Population-Level Benefits from Providing Effective HIV Prevention Means to Pregnant Women in High Prevalence Settings

Background:HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention.Methods and Findings:A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RRHIV/preg = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RRHIV/preg = 1) to 25% (RRHIV/preg = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RRHIV/preg = 1, RRMTCT/preg = 1) and 25% (RRHIV/preg = 2, RRMTCT/preg = 4) to the reduction in the residual MTCT.Conclusion:Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. © 2013 Dimitrov et al

Brachytherapy for cervix cancer: low-dose rate or high-dose rate brachytherapy – a meta-analysis of clinical trials

<p>Abstract</p> <p>Background</p> <p>The literature supporting high-dose rate brachytherapy (HDR) in the treatment of cervical carcinoma derives primarily from retrospective series. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy, in particular, due to inadequate tumor coverage for stage III patients. Whether LDR or HDR brachytherapy produces better results for these patients in terms of survival rate, local control rate and the treatment complications remain controversial.</p> <p>Methods</p> <p>A meta-analysis of RCT was performed comparing LDR to HDR brachytherapy for cervix cancer treated for radiotherapy alone. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. We used "recommend" for strong recommendations, and "suggest" for weak recommendations.</p> <p>Results</p> <p>Pooled results from five randomized trials (2,065 patients) of HDR brachytherapy in cervix cancer showed no significant increase of mortality (p = 0.52), local recurrence (p = 0.68), or late complications (rectal; p = 0.7, bladder; p = 0.95 or small intestine; p = 0.06) rates as compared to LDR brachytherapy. In the subgroup analysis no difference was observed for overall mortality and local recurrence in patients with clinical stages I, II and III. The quality of evidence was low for mortality and local recurrence in patients with clinical stage I, and moderate for other clinical stages.</p> <p>Conclusion</p> <p>Our meta-analysis shows that there are no differences between HDR and LDR for overall survival, local recurrence and late complications for clinical stages I, II and III. By means of the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402