Pekka Lähteenmäki

Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial

BACKGROUND Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. METHODS We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. FINDINGS For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3.3 per 100 woman-years (95% CI 2.8-3.9) in the Carraguard group (134 events) and 3.8 per 100 woman-years (95% CI 3.2-4.4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0.30). The covariate-adjusted hazard ratio was 0.87 (95% CI 0.69-1.09). Rates of self-reported gel use (96.2% Carraguard, 95.9% placebo) and condom use (64.1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42.1% of sex acts, on average (41.1% Carraguard, 43.1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). INTERPRETATION This study did not show Carraguards efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy.

OBJECTIVES To assess whether the levonorgestrel intrauterine system could provide a conservative alternative to hysterectomy in the treatment of excessive uterine bleeding. DESIGN Open randomised multicentre study with two parallel groups: a levonorgestrel intrauterine system group and a control group. SETTING Gynaecology departments of three hospitals in Finland. SUBJECTS Fifty six women aged 33-49 years scheduled to undergo hysterectomy for treatment of excessive uterine bleeding. INTERVENTIONS Women were randomised either to continue with their current medical treatment or to have a levonorgestrel intrauterine system inserted. MAIN OUTCOME MEASURE Proportion of women cancelling their decision to undergo hysterectomy. RESULTS At 6 months, 64.3% (95% confidence interval 44.1 to 81.4%) of the women in the levonorgestrel intrauterine system group and 14.3% (4.0 to 32.7%) in the control group had cancelled their decision to undergo hysterectomy (P < 0.001). CONCLUSIONS The use of the levonorgestrel intrauterine system is a good conservative alternative to hysterectomy in the treatment of menorrhagia and should be considered before hysterectomy or other invasive treatments.

Levonorgestrel-Releasing Intrauterine Device

The levonorgestrel-releasing (LNG) IUD is a simple Nova T device with a Silastic reservoir of levonorgestrel in the vertical arm. It releases 20 mcg/day over 5 years. LNG IUD is very effective (about 99%) at preventing unplanned pregnancies. Circulating levels of levonorgestrel peak within 24 hours after LNG IUD insertion and are much lower than the levels in the endometrium. The high endometrial concentrations of levonorgestrel bring about a considerable reduction in the amount of bleeding, particularly oligomenorrhea. Other beneficial effects include prevention of iron deficiency anemia and protection against pelvic inflammatory disease (PID). Special counseling about changes in menstruation patterns for both providers and users is needed to prevent unwarranted discontinuation of LNG IUD. Hormonal side effects should also be discussed. Discontinuation for amenorrhea is more likely in LNG IUD users than copper IUD users (4.5% vs. 0; p = .001). LNG IUD hormonal side effects are more likely to result in discontinuation than those of the copper-releasing IUD (9% vs. 1.7%; p = .001). On the other hand, LNG IUD users are less likely to stop use for pregnancy, bleeding, and PID than copper IUD users (0.3% vs. 4.1%, p = .001; 11.3% vs. 17.9%, p = .002; and 0.5% vs. 1.5%, p = .022, respectively). Levonorgestrel generally has an effect on the ovaries just during the 1st year of use. It causes scanty and thick cervical mucus, its major contraceptive mode of action. LNG IUD can treat idiopathic excessive menstrual bleeding.

Five years' experience with levonorgestrel-releasing IUDs

Two levonorgestrel-releasing IUDs and a copper-releasing IUD of the same shape were studied in a randomized comparative study over five years. The levonorgestrel-releasing IUDs released 20 micrograms or 30 micrograms per day. The Pearl index during the 10,600 woman-months of LNG-IUD use was 0.11. The control device releasing copper had a Pearl index of 1.6. The amount and duration of menstrual bleeding was greatly reduced, leading to a high incidence of oligo- or amenorrhea. The continuation rate in this pioneer trial was 53 per 100 users for the levonorgestrel-releasing IUD (LNG-IUDs) and 50 per 100 users for the copper-releasing IUD (Nova T). The removal rates for reasons other than amenorrhea were not significantly different. Discontinuation because of amenorrhea occurred during the first two years, the cumulative termination rate for this reason was 11.6 per 100 users at five years. The LNG-IUDs removed for investigation after five years of use revealed that the devices contained about 40 percent of the original load. The effective lifespan of the device has been demonstrated by this study to be five years; the residual steroid gives an additional safety period of two more years. The LNG-IUD is a highly effective reversible contraceptive method, which strongly reduced the amount and duration of bleeding. During the first two months there is scanty but frequent spotting which, like the high incidence of oligo- and/or amenorrhea, requires counselling of health personnel and women using LNG-IUDs.

Pharmacokinetics and metabolism of RU 486.

The effects of dose on the initial pharmacokinetics and metabolism of an antiprogesterone steroid RU 486 (mifepristone) were studied in healthy female volunteers after administration of RU 486 as a single dose of 50-800 mg. The concentrations of RU 486 and its monodemethylated, dimethylated and hydroxylated non-demethylated metabolites were measured specifically after Chromosorb-column chromatography by HPLC. Their relative binding affinities to the human uterine progesterone receptor were also determined. Micromolar concentrations of the parent compound in blood were reached within the first hour after oral administration. The pharmacokinetics of RU 486 followed two distinct patterns in a dose-dependent fashion. With a low dose of 50 mg the pharmacokinetics followed an open two-compartment model with a half-life of over 27 h. With the doses of 100-800 mg the initial redistribution phase of 6-10 h was followed by zero-order kinetics up to 24 h or more. Importantly, after ingestion of doses higher than 100 mg of RU 486 there were no significant differences in plasma concentrations of RU 486 within the first 48 h, with the exception of plasma RU 486 concentrations at 2 h. After single oral administration of 200 mg unchanged RU 486 was found 10 days later in two subjects. The elimination phase half-life with this dose, calculated between day 5 and 6, was 24 h. Micromolar concentrations of monodemethylated, didemethylated and non-demethylated hydroxylated metabolites were measured within 1 h after oral administration of RU 486. In contrast to plasma RU 486 concentrations, circulating plasma concentrations of metabolites increased in a dose-dependent fashion. With higher doses the metabolite concentrations were close to, or even in excess to the parent compound. The relative binding affinities of RU 486, monodemethylated, didemethylated and hydroxylated metabolites (progesterone = 100%) to the human progesterone receptor were 232, 50, 21, and 36, respectively. The existence of a high affinity-limited capacity serum binding protein would explain the long half-life and the observed diverging dose-dependent pharmacokinetics. The extravasation of RU 486 after the saturation of serum binding sites would explain the blunted serum peak concentrations of RU 486 with higher doses. The return of the drug back to circulation thereafter explains the zero-order kinetics. High concentrations of circulating metabolites capable of binding to the progesterone receptor suggest a significant contribution of these steroids in the overall antiprogestational action.

Detailed analysis of menstrual bleeding patterns after postmenstrual and postabortal insertion of a copper IUD or a levonorgestrel-releasing intrauterine system

Detailed information on the menstrual bleeding patterns in users of copper-releasing intrauterine devices (IUDs) and levonorgestrel-releasing intrauterine systems (IUSs) is lacking. Even less is known about the menstrual bleeding patterns associated with postabortal insertion of IUDs. We postulated that the scarcity of IUD studies including detailed analysis of bleeding could be a result of the lack of an easy-to-use computer program designed for this purpose. We therefore developed a set of graphical user interface (Windows) programs for entering, editing, and analyzing menstrual diary data. With these programs, we reanalyzed the menstrual diaries of the subjects of one of the hospital clinics that participated in a previous multicenter study comparing copper IUDs and LNg IUSs. The group included patients who had the IUD inserted postabortally. Copper IUD users had patterns of bleeding that were stable over time, and clearly more bleeding than LNg IUS users, many of whom had either infrequent bleeding, bleeding completely replaced by regularly occurring spotting, or amenorrhea. Postabortal insertion of LNg IUSs was associated with slightly better patterns of bleeding than postmenstrual insertion. Detailed statistics on bleeding help clinicians in counseling patients regarding these methods. The statistics permit assumptions to be made about the probabilities of specific menstrual disturbances and their changes over time.

Hormonal contraception and the risk of HIV acquisition among women in South Africa

Objectives:To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. Design/methods:We analyzed data from 5567 women aged 16–49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16–24 years) in particular. Results:Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51–1.39], 1.28 (95% CI 0.92–1.78) and 0.92 (95% CI 0.64–1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46–2.28) for COCs, 1.68 (95% CI 0.96–2.94) for DMPA and 1.36 (95% CI0.78–2.35) for Net-En users. Conclusions:In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.

Effects of the antiprogesterone RU 486 in normal women

The response to a single oral dose of the antiprogesterone RU 486 was studied in the midluteal phase in 26 normal women. Each subject received a dose between 50 and 800 mg RU 486 on days 6 to 8 after the luteinizing hormone surge and blood samples were taken over the following 48 hours. Another group of five patients received a single oral dose of 200 mg RU 486 and blood sampling was extended for 14 days. Menses were induced in all women but one within 3 days after RU 486 administration. Two distinct patient populations emerged. In nine of the subjects, there was a single bleeding episode and the treatment cycle was significantly shorter (p less than 0.05) than the following cycle. In 16 of these 25 patients a second bleeding episode occurred 19.0 +/- 0.8 days after the luteinizing hormone surge. The total treatment cycle was significantly prolonged (p less than 0.05) when compared with the following cycle. In the group with a single bleeding episode, there was a significant decline in follicle-stimulating hormone, estradiol, and progesterone over the 48-hour sampling period, but there was no change in these values in the group with two bleeding episodes. These two groups could not be separated on the basis of RU 486 dose or serum levels. After the four higher doses, there was a dose-dependent rise in serum prolactin. There were no alterations in mean cortisol values with the three lower doses, but there was a significant increase at 24 and 48 hours after the higher doses. Serum levels of RU 486 were maximal between 1 and 4 hours and the half-life of serum RU 486 was determined to be 24 hours.

Distribution and percentages of non-protein bound contraceptive steroids in human serum.

It has been shown that albumin bound steroids are taken up by the rat brain in addition to nonprotein bound steroids and it has also been suggested that cortisol binding globulin (CBG) may facilitate progesterone uptake by the rat uterus but not the brain. Recently serum sex-hormone binding globulin (SHBG) has been identified in the cytoplasm of sex steroid target cells. Thus the distribution of synthetic steroids between various protein bound and nonprotein bound components in serum may influence their bioavailability at different target tissues. The authors employed a newly developed technique, centrifugal ultrafiltration-dialysis. The results showed that there are no differences in percentages of nonprotein bound ethinyl estradiol (EE2), and cyproterone acetate (CA) with respect to sex or serum SHBG and CBG binding capacities. However serum percentages of nonprotein bound norethisterone (NET) (p0.05) are significantly lower in women than in men. Also the percentages of nonprotein bound NET and D-norgestrel are both very much lower (p0.001) in serum from pregnant women when compared to nonpregnant women. These differences appear to be inversely related to serum SHBG binding capacity. The percentages of nonprotein bound NET and D-norgestrel in heat treated serum from men and nonpregnant women are identical and largely represent the contribution of albumin binding alone. In addition heat labile binding proteins do not appear to influence the percentages of nonprotein bound EE2 and CA and it can be inferred that EE2 and CA are almost exclusively bound by albumin in native serum; 98.5% of EE2 and 93% of CA are bound to albumin. In contrast the percentages of nonprotein bound NET and D-norgestrel in native serum are inversely related to SHBG binding capacity. This data indicate that the nonprotein bound and albumin bound factors of NET and D-norgestrel may vary by as much as 2-3 fold between women who are known to have subnormal or supranormal levels of serum SHBG binding capacity and it is suggested that measurements of serum SHBG binding capacity may provide a method of assessing the lowest effective dose of these 2 progestins in individual subjects to help reduce side effects associated with their use. Future studies should address the effect of serum steroid concentrations on the actual nonprotein bound serum concentrations and distribution of these progestins.

Levonorgestrel plasma concentrations and hormone profiles after insertion and after one year of treatment with a levonorgestrel-IUD

Plasma concentrations of levonorgestrel, progesterone, estradiol, FSH and LH were measured in seven volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. Blood samples were collected twice weekly during a mean of 93 days immediately postmenstrually and during a mean of 41 days over the twelfth to fifteenth month of treatment. Patterns of bleeding were studied during the first year of treatment. The IUDs used were designed to release 25 micrograms/day of levonorgestrel. The mean +/- SD plasma concentration of levonorgestrel for all subjects during the first three months was 260 +/- 68 pg/ml, and 129 +/- 28 pg/ml after one year of treatment. During the initial period of blood sampling only two of the subjects ovulated, while only two did not ovulate after one year of treatment. Intermenstrual spotting occurred during the first sixty days of treatment. Three subjects developed amenorrhea at the end of the first year. All the subjects continued the use of the IUD and no pregnancies occurred.