Use of Third Line Antiretroviral Therapy in Latin America

Background

Access to highly active antiretroviral therapy (HAART) is expanding in Latin America. Many patients require second and third line therapy due to toxicity, tolerability, failure, or a combination of factors. The need for third line HAART, essential for program planning, is not known.

Methods

Antiretroviral-naïve patients ≥18 years who started first HAART after January 1, 2000 in Caribbean, Central and South America Network (CCASAnet) sites in Argentina, Brazil, Honduras, Mexico, and Peru were included. Clinical trials participants were excluded. Third line HAART was defined as use of darunavir, tipranavir, etravirine, enfuvirtide, maraviroc or raltegravir. Need for third line HAART was defined as virologic failure while on second line HAART.

Results

Of 5853 HAART initiators followed for a median of 3.5 years, 310 (5.3%) failed a second line regimen and 44 (0.8%) received a third line regimen. Cumulative incidence of failing a 2nd or starting a 3rd line regimen was 2.7% and 6.0% three and five years after HAART initiation, respectively. Predictors at HAART initiation for failing a second or starting a third line included female sex (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.18–2.00, p = 0.001), younger age (HR = 2.76 for 20 vs. 40 years, 95% CI 1.86–4.10, p<0.001), and prior AIDS (HR = 2.17, 95% CI 1.62–2.90, p<0.001).

Conclusions

Third line regimens may be needed for at least 6% of patients in Latin America within 5 years of starting HAART, a substantial proportion given the large numbers of patients on HAART in the region. Improved accessibility to third line regimens is warranted.     

Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

Background

Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.

Methods

Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed.

Results

Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based).

Conclusions

The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.     

Reduction of Thromboembolic Events in Meningioma Surgery: A Cohort Study of 724 Consecutive Patients

Background

Meningiomas are associated with the highest postoperative rate of venous thromboembolic events (VTE) among all intracranial tumors. The aim of this study is to compare two entirely different VTE prophylaxis regimens in 724 consecutive patients undergoing meningioma surgery.

Methods

Two cohorts at a single institution treated with different regimens to prevent VTE were reviewed retrospectively. Cohort A (n = 482; 314 females, mean age 57 years, range: 11–87 years) received our institutional regimen during the years 1999–2006, consisting of low-molecular-weight heparin (LMWH) and compression stockings. For cohort B (n = 242; 163 females, mean age 56.8 years, range: 16–90 years), during the years 2008–2010, the management included intraoperative 10°–20° leg elevation with intermittent pneumatic compression (IPC), heparin and LMWH administration. We compared the incidence of the endpoints pulmonary embolism (PE), deep venous thrombosis (DVT), hemorrhage and death, taking into account several known associated risk factors.

Results

For all endpoints, we observed a more favorable outcome with the new regimen. The difference in incidence of PEs (cohort A: 38/482, 8%; cohort B: 6/242, 2.5%) reached statistical significance (p = 0.002). In general, patients with skull base meningiomas had a higher risk for PE (OR 2.77). Regarding VTE prophylaxis, an adjusted subgroup analysis suggests that the new regimen is particularly beneficial for patients with skull base meningiomas.

Conclusions

We recommend perioperative prophylaxis using a management composed of intraoperative leg-elevation, IPC, early heparin administration and LMWH to reduce the risk for PE.     

Effectiveness of Multidrug Antiretroviral Regimens to Prevent Mother-to-Child Transmission of HIV-1 in Routine Public Health Services in Cameroon

Background

Multidrug antiretroviral (ARV) regimens including HAART and short-course dual antiretroviral (sc-dARV) regimens were introduced in 2004 to improve Prevention of Mother-to-Child Transmission (PMTCT) in Cameroon. We assessed the effectiveness of these regimens from 6–10 weeks and 12 months of age, respectively.

Methodology/Findings

We conducted a retrospective cohort study covering the period from October 2004 to March 2008 in a reference hospital in Cameroon. HIV-positive pregnant women with CD4 ≤350 cells/mm³ received first-line HAART [regimen 1] while the others received ARV prophylaxis including sc-dARV or single dose nevirapine (sd-NVP). Sc-dARV included at least two drugs according to different gestational ages: zidovudine (ZDV) from 28–32 weeks plus sd-NVP [regimen 2], ZDV and lamuvidine (3TC) from 33–36 weeks plus sd-NVP [regimen 3]. When gestational age was ≥37 weeks, women received sd-NVP during labour [regimen 4]. Infants received sd-NVP plus ZDV and 3TC for 7 days or 30 days. Early diagnosis (6–10 weeks) was done, using b-DNA and subsequently RT-PCR. We determined early MTCT rate and associated risk factors using logistic regression. The 12-month HIV-free survival was assessed using Cox regression. Among 418 mothers, 335 (80%) received multidrug ARV regimens (1, 2, and 3) and MTCT rate with multidrug regimens was 6.6% [95%CI: 4.3–9.6] at 6 weeks, without any significant difference between regimens. Duration of mother''s ARV regimen <4 weeks [OR = 4.7, 95%CI: 1.3–17.6], mother''s CD4 <350 cells/mm³ [OR = 6.4, 95%CI: 1.8–22.5] and low birth weight [OR = 4.0, 95%CI: 1.4–11.3] were associated with early MTCT. By 12 months, mixed feeding [HR = 8.7, 95%CI: 3.6–20.6], prematurity [HR = 2.3, 95%CI: 1.2–4.3] and low birth weight were associated with children''s risk of progressing to infection or death.

Conclusions

Multidrug ARV regimens for PMTCT are feasible and effective in routine reference hospital. Early initiation of ARV during pregnancy and proper obstetrical care are essential to improve PMTCT.     

Platinum-Based Versus Non-Platinum-Based Chemotherapy as First Line Treatment of Inoperable,Advanced Gastric Adenocarcinoma: A Meta-Analysis

Background

Although the platinum regimen is adopted widely nowadays in spite of the excessive side effects, there is still no international standard for palliative chemotherapy of advanced gastric cancer. This meta-analysis assessed the efficacy and tolerability of platinum versus non–platinum chemotherapy as first-line palliative treatment in patients with inoperable, advanced gastric cancer.

Methods

Randomized phase II and III clinical trials on first-line palliative chemotherapy in inoperable, advanced gastric cancer were identified by electronic searches of PubMed, Embase, and the Cochrane Controlled Trial Register, and hand searches of relevant abstract books and reference lists. Response rates, overall survival, and toxicity were analyzed. Depending on whether new-generation agents (S-1, taxanes and irinotecan) were utilized, the non–platinum regimens were divided into two subgroup.

Results

Compared to non-platinum regimens containing new-generation agents, the use of platinum-based regimens was associated with better response (risk ratio (RR) = 1.94, 95%CI[1.48, 2.55], p<0.001), an increase of overall survival (hazard ratio (HR) = 0.85, 95%CI[0.78, 0.92], p<0.001), a higher risk of hematological and non-hematological toxicity. No statistically significant increase in response (RR = 1.03, 95%CI [0.85, 1.24], p = 0.76) or overall survival (HR = 1.07, 95%CI [0.88, 1.30], p = 0.49) was found when platinum therapies were compared to new-generation agent based combination regimens. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nausea and vomiting, and neurotoxicity, but not for diarrhea and toxic death rate.

Conclusion

New-generation agent based combination regimens achieved similar response rate and overall survival as platinum-based therapy that had generally higher side effects. S-1, taxanes and irinotecan seemed to be valid options for patients with inoperable, advanced gastric cancer as first-line chemotherapy.     

Iterative Thoracentesis as First-Line Treatment of Complicated Parapneumonic Effusion

Rationale

Optimal management of complicated parapneumonic effusions (CPPE) remains controversial.

Objectives

to assess safety and efficacy of iterative therapeutic thoracentesis (ITTC), the first-line treatment of CPPE in Rennes University Hospital.

Methods

Patients with CPPE were identified through our computerized database. We retrospectively studied all cases of CPPE initially managed with ITTC in our institution between 2001 and 2010. ITTC failure was defined by the need for additional treatment (i.e. surgery or percutaneous drainage), or death.

Results

Seventy-nine consecutive patients were included. The success rate was 81% (n = 64). Only 3 patients (4%) were referred to thoracic surgery. The one-year survival rate was 88%. On multivariate analysis, microorganisms observed in pleural fluid after Gram staining and first thoracentesis volume ≥450 mL were associated with ITTC failure with adjusted odds-ratios of 7.65 [95% CI, 1.44–40.67] and 6.97 [95% CI, 1.86–26.07], respectively. The main complications of ITTC were iatrogenic pneumothorax (n = 5, 6%) and vasovagal reactions (n = 3, 4%). None of the pneumothoraces required chest tube drainage, and no hemothorax or re-expansion pulmonary edema was observed.

Conclusions

Although not indicated in international recommendations, ITTC is safe and effective as first-line treatment of CPPE, with limited invasiveness.     

A Very Low Geno2pheno False Positive Rate Is Associated with Poor Viro-Immunological Response in Drug-Na?ve Patients Starting a First-Line HAART

Background

We previously found that a very low geno2pheno false positive rate (FPR ≤2%) defines a viral population associated with low CD4 cell count and the highest amount of X4-quasispecies. In this study, we aimed at evaluating whether FPR ≤2% might impact on the viro-immunological response in HIV-1 infected patients starting a first-line HAART.

Methods

The analysis was performed on 305 HIV-1 B subtype infected drug-naïve patients who started their first-line HAART. Baseline FPR (%) values were stratified according to the following ranges: ≤2; 2–5; 5–10; 10–20; 20–60; >60. The impact of genotypically-inferred tropism on the time to achieve immunological reconstitution (a CD4 cell count gain from HAART initiation ≥150 cells/mm³) and on the time to achieve virological success (the first HIV-RNA measurement <50 copies/mL from HAART initiation) was evaluated by survival analyses.

Results

Overall, at therapy start, 27% of patients had FPR ≤10 (6%, FPR ≤2; 7%, FPR 2–5; 14%, FPR 5–10). By 12 months of therapy the rate of immunological reconstitution was overall 75.5%, and it was significantly lower for FPR ≤2 (54.1%) in comparison to other FPR ranks (78.8%, FPR 2–5; 77.5%, FPR 5–10; 71.7%, FPR 10–20; 81.8%, FPR 20–60; 75.1%, FPR >60; p = 0.008). The overall proportion of patients achieving virological success was 95.5% by 12 months of therapy. Multivariable Cox analyses showed that patients having pre-HAART FPR ≤2% had a significant lower relative adjusted hazard [95% C.I.] both to achieve immunological reconstitution (0.37 [0.20–0.71], p = 0.003) and to achieve virological success (0.50 [0.26–0.94], p = 0.031) than those with pre-HAART FPR >60%.

Conclusions

Beyond the genotypically-inferred tropism determination, FPR ≤2% predicts both a poor immunological reconstitution and a lower virological response in drug-naïve patients who started their first-line therapy. This parameter could be useful to identify patients potentially with less chance of achieving adequate immunological reconstitution and virological undetectability.     

Reduction of Maternal Mortality with Highly Active Antiretroviral Therapy in a Large Cohort of HIV-Infected Pregnant Women in Malawi and Mozambique

Background

HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002.

Methods

Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2).

Results

10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23–30), CD4 count 392 cells/mm³ (IQR:258–563), Viral Load log₁₀ 3.9 (IQR:3.2–4.4), BMI 23.4 (IQR:21.5–25.7), Hemoglobin 10.0 (IQR: 9.0–11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with <than 350 CD4 cells/mm³ and 0.7% in women with greater than 350 CD4s cells/mm³ [OR = 1.9 (CL 1.3–2.9) p = 0.001]. Mortality was higher in patients with shorter antenatal HAART: 22/991 (2.2%) if less than 30 days and 79/9159 (0.9%) if 31 days or greater [OR = 2.6 (CL 1.6–4.2) p<0.001]. By multivariate analysis, shorter antenatal HAART (p<0.001), baseline values for CD4 cell count (p = 0.012), hemoglobin (p = 0.02), and BMI (p<0.001) were associated with mortality. Four years later, survival was 92% for women with shorter antenatal HAART and 98% for women on established therapy prior to pregnancy, p = 0.001.

Conclusions

Antiretrovirals for PMTCT purposes have significant impact on maternal mortality as do CD4 counts and nutritional status. In resource-limited settings, PMTCT programs should provide universal HAART to all HIV+ pregnant women given its impact in prevention of maternal death.     

Cost-effectiveness of early treatment with first-line NNRTI-based HAART regimens in the UK, 1996-2006

Aim

Calculate time to first-line treatment failure, annual cost and cost-effectiveness of NNRTI versus PIboosted first-line HAART regimens in the UK, 1996–2006.

Background

Population costs for HIV services are increasing in the UK and interventions need to be effective and efficient to reduce or stabilize costs. 2NRTIs + NNRTI regimens are cost-effective regimens for first-line HAART, but these regimens have not been compared with first-line PI_boosted regimens.

Methods

Times to first-line treatment failure and annual costs were calculated for first-line HAART regimens by CD4 count when starting HAART (2006 UK prices). Cost-effectiveness of 2NRTIs+NNRTI versus 2NRTIs+PI_boosted regimens was calculated for four CD4 strata.

Results

55% of 5,541 people living with HIV (PLHIV) started HAART with CD4 count ≤200 cells/mm3, many of whom were Black Africans. Annual treatment cost decreased as CD4 count increased; most marked differences were observed between starting HAART with CD4 ≤200 cells/mm3 compared with CD4 count >200 cells/mm3. 2NRTI+PI_boosted and 2NRTI+NNRTI regimens were the most effective regimens across the four CD4 strata; 2NRTI+NNRTI was cost-saving or cost-effective compared with 2NRTI + PI_boosted regimens.

Conclusion

To ensure more effective and efficient provision of HIV services, 2NRTI+NNRTI should be started as first-line HAART regimen at CD4 counts ≤350 cell/mm3, unless specific contra-indications exist. This will increase the number of PLHIV receiving HAART and will initially increase population costs of providing HIV services. However, starting PLHIV earlier on cost-effective regimens will maintain them in better health and use fewer health or social services, thereby generating fewer treatment and care costs, enabling them to remain socially and economically active members of society. This does raise a number of ethical issues, which will have to be acknowledged and addressed, especially in countries with limited resources.     

Comparison of the Efficacy and Safety of S-1-Based and Capecitabine-Based Regimens in Gastrointestinal Cancer: A Meta-Analysis

Purpose

Oral fluoropyrimidine (S-1, capecitabine) has been considered as an important part of various regimens. We aimed to evaluate the efficacy and safety of S-1-based therapy versus capecitabine -based therapy in gastrointestinal cancers.

Methods

Eligible studies were identified from Pubmed, EMBASE. Additionally, abstracts presented at American Society of Clinical Oncology (ASCO) conferences held between 2000 and 2013 were searched to identify relevant clinical trials. The outcome included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and advent events.

Results

A total of 6 studies (4 RCTs and 2 retrospective analysis studies) containing 790 participants were included in this meta-analysis, including 401 patients in the S-1-based group and 389 patients in the capecitabine-based group. Results of our meta-analysis indicated that S-1-based and capecitabine-based regimens showed very similar efficacy in terms of PFS (HR 0.92, 95% CI 0.78–1.09, P = 0.360), OS (HR 1.01, 95% CI 0.84–1.21, P = 0.949), ORR (HR 1.04, 95% CI 0.87–1.25, P = 0.683) and DCR (HR 1.02, 95% CI 0.94–1.10, P = 0.639). There was also no significant difference in toxicity between regimens other than mild more hand–foot syndrome in capecitabine-based regimens.

Conclusion

Both the S-1-based and capecitabine-based regimens are equally active and well tolerated, and have the potential of backbone chemotherapy regimen in further studies of gastrointestinal cancers.     

Sleep Disordered Breathing,Fatigue, and Sleepiness in HIV-Infected and -Uninfected Men

Study Objectives

We investigated the association of HIV infection and highly active antiretroviral therapy (HAART) with sleep disordered breathing (SDB), fatigue, and sleepiness.

Methods

HIV-uninfected men (HIV−; n = 60), HIV-infected men using HAART (HIV+/HAART+; n = 58), and HIV-infected men not using HAART (HIV+/HAART−; n = 41) recruited from two sites of the Multicenter AIDS cohort study (MACS) underwent a nocturnal sleep study, anthropometric assessment, and questionnaires for fatigue and the Epworth Sleepiness Scale. The prevalence of SDB in HIV- men was compared to that in men matched from the Sleep Heart Health Study (SHHS).

Results

The prevalence of SDB was unexpectedly high in all groups: 86.7% for HIV−, 70.7% for HIV+/HAART+, and 73.2% for HIV+/HAART−, despite lower body-mass indices (BMI) in HIV+ groups. The higher prevalence in the HIV− men was significant in univariate analyses but not after adjustment for BMI and other variables. SDB was significantly more common in HIV− men in this study than those in SHHS, and was common in participants with BMIs <25 kg/m². HIV+ men reported fatigue more frequently than HIV− men (25.5% vs. 6.7%; p = 0.003), but self-reported sleepiness did not differ among the three groups. Sleepiness, but not fatigue, was significantly associated with SDB.

Conclusions

SDB was highly prevalent in HIV− and HIV+ men, despite a normal or slightly elevated BMI. The high rate of SDB in men who have sex with men deserves further investigation. Sleepiness, but not fatigue, was related to the presence of SDB. Clinicians caring for HIV-infected patients should distinguish between fatigue and sleepiness when considering those at risk for SDB, especially in non-obese men.     

Anemia and Risk Factors in HAART Na?ve and HAART Experienced HIV Positive Persons in South West Ethiopia: A Comparative Study

Background

Human immunodeficiency virus (HIV) infection and its treatment cause a range of hematological abnormalities. Anemia is one of the commonly observed hematologic manifestations in HIV positive persons and it has multifactorial origin.

Objective

We aimed to determine the prevalence and risk factors of anemia in highly active antiretroviral therapy (HAART) naïve and HAART experienced HIV positive persons.

Methods

A facility-based comparative cross sectional study was conducted in Jimma University Specialized Hospital from February 1 to March 30, 2012. A total of 234 HIV positive persons, 117 HAART naïve and 117 HAART experienced, were enrolled in this study. Blood and stool specimens were collected from each participant. Blood specimens were examined for complete blood count, CD4 count and blood film for malaria hemoparasite; whereas stool specimens were checked for ova of intestinal parasites. Socio-demographic characteristics and clinical data of the participants were collected using pre-tested questionnaire. Statistical analysis of the data (Chi-square, student’s t-test, logistic regression) was done using SPSS V-16.

Results

The overall prevalence of anemia was 23.1%. The prevalence of anemia in HAART naïve and HAART experienced persons was 29.9% and 16.2%, respectively (P = 0.014). Presence of opportunistic infections (P = 0.004, 95% CI = 1.69–15.46), CD4 count <200 cells/µl (P = 0.001, 95% CI = 2.57–36.89) and rural residence (P = 0.03, 95% CI = 1.12–10.39) were found to be predictors of anemia for HAART naïve participants. On the other hand, HAART regimen (ZDV/3TC/NVP) (P = 0.019, 95% CI = 0.01–1.24) and the duration of HAART (P = 0.007, 95% CI = 0.003–0.40.24) were found to be predictors of anemia for HAART experienced groups.

Conclusion

The prevalence of anemia in HAART naïve persons was higher than HAART experienced persons. Risk factors for anemia in HAART naïve and HAART experienced HIV positive persons were different. Hence, there is a need for longitudinal study to further explore the causes of HIV associated anemia and the pattern of hemoglobin changes with initiation of HAART.     

Hepatitis B Vaccine Responsiveness and Clinical Outcomes in HIV Controllers

Background

Hepatitis B virus (HBV) vaccine responsiveness is associated with reduced risk of AIDS or death in HIV-infected individuals. Although HIV controllers (HIC) typically have favorable immunologic and clinical characteristics compared to non-controllers, vaccine responsiveness has not been studied.

Methods and Findings

In the U.S. Military HIV Natural History Study, HBV vaccine response was defined as antibody to hepatitis B surface antigen (anti-HBs) ≥10 IU/L after last vaccination. For determination of vaccine responsiveness, HIC (n = 44) and treatment-naïve non-controllers (n = 476) were not on highly active antiretroviral therapy (HAART) when vaccinated while treated non-controllers (n = 284) received all HBV vaccine doses during viral load (VL)-suppressive HAART. Progression to AIDS or death was also compared for all HIC (n = 143) and non-controllers (n = 1566) with documented anti-HBs regardless of the timing of HBV vaccination. Positive vaccine responses were more common in HIC (65.9%) compared to HAART-naïve non-controllers (36.6%; P<0.001), but similar to non-controllers on HAART (59.9%; P = 0.549). Factors associated with vaccine response for HIC compared to HAART-naïve non-controllers include HIC status (OR 2.65, 95% CI 1.23–5.89; P = 0.014), CD4 count at last vaccination (OR 1.28, 1.15–1.45 for every 100 cells/uL; P<0.001), and number of vaccine doses administered (OR 0.56, 0.35–0.88; P = 0.011). When HIC were compared to non-controllers on HAART, only CD4 count at last vaccination was significant (OR 1.23, 1.1–1.38 for every 100 cells/uL; P<0.001). The rate of AIDS or death per 100 person/years for HIC compared to non-controllers was 0.14 (95% CI 0–0.76) versus 0.98 (95% CI 0.74–1.28) for vaccine responders and 0 (95% CI 0–2.22) versus 4.11 (95% CI 3.38–4.96) for non-responders, respectively.

Conclusions

HIC have improved HBV vaccine responsiveness compared to treatment-naïve non-controllers, but similar to those on VL-suppressive HAART. Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIC.     

Impact of Baseline BMI on Glycemic Control and Weight Change with Metformin Monotherapy in Chinese Type 2 Diabetes Patients: Phase IV Open-Label Trial

Background

Differences exist between treatment recommendations regarding the choice of metformin as first-line therapy for type 2 diabetes patients according to body mass index (BMI). This study compared the efficacy of metformin monotherapy among normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes.

Methods

In this prospective, multicenter, open-label study in China, patients aged 23–77 years were enrolled 1∶1:1 according to baseline BMI: normal-weight (BMI 18.5−23.9 kg/m²; n = 125); overweight (BMI 24.0−27.9 kg/m²; n = 122) or obese (BMI ≥28 kg/m²; n = 124). Extended-release metformin was administered for 16 weeks (500 mg/day, up-titrated weekly to a maximum 2,000 mg/day). The primary efficacy endpoint was the effect of baseline BMI on glycemic control with metformin monotherapy, measured as the change from baseline in glycosylated hemoglobin (HbA_1c) at week 16 compared among BMI groups using ANCOVA. Other endpoints included comparisons of metformin’s effects on fasting plasma glucose (FPG), lipid levels and body weight.

Results

Mean HbA_1c decreases at week 16, adjusted for baseline values, were –1.84%, –1.78% and –1.78% in normal-weight, overweight and obese patients, (P = 0.664); body weight decreased by 2.4%, 3.9% and 3.5%, respectively. FPG levels decreased similarly over time in all BMI groups (P = 0.461) and changes from baseline in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) did not differ significantly among BMI groups at week 16 (P = 0.143 and 0.451, respectively).

Conclusions

Baseline BMI had no impact on glycemic control, weight change or other efficacy measures with metformin monotherapy. These data suggest that normal-weight type 2 diabetes patients would derive the same benefits from first-line treatment with metformin as overweight and obese patients, and are not at increased risk of excess weight loss.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00778622","term_id":"NCT00778622"}}NCT00778622     

Cranialization of the Frontal Sinus for Secondary Mucocele Prevention following Open Surgery for Benign Frontal Lesions

Objective

To compare frontal sinus cranialization to obliteration for future prevention of secondary mucocele formation following open surgery for benign lesions of the frontal sinus.

Study Design

Retrospective case series.

Setting

Tertiary academic medical center.

Patients

Sixty-nine patients operated for benign frontal sinus pathology between 1994 and 2011.

Interventions

Open excision of benign frontal sinus pathology followed by either frontal obliteration (n = 41, 59%) or frontal cranialization (n = 28, 41%).

Main Outcome Measures

The prevalence of post-surgical complications and secondary mucocele formation were compiled.

Results

Pathologies included osteoma (n = 34, 49%), mucocele (n = 27, 39%), fibrous dysplasia (n = 6, 9%), and encephalocele (n = 2, 3%). Complications included skin infections (n = 6), postoperative cutaneous fistula (n = 1), telecanthus (n = 4), diplopia (n = 3), nasal deformity (n = 2) and epiphora (n = 1). None of the patients suffered from postoperative CSF leak, meningitis or pneumocephalus. Six patients, all of whom had previously undergone frontal sinus obliteration, required revision surgery due to secondary mucocele formation. Statistical analysis using non-inferiority test reveal that cranialization of the frontal sinus is non-inferior to obliteration for preventing secondary mucocele formation (P<0.0001).

Conclusion

Cranialization of the frontal sinus appears to be a good option for prevention of secondary mucocele development after open excision of benign frontal sinus lesions.     

Factors Impacting Early Mortality in Tuberculosis/HIV Patients: Differences between Subjects Na?ve to and Previously Started on HAART

Background

Mortality among patients with tuberculosis (TB)/HIV is highest during the first few months of antituberculous therapy. The objective of this study was to assess the factors associated with early mortality among TB/HIV patients and whether these factors are similar for HAART naïve and those with prior HAART initiation.

Methods

Prospective cohort study including HIV patients with tuberculosis confirmed by culture, cared for at a referral center in Rio de Janeiro, Brazil. Multivariable Cox analysis was used to assess predictors of mortality within 3 months of antituberculous therapy.

Results

Among 227 patients included, 90 (40%) started HAART before TB diagnosis. The median time to TB diagnosis after ARV initiation was 5.9 months (interquartile range [IQR] 3.0–8.9 months). Fourteen patients (6%) died within the first 3 months. Mortality was not different between patients previously started on HAART and those who were naïve to it. In the overall adjusted analysis, HAART use during TB treatment (hazard ratio [HR] = 0.21, 95% confidential interval [CI] = 0.06–0.72) and CD4 lymphocyte count >100 cells/mm3 (HR = 0.21, 95% CI = 0.04–0.99) were associated with lower mortality, while subjects with unknown baseline CD4 lymphocyte count (HR = 9.39, 95% CI = 2.56–34.5) had higher mortality. In subgroup analysis, among HAART naïve subjects, disseminated TB (HR = 5.32, 95% CI = 1.09–25.8) and unknown baseline CD4 lymphocyte count (HR = 13.2, 95% CI = 2.71–64.5) were associated with significantly higher mortality, while HAART (HR = 0.14, 95% CI = 0.03–0.69) predicted a better outcome. Among subjects previously started on HAART, mortality was significantly associated with duration of TB symptoms >120 days (HR = 6.15, 95% CI = 1.15–32.9).

Conclusions

Predictors of early mortality among TB/HIV patients may vary according to the timing of HAART initiation. Among HAART naïve patients, mortality was influenced by baseline clinical severity, HAART use and, possibly, the quality of care preceding TB diagnosis. For patients with prior HAART initiation, longer delays in TB diagnosis predicted a significantly higher mortality.