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1.  Anal Sex, Vaginal Practices, and HIV Incidence in Female Sex Workers in Urban Kenya: Implications for the Development of Intravaginal HIV Prevention Methods 
AIDS Research and Human Retroviruses  2011;27(10):1067-1072.
Abstract
Multiple intravaginal HIV prevention methods, including microbicide gels, barriers, and intravaginal rings, are in clinical development in Africa. Development of intravaginal HIV prevention products requires an understanding of sexual behavior, sexually transmitted infection (STI), and vaginitis prevalences, and sexual and vaginal practices in potential target populations. We assessed these factors in a cohort of Kenyan female sex workers (FSW). Women who reported exchanging sex for money/gifts at least three times in the past month and who were HIV uninfected were enrolled and followed for 6 months. STI prevalence and HIV incidence were analyzed by multivariate logistic regression analysis, controlling for demographic and behavioral factors. Thirty-seven percent (74/200) reported having had anal sex. Frequency of anal sex was higher with regular and casual partners than with primary partners. Women were less likely to use condoms for anal sex than for vaginal sex with regular or casual partners. Vaginal washing was universal (100%). HIV incidence was 5.6 per 100 person-years (95% CI 1.62, 11.67). HIV incidence was not associated with any demographic or risk behavior. The relatively high rate of anal sex and universal vaginal washing may complicate both safety and efficacy evaluation of intravaginal products and should be taken into account in trial design. This FSW population had significant HIV incidence and needs continued HIV prevention interventions.
doi:10.1089/aid.2010.0362
PMCID: PMC3186689  PMID: 21406032
2.  Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target 
Science (New York, N.y.)  2009;326(5950):285-289.
Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1 infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1,800 HIV-1 infected individuals, primarily infected with non-clade B viruses, and selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from approximately 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. The previously undescribed epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.
doi:10.1126/science.1178746
PMCID: PMC3335270  PMID: 19729618
3.  Selective removal of stratum corneum by microdermabrasion to increase skin permeability 
This study sought to determine if microdermabrasion can selectively remove stratum corneum to increase skin permeability. Although, microdermabrasion has been used for cosmetic treatment of skin for decades, no study has assessed the detailed effects of microdermabrasion conditions on the degree of skin tissue removal. Therefore, we histologically characterized the skin of rhesus macaques and human volunteers after microdermabrasion at different conditions. Using mobile tip microdermabrasion, an increase in the number of treatment passes led to greater tissue removal ranging from minimal effects to extensive damage to deeper layers of the skin. Of note, these data showed for the first time that at moderate microdermabrasion conditions selective yet full-thickness removal of stratum corneum could be achieved with little damage to deeper skin tissues. In the stationary mode of microdermabrasion, selective stratum corneum removal was not observed, but micro-blisters could be seen. Similar tissue removal trends were observed in human volunteers. As proof of concept for drug delivery applications, a model fluorescent drug (fluorescein) was delivered through microdermabraded skin and antibodies were generated against vaccinia virus after its topical application in monkeys. In conclusion, microdermabrasion can selectively remove full-thickness stratum corneum with little damage to deeper tissues and thereby increase skin permeability.
doi:10.1016/j.ejps.2009.06.004
PMCID: PMC2731013  PMID: 19559791
microdermabrasion; transdermal drug delivery; vaccination; vaccinia virus; skin histology; skin permeability; stratum corneum removal
4.  Human Immunodeficiency Virus Type 1 Elite Neutralizers: Individuals with Broad and Potent Neutralizing Activity Identified by Using a High-Throughput Neutralization Assay together with an Analytical Selection Algorithm▿ † 
Journal of Virology  2009;83(14):7337-7348.
The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of ≥100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.
doi:10.1128/JVI.00110-09
PMCID: PMC2704778  PMID: 19439467
5.  Safety and Immunogenicity of Adenovirus-Vectored Near-Consensus HIV Type 1 Clade B gag Vaccines in Healthy Adults 
Abstract
Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-γ ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers <200 versus ≥200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers <200 versus ≥200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers <200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.
doi:10.1089/aid.2008.0212
PMCID: PMC3256563  PMID: 19108693
6.  Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial 
PLoS ONE  2013;8(9):e74314.
Background
Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens.
Design
Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment.
Methods
Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT.
Results
Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen.
Conclusions
Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing.
Registration
Clinicaltrials.gov number NCT00931346
doi:10.1371/journal.pone.0074314
PMCID: PMC3784443  PMID: 24086333
7.  Safety and Adherence to Intermittent Pre-Exposure Prophylaxis (PrEP) for HIV-1 in African Men Who Have Sex with Men and Female Sex Workers 
PLoS ONE  2012;7(4):e33103.
Background
Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW).
Methods/Principal Findings
MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2∶1∶2∶1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen.
Conclusions/Significance
Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens.
Trial Registration
ClinicalTrials.gov NCT00971230
doi:10.1371/journal.pone.0033103
PMCID: PMC3325227  PMID: 22511916
8.  An Evaluation of Intravaginal Rings as a Potential HIV Prevention Device in Urban Kenya: Behaviors and Attitudes That Might Influence Uptake within a High-Risk Population 
Journal of Women's Health  2008;17(6):1025-1034.
Abstract
Purpose
We sought to assess the potential acceptability of intravaginal rings (IVRs) as an HIV prevention method among at-risk women and men.
Methods
We conducted a qualitative assessment of initial attitudes toward IVRs, current HIV prevention methods, and common behavioral practices among female sex workers (FSWs) and men who frequent FSWs in Mukuru, an urban slum community in Nairobi, Kenya. Nineteen women and 21 men took part in six focus group discussions.
Results
Most participants, both male and female, responded positively to the concept of an IVR as a device for delivering microbicides. Women particularly liked the convenience offered by its slow-release capacity. Some female respondents raised concerns about whether male customers would discover the ring and respond negatively, whereas others thought it unlikely that their clients would feel the ring. Focus groups conducted with male clients of FSWs suggested that many would be enthusiastic about women, and particularly sex workers, using a microbicide ring, but that women's fears about negative responses to covert use were well founded. Overall, this high-risk population of FSWs and male clients in Nairobi was very open to the IVR as a potential HIV prevention device.
Conclusion
Themes that emerged from the focus groups highlight the importance of understanding attitudes toward IVRs as well as cultural practices that may impact IVR use in high-risk populations when pursuing clinical development of this potential HIV prevention device.
doi:10.1089/jwh.2007.0529
PMCID: PMC2942749  PMID: 18681822

Results 1-8 (8)