Thanomsak Anekthananon

Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups. Conclusion/Significance This study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness. Trial Registration ClinicalTrials.gov NCT00765024

Cryptococcal Immune Reconstitution Inflammatory Syndrome after Antiretroviral Therapy in AIDS Patients with Cryptococcal Meningitis: A Prospective Multicenter Study

A prospective multicenter study of cryptococcal immune reconstitution inflammatory syndrome (IRIS) was conducted as a substudy of the Bacteriology and Mycology Study Group 3-01. Of 101 AIDS patients with cryptococcal meningitis who received highly active antiretroviral therapy (HAART), 13 experienced cryptococcal IRIS. No association between the timing of HAART initiation and the diagnosis of IRIS was identified. Increased baseline serum cryptococcal antigen (CrAg) titer was a risk factor for cryptococcal IRIS.

Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study

In a comparative cohort study, Jeffrey Stringer and colleagues investigate the risk of ART failure in women who received single-dose nevirapine for PMTCT, and assess the duration of increased risk.

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand

New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm3 is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm3 or with CD4 cell counts >50 cells/mm3 who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm3 and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines.

High rate multiple drug resistances in HIV-infected patients failing nonnucleoside reverse transcriptase inhibitor regimens in Thailand, where subtype A/E is predominant.

The prevalence of drug resistance was determined among 64 HIV-infected Thai patients who were failed while receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens. Eighty-nine percent of patients had 1 or more NNRTI mutation resistances. Almost all patients had resistance to at least 1 nucleoside reverse transcriptase inhibitor (NRTI), and 42% had multiple-NRTI resistance.

Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes.

Efficacy and tolerability of a double boosted protease inhibitor (lopinavir + saquinavir/ritonavir) regimen in HIV‐infected patients who failed treatment with nonnucleoside reverse transcriptase inhibitors

Long‐term nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based antiretroviral treatment failure in most developing countries has led to broad cross‐resistance within NNRTI and nucleoside reverse transcriptase inhibitor (NRTI) classes. In this study, we investigated the efficacy and tolerability of a double boosted protease inhibitor (PI) regimen in this setting.

Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients

Objectives The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections.

Body Shape and Metabolic Abnormalities in Thai HIV-Infected Patients

Fat and metabolic abnormalities and their associated factors in HIV-infected patients in Thailand were examined. Body fat and fasting lipids (total cholesterol, TC; triglyceride, TG; and HDL-cholesterol, HDL-c) were evaluated in 247 HIV-infected Thais. Body fat was evaluated by subjects and blinded observers, and measured using dual-energy X-ray absorptiometry. Descriptive statistics and logistic regression were used for analyses. Antiretroviral (ARV)-treated Thais were significantly older, more likely to be male, and had higher education and income compared to untreated subjects. The prevalence of lipoatrophy was 10.3% in ARV-naive patients, 36.7% in patients receiving non-protease inhibitor (PI)-based ARV, and 78.7% in PI-based ARV-treated patients (p < 0.001). Excess abdominal or neck fat was found in 0.8%, 6.7%, and 24.6% of the naive, non-PI-treated, and PI-treated, respectively (p < 0.001). Hypercholesterolemia (TC > or = 240 mg/dl) was found in 4.8%, 26.6%, and 42.6%; hypertriglyceridemia (TG > or = 150 mg/dl) in 8.2%, 48.3%, and 75.4%; and low HDL-c (HDL-c < 40 mg/dl) in 42.9%, 20.0%, and 31.2% of the naive, non-PI treated, and PI-treated, respectively (p < 0.05 for all). Central to peripheral fat ratios were 1.11 +/- 0.03, 1.45 +/- 0.06, and 1.93 +/- 0.08 for the naive, non-PI, and PI-treated, respectively (p < 0.001). Treatment was associated with abnormal fat. The adjusted ORs (95% CI) of lipoatrophy for excess fat were 4.6 (2.0-10.7); 6.3 (0.6-71.1) for ARV-naive vs. non-PI; 5.6 (3.4-9.1); 10.7 (3.4-33.8) for ARV-naive vs. PI, and 5.7 (2.4-13.9); 5.3 (1.2-11.4-13.9) for ARV-naive vs. PI. ARV-associated metabolic abnormalities are common in this non-Western population. Appropriate selection and monitoring of ARV treatment are critical to minimize the risk of long-term complications.

Effect of high-dose fluconazole on QT interval in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis

Sir, Azoles may cause prolongation of the QT interval either directly or by inhibiting the hepatic metabolism of other QT-prolonging agents. Ketoconazole is known to block the human ether-a-go-go-related gene (hERG) product and thereby inhibit the potassium IKr current in the heart [1]. Whether fluconazole also inhibits hERG is currently unknown. The BAMSG 3-01 study was a Phase II trial for the treatment of cryptococcal meningitis in acquired immune deficiency syndrome (AIDS) patients [2]. Patients were randomly assigned to receive amphotericin B (0.7 mg/kg/day) either alone or plus fluconazole (400 mg/day or 800 mg/day) for the first 14 days. Patients’ QT intervals were assessed at baseline to identify those at risk of QT prolongation as well as after 7 days of therapy to determine whether the daily fluconazole dose or Day 14 trough serum concentration (Cmin) (24 h after dosing) was associated with QT prolongation. Serum concentration results were obtained using gas–liquid chromatography [3]. To calculate the corrected QT (QTc) interval, Fridericia’s formula was used (QTcF = QT/RR0.33) as it is more accurate than Bazett’s formula (QTcB = QT/RR0.50) in patients with altered heart rate [4]. Patients with a baseline QTcF > 500 ms were excluded; at Day 7, subjects with a QTcF > 500 ms or a QTcF prolongation (>60 ms above baseline) were discontinued. Details on the study design have been described previously [2]. P-values comparing all treatment arms were obtained by analysis of covariance (ANCOVA) and Mantel–Haenszel χ2 test. The percentages of subjects with QTc > 500 ms or QTc prolongation were compared. ANCOVA models were constructed to identify baseline characteristics associated with baseline QTc intervals, Day 7 parameters associated with Day 7 QTc intervals, and baseline characteristics predictive of Day 7 QTc intervals. Models with an outcome of Day 7 QTc interval were adjusted for baseline QTc interval. The relationship of Day 7 QTcF interval change from baseline and Day 14 Cmin was assessed by calculating the Spearman rank correlation coefficient. In total, 141 subjects received therapy, with 139 and 127 subjects having baseline and Day 7 electrocardiogram (ECG) assessments performed, respectively. All baseline ECG measures except QTcF interval were comparable between arms (P > 0.05). The mean ± standard deviation (S.D.) baseline QTcF intervals for the amphotericin B (AmB), amphotericin B plus fluconazole 400 mg (AmB+Fluc400) and amphotericin B plus fluconazole 800 mg (AmB+Fluc800) arms were 395.5 ± 24.67, 406.8 ± 22.16 and 407.9 ± 24.88 ms, respectively (P = 0.033). At Day 7, all ECG measures except percent of subjects experiencing abnormalities were similar among arms (P > 0.05). However, the percent of patients experiencing clinically significant abnormalities was comparable (P = 0.829). After adjusting for baseline QTc, the Day 7 QTc interval adjusted means for each of the combination therapy arms were comparable with the AmB arm (P > 0.10). However, Day 7 median and adjusted mean change from baseline to Day 7 estimates were higher in the AmB+Fluc800 arm compared with the AmB arm (Fig. 1). Based on multivariate models, lower baseline Karnofsky scales were associated with higher baseline QTcF and QTcB intervals; lower Day 7 potassium levels were associated with higher Day 7 QTcF intervals; and no Day 7 characteristics were associated with QTcB intervals (P < 0.05). For predictive factors, higher baseline cerebrospinal fluid (CSF) opening pressure and Karnofsky scales were predictive of higher Day 7 QTcF intervals; and higher baseline CSF opening pressure, potassium, age and lower CD4+ count were predictive of higher Day 7 QTcB intervals (P < 0.05). Fig. 1 (A) QTc intervals at Day 7 among three treatment arms [with the percentage of patients experiencing high QTc interval values (>500 ms)] and (B) QTc intervals change from baseline to Day 7 among three treatment arms [with the percentage of patients ... Fluconazole concentration samples were only obtained for a subset of subjects; specifically, 47 patients had ECG and non-zero Day 14 fluconazole measurements (36 received AmB+Fluc800, 9 AmB+Fluc400 and 2 AmB). The mean ± S.D. QTcF interval at baseline was 407.6 ± 24.5 ms and at Day 7 was 410.8 ± 27.2 ms (P = 0.504, paired t-test). The geometric mean Day 14 Cmin was 35.6 mg/L (range 4.2–84.1 mg/L). The Spearman rank correlation for QTcF interval change from baseline and Day 14 Cmin was 0.282 (P = 0.074). Based on the linear regression model, the predicted Day 14 Cmin (90% confidence interval for the mean) associated with Day 7 QTcF interval change from baseline of 30 was 42.0 (33.7–52.2) and of 60 was 49.2 (34.6–69.8) (P = 0.065). No comparative trial evaluating the direct effect of high-dose oral fluconazole on the QT interval has previously been conducted. We show that AmB+Fluc800 was not associated with increased risk of either QTcB or QTcF interval prolongation compared with AmB+Fluc400 and AmB treatment. Percentages of subjects experiencing Day 7 QTc > 500 ms or prolongation were similar. However, patients receiving AmB+Fluc800 had a slight increase in QTc compared with baseline. High trough concentrations appear to be associated with a trend towards increased risk of QTc prolongation at Day 7, although the sample size for the number of subjects with both ECG and non-zero Day 14 fluconazole measurements was relatively small. Thus, ECG monitoring of high-dose fluconazole should be conducted and physicians should be aware of other potential risk factors for prolongation, particularly hypokalaemia. A larger-scale study is required to clarify the correlation between QT prolongation and high-dose fluconazole.