Harold L. Martin

Vaginal Lactobacilli, Microbial Flora, and Risk of Human Immunodeficiency Virus Type 1 and Sexually Transmitted Disease Acquisition

A prospective cohort study was conducted to examine the relationship between vaginal colonization with lactobacilli, bacterial vaginosis (BV), and acquisition of human immunodeficiency virus type 1 (HIV-1) and sexually transmitted diseases in a population of sex workers in Mombasa, Kenya. In total, 657 HIV-1-seronegative women were enrolled and followed at monthly intervals. At baseline, only 26% of women were colonized with Lactobacillus species. During follow-up, absence of vaginal lactobacilli on culture was associated with an increased risk of acquiring HIV-1 infection (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-3.5) and gonorrhea (HR, 1.7; 95% CI, 1.1-2.6), after controlling for other identified risk factors in separate multivariate models. Presence of abnormal vaginal flora on Grams stain was associated with increased risk of both HIV-1 acquisition (HR, 1.9; 95% CI, 1.1-3.1) and Trichomonas infection (HR, 1.8; 95% CI, 1.3-2.4). Treatment of BV and promotion of vaginal colonization with lactobacilli should be evaluated as potential interventions to reduce a womans risk of acquiring HIV-1, gonorrhea, and trichomoniasis.

Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina

BACKGROUND Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells. METHODS Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of gag DNA sequences. FINDINGS HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p = 0.00001 and p = 0.003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2.9, 95% CI 1.5-5.7), and with use of low-dose and high-dose oral contraceptive pills (3.8, 1.4-9.9 and 12.3, 1.5-101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3.1, 1.1-9.8) and vaginal candidiasis (2.6, 1.2-5.4) were also correlated with significant increases in HIV-1 DNA detection, but Chlamydia trachomatis and Trichomonas vaginalis were not. INTERPRETATION Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.

Hormonal Contraception, Sexually Transmitted Diseases, and Risk of Heterosexual Transmission of Human Immunodeficiency Virus Type 1

To examine associations between method of contraception, sexually transmitted diseases (STDs), and incident human immunodeficiency virus type 1 (HIV-1) infection, a prospective observational cohort study was done among female sex workers attending a municipal STD clinic in Mombasa, Kenya. Demographic and behavioral factors significantly associated with HIV-1 infection included type of workplace, condom use, and parity. In multivariate models, vulvitis, genital ulcer disease, vaginal discharge, and Candida vaginitis were significantly associated with HIV-1 seroconversion. Women who used depo medroxyprogesterone acetate (DMPA) had an increased incidence of HIV-1 infection (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.4-3.4). In a multivariate model controlling for demographic and exposure variables and biologic covariates, the adjusted HR for HIV-1 infection among DMPA users was 2.0 (CI, 1.3-3.1). There was a trend for an association between use of high-dose oral contraceptive pills and HIV-1 acquisition (HR, 2.6; CI, 0.8-8.5).

Gender differences in HIV-1 diversity at time of infection

To develop an HIV-1 vaccine with global efficacy, it is important to identify and characterize the viruses that are transmitted, particularly to individuals living in areas of high incidence. Several studies have shown that virus from the blood of acutely infected adults was homogeneous, even when the virus population in the index case was genetically diverse. In contrast to those results with mainly male cohorts in America and Europe, in several cases a heterogeneous virus population has been found early in infection in women in Africa. Thus, we more closely compared the diversity of transmitted HIV-1 in men and women who became infected through heterosexual contact. We found that women from Kenya were often infected by multiple virus variants, whereas men from Kenya were not. Moreover, a heterogeneous virus was present in the women before their seroconversion, and in each woman it was derived from a single index case, indicating that diversity was most likely to be the result of transmission of multiple variants. Our data indicate that there are important differences in the transmitted virus populations in women and men, even when cohorts from the same geographic region who are infected with the same subtypes of HIV-1 are compared.

Hormonal Contraception And Risk Of Hiv-1 Acquisition: Results Of A 10-year Prospective Study.

The use of hormonal contraception has been associated with an increased risk of HIV-1 in some studies but not in others. We analysed data from a 10-year prospective cohort study of female sex workers in Mombasa, Kenya. In multivariate analysis, women using the injectable contraceptive depot medroxyprogesterone acetate and women using oral contraceptive pills were at increased risk of HIV-1 acquisition compared with women using no contraceptive method.

Evaluation of a low-dose nonoxynol-9 gel for the prevention of sexually transmitted diseases: a randomized clinical trial.

Background Low-dosenonoxynol-9 products have a potential advantage of reduced toxicity. However,little is known about their efficacy in reducing the incidence of sexuallytransmitted diseases(STDs). Goal Todetermine the effect that an intravaginal gel containing 52.5 mg ofnonoxynol-9 has on the acquisition of STDs in a cohort ofHIV-1–seronegative female sex workers in Mombasa,Kenya. StudyDesign A randomized double-blind placebo controlled trialwasperformed. Results Inthis study, 139 women were randomized to the nonoxynol-9 group and 139 to theplacebo group. No significant differences were found between the two studygroups in terms of safety outcomes and reported symptoms, except for a lowerincidence of vaginal erythema in the nonoxynol-9 group. There was asignificantly higher incidence of gonorrhea in the nonoxynol-9 group than inthe placebo group. No significant differences were observed between the groupsfor acquisition of Candida, trichomonas, bacterial vaginosis, Ctrachomatis, syphilis, or HIV-1, although the statistical power todetect differences for some of these STDs waslimited. Conclusions Inthis randomized placebo-controlled trial of a low-dose nonoxynol-9 gel, asignificantly higher incidence of gonorrhea was found in the nonoxynol-9group, but no significant differences between the groups were found for Candida, trichomonas, bacterialvaginosis, C trachomatis, syphilis, orHIV-1.

Primary Human Immunodeficiency Virus Type 1 Infection: Clinical Manifestations among Women in Mombasa, Kenya

The occurrence of clinical manifestations associated with primary human immunodeficiency virus type 1 (HIV-1) infection was evaluated in a prospective cohort study of female sex workers in Mombasa, Kenya. Among 103 women who seroconverted to HIV-1, fever, vomiting, diarrhea, headache, arthralgia, myalgia, skin rash, swollen lymph nodes, extrainguinal lymphadenopathy, inguinal lymphadenopathy, and vaginal candidiasis were noted significantly more frequently at visits in which seroconversion first became evident. Eighty-one percent of seroconverting women had >/=1 of these 11 symptoms or signs. Among 44% of the women, the acute illness was severe enough to prevent them from working. Having >/=2 of 6 selected symptoms and signs yielded a sensitivity of 51%, specificity of 83%, positive likelihood ratio of 3.2, and negative likelihood ratio of 0.5 for acute HIV-1 infection. The recognition of primary HIV-1-infection illness in high-risk populations and subsequent risk-reduction counseling could potentially reduce secondary HIV-1 transmission during this highly infectious period.

Factors Associated with Prevalent Abnormal Anal Cytology in a Large Cohort of HIV-Infected Adults in the United States

BACKGROUND The prevalence of and risk factors for abnormal anal cytology among men and women with human immunodeficiency virus (HIV) infection have not been extensively investigated. METHODS The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN study) is a prospective cohort study of HIV-infected patients in 4 US cities. Baseline questionnaires were administered and anal samples for cytology and human papillomavirus (HPV) detection and genotyping were collected. RESULTS Among 471 men and 150 women (median age, 41 years), 78% of participants were receiving combination antiretroviral therapy, 41% had a CD4(+) cell count of ≥500 cells/μL, and 71% had an HIV RNA viral load of <400 copies/mL. The anal cytology results were as follows: 336 participants (54%) had negative results, 96 participants (15%) had atypical squamous cells, 149 participants (24%) had low-grade squamous intraepithelial lesions, and 40 participants (6%) had high-grade squamous intraepithelial lesions. In a multivariate analysis, abnormal anal cytology was associated with number of high-risk and low-risk HPV types (adjusted odds ratio [AOR] for both, 1.28; P < .001), nadir CD4(+) cell count of <50 cells/μL (AOR, 2.38; P = .001), baseline CD4(+) cell count of <500 cells/μL (AOR, 1.75; P = .004), and ever having receptive anal intercourse (AOR, 2.51; P < .001). CONCLUSION HIV-infected persons with multiple anal HPV types or a nadir CD4(+) cell count of <50 cells/μL have an increased risk for abnormal anal cytology.

Trends in HIV-1 incidence in a cohort of prostitutes in Kenya: implications for HIV-1 vaccine efficacy trials.

Background: Accurate predictions of HIV‐1 incidence in potential study populations are essential for designing HIV‐1 vaccine efficacy trials. Little information is available on the estimated incidence of HIV‐1 in such populations, especially information on incidence over time and incidence while participating in risk‐reduction programs. Objectives: To examine time trends in HIV‐1 incidence in a vaccine preparedness cohort. Design: Prospective cohort study of female prostitutes in Mombasa, Kenya. Methods: HIV‐1 incidence was determined using open and closed cohort designs. Generalized estimating equations were used to model HIV‐1 and sexually transmitted disease (STD) incidence and sexual risk behaviors over time. Results: When analyzed as a closed cohort, HIV‐1 incidence declined 10‐fold during 3 years of follow‐up (from 17.4 to 1.7 cases/100 person‐years; p < .001). More than 50% of the cases of HIV‐1 occurred during the first 6 months after enrollment, and 73% during the first 12 months. When analyzed as an open cohort, HIV‐1 incidence density fell during the first 4 calendar years, influenced by accumulation of lower risk participants and variations in study recruitment. Significant declines occurred in both STD incidence and high‐risk sexual behaviors during follow‐up. Conclusions: This study documents a dramatic decline in the risk of HIV‐1 infection while participating in a prospective cohort, with most seroconversions occurring within 1 year of enrollment. Variations in HIV‐1 incidence within high‐risk populations should be anticipated during the design of vaccine trials.

Use of Nonoxynol-9 and Changes in Vaginal Lactobacilli

Several in vitro studies have shown nonoxynol-9 (N-9) to be toxic to lactobacilli, especially to strains that produce H2O2. Data from a randomized, double-blind, placebo-controlled crossover trial that investigated the safety and toxicity of 2 weeks of daily vaginal application of an N-9 gel were analyzed, to examine the effect of N-9 use on vaginal lactobacilli and bacterial vaginosis. In vivo, N-9 promoted sustained colonization by H2O2-producing lactobacilli among women already colonized (relative risk [RR], 1.8; 95% confidence interval [CI], 1.2-2.7). In addition, use of N-9 for 2 weeks reduced the likelihood of bacterial vaginosis (RR, 0.5; 95% CI, 0.3-1.0). In contrast, N-9 use by women initially colonized only by non-H2O2-producing lactobacilli resulted in loss of vaginal lactobacilli (RR, 2.5; 95% CI, 1.2-5.3). These data suggest that daily use of N-9 does not adversely affect vaginal colonization by H2O2-producing lactobacilli but that such use may promote loss of non-H2O2-producing strains.