Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam.

BACKGROUND: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. METHODS: This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. RESULTS: Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. CONCLUSIONS: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00651066

The risk factors for unexplained antepartum stillbirths in Scotland, 1994 to 2003

Objective: To determine the factors contributing to unexplained antepartum stillbirth in Scotland. Study Design: A 10-year birth database in Scotland was used to compare the unexplained antepartum stillbirth with other birth outcomes. The sample unit was a pregnant mother with a gestational age of 20 weeks and above and with a fetal birth weight of 200 g and above. Result: Maternal age of 35 years and above, lower deprivation category, inaccessible area of residence, maternal smoking, maternal height of <160 cm and gestational age of above 39 weeks were significantly associated with unexplained antepartum stillbirth. In multivariable analysis only maternal age (adjusted odds ratio (OR): 1.8, confidence interval (CI): 1.1 to 3.0, P=0.02), smoking during pregnancy (adjusted OR: 2.0, CI: 1.1 to 3.5, P=0.02), and maternal height (adjusted OR: 1.4, CI: 1.1 to 1.8, P=0.01), remain significant. Screening of pregnancies based on these three risk factors had 4.2% sensitivity and 99.4% specificity. The prevalence of stillbirth for this population was 0.2%. A positive predictive value of only 1.2% implies that only 1 in 83 women with these three risk factors will have antepartum stillbirth. The remaining 82 will suffer needless anxiety and potentially diagnostic procedures. Conclusion: Advanced maternal age, maternal smoking, and shorter maternal height were associated risk for unexplained antepartum stillbirth but screening based on these factors would be of limited value

Comparison of two doses of mifepristone in combination with misoprostol for early medical abortion: A randomised trial

Objectives. To compare the efficacy of two different regimens of mifepristone followed by misoprostol for medical abortion in women with menstrual delay of ≤ 35 days. Design. Double-blind, randomised controlled trial. Setting. Seventeen centres internationally. Participants. We enrolled 1589 healthy pregnant women with menstrual delay of ≤ 35 days who were requesting nonsurgical abortion. Interventions. Within gestational age strata, we randomly assigned women to receive a single oral dose of mifepristone, either 200 mg or 600 mg, followed in 48 h by misoprostol 400 μg by mouth. We concealed the allocation assignments from investigators and participants and maintained double-blinding throughout the study. Main outcome measures. Complete abortion was the principal outcome measure. We also compared rates of side effects such as abdominal pain. Results. The complete abortion rate with the lower dose of mifepristone was similar to that with the higher dose (89.3% vs 88.1%) The crude relative risk of failure to achieve complete abortion with the 200 mg dose compared with the 600 mg dose was 0.9 (95% CI 0.7 to 1.2). The likelihood of complete abortion was inversely related to gestational age, although this finding is exploratory in nature. Among failures the percentage of women with continuing pregnancies increased from 1.4% at menstrual delay of two weeks or less to 9.0% when the delay was 4-5 weeks. Low efficacy led to stopping enrolment at 29 to 35 days' menstrual delay. Stopping criteria were also met at completion of the study in the group with 22-28 days' menstrual delay. No significant differences emerged in the frequency of side effects between the two mifepristone groups. Conclusions. Both regimens had similar efficacy. Women with a menstrual delay of four to five weeks had twice the risk of failure to abort compared with those who received treatment within two weeks of the expected menses. The efficacy of the mifepristone-prostaglandin regimen was not reduced by decreasing the dose of mifepristone from 600 mg to 200 mg. The regimens of 600 mg or 200 mg of mifepristone, followed by a single oral dose of misoprostol 400 μg 48 hours later, were not sufficiently efficient in inducing abortion when the menstrual delay was > 21 days.link_to_subscribed_fulltex

High maternal mortality in rural south-west Ethiopia: estimate by using the sisterhood method

<p>Abstract</p> <p>Background</p> <p>Estimation of maternal mortality is difficult in developing countries without complete vital registration. The indirect sisterhood method represents an alternative in places where there is high fertility and mortality rates. The objective of the current study was to estimate maternal mortality indices using the sisterhood method in a rural district in south-west Ethiopia.</p> <p>Method</p> <p>We interviewed 8,870 adults, 15–49 years age, in 15 randomly selected rural villages of Bonke in Gamo Gofa. By constructing a retrospective cohort of women of reproductive age, we obtained sister units of risk exposure to maternal mortality, and calculated the lifetime risk of maternal mortality. Based on the total fertility for the rural Ethiopian population, the maternal mortality ratio was approximated.</p> <p>Results</p> <p>We analyzed 8503 of 8870 (96%) respondents (5262 [62%] men and 3241 ([38%] women). The 8503 respondents reported 22,473 sisters (average = 2.6 sisters for each respondent) who survived to reproductive age. Of the 2552 (11.4%) sisters who had died, 819 (32%) occurred during pregnancy and childbirth. This provided a lifetime risk of 10.2% from pregnancy and childbirth with a corresponding maternal mortality ratio of 1667 (95% CI: 1564–1769) per 100,000 live births. The time period for this estimate was in 1998. Separate analysis for male and female respondents provided similar estimates.</p> <p>Conclusion</p> <p>The impoverished rural area of Gamo Gofa had very high maternal mortality in 1998. This highlights the need for strengthening emergency obstetric care for the Bonke population and similar rural populations in Ethiopia.</p