Debra H. Weiner

Is the intrauterine device appropriate contraception for HIV-1-infected women?

Objective To assess whether the risk of complications is higher in HIV‐1‐infected women compared with non‐infected women in the two years following insertion of the intrauterine contraceptive device.

Effect of intrauterine device use on cervical shedding of Hiv-1 Dna

OBJECTIVE Hormonal contraception has been associated with an increased prevalence of cervical shedding of HIV-1 DNA among infected women. We conducted this study to evaluate the effect of the use of an intrauterine device (IUD) on the detection of HIV-1 DNA in cervical secretions. DESIGN A prospective study of HIV-1-seropositive women undergoing IUD insertion at two public family planning clinics in Nairobi, Kenya. METHODS Cervical swab samples were collected before IUD insertion and approximately 4 months thereafter for the detection of HIV-1-infected cells using polymerase chain reaction (PCR) amplification of HIV-1 gag DNA sequences. RESULTS Ninety-eight women were enrolled and followed after IUD insertion. The prevalence of HIV-1 DNA cervical shedding was 50% at baseline and 43% at follow-up [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5-1.2]. There was no statistically significant difference between the baseline and follow-up shedding rates in a multivariate model that controlled for previous hormonal contraceptive use, condom use, cervical ectopy, friable cervix, cervical infections at an interim visit, and CD4 lymphocyte levels (OR 0.6, 95% CI 0.3-1.1). CONCLUSION The insertion of an IUD did not significantly alter the prevalence of cervical shedding of HIV-1-infected cells. The use of IUDs, in conjunction with condoms, may be an appropriate method of contraception for HIV-1-infected women from the standpoint of potential infectivity to the male partner through exposure to genital HIV-1.

Comparative crossover study of the PATH Woman's Condom and the FC Female Condom®

BACKGROUND Only one female condom [FC1 Female Condom (FC1)] is currently marketed, but it is poorly utilized, perhaps due to difficulty with insertion, discomfort and suboptimal functional performance during intercourse. The Program for Appropriate Technology in Health (PATH) Womans Condom (WC) was developed in an effort to overcome these obstacles. STUDY DESIGN This was a randomized crossover study to evaluate the functional performance, safety and acceptability of the FC1 and WC. Seventy-five couples were assigned to one of two condom use sequences (WC/FC1 or FC1/WC) at three centers. Four condoms of the first type were used by couples in four acts of intercourse at home over a 2-4-week period. After a follow-up visit, these procedures were repeated with the second assigned condom type. In a substudy of participants (n=25), a colposcopy was performed prior and subsequent to the first condom use of each of the two condom types. Condom performance was evaluated by calculating measures of function from questionnaires completed by the couple after each condom use. Safety was evaluated by reported urogenital symptoms with a given condom during or immediately following condom use and colposcopic signs of genital irritation in the substudy. Acceptability of each given condom type was measured by questionnaire. RESULTS Total condom failure (slippage, breakage, etc., divided by the number of female condoms opened) was 31% for the WC and 42% for the FC1. Total clinical failure (slippage, breakage, etc., divided by the number of female condoms used) was 17% for the WC and 24% for the FC1. The proportion of condom failures was 10.9 percentage points less, and the proportion of clinical failure 6.7 percentage points less, when couples used the WC compared to the FC1 [90% CI: -18.5 to -3.3 and -12.6 to -0.8, respectively). Fewer women reported symptoms of urogenital irritation when using the WC vs. the FC1 either overall or when analyzing each use of the condom [woman as unit: -20 percentage points (90% CI: -30.5 to -9.3); condom use as unit: -12.3 percentage points (90% CI: -18.0 to -6.7)]. A similar result was seen for signs of urogenital irritation [woman as unit: -20 percentage points (90% CI: -42.7 to 4.8)]. Among participants with a preference, WC was preferred over the FC1 by twice as many males and by 2.6 times as many females. CONCLUSIONS While both female condoms were safe and acceptable in short-term use, the PATH Womans Condom leads to less failure, was associated with fewer adverse events, and was more acceptable than the FC1 Female Condom.

Phase I safety trial of two vaginal microbicide gels (Acidform or BufferGel) used with a diaphragm compared to KY Jelly used with a diaphragm

Objectives: To assess the safety and acceptability of 2 vaginal microbicide gels (Acidform and BufferGel) used with a diaphragm compared to KY Jelly used with a diaphragm among low-risk, sexually abstinent women. Study Design: Eighty-one women enrolled in a randomized, masked, phase I safety study using a diaphragm with Acidform, BufferGel, or KY Jelly for 6 to 10 hours nightly for 14 nights. Physical examination, colposcopy, and lab studies were performed after 1 and 2 weeks of use. Diaries and questionnaires were used to assess user acceptability. Results: Sixty-nine participants (85%) completed the study. Safety and acceptability appeared similar among the 3 study groups and no serious adverse events related to the study products were reported. Adverse events were mild and anticipated. Conclusions: Acidform and BufferGel compared to KY Jelly, when used with diaphragm daily for 14 days, appeared to be safe and acceptable in a small study of low-risk abstinent women.

A comparative study of the safety and efficacy of femcap®, a new vaginal barrier contraceptive, and the ortho all-flex® diaphragm

The FemCap is a new silicone rubber barrier contraceptive shaped like a sailors hat, with a dome that covers the cervix, a rim that fits into the fornices, and a brim that conforms to the vaginal walls around the cervix. It was designed to result in fewer dislodgments and less pressure on the urethra than the cervical cap and diaphragm, respectively, and to require less clinician time for fitting. This was a phase II/III, multicenter, randomized, open-label, parallel group study of 841 women at risk for pregnancy. A subset of 42 women at one site underwent colposcopy. Women were randomized to use the FemCap or Ortho All-Flex contraceptive diaphragm, both with 2% nonoxynol-9 spermicide, for 28 weeks. The objectives were to compare the two devices with regard to their safety and acceptability and to determine whether the probability of pregnancy among FemCap users was no worse than that of the diaphragm (meaning not more than 6 percentage points higher). The 6-month Kaplan-Meier cumulative unadjusted typical use pregnancy probabilities were 13.5% among FemCap users and 7.9% among diaphragm users. The adjusted risk of pregnancy among FemCap users was 1.96 times that among diaphragm users, with an upper 95% confidence limit of 3.01. Clinical equivalence (noninferiority) of the FemCap compared with the diaphragm, as defined in this study, would mean that the true risk of pregnancy among FemCap users was no more than 1.73 times the pregnancy risk of diaphragm users. Because the observed upper 95% confidence limit (and even the point estimate) exceeded 1.73, the probability of pregnancy among FemCap users, compared with that among diaphragm users, did not meet the definition of clinical equivalence used in this study. The FemCap was believed to be safe and was associated with significantly fewer urinary tract infections. More women reported problems with the FemCap with regard to insertion, dislodgement, and especially removal, although their general assessments were positive. The two devices were comparable with regard to safety and acceptability, but a 6-point difference in the true 6-month pregnancy probabilities of the two devices could not be ruled out. Further studies are needed to determine whether design modifications can simplify insertion and removal.

Use of sexually transmitted disease risk assessment algorithms for selection of intrauterine device candidates.

Sexually transmitted diseases (STD) are an important contraindication for intrauterine device (IUD) insertion. Nevertheless, laboratory testing for STD is not possible in many settings. The objective of this study is to evaluate the use of risk assessment algorithms to predict STD and subsequent IUD-related complications among IUD candidates. Among 615 IUD users in Kenya, the following algorithms were evaluated: 1) an STD algorithm based on US Agency for International Development (USAID) Technical Working Group guidelines: 2) a Centers for Disease Control and Prevention (CDC) algorithm for management of chlamydia; and 3) a data-derived algorithm modeled from study data. Algorithms were evaluated for prediction of chlamydial and gonococcal infection at 1 month and complications (pelvic inflammatory disease [PID], IUD removals, and IUD expulsions) over 4 months. Women with STD were more likely to develop complications than women without STD (19% vs 6%; risk ratio = 2.9; 95% CI 1.3-6.5). For STD prediction, the USAID algorithm was 75% sensitive and 48% specific, with a positive likelihood ratio (LR+) of 1.4. The CDC algorithm was 44% sensitive and 72% specific, LR+ = 1.6. The data-derived algorithm was 91% sensitive and 56% specific, with LR+ = 2.0 and LR- = 0.2. Category-specific LR for this algorithm identified women with very low (< 1%) and very high (29%) infection probabilities. The data-derived algorithm was also the best predictor of IUD-related complications. These results suggest that use of STD algorithms may improve selection of IUD users. Women at high risk for STD could be counseled to avoid IUD, whereas women at moderate risk should be monitored closely and counseled to use condoms.

Baseline variation and associations between subject characteristics and five cytokine biomarkers of vaginal safety among healthy non-pregnant women in microbicide trials.

Interleukins (IL)-8, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA) have emerged as indicators of vaginal inflammation and HIV-1 transmission risk. We provide values and factors of normal variation of these immune mediators in premenopausal women to allow their wider clinical application as biomarkers of vaginal health. Cross-sectional analyzes (Kruskal-Wallis and Wilcoxon exact tests) of cytokine concentrations in relation to sociodemographic variables and Nugent score were performed on baseline (prior to product) cervicovaginal lavage from two Phase I randomized microbicide trials. All women in the analysis had regular menstrual cycles, 72 h abstinence, normal blood and Pap tests, and absence of genitourinary infections, study-relevant allergies, antibiotics use and history of substance abuse. Cytokine norms were defined as the values among those with Nugent score <4. Among women with normal Nugent score (n=92), IL-8 and IL-1β were lowest in those using abstinence as compared to hormonal contraceptives or male/female sterilization as their primary method for birth control. No difference was found by age, prior pregnancy, or education, and also by race after controlling for contraceptive method. Women with abnormal (>7) and borderline (4-6) Nugent scores had elevated IL-1α and/or IL-1β although their IL-1RA-to-IL(α+β) ratio remained within the normal range due to higher IL-1RA. Women with borderline Nugent scores had IL-8 levels above the normal range. IL-8 and the IL-1RA-to-IL-1 ratio can be used as independent biomarkers of vaginal immune balance. More studies must determine the role of sexual activity, contraceptive method, and borderline Nugent scores, which normally are not exclusion criteria for enrollment in microbicide trials but may affect product tolerability and HIV-1 risk due to the aberrant cytokine levels.

Safety of quinacrine contraceptive pellets: results from 10-year follow-up in Vietnam.

BACKGROUND This study was conducted to evaluate long-term safety of quinacrine pellets for nonsurgical sterilization among women in Vietnam. STUDY DESIGN Observational cohort study of 2735 women who had quinacrine insertions between 1989 and 1993 compared to 1623 women who received an intrauterine device (IUD). RESULTS Cumulative follow-up times for the quinacrine and IUD cohorts were 28,697 and 17,382 person-years, respectively, and losses to follow-up were 6% and 7%, respectively. Quinacrine users had a higher incidence of ectopic pregnancy compared to IUD users (risk ratio, 2.2; 95% confidence interval, 1.06-4.54); the risks of cancer, hysterectomy, pelvic/gynecologic surgery and death were similar in the two groups. Two quinacrine insertions appeared to lower the risk of ectopic pregnancy to that of surgical tubal occlusion. CONCLUSIONS Use of quinacrine in this cohort appeared to have minimal health risks. Other research, including preclinical studies, needs to be considered in an overall evaluation of whether the combination of safety and efficacy provide a basis for quinacrines approval by appropriate regulatory agencies.

Six-day randomized safety trial of intravaginal lime juice

Objectives:Nigerian women reportedly apply lime juice intravaginally to protect themselves against HIV. In vitro data suggest that lime juice is virucidal, but only at cytotoxic concentrations. This is the first controlled, randomized safety trial of lime juice applied to the human vagina. Methods:Forty-seven women were randomized to apply water or lime juice (25%, 50%, or undiluted) intravaginally twice daily for two 6-day intervals, separated by a 3-week washout period. Product application also was randomized: during 1 interval, product was applied using a saturated tampon and in the other by douche. Vaginal pH, symptoms, signs of irritation observed via naked eye examination and colposcopy, microflora, and markers of inflammation in cervicovaginal lavages were evaluated after 1 hour and on days 3 and 7. Results:The largest reduction in pH was about one-half a pH unit, seen 1 hour after douching with 100% lime juice. We observed a dose-dependent pattern of symptoms and clinical and laboratory findings that were consistent with a compromised vaginal barrier function. Conclusions:The brief reduction in pH after vaginal lime juice application is unlikely to be virucidal in the presence of semen. Lime juice is unlikely to protect against HIV and may actually be harmful.

Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the upper arm

BACKGROUND The abdomen and thigh are recommended injection sites in the label for Depo-SubQ Provera 104™. We evaluated the pharmacokinetic profile of medroxyprogesterone acetate (MPA) following injection of Depo-SubQ Provera 104 in the upper arm, a preferred injection site in developing countries. STUDY DESIGN Twenty-six women in Norfolk, VA, received a single injection of Depo-SubQ Provera 104 in the upper arm in this prospective noncomparative study. We measured MPA serum concentrations prior to injection (day 1) and 11 times postinjection (days 2, 4, 8, 14, 30, 44, 60, 74, 91, 104 and 120). RESULTS Serum MPA levels peaked at 0.953 ng/mL 2-14 days (interquartile range; median=8) after dosing. Mean AUC0-91 was 45.1 ng·day/mL. Mean MPA levels at days 91, 104 and 120 were 0.427, 0.367 and 0.327 ng/mL, respectively. A total of 15 individual measurements of MPA were below 0.2 ng/mL. All women but one had MPA levels above 0.1 ng/mL on day 91. CONCLUSIONS Injection of Depo-SubQ Provera 104™ in the upper arm provided sufficient MPA levels for contraceptive protection for 3 months (13 weeks). The uptake and metabolism of MPA when injected in the upper arm may be different from the abdomen and thigh.