BACKGROUND The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV). METHODS We enrolled 99 women aged 16-23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose. RESULTS The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted. CONCLUSIONS In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated.