Smita Joshi

High rates of syphilis among STI patients are contributing to the spread of HIV-1 in India

Background: Recent syphilis outbreaks have raised concern regarding the potential enhancement of HIV transmission. The incidence of syphilis and its association with HIV-1 infection rates among a cohort of sexually transmitted infection (STI) clinic attendees was investigated. Methods: 2732 HIV-1 seronegative patients attending three STI and one gynaecology clinic, were enrolled from 1993–2000 in an ongoing prospective cohort study of acute HIV-1 infection in Pune, India. At screening and quarterly follow up visits, participants underwent HIV-1 risk reduction counselling, risk behaviour assessment and HIV/STI screening that included testing for serological evidence of syphilis by RPR with TPHA confirmation. Patients with genital ulcers were screened with dark field microscopy. Results: Among 2324 participants who were HIV-1 and RPR seronegative at baseline, 172 participants were found to have clinical or laboratory evidence of syphilis during follow up (5.4 per 100 person years, 95% CI 4.8 to 6.5 per 100 person years). Independent predictors of syphilis acquisition based on a Cox proportional hazards model included age less than 20 years, lack of formal education, earlier calendar year of follow up, and recent HIV-1 infection. Based on a median follow up time of 11 months, the incidence of HIV-1 was 5.8 per 100 person years (95% CI 5.0 to 6.6 per 100 person years). Using a Cox proportional hazards model to adjust for known HIV risk factors, the adjusted hazard ratio of HIV-1 infection associated with incident syphilis was 4.44 (95% CI 2.96 to 6.65; p<0.001). Conclusions: A high incidence rate of syphilis was observed among STI clinic attendees. The elevated risk of HIV-1 infection that was observed among participants with incident syphilis supports the hypothesis that syphilis enhances the sexual transmission of HIV-1 and highlights the importance of early diagnosis and treatment of syphilis.

phase 1 Trial of the Topical Microbicide Buffergel: Safety Results From Four International Sites

Aim: To evaluate the safety of BufferGel (ReProtect LLC, Baltimore, MD), a spermicidal microbicide that acidifies semen and maintains the protective acidity of the vagina, in a high‐dose tolerance trial. Methods: HIV/STD negative, sexually abstinent, and sexually active women in India, Thailand, Malawi, and Zimbabwe were asked to insert one applicator (˜5 ml) of BufferGel vaginally twice per day for 14 days. Sexually active women agreed to have sex (while using BufferGel and nonlubricated condoms) at least twice per week. Results: In total, 98 women (30 sexually abstinent and 68 sexually active) were enrolled. Overall compliance with product use was 93%. Epithelial abnormalities detected by pelvic examination or colposcopy were uncommon (8 cases in 271 examinations). Irritation was reported by approximately one quarter of the women (0.58 events per woman‐week) but was generally mild and of short duration. The prevalence of bacterial vaginosis (BV) fell significantly, from 30% at enrollment to 6% at one week, and 7% at two weeks of BufferGel use. Thirty‐two women acquired microscopically detectable yeast during BufferGel exposure, but only 3 developed symptomatic vaginitis. Conclusion: BufferGel appears to be safe and well tolerated by the cervicovaginal epithelium. Its effect on BV and yeasts merits further study.

Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India.

Human immunodeficiency virus (HIV)‐infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)‐induced cervical cancer remains unabated because of lack of cost‐effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV‐infected women. We evaluated 303 nonpregnant HIV‐infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low‐grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high‐grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV‐positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 μL−1. Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV‐infected women. Implementing VIA‐based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low‐cost HPV‐based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.

Prevalence and Predictors of Colposcopic-Histopathologically Confirmed Cervical Intraepithelial Neoplasia in HIV-Infected Women in India

Background Prevalence estimates of cervical intraepithelial neoplasia (CIN) among HIV-infected women in India have been based on cervical cytology, which may have underestimated true disease burden. We sought to better establish prevalence estimates and evaluate risk factors of CIN among HIV-infected women in Pune, India using colposcopy and histopathology as diagnostic tools. Methodology Previously unscreened, non-pregnant HIV-infected women underwent cervical cancer screening evaluation including standardized diagnostic colposcopy by a gynecologist. Histopathologic confirmation was conducted among consenting women with clinical suspicion of CIN. The prevalence of CIN was evaluated by a composite diagnosis based on colposcopy and histopathology results. Multivariable ordinal logistic regression analysis was conducted to determine independent predictors of increasing severity of CIN. Results The median age of the nu200a=u200a303 enrolled HIV-infected women was 30 years (interquartile range, 27–34). A majority of the participants were widowed or separated (187/303, 61.7%), more than one-third (114/302, 37.7%) were not educated beyond primary school, and nearly two-thirds (196/301, 64.7%) had a family per capita income of <1,000 Indian Rupees (∼US

Expanded safety study of Praneem polyherbal vaginal tablet among HIV-uninfected women in Pune, India: a phase II clinical trial report

22) per month. Cervical high-risk HPV-DNA was detected in 41.7% (124/297) of participants. The composite colposcopic-histopathologic diagnoses revealed no evidence of CIN in 220 out of 303 (72.6%) women, CIN1 in 33/303 (10.9%), CIN2 in 31/303 (10.2%), CIN3 in 18/303 (5.9%) and 1 (0.3%) woman was diagnosed with ICC. Thus, over a quarter of the participants [83/303: 27.7% (95% CI: 22.7–33.1)] had ≥CIN1 lesions and a sixth [50/303: 16.5% (95% CI: 12.2–21.9)] had evidence of advanced (≥CIN2) neoplastic disease. The independent predictors of increasing severity of CIN as revealed by a proportional odds model using multivariable ordinal logistic regression included (i) currently receiving antiretroviral therapy [adjusted odds ratios (aOR): 2.24 (1.17, 4.26), pu200a=u200a0.01] and (ii) presence of cervical high-risk HPV-DNA [aOR: 1.93 (1.13, 3.28), pu200a=u200a0.02]. Conclusions HIV-infected women in Pune, India have a substantial burden of cervical precancerous lesions, which may progress to invasive cervical cancer unless appropriately detected and treated. Increased attention should focus on recognizing and addressing this entirely preventable cancer among HIV-infected women, especially in the context of increasing longevity due to antiretroviral therapy.

Reddy female condom: functional performance of a 90-mm shaft length in two clinical studies

Background: Praneem, a candidate vaginal microbicide with reported anti-HIV and contraceptive properties was evaluated for its long-term safety through a double-blind, placebo-controlled, randomised phase II trial. Methodology: 142 women were screened and 100 HIV-uninfected, eligible women were enrolled, after obtaining written informed consents. Of these, 50 were randomly assigned to the study product arm and 50 to the placebo arm. Participants were requested to use the study product at least half an hour before each sexual act for 6 months. Results: Participants in both treatment groups contributed 601 person-months of follow-up and 95% of the participants completed the last follow-up. Although transient genital discomfort was the main reported adverse experience, none of the study participants discontinued product use. Most of the adverse events were mild and there were no serious adverse events related to study product use and no HIV seroconversions. Discussion: Praneem polyherbal tablet was safe for vaginal use up to 6 months with each act of sex among low-risk women. In light of the failure of Nonoxynol-9, cellulose sulphate and Carraguard in preventing HIV infections among women, additional preclinical evaluations should be undertaken urgently before moving into effectiveness studies.

Colposcopically observed vascular changes in the cervix in relation to the hormonal levels and menstrual cycle.

BACKGROUNDnWe report on the functional performance, safety and acceptability of the 90-mm Reddy female condom in two clinical trials, one in Los Angeles, CA, and one in Pune, Maharashtra, India.nnnSTUDY DESIGNnBoth studies used a Phase I, crossover design involving 25 couples. Each couple used three condoms of each of two shaft lengths: in Los Angeles, shaft lengths of 150 and 90 mm were used; in Pune, shaft lengths of 120 and 90 mm were used. This paper focuses on the 90-mm condom since it is commercially available. The primary endpoint of each study was invagination, defined as the outer frame of the condom being pushed into the vagina during intercourse. Secondary functionality endpoints included nonclinical breakage, clinical breakage, penile misdirection and complete slippage.nnnRESULTSnInvagination occurred in 26.9% of uses in Los Angeles vs. 6.8% of uses in Pune. Penile misdirection and complete slippage were reported only in Pune during 4.0% and 9.5% of uses, respectively. There were two clinical breaks in Pune and none in Los Angeles. Total clinical failure was 26.9% in Los Angeles and 23.0% in Pune.nnnCONCLUSIONSnTwo clinical studies of the 90-mm Reddy female condom suggest that its functional performance is inferior to other female condoms.

The CONRAD/WHO Update 2000 Colposcopy Manual: how well is it working?

Objective. We assessed colposcopically observed vascular changes occurring in the cervix in relation to cyclical hormonal variation in healthy women. Materials and Methods. Thirty women with regular menstrual cycles and willing to remain sexually abstinent during a menstrual cycle were enrolled. Colposcopy was performed during the peak of the estrogen and progesterone levels. Results. The mean (±SD) diameter of the largest visible blood vessel differed significantly between the estrogenic phase (0.38 ± 0.14 mm) as compared with the progestogenic phase (0.47 ± 0.12 mm; p <.01). The blood vessels were more prominent and dense and had a well-defined outline during the progestogenic phase than the estrogenic phase; however, these differences were not statistically significant. There was borderline increase in the interleukin 8 level during the estrogenic phase. Conclusions. Physiological changes of increased vascularity of the cervix observed colposcopically during the progestogenic phase are normal. If such changes do not correspond to the menstrual cycle phase in women using vaginal microbicides in early-phase clinical trials, presence of inflammatory markers should be evaluated. Elevated interleukin 8 during the estrogenic phase needs further evaluation.

Documenting intermenstrual bleeding in a vaginal microbicide study: case reports and lessons learned.

with the Update 2000 manual. Their responses had many commonalities and have been combined into this single manuscript. The panelists’ experience came from clinical trials of Pro2000, BufferGel, cellulose sulfate, dextrin sulfate, nonoxynol-9, K-Y Jelly, tenofovir, Praneem, and vaginal diaphragms. In general, it was felt that the Update 2000 manual was clear, concise, and easy to follow. The procedure is short (5–7 min) and simple once the colposcopist has been properly trained. The use of digital imaging was endorsed as a way to reduce both inter and intra-observer variability, and to ensure good image quality when the examination was still in progress. The need for equipment, reliable electricity, and training were limitations of the procedure. The most common recommendation was the reintroduction of ‘terms’, namely clinical labels for changes seen, such as erythema, edema, abrasion, ulcer, etc. These had been removed from the Update 2000 manual in favor of simply recording the status of the epithelium and blood vessels as either intact or not intact. The latter was felt to be more meaningful in terms of HIV/sexually transmitted infection risk, and the previously used terms had for some time been analysed only with respect to the intactness they represented. However, the panelists pointed out that the terms were still being used during discussions among clinicians and study staff, as they were more easily visualized than descriptions of intactness. CONRAD has found that in studies in which both the intactness and terms were recorded and there were discrepancies, it was usually the term that was correct. As a result of this feedback, the new Update 2004 includes places for recording both terms and intactness. Several aspects of the lavage step were discussed. Different types of syringes for lavaging were described, with each having different merits that are somewhat dependent on the type of study being carried out. As a result, the type of syringe is no longer specified in the Update 2004 manual, but can be protocol-specific. Several panelists reported that lavage was often inadequate for the removal of product, and that saline-moistened swabs had to be used. This was added to the Update 2004 manual. Also, when microbiology specimens from the endocervix were taken before lavage, the lavage samples were frequently contaminated with blood, which confounded the results of viral load and cytokine analyses when the lavage was used for this purpose. The Update 2004 manual states that if the collection of lavage fluid for the measurement of inflammatory markers is felt to be of higher priority than the collection of cervical or vaginal specimens, it may be collected first. It was suggested that the degree of cervical ectopy be recorded, and the recording of findings such as cervical polyps be addressed; both were added to in Update 2004. The recording of blood observed on the examination was also added. Possible changes in colposcopically observed vascular patterns because of the day of the menstrual cycle or other hormonal influences were brought up as an area deserving investigation. Several panelists brought up the cumbersome nature of the reporting forms, which required many pages for each finding. One speaker had redesigned the form so that up to 10 findings could be recorded on one form. This change was incorporated into the Update 2004 manual. In addition, the numbering of the anatomical sites was changed so that a single numbering sequence incorporated both the vagina and cervix, rather than having separate sequences for each. The date of first observation and the date when findings were noticed to have resolved was added. Other suggestions included examining the anterolateral and posterolateral fornices rather than the anterior, posterior, and lateral fornices, and always starting with the same fornix. It was also reported that rotating the speculum 90° was well tolerated by some women and allowed the examination of the