Biomedical subjects

Susan Buchbinder

Publications and source records attributed to Susan Buchbinder.

At least 19 recordsLinked to original sources

PubMed2026

Safety and Tolerability of Oral Islatravir Once Monthly as Pre-exposure Prophylaxis in Cisgender Men and Transgender Women Who Have an Elevated Likelihood of HIV-1 Exposure: Results From the IMPOWER-24 Randomized Phase 3 Study.

BACKGROUND: Islatravir once monthly (qm), a nucleoside reverse transcriptase translocation inhibitor with a long half-life, was evaluated for safety and tolerability in cisgender men and transgender women who have sex with men and are at increased likelihood of HIV-1 (HIV) exposure. METHODS: IMPOWER-24 (NCT04652700) was a double-blind, Phase 3 study. Participants were randomized 2:1 to islatravir 60 mg oral qm or emtricitabine (FTC; 200 mg) coformulated with either tenofovir disoproxil (245 mg) or tenofovir alafenamide (TAF; 25 mg) once daily (qd). After ∼9 months, blinded islatravir was discontinued due to lymphocyte reductions; participants were offered open-label comparator for 20 months. RESULTS: In total, 494 participants were enrolled (328 islatravir; 166 comparator): 91.5% were cisgender men, 41.7% were White, and median age was 27 years. Mean blinded dosing duration was 4.7 months (islatravir) versus 4.3 months (comparator). Overall, 211 participants (64.3%) in the islatravir group and 128 (77.1%) in the comparator group had ≥1 adverse event (AE). Most AEs were mild or moderate, with 1 AE leading to product discontinuation (islatravir; gastroesophageal reflux). Serious AEs occurred in <2%; none were related to study product. Change in total lymphocytes in the islatravir group at Month 3 was -7.4%; a trend toward recovery was observed after islatravir was stopped. Mean total lymphocytes remained within normal range. No HIV infections occurred in either group during the double-blind phase. CONCLUSIONS: Islatravir qm was generally well tolerated; decreases in total lymphocytes were observed with islatravir. Original primary efficacy objectives were not assessed due to early study stoppage.

Humans↗

PubMed2006

Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection.

TRIM5alpha acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5alpha on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5alpha 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5alpha 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5alpha R136 protein. The 43Y variant of TRIM5alpha was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts.

Adolescent↗

PubMed2006

Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression.

CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Chemokine CCL3↗

PubMed2006

Risk factors for HIV infection among men who have sex with men.

OBJECTIVES: Risk factors for HIV acquisition were examined in a recent cohort of men who have sex with men (MSM). DESIGN: A longitudinal analysis of 4295 HIV-negative MSM enrolled in a randomized behavioral intervention trial conducted in six US cities. METHODS: MSM were enrolled and assessed for HIV infection and risk behaviors semi-annually, up to 48 months. RESULTS: In multivariate analysis, men reporting four or more male sex partners, unprotected receptive anal intercourse with any HIV serostatus partners and unprotected insertive anal intercourse with HIV-positive partners were at increased risk of HIV infection, as were those reporting amphetamine or heavy alcohol use and alcohol or drug use before sex. Some depression symptoms and occurrence of gonorrhea also were independently associated with HIV infection. The attributable fractions of high number of male partners, use of alcohol or drugs before sex, and unprotected receptive anal intercourse with unknown status partners and the same with presumed negative partners accounted for 32.3, 29.0, 28.4 and 21.6% of infections, respectively. CONCLUSIONS: The challenge is to develop strategies to identify men in need. Interventions are needed to help men reduce their number of sexual partners, occurrences of unprotected anal intercourse, alcohol or drug use before sex and address other mental health issues.

Adult↗

PubMed2006

Consistent effects of TSG101 genetic variability on multiple outcomes of exposure to human immunodeficiency virus type 1.

Tumor susceptibility gene 101 (TSG101) encodes a host cellular protein that is appropriated by human immunodeficiency virus type 1 (HIV-1) in the budding process of viral particles from infected cells. Variation in the coding or noncoding regions of the gene could potentially affect the degree of TSG101-mediated release of viral particles. While the coding regions of the gene were found to lack nonsynonymous variants, two polymorphic sites in the TSG101 5' area were identified that were associated with the rate of AIDS progression among Caucasians. These single-nucleotide polymorphisms (SNPs), located at positions -183 and +181 relative to the translation start, specify three haplotypes termed A, B, and C, which occur at frequencies of 67%, 21%, and 12%, respectively. Haplotype C is associated with relatively rapid AIDS progression, while haplotype B is associated with slower disease progression. Both effects were dominant over the intermediate haplotype A. The haplotypes also demonstrated parallel effects on the rate of CD4 T-cell depletion and viral load increase over time, as well as a possible influence on HIV-1 infection. The data raise the hypothesis that noncoding variation in TSG101 affects the efficiency of TSG101-mediated release of viral particles from infected cells, thereby altering levels of plasma viral load and subsequent disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed2006

KIR/HLA pleiotropism: protection against both HIV and opportunistic infections.

The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS.

AIDS-Related Opportunistic Infections↗

PubMed2005

AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis.

An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease.

Acquired Immunodeficiency Syndrome↗

PubMed2005

AIDS. Promote HIV chemoprophylaxis research, don't prevent it.

Explore the source record for details and available documents.

Adenine↗

PubMed2005

Motivations for participating in an HIV vaccine efficacy trial.

Understanding why people join HIV vaccine efficacy trials is critical for trial recruitment and education efforts. We assessed participants' motivations for joining the VaxGen VAX004 study, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial. Of 5417 participants, 94% were men who have sex with men (MSM) and 6% were women at risk for heterosexual transmission of HIV. Most participants gave altruistic reasons for trial participation: 99% reported having joined to help find an HIV vaccine, and 98% reported having joined to help their community. Some gave more personal reasons: 56% joined to reduce risk behavior and 46% joined to get protection from HIV. Additional reasons related to receiving services or compensation included to obtain information about HIV (75%), to receive free HIV testing (34%), and for financial reimbursement (14%). Multivariate logistic regression analysis showed that female participants were significantly more motivated than male participants to join the trial for protection and to receive services or compensation (all P<0.05). Participants with 13 or more sex partners in the 6 months before enrollment were more likely than those with fewer sex partners to report having joined the trial for protection but less likely to have joined to reduce risk behavior (both P<0.05). Because many participants reported personal protection from HIV as their reason for joining, vaccine trial risk-reduction counseling should continue to emphasize the placebo-controlled trial design and unknown efficacy of the test product, particularly for women and persons with large numbers of sex partners. Because a significant minority of participants reported joining to receive HIV information, HIV testing, and financial reimbursement, a need is indicated for provision of HIV prevention services outside research trials and for monitoring to ensure that participants are not motivated to join trials for financial gain.

AIDS Vaccines↗

PubMed2005

Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study.

BACKGROUND: Infection with human papillomavirus (HPV) is causally linked to the development of anal and cervical cancer. In the United States, the incidence of anal cancer among men who have sex with men (MSM) is higher than the incidence of cervical cancer among women. Anal squamous intraepithelial lesions (ASILs) are anal cancer precursors comprising low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). The prevalence of cervical cancer precursor lesions peaks at around 30 years of age. The age-related prevalence of ASILs in HIV-negative MSM is unknown. METHODS: We conducted a cross-sectional analysis of the prevalence and determinants of ASILs in 1262 HIV-negative MSM aged 18-89 years recruited from four U.S. cities. Anal cytology and behavioral data were obtained. Anal HPV infection status was assessed by polymerase chain reaction. Independent predictors of ASILs were identified using logistic regression. All statistical tests were two-sided. RESULTS: The prevalences of LSILs and HSILs were 15% and 5%, respectively, and did not change with age. In a multivariable analysis, the risk of LSILs was associated with having more than five male receptive anal sex partners (P = .03), any use of poppers (alkyl nitrites) in the previous 6 months [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.1 to 2.5; P = .03] or use of injection drugs two or more times per month during the previous 6 months [OR = 19, 95% CI = 1.3 to 277; P = .03], older age at first receptive anal intercourse (P = .004), and infection with a greater number of HPV types (P < .001 for linear trend). The risk of HSILs was associated with any anal HPV infection (OR = 3.2, 95% CI = 1.1 to 9.4; P = .039) and infection with an increasing number of HPV types (P < .001 for linear trend). CONCLUSIONS: Sexually active HIV-negative MSM in all age groups have a high prevalence of ASILs, possibly reflecting their ongoing sexual exposure to HPV.

Adult↗

PubMed2005

HIV sexual risk behavior over 36 months of follow-up in the world's first HIV vaccine efficacy trial.

Increased risk behavior among participants in HIV vaccine efficacy trials has been a concern. This study evaluated HIV sexual risk behavior among 5095 HIV-negative men who have sex with men (MSM) and 308 women enrolled in a randomized, double-blind, placebo-controlled efficacy trial of a bivalent rgp120 vaccine at 61 sites, primarily in North America. Sexual risk behavior data were collected at baseline and semiannually for 36 months. Overall, sexual risk behavior did not exceed baseline levels during the trial. Among MSM, younger age (< or =30 years), perceived assignment to vaccine, and nonblack race were associated with an increased probability of unprotected anal sex. Among women, unprotected vaginal sex initially decreased but was statistically equivalent to baseline by 24 months, whereas unprotected vaginal sex with HIV-infected partners decreased from baseline, where it remained throughout the trial. HIV sexual risk behavior did not increase among trial participants; however, it was substantial throughout the trial. Consistently high levels of risk behavior and the association of these behaviors to perceived assignment and demographic variables underscore the need for vigilant HIV risk reduction counseling, informed consent, and educational processes in the context of HIV vaccine efficacy trials.

AIDS Vaccines↗

PubMed2005

Longitudinal patterns of methamphetamine, popper (amyl nitrite), and cocaine use and high-risk sexual behavior among a cohort of san francisco men who have sex with men.

Most prior studies examining drug use among men who have sex with men (MSM) have been cross-sectional or retrospective and have not determined whether periods of increased drug use are associated with high-risk sexual behavior at the individual level. In this article, we describe patterns of use of methamphetamines, poppers, and sniffed cocaine and sexual risk behavior among 736 San Francisco MSM enrolled in the EXPLORE study and followed for up to 48 months. In longitudinal analysis, use of methamphetamines, poppers, and sniffed cocaine declined during follow-up. However, compared with older participants, younger participants were more likely to increase their drug use over time. Results of conditional logistic regression demonstrated that high-risk sexual behavior was more common during reporting periods characterized by increased methamphetamine, poppers, or sniffed cocaine use. This within-person analysis found that compared with periods of no drug use, periods of both light drug use (less than weekly use of drugs) and heavier drug use (at least weekly use of at least one drug) were significantly associated with increased risk of engaging in unprotected anal sex with an HIV-positive or unknown-status partner. These results suggest that even intermittent, recreational use of these drugs may lead to high-risk sexual behavior, and that, to reduce and prevent risks of HIV, no level of use of these drugs should be considered "safe." HIV prevention interventions should target MSM who report either light or heavy use of methamphetamines, poppers, and sniffed cocaine.

Adolescent↗

PubMed2005

Negotiated safety relationships and sexual behavior among a diverse sample of HIV-negative men who have sex with men.

OBJECTIVE: To examine the prevalence of negotiated safety (NS) in a diverse sample of HIV-negative men who have sex with men (MSM), characteristics of MSM practicing NS, and adherence to NS. METHODS: This was a cross-sectional survey of San Francisco MSM recruited from venues and community organizations. NS relationships were defined as those in which HIV-negative men were in seroconcordant primary relationships for >/=6 months, had unprotected anal intercourse (UA) together, and had rules prohibiting UA with others. Adherence to NS was determined from self-reported sexual behavior in the prior 3 months. Presence of an agreement with NS partners to disclose rule breaking was also determined. RESULTS: Of 340 HIV-negative participants, 76 (22%) reported a current seroconcordant primary relationship for >/=6 months. Of these 76 men, 38 (50%) had NS relationships, 30 (39%) had no UA with primary partners, and 8 (11%) had UA with primary partners without rules prohibiting UA with others. In multivariate analysis, NS was more common than no UA with primary partners in younger men. Among 38 NS men, 29% violated their NS-defining rule in the prior 3 months, including 18% who reported UA with others, and 18% reported a sexually transmitted infection (STI) in the prior year. Only 61% of NS men adhered fully to rules and agreed to disclose rule breaking. CONCLUSIONS: Although NS was commonly practiced among HIV-negative men in seroconcordant relationships, some men violated NS-defining rules, placing themselves and potentially their primary partners at risk for HIV infection. Prevention efforts regarding NS should emphasize the importance of agreement adherence, disclosure of rule breaking, and routine STI testing.

Adolescent↗

PubMed2004

Age-Specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study.

BACKGROUND: In the United States, anal cancer in men who have sex with men (MSM) is more common than cervical cancer in women. Human papillomavirus (HPV) is causally linked to the development of anal and cervical cancer. In women, cervical HPV infection peaks early and decreases after the age of 30. Little is known about the age-specific prevalence of anal HPV infection in human immunodeficiency virus (HIV)-negative MSM. METHODS: We studied the prevalence and determinants of anal HPV infection in 1218 HIV-negative MSM, 18-89 years old, who were recruited from 4 US cities. We assessed anal HPV infection status by polymerase chain reaction. RESULTS: HPV DNA was found in the anal canal of 57% of study participants. The prevalence of anal HPV infection did not change with age or geographic location. Anal HPV infection was independently associated with receptive anal intercourse (odds ratio [OR], 2.0; P<.0001) during the preceding 6 months and with >5 sex partners during the preceding 6 months (OR, 1.5; P<.0001). CONCLUSIONS: Urban, HIV-negative MSM have a stable, high prevalence of anal HPV infection across all age groups. These results differ substantially from the epidemiologic profile of cervical HPV infection in women. This may reflect differences between these populations with respect to the number of new sex partners after the age of 30 and may explain the high incidence of anal cancer in MSM.

Adult↗

PubMed2004

Absence of immunodominant anti-Gag p17 (SL9) responses among Gag CTL-positive, HIV-uninfected vaccine recipients expressing the HLA-A*0201 allele.

According to a number of previous reports, control of HIV replication in humans appears to be linked to the presence of anti-HIV-1 Gag-specific CD8 responses. During the chronic phase of HIV-1 infection, up to 75% of the HIV-infected individuals who express the histocompatibility leukocyte Ag (HLA)-A*0201 recognize the Gag p17 SLYNTVATL (aa residues 77-85) epitope (SL9). However, the role of the anti-SL9 CD8 CTL in controlling HIV-1 infection remains controversial. In this study we determined whether the pattern of SL9 immunodominance in uninfected, HLA-A*0201 HIV vaccine recipients is similar to that seen in chronically HIV-infected subjects. The presence of anti-SL9 responses was determined using a panel of highly sensitive cellular immunoassays, including peptide:MHC tetramer binding, IFN-gamma ELISPOT, and cytokine flow cytometry. Thirteen HLA-A*0201 vaccinees with documented anti-Gag CD8 CTL reactivities were tested, and none had a detectable anti-SL9 response. These findings strongly suggest that the pattern of SL9 epitope immunodominance previously reported among chronically infected, HLA-A*0201-positive patients is not recapitulated in noninfected recipients of Gag-containing canarypox-based candidate vaccines and may be influenced by the relative immunogenicity of these constructs.

AIDS Vaccines↗

PubMed2004

Substance use and sexual risk: a participant- and episode-level analysis among a cohort of men who have sex with men.

Prior reports associating substance use with sexual risk behavior have generally used summary measures and have not adjusted for participants' background levels of substance use. In this 1999-2001 US study (the EXPLORE study), the authors determined whether substance use during sex was independently associated with sexual risk during recent sexual episodes, as reported by 4,295 human immunodeficiency virus-negative men who have sex with men. The main outcome measure was serodiscordant unprotected anal sex (SDUA). The influence of participant-level characteristics was examined by using repeated-measures logistic models. In assessing the influence of episode-level predictors on SDUA, the influence of participant-level characteristics, including 6-month substance use, was removed by using conditional logistic regression, in effect making each participant his own control. The authors also adjusted for partner characteristics. Eleven percent of participants reported heavy alcohol use, 37% used poppers, 19% sniffed cocaine, and 13% used amphetamines. In the participant-level analysis, use of poppers, amphetamines, and sniffed cocaine as well as heavy alcohol use in the prior 6 months were independently associated with SDUA. In the conditional analysis, consumption of > or = 6 alcoholic drinks or use of poppers, amphetamines, or sniffed cocaine just before or during sex was independently associated with SDUA. The authors concluded that programs aimed at preventing human immunodeficiency virus transmission should emphasize the influence of substance use during sex on increased risk behavior.

Adolescent↗

PubMed2004

Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not restricted to certain risk groups or specific HIV-1 subtypes.

African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.

Female↗

PubMed2004

APOBEC3G genetic variants and their influence on the progression to AIDS.

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.

APOBEC-3G Deaminase↗