Preeyaporn Srasuebkul

A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection

BACKGROUND Structured treatment interruption was evaluated in 74 patients who had been pretreated with antiretrovirals, consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for 1 year followed by 3 years of highly active antiretroviral therapy containing a protease inhibitor. METHODS Patients with a CD4 cell count of > or =350 cells/microL and a plasma viral load of <50 copies/mL were randomized to 3 therapy arms: (1) continuous therapy, (2) CD4 cell count-guided theory, and (3) week-on/week-off (WOWO) therapy. The efficacy and safety of structured treatment interruption and antiretroviral use were evaluated in human immunodeficiency type 1 (HIV-1)-infected patients. The study end points were percentage of patients who developed AIDS or who died and a CD4 cell count of > or =350 cells/microL. Intergroup differences were analyzed using analysis of variance and Kruskal-Wallis tests. RESULTS Baseline characteristics at the start of the structured treatment interruption were similar. At week 48, no patient had died, and 1 patient in the WOWO group had an AIDS-defining condition. The proportions of patients with a CD4 cell count of > or =350 cells/microL were 100%, 87%, and 96% in treatment arms 1, 2, and 3, respectively. The percentages of weeks of antiretroviral use were 100%, 41.1%, and 69.8% in arms 1, 2, and 3, respectively. The adverse events were not significantly different among arms (P=.27). Thirty-one percent of patients in the WOWO group experienced virological failure. CONCLUSION WOWO therapy maintained a CD4 cell count of > or =350 cells/microL in almost all patients but was associated with high virological failures rates (possibly resulting from previous dual-NRTI therapy), indicating that this strategy is less useful. Receipt of CD4 cell count-guided therapy resulted in comparable clinical outcomes to continuous therapy and may save antiretroviral-associated costs, but this needs to be confirmed by a larger trial.

Efavirenz versus Boosted Atazanavir or Zidovudine and Abacavir in Antiretroviral Treatment-Naive, HIV-Infected Subjects: Week 48 Data from the Altair Study

BACKGROUND Antiretroviral therapy is complicated by drug interactions and contraindications. Novel regimens are needed. METHODS This open label study randomly assigned treatment-naive, human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz (Arm I), with ritonavir-boosted atazanavir (Arm II), or with zidovudine/abacavir (Arm III). Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis. Treatment arms were noninferior if the upper limit of the 95% confidence interval (CI) was <0.5 log(10) copies/mL. Secondary objectives included virologic, immunologic and safety end points. RESULTS The intention-to-treat population comprised 322 patients (Arm I, n = 114; Arm II, n = 105; and Arm III, n = 103). Noninferiority for the primary end point was established. Analysis for superiority showed that Arm III was significantly less potent than Arm I (-0.20 log(10) copies/mL; 95% CI, -0.39 to -0.01 log(10) copies/mL; P = .038). The proportions of patients on each of Arm I (95%) and Arm II (96%) with <200 copies/mL were not different (P = .75), but the percentage of patients in Arm III with <200 copies/mL (82%) was significantly lower (P = .005). CD4+ cell counts did not differ. Serious adverse events were more frequent in Arm III (n = 30) than in Arm I or Arm II (n = 15 for each; P = .062). CONCLUSIONS A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication, compared with the suppression demonstrated by standard antiretroviral therapy regimens, although it did meet the predetermined formal definition of noninferiority. Secondary analyses indicated statistically inferior virologic and safety performance. Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety.

Serum Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15): A Potential Screening Tool for the Prevention of Colon Cancer?

Background: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates nonsteroidal anti-inflammatory drug (NSAID) protection from colonic polyps in mice and is linked to the development of colorectal carcinoma in humans. Therefore, changes in serum MIC-1/GDF15 levels could predict the presence of premalignant colonic polyposis and assist in population screening strategies. Methods: Serum MIC-1/GDF15 levels were measured in subjects in the Polyp Prevention Trial, in which NSAID use and colon cancer risk factors were defined. Subjects had an initial adenoma removed, a repeat colonoscopy removing previously unidentified polyps, and serum MIC-1/GDF15 estimation. Three years later recurrent adenomas were identified and serum MIC-1/GDF15 levels reestimated. The relationship between serum MIC-1/GDF15 levels and adenoma presence or recurrence was examined. Results: Serum MIC-1/GDF15 levels differed by adenoma status and were significantly related to colon cancer risk factors. In addition, mean serum MIC-1/GDF15 levels rose with increasing numbers of adenomas present and high-risk adenoma recurrence. NSAID users had higher serum MIC-1/GDF15 concentrations, which were related to protection from adenoma recurrence. Furthermore, adjusted serum MIC-1/GDF15 levels at final follow-up were related to adenoma recurrence (highest quartile MIC-1/GDF15; OR = 14.7, 95% CI: 3.0–73). Conclusions: These data suggest that MIC-1/GDF15 mediates at least some of the protection afforded by NSAIDs against human colonic polyposis. Furthermore, serum MIC-1/GDF15 levels vary with the development of adnenomatous colonic polyps. Impact: Serum MIC-1/GDF15 determination may hold promise as the first serum screening test to assist the detection of premalignant adenomatous colonic polyposis. Cancer Epidemiol Biomarkers Prev; 21(2); 337–46. ©2011 AACR.

Interruptions of tenofovir/emtricitabine-based antiretroviral therapy in patients with HIV/hepatitis B virus co-infection

Thai patients enrolled in STACCATO with HIV/hepatitis B virus (HBV) co-infection and tenofovir/emtricitabine-based antiretroviral therapy (ART) were randomly assigned to continuous treatment or CD4 cell count-guided interruptions. HBV replication was suppressed below detection in 15/16 patients. Structured treatment interruption increased transaminases and HBV viraemia in five of six patients; one flare was severe. Conversion to anti-hepatitis Be occurred with continuous treatment only. Tenofovir/emtricitabine-containing ART is highly effective in controlling chronic HIV/HBV co-infection but treatment should not be interrupted.

Changes in Body Composition and Mitochondrial Nucleic Acid Content in Patients Switched from Failed Nucleoside Analogue Therapy to Ritonavir-Boosted Indinavir and Efavirenz

BACKGROUND Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated. We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz. METHODS Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mononuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks. RESULTS At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P=.003), L4 subcutaneous adipose tissue (+20 [35] cm(2); P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm(2); P<.001), and L4 visceral adipose tissue (+11 [34] cm(2); P=.01), but we also observed reduced lean limb mass (-831 [1,100] g; P=.3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96). CONCLUSIONS This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed.

Prior antiretroviral therapy experience protects against zidovudine-related anaemia

We investigated the use of antiretroviral therapy regimens containing zidovudine or stavudine, using data from the TREAT Asia HIV Observational Database (TAHOD), a multicentre, prospective, observational study of an HIV‐infected cohort in the Asia‐Pacific Region.

Antiretroviral therapy outcomes of HIV-infected children in the TREAT Asia pediatric HIV observational database.

Introduction:We report responses to combination antiretroviral therapy (cART) in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database. Methods:Children included were those who had received cART (ie, ≥3 antiretrovirals) at <18 years. The analysis was intention-to-treat by the first cART regimen. Median values are provided with interquartile ranges; hazard ratios (HRs) with 95% confidence intervals. Results:Of the 1655 children included, 50.4% were male, with a median age at cART of 7.0 (3.9-9.8) years and CD4 of 8% (2.0%-15%); 92.5% were started on an NNRTI; median duration of follow-up was 2.9 (1.4-4.6) years. Loss-to-follow-up and death rates were 4.2 (3.7-4.8) and 2.1 (1.7-2.5) per 100 person-years, respectively. At 36 months, median CD4 was 26% (21%-31%); 81% of those with viral load (n = 302) were <400 copies per milliliter. Children who reached CD4 ≥25% within 5 years were more likely to be females (HR: 1.4; 1.2-1.7), start before 18 months old (HR: 3.8; 2.4-6.2), lack a history of monotherapy/dual therapy (HR: 1.7; 1.4-2.5), and have a higher baseline CD4 (per 10% increase: HR: 2; 1.9-2.2). Conclusions:These data underscore the need for early diagnosis and cART initiation to preserve immune function.

Short-Term Clinical Disease Progression in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Results from the TREAT Asia HIV Observational Database

OBJECTIVE The aim of our study was to develop, on the basis of simple clinical data, predictive short-term risk equations for AIDS or death in Asian patients infected with human immunodeficiency virus (HIV) who were included in the TREAT Asia HIV Observational Database. METHODS Inclusion criteria were highly active antiretroviral therapy initiation and completion of required laboratory tests. Predictors of short-term AIDS or death were assessed using Poisson regression. Three different models were developed: a clinical model, a CD4 cell count model, and a CD4 cell count and HIV RNA level model. We separated patients into low-risk, high-risk, and very high-risk groups according to the key risk factors identified. RESULTS In the clinical model, patients with severe anemia or a body mass index (BMI; calculated as the weight in kilograms divided by the square of the height in meters) <or= 18 were at very high risk, and patients who were aged <40 years or were male and had mild anemia were at high risk. In the CD4 cell count model, patients with a CD4 cell count <50 cells/microL, severe anemia, or a BMI <or=18 were at very high risk, and patients who had a CD4 cell count of 51-200 cells/microL, were aged <40 years, or were male and had mild anemia were at high risk. In the CD4 cell count and HIV RNA level model, patients with a CD4 cell count <50 cells/microL, a detectable viral load, severe anemia, or a BMI <or=18 were at very high risk, and patients with a CD4 cell count of 51-200 cells/microL and mild anemia were at high risk. The incidence of new AIDS or death in the clinical model was 1.3, 4.9, and 15.6 events per 100 person-years in the low-risk, high-risk, and very high-risk groups, respectively. In the CD4 cell count model the respective incidences were 0.9, 2.7, and 16.02 events per 100 person-years; in the CD4 cell count and HIV RNA level model, the respective incidences were 0.8, 1.8, and 6.2 events per 100 person-years. CONCLUSIONS These models are simple enough for widespread use in busy clinics and should allow clinicians to identify patients who are at high risk of AIDS or death in Asia and the Pacific region and in resource-poor settings.

Impact of drug classes and treatment availability on the rate of antiretroviral treatment change in the TREAT Asia HIV Observational Database (TAHOD).

BackgroundIt is critical to understand the pattern of antiretroviral treatment (ART) prescription in different regions of the world as ART procurement needs to be anticipated. We aimed at exploring rates and predictors of ART combination changes in clinical practice in Treat Asia HIV Observational Database (TAHOD).MethodsRates of ART changes were examined in patients who started first line triple or more ART combination in TAHOD, and had at least one follow-up visit. Rates of ART changes were summarised per follow-up year, and factors associated with changes assessed using random-effect Poisson regression. The Kaplan-Meier method was used to determine durations of patients in their first, second and third regimen.ResultsA total of 1846 patients initiated an ART combination with at least three drugs. Median follow up time for the first treatment was 3.2 years. The overall rate of ART change was 29 per 100-person-year.In univariate analyses, rate of treatment change was significantly associated with exposure category, the country income category, the drug class combination, calendar year and the number of combinations. In multivariate analysis, compared to d4T/3TC/NVP, starting ART with another NNRTI-containing regimen, with PI only or with a triple NRTI regimen was associated with a higher risk of combination change (relative risk (RR) 1.6 (95% CI 1.64 – 1.96), p < 0.001, RR 3.39 (2.76 – 4.16) p < 0.001, RR 6.37 (4.51 – 9.00), p < 0.001). Being on a second or a third combination regimen was also associated with a decreased rate of ART change, compared with first ART combination (RR 0.82 (0.68 – 0.99), p = 0.035, RR 0.77 (0.61 – 0.97), p = 0.024). Sites with fewer than 12 drugs used had an increased rate of treatment changes (1.31 (1.13 – 1.51), p < 0.001). Injecting drug users, and other/unknown exposure was found to increase rate of treatment change (1.24 (1.00 – 1.54), p = 0.055). Percentages of patients who stopped treatment due to adverse events were 31, 27 and 32 in 1st, 2nd and 3rd treatment combinations, respectively.ConclusionOur study suggests that drug availability impacts on ART prescription patterns. Our data, reflecting real clinic use in Asia, suggest that around half of all patients require second combination ART by 3 years after treatment initiation.

Trastuzumab therapy in Australia: Which patients with HER2+ metastatic breast cancer are assessed for cardiac function?

PURPOSE To manage the potential trastuzumab mediated cardiotoxicity, clinical guidelines recommend pre-treatment cardiac function assessment and 3-monthly reassessment during therapy. This study examined rates of cardiac function assessment and predictors of assessment among patients receiving trastuzumab for HER2+ metastatic breast cancer treatment in routine clinical care. METHODS Our cohort comprised 3418 women receiving trastuzumab for HER2+ metastatic breast cancer under Australias nationally funded Herceptin Program (2001-2010). We examined rates of pre-treatment and during-treatment assessment. We used logistic regression and zero-inflated Poisson regression to examine predictors of pre-treatment and during-treatment assessment respectively. RESULTS 37.7% of patients were assessed pre-treatment, 50.4% during therapy, and 26.4% both before and during therapy. Among patients assessed for cardiac function, reassessment occurred regularly (median of 3.9 months). History of cardiovascular conditions and prior anthracycline use predicted pre-treatment assessment (OR = 1.32, 95% CI: 1.08-1.61; OR = 1.23, 95% CI: 1.05-1.44 respectively). Concurrent trastuzumab and taxane use, exposure to anthracyclines, and older age predicted during-treatment assessment (IRR = 1.17, 95% CI: 1.06-1.29; IRR = 1.12, 95% CI: 1.02-1.23; and IRR = 1.05, 95% CI: 1.01-1.09 respectively). Patients with multi-morbidities were less likely to receive during-treatment assessment. CONCLUSION Over the last decade, cardiac function assessment in a large cohort of patients receiving trastuzumab was not consistent with guideline recommendations. The association between cardiac monitoring and risk factors for cardiac dysfunction suggest clinicians are triaging patients prior to implementing cardiac assessment. Efforts are needed to identify barriers to implementing current guidelines for cardiac monitoring in metastatic breast cancer patients undergoing trastuzumab treatment, particularly those with multi-morbidities.