Clinical and population-based study design considerations to accelerate the investigation of new antiretrovirals during pregnancy.

INTRODUCTION: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies. DISCUSSION: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias. CONCLUSIONS: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.

Use of surgical task shifting to scale up essential surgical services: a feasibility analysis at facility level in Uganda.

BACKGROUND: The shortage and mal-distribution of surgical specialists in sub-Saharan African countries is born out of shortage of individuals choosing a surgical career, limited training capacity, inadequate remuneration, and reluctance on the part of professionals to work in rural and remote areas, among other reasons. This study set out to assess the views of clinicians and managers on the use of task shifting as an effective way of alleviating shortages of skilled personnel at a facility level. METHODS: 37 in-depth interviews with key informants and 24 focus group discussions were held to collect qualitative data, with a total of 80 healthcare managers and frontline health workers at 24 sites in 15 districts. Quantitative and descriptive facility data were also collected, including operating room log sheets to identify the most commonly conducted operations. RESULTS: Most health facility managers and health workers supported surgical task shifting and some health workers practiced it. The practice is primarily driven by a shortage of human resources for health. Personnel expressed reluctance to engage in surgical task shifting in the absence of a regulatory mechanism or guiding policy. Those in favor of surgical task shifting regarded it as a potential solution to the lack of skilled personnel. Those who opposed it saw it as an approach that could reduce the quality of care and weaken the health system in the long term by opening it to unregulated practice and abuse of privilege. There were enough patient numbers and basic infrastructure to support training across all facilities for surgical task shifting. CONCLUSION: Whereas surgical task shifting was viewed as a short-term measure alongside efforts to train and retain adequate numbers of surgical specialists, efforts to upscale its use were widely encouraged.

Updated evidence on early statin therapy for acute coronary syndromes: meta-analysis of 18 randomized trials involving over 14,000 patients.

BACKGROUND: The short-term effects of early statin therapy in acute coronary syndromes (ACS) on clinical outcomes remain unclear. Our objective was to update the evidence on patient relevant outcomes from all randomized trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. METHODS: We performed a systematic review and meta-analysis of randomized trials that compared statins to control, initiated within 14 days after onset of ACS and with minimal follow-up of 30 days. Data were extracted in duplicate and analyzed by a random effects model. Investigators from individual trials contributed additional data where needed. RESULTS: A total of 18 trials involving 14,303 patients with ACS were included in the meta-analysis. We found no evidence for further trials on the topic. Risk ratios for the combined endpoint of death, myocardial infarction, and stroke of early statin therapy compared to control were 0.93 (95% confidence interval [CI], 0.80-1.08; P=0.34) at 1 month and 0.93 (95% CI, 0.81-1.06; P=0.27) at 4 months following ACS. There were favorable trends related to statin use for all individual secondary endpoints but there was no statistically significant risk reduction except for unstable angina with a risk ratio of 0.76 (95% CI, 0.59-0.96; P=0.02) at 4 months following ACS. CONCLUSIONS: Initiation of statin therapy within 14 days following ACS results in directionally favorable but non-significant reduction in death, myocardial infarction, or stroke up to 4 months, and significant reduction in the occurrence of unstable angina at 4 months following ACS.

Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid.

OBJECTIVE: To test the reliability and validity of specific instructions to classify blinding, when unclearly reported in randomized trials, as "probably done" or "probably not done." STUDY DESIGN AND SETTING: We assessed blinding of patients, health care providers, data collectors, outcome adjudicators, and data analysts in 233 randomized trials in duplicate and independently using detailed instructions. The response options were "definitely yes," "probably yes," "probably no," and "definitely no." We contacted authors for data verification (46% response). For each of the five questions, we assessed reliability by calculating the agreement between the two reviewers and validity by calculating the agreement between reviewers' consensus and verified data. RESULTS: The percentage with unclear blinding status varied between 48.5% (patients) and 84.1% (data analysts). Reliability was moderate for blinding of outcome adjudicators (κ=0.52) and data analysts (κ=0.42) and substantial for blinding of patients (κ=0.71), providers (κ=0.68), and data collectors (κ=0.65). The raw agreement between the consensus record and the author-verified record varied from 84.1% (blinding of data analysts) to 100% (blinding of health care providers). CONCLUSION: With the possible exception of blinding of data analysts, use of "probably yes" and "probably no" instead of "unclear" may enhance the assessment of blinding in trials.

Comparison of first antiretroviral treatment duration and outcome in HIV, HIV-HBV and HIV-HCV infection.

Hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection may differentially influence HIV treatment duration and outcome. This was assessed at The Ottawa Hospital Immunodeficiency Clinic in first-time highly active antiretroviral therapy (HAART) recipients visited between January 2000 and December 2004. Of 968 patients, 526/700 (75%) HIV, 173/230 (75%) HIV-HCV and 30/38 (79%) HIV-HBV-infected patients initiated HAART. Co-infected patients stopped treatment sooner (HBV - 10 months, HCV - 9 months) than HIV mono-infected (17 months) (P<0.001). Injection drug history predicted shorter treatment duration (odds ratio [OR]1.59, P<0.001). Use of non-nucleoside-reverse-transcriptase-inhibitor-containing HAART (OR 0.76, P<0.01) and low-dose ritonavir (<400 mg twice daily)-based HAART (OR 0.83, P = 0.06) predicted longer treatment duration. HCV co-infection did not predict duration of therapy (OR 1.19, P=0.19) once controlled for by these three variables. Poor adherence was a major explanation for eventual treatment interruption in those with HIV-HCV (22% versus 5% in HIV alone; P<0.001) as was substance abuse (7% versus < 1% in HIV; P<0.001). Metabolic complications resulted in HAART interruption in HIV mono-infection (8%) but not with HBV or HCV co-infection (both <1%; P<0.001). Antiretroviral selection is critical to the longevity of initially prescribed regimens, irrespective of viral hepatitis co-infection. Attention to this and strategies targeting substance abuse and adherence in HIV-HCV are predicted to increase the duration of HAART.

A systematic review of studies comparing health outcomes in Canada and the United States.

BACKGROUND: Differences in medical care in the United States compared with Canada, including greater reliance on private funding and for-profit delivery, as well as markedly higher expenditures, may result in different health outcomes. OBJECTIVES: To systematically review studies comparing health outcomes in the United States and Canada among patients treated for similar underlying medical conditions. METHODS: We identified studies comparing health outcomes of patients in Canada and the United States by searching multiple bibliographic databases and resources. We masked study results before determining study eligibility. We abstracted study characteristics, including methodological quality and generalizability. RESULTS: We identified 38 studies comparing populations of patients in Canada and the United States. Studies addressed diverse problems, including cancer, coronary artery disease, chronic medical illnesses and surgical procedures. Of 10 studies that included extensive statistical adjustment and enrolled broad populations, 5 favoured Canada, 2 favoured the United States, and 3 showed equivalent or mixed results. Of 28 studies that failed one of these criteria, 9 favoured Canada, 3 favoured the United States, and 16 showed equivalent or mixed results. Overall, results for mortality favoured Canada (relative risk 0.95, 95% confidence interval 0.92-0.98, p= 0.002) but were very heterogeneous, and we failed to find convincing explanations for this heterogeneity. The only condition in which results consistently favoured one country was end-stage renal disease, in which Canadian patients fared better. INTERPRETATION: Available studies suggest that health outcomes may be superior in patients cared for in Canada versus the United States, but differences are not consistent.

Fiber for the treatment of hemorrhoids complications: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the impact of laxatives on a wide range of symptoms in patients with symptomatic hemorrhoids. METHODS: We searched using the following sources: MEDLINE, EMBASE, CINAHL and CENTRAL, BIOSIS, AMED, Papers First and Proceedings; study authors, industry, and experts in the field. We included all published and unpublished parallel group randomized controlled trials comparing any type of laxative to placebo or no therapy in patients with symptomatic hemorrhoids. Two reviewers independently screened studies for inclusion, retrieved all potentially relevant studies, and extracted data on study population, intervention, prespecified outcomes, and methodology. RESULTS: Seven trials randomized 378 patients to fiber or a nonfiber control. Studies were of moderate quality for most outcomes. Meta-analyses using random effects models suggested that fiber has an apparent beneficial effect. The risk of not improving/persisting symptoms decreased by 47% in the fiber group (RR = 0.53, 95% CI 0.38-0.73) and the risk of bleeding by 50% (RR = 0.50, 95% CI 0.28-0.89). Studies with multiple follow-ups, usually at 6 wk and at 3 months, showed consistent results over time. Results are also compatible with large treatment effects in prolapse, pain, and itching, but even in the pooled analyses confidence intervals were wide and compatible with no effect (RR = 0.79, 95% CI 0.37-1.67; RR = 0.33, 95% CI 0.07-1.65; and RR = 0.71, 95% CI 0.24-2.10, respectively). One study suggested a decrease in recurrence. Results showed a nonsignificant trend toward increases in mild adverse events in the fiber group (RR = 6.0, 95% CI 0.57-64.8). CONCLUSIONS: Trials of fiber show a consistent beneficial effect for symptoms and bleeding in the treatment of symptomatic hemorrhoids.

Effect of high-dose vitamin C on hepatic cytochrome P450 3A4 activity.

STUDY OBJECTIVES: To investigate the effect of high-dose vitamin C on cytochrome P450 (CYP) 3A4 activity, and to evaluate possible sex-specific effects on CYP3A4 activity. DESIGN: Single-center longitudinal study. SETTING: Tertiary- and specialty-care teaching hospital. SUBJECTS: Fourteen healthy Caucasian adult volunteers (seven men, seven women). INTERVENTION: Subjects self-administered vitamin C 500 mg twice/day for 14 days. MEASUREMENTS AND MAIN RESULTS: Hepatic CYP3A4 activity was measured by using the erythromycin breath test on days 1 (baseline) and 15. Overall, no significant effect of vitamin C on CYP3A4 activity was observed. Sex and baseline results were significant predictors of changes in CYP3A4 activity. In men, mean activity increased by 21.9% (95% confidence interval -3.88-47.6%). The effect in women was not consistent. CONCLUSION: Sex and baseline CYP3A4 activity appeared to influence the effect of vitamin C on CYP3A4 activity.

A survey of attitudes towards paediatric vaccinations amongst Canadian naturopathic students.

Previous studies have suggested that providers of alternative medicine may harbour anti-vaccination attitudes and that these attitudes may develop at an early stage in their careers. We further explored this question by conducting a survey to determine the attitudes of students of naturopathic medicine, a growing alternative medicine discipline, towards recommended paediatric vaccines. We sampled all 4 years of students at the Canadian College of Naturopathic Medicine (CCNM) and obtained a response rate of 59.4% (312 of 525). We found that only 12.8% (40 of 312) of the respondents would advise full vaccination; however, 74.4% (232 of 312) of the respondents would advise partial vaccination. Importantly, both willingness to advise full vaccination and trust in public health and conventional medicine decreased in students in the later years of the programme. Our findings suggest that public health and conventional medical supporters of vaccination need to identify mechanisms for engaging in discussion with this population of complementary/alternative medical professionals at an early stage in their careers.

Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: a systematic review of current epidemiological evidence.

OBJECTIVE: To systematically review the evidence for and against the existence of an association between autistic spectrum disorder (ASD) and the measles, mumps, and rubella (MMR) vaccine. STUDY DESIGN: We conducted a systematic review of the medical literature to identify all controlled epidemiological articles examining for an association between ASD and the MMR vaccine. We extracted data from the articles on the characteristics and objectives of the study as well as evidence of an association. RESULTS: Twelve articles met the inclusion criteria. One study found no difference in the rates of ASD and the MMR vaccine in children who were vaccinated and those who were not. Six studies examined for evidence of an increase in ASD associated with an increase in the MMR vaccine coverage, none of which showed evidence of an association. Four studies examined if a variant form of ASD was associated with the MMR vaccine, none of which showed evidence of an association. Eight studies attempted to determine if there was a temporal association between developing ASD and receiving the MMR vaccine. Of these, 1 study identified an increase in parental concern in the 6-month period following vaccination with MMR in one of its analyses. The results of all other studies showed no association between ASD and the MMR vaccine. CONCLUSIONS: The current literature does not suggest an association between ASD and the MMR vaccine; however, limited epidemiological evidence exists to rule out a link between a rare variant form of ASD and the MMR vaccine. Given the real risks of not vaccinating and that the risks and existence of variant ASD remain theoretical, current policies should continue to advocate the use of the MMR vaccine.