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Emergence of HIV-1 drug resistance mutations among antiretroviral-na ve HIV-1-infected patients after rapid scaling up of antiretroviral therapy in Thailand
Sungkanuparph Somnuek,Sukasem Chonlaphat,Kiertiburanakul Sasisopin,Pasomsub Ekawat
Journal of the International AIDS Society , 2012, DOI: 10.1186/1758-2652-15-12
Abstract: Background After rapid scaling up of antiretroviral therapy in HIV-1-infected patients, the data of primary HIV-1 drug resistance in Thailand is still limited. This study aims to determine the prevalence and associated factors of primary HIV-1 drug resistance in Thailand. Methods A prospective observational study was conducted among antiretroviral-na ve HIV-1-infected Thai patients from 2007 to 2010. HIV-1 subtypes and mutations were assayed by sequencing a region of HIV-1 pol gene. Surveillance drug resistance mutations recommended by the World Health Organization for surveillance of transmitted HIV-1 drug resistance in 2009 were used in all analyses. Primary HIV-1 drug resistance was defined as the presence of one or more surveillance drug resistance mutations. Results Of 466 patients with a mean age of 38.8 years, 58.6% were males. Risks of HIV-1 infection included heterosexual (77.7%), homosexual (16.7%), and intravenous drug use (5.6%). Median (IQR) CD4 cell count and HIV-1 RNA were 176 (42-317) cells/mm3 and 68,600 (19,515-220,330) copies/mL, respectively. HIV-1 subtypes were CRF01_AE (86.9%), B (8.6) and other recombinants (4.5%). The prevalence of primary HIV-1 drug resistance was 4.9%; most of these (73.9%) had surveillance drug resistance mutations to only one class of antiretroviral drugs. The prevalence of patients with NRTI, NNRTI, and PI surveillance drug resistance mutations was 1.9%, 2.8% and 1.7%, respectively. From logistic regression analysis, there was no factor significantly associated with primary HIV-1 drug resistance. There was a trend toward higher prevalence in females [odds ratio 2.18; 95% confidence interval 0.896-5.304; p = 0.086]. Conclusions There is a significant emergence of primary HIV-1 drug resistance in Thailand after rapid scaling up of antiretroviral therapy. Although HIV-1 genotyping prior to antiretroviral therapy initiation is not routinely recommended in Thailand, our results raise concerns about the risk of early treatment failure in patients with primary HIV-1 drug resistance. Interventions to prevent the transmission of HIV-1 drug resistance and continuation of surveillance for primary HIV-1 drug resistance in Thailand are indicated.
Treatment outcomes and plasma level of ritonavir-boosted lopinavir monotherapy among HIV-infected patients who had NRTI and NNRTI failure
Weerawat Manosuthi, Sasisopin Kiertiburanakul, Wannarat Amornnimit, Wisit Prasithsirikul, Supeda Thongyen, Samruay Nilkamhang, Kiat Ruxrungtham, Somnuek Sungkanuparph
AIDS Research and Therapy , 2009, DOI: 10.1186/1742-6405-6-30
Abstract: A prospective study was conducted among HIV-infected patients who failed NNRTI-based antiretroviral therapy with M184V, TAMs, and NNRTI mutations, and were na?ve to protease inhibitor. LPV/r at 400/100 mg and lamivudine 150 mg were given twice daily. CD4 and HIV-1 RNA were monitored at week 0, 12, 24, and 48. LPV Cmin was assayed for the first 14 patients using HPLC.There were 40 patients with a mean age of 37 years and 70% were male. Median (IQR) baseline CD4 was 123 (37-245) cells/mm3 and median (IQR) HIV-1 RNA was 55,800 (9,670-100,000) copies/mL. By intend-to-treat analysis, 30 (75%) and 24 (60%) patients achieved HIV-1 RNA at <400 and <50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 29 (83%) and 23 (67%), respectively. Low-level viral rebound was found in 6 (15%) patients at week 48. Medians CD4 at week 12, 24, 36 and 48 were 249, 283, 307, and 351 cells/mm3 and significantly changed from baseline (all, P < 0.05). At 6 and 12 weeks, median (min-max) LPV Cmin was 6.52 (1.62-11.64) mg/L and 5.79 (0.75-16.31) mg/L, respectively. There were increments of mean total cholesterol and triglyceride at 48 weeks from baseline (P < 0.05).LPV/r monotherapy with recycled lamivudine can maintain virological suppression in a substantial proportion of patients failing NNRTI-based regimen and provides adequate plasma concentrations of LPV although the incidence of low-level viremia is relatively high.Currently, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) is widely prescribed as an initial therapy for treatment na?ve HIV-infected patients, particularly in many resource-constrained countries [1]. However, in patients who have delayed detection of treatment failure in this setting, the virus is often resistant to most existing nucleoside reverse transcriptase inhibitors (NRTIs) and NNRTIs even failing from the first regimen [2]. As a consequence, constructing the potent salvage regimens t
Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting
Somnuek Sungkanuparph, Sasisopin Kiertiburanakul, Anucha Apisarnthanarak, Kumthorn Malathum, Siriorn Watcharananan, Boonmee Sathapatayavongs
AIDS Research and Therapy , 2007, DOI: 10.1186/1742-6405-4-26
Abstract: A prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA <50 copies/mL, CD4 > 350 cells/mm3, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to <250 cells/mm3 or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI)] prior to TI.There were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm3, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI) and -105 (PI) cells/mm3 (p = 0.038). At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI) and 29% (PI) of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI) and 36% (PI) of patients (p = 0.022). By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI) and 14.2 (PI) months (log rank test, p = 0.026). By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5–16.3), nadir CD4 <100 cells/mm3 (HR 2.7; 95%CI 1.4–5.3) and baseline CD4 <500 cells/mm3 (HR 1.6; 95%CI, 1.2–3.1) were predictors for early ART resumption.TI of NNRTI-based ART leads to rapid CD4 decline and high probability of early ART resumption and should be avoided. It is necessary to scale-up the options for HIV-infected patients with lipodystrophy in resource-limited settings.Highly active antiretroviral therapy (HAART) has dramatically changed the course of human immunodeficiency virus type 1 (HIV-1) disease, with a substantial reduction in morbidity and mortality [1-3]. New antiretroviral drugs and combinations with better safety and tolerability profiles have become available in developed countries [4,5], but these options are still not available or are not affordable in resource-limited settings. Non-nucleoside re
Comparisons of Primary HIV-1 Drug Resistance between Recent and Chronic HIV-1 Infection within a Sub-Regional Cohort of Asian Patients
Sasisopin Kiertiburanakul, Romanee Chaiwarith, Sunee Sirivichayakul, Rossana Ditangco, Awachana Jiamsakul, Patrick C. K. Li, Pacharee Kantipong, Christopher Lee, Winai Ratanasuwan, Adeeba Kamarulzaman, Annette H. Sohn, Somnuek Sungkanuparph, for the TREAT Asia Studies to Evaluate Resistance Surveillance and Monitoring Studies
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062057
Abstract: Background The emergence and transmission of HIV-1 drug resistance (HIVDR) has raised concerns after rapid global antiretroviral therapy (ART) scale-up. There are limited data on the epidemiology of primary HIVDR in resource-limited settings in Asia. We aimed to determine the prevalence and compare the distribution of HIVDR in a cohort of ART-na?ve Asian patients with recent and chronic HIV-1 infection. Methods Multicenter prospective study was conducted in ART-na?ve patients between 2007 and 2010. Resistance-associated mutations (RAMs) were assessed using the World Health Organization 2009 list for surveillance of primary HIVDR. Results A total of 458 patients with recent and 1,340 patients with chronic HIV-1 infection were included in the analysis. The overall prevalence of primary HIVDR was 4.6%. Recently infected patients had a higher prevalence of primary HIVDR (6.1% vs. 4.0%, p = 0.065) and frequencies of RAMs to protease inhibitors (PIs; 3.9% vs. 1.0%, p<0.001). Among those with recent infection, the most common RAMs to nucleoside reverse transcriptase inhibitors (NRTIs) were M184I/V and T215D/E/F/I/S/Y (1.1%), to non-NRTIs was Y181C (1.3%), and to PIs was M46I (1.5%). Of patients with chronic infection, T215D/E/F/I/S/Y (0.8%; NRTI), Y181C (0.5%; non-NRTI), and M46I (0.4%; PI) were the most common RAMs. K70R (p = 0.016) and M46I (p = 0.026) were found more frequently among recently infected patients. In multivariate logistic regression analysis in patients with chronic infection, heterosexual contact as a risk factor for HIV-1 infection was less likely to be associated with primary HIVDR compared to other risk categories (odds ratio 0.34, 95% confidence interval 0.20–0.59, p<0.001). Conclusions The prevalence of primary HIVDR was higher among patients with recent than chronic HIV-1 infection in our cohort, but of borderline statistical significance. Chronically infected patients with non-heterosexual risks for HIV were more likely to have primary HIVDR.
Loss to Followup in HIV-Infected Patients from Asia-Pacific Region: Results from TAHOD
Jialun Zhou,Junko Tanuma,Romanee Chaiwarith,Christopher K. C. Lee,Matthew G. Law,Nagalingeswaran Kumarasamy,Praphan Phanuphak,Yi-Ming A. Chen,Sasisopin Kiertiburanakul,Fujie Zhang,Saphonn Vonthanak,Rossana Ditangco,Sanjay Pujari,Jun Yong Choi,Tuti Parwati Merati,Evy Yunihastuti,Patrick C. K. Li,Adeeba Kamarulzaman,Van Kinh Nguyen,Thi Thanh Thuy Pham,Poh Lian Lim
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/375217
Abstract: This study examined characteristics of HIV-infected patients in the TREAT Asia HIV Observational Database who were lost to follow-up (LTFU) from treatment and care. Time from last clinic visit to 31 March 2009 was analysed to determine the interval that best classified LTFU. Patients defined as LTFU were then categorised into permanently LTFU (never returned) and temporary LTFU (re-entered later), and these groups compared. A total of 3626 patients were included (71% male). No clinic visits for 180 days was the best-performing LTFU definition (sensitivity 90.6%, specificity 92.3%). During 7697 person-years of follow-up, 1648 episodes of LFTU were recorded (21.4 per 100-person-years). Patients LFTU were younger ( ), had HIV viral load ≥500?copies/mL or missing ( ), had shorter history of HIV infection ( ), and received no, single- or double-antiretroviral therapy, or a triple-drug regimen containing a protease inhibitor ( ). 48% of patients LTFU never returned. These patients were more likely to have low or missing haemoglobin ( ), missing recent HIV viral load ( ), negative hepatitis C test ( ), and previous temporary LTFU episodes ( ). Our analyses suggest that patients not seen at a clinic for 180 days are at high risk of permanent LTFU, and should be aggressively traced. 1. Introduction Loss to followup (LTFU) in patients receiving antiretroviral therapy can cause serious consequences such as discontinuation of treatment and increased risk of death [1–3]. At a program level, LTFU can make it difficult to evaluate outcomes of treatment and care [4, 5]. In resource-limited settings, where treatment has become rapidly available following the rollout of antiretroviral therapy, LTFU presents even more challenging obstacles that require special consideration and approaches [6, 7]. One of the key questions in patient followup is how to define a patient as LTFU. This has varied in studies conducted in different settings [8–10]. Defining LTFU using a very early threshold, for example, a patient with no clinic visit in the last three months, may result in many patients being considered as LTFU who would return to clinic naturally at a later date. Defining LTFU with a long threshold, for example, one year, may mean delaying too long before any effort is made to track patients potentially at risk of LTFU. The majority of research into LTFU in HIV-infected patients receiving antiretroviral treatment in resource-limited settings has been conducted in the sub-Saharan Africa region [3, 10–13]. A few studies have been conducted among Asian, mostly female, patients
Risk and prognostic significance of tuberculosis in patients from The TREAT Asia HIV Observational Database
Jialun Zhou, Julian Elliott, Patrick CK Li, Poh Lim, Sasisopin Kiertiburanakul, Nagalingeswaran Kumarasamy, Tuti Merati, Sanjay Pujari, Yi-Ming A Chen, Praphan Phanuphak, Saphonn Vonthanak, Thira Sirisanthana, Somnuek Sungkanuparph, Christopher KC Lee, Adeeba Kamarulzaman, Shinichi Oka, Fujie Zhang, Goa Tau, Rossana Ditangco
BMC Infectious Diseases , 2009, DOI: 10.1186/1471-2334-9-46
Abstract: The risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival.At baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001).The risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.The use of highly active antiretroviral therapy (HAART) has led to dramatic reductions in morbidity and mortality in HIV patients [1,2]. However, tuberculosis (TB) remains a common opportunistic infections and a major cause of death among patients with HIV, especially in sub-Saharan African and Asian countries [3-5], where there is a high background prevalence of TB [5-7].The risk of TB in HIV-infected patients and the impact of TB diagnosis on disease progression in HIV infected patients have been well described in Africa [3,8-10]. The Asia-Pacific region has a large burden of both tuberculosis [7], with nearly 5 million prevalent cases and over 3 million new cases in 2006, and HIV, with an estimated 5 million people living with HIV and 380,000 new infections occurring in 2007 [11]. It is estimated that 2.5 million people are living with both infections in the region [5]. Despite the importance of these inter-related epidemics in the region, fe
Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT Asia HIV Observational Database
Jialun Zhou, Thira Sirisanthana, Sasisopin Kiertiburanakul, Yi-Ming A Chen, Ning Han, Poh_Lian Lim, Nagalingeswaran Kumarasamy, Jun Choi, Tuti Merati, Evy Yunihastuti, Shinichi Oka, Adeeba Kamarulzaman, Praphan Phanuphak, Christopher KC Lee, Patrick CK Li, Sanjay Pujari, Vanthanak Saphonn, Matthew G Law
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-361
Abstract: Treatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models.A total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20 000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5 000, 4 000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation.After cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.Studies show that latent infection of CD4 cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy [1]. To suppress viral replication so that the VL is below the level of detection with standard assays is thus one of the aims at the start of antiretroviral treatment. Maximal and durable suppression of HIV VL prevents or delays development of drug resistant mutations, preserves CD4 cells, and eventually results in better clinical outcomes. According to the US guidelines, if HIV VL suppression is not achieved, it is necessary to change to a new regimen, a second or third line regimen, with at least two active drugs [2].HIV-infected patients in most developing countries h
Tuberculosis in Antiretroviral Treatment Programs in Lower Income Countries: Availability and Use of Diagnostics and Screening
Lukas Fenner, Marie Ballif, Claire Graber, Venerandah Nhandu, Jean Claude Dusingize, Claudia P. Cortes, Gabriela Carriquiry, Kathryn Anastos, Daniela Garone, Eefje Jong, Joachim Charles Gnokoro, Omar Sued, Samuel Ajayi, Lameck Diero, Kara Wools-Kaloustian, Sasisopin Kiertiburanakul, Barbara Castelnuovo, Charlotte Lewden, Nicolas Durier, Timothy R. Sterling, Matthias Egger, for the International epidemiological Databases to Evaluate AIDS (IeDEA)
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077697
Abstract: Objectives In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. Methods and findings We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient-level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). Conclusions Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge.
Burkholderia pseudomallei: abscess in an unusual site.
Kiertiburanakul S,Sungkanuparph S,Kositchiwat S,Vorachit M
Journal of Postgraduate Medicine , 2002,
Abstract: Melioidosis is an infection caused by Burkholderia pseudomallei. It is an important human pathogen in tropical area. The clinical manifestations are protean and multisystem involvement. We report an unusual case of melioidosis with abscess at root of mesentery in an elderly, non-insulin dependent diabetic Thai women. She presented with prolonged fever and chronic abdominal pain. The early clinical diagnosis was carcinomatous mass with peritonitis. Diagnosis of melioidosis arose from the surgical finding and pus culture. Treatment with surgical drainage and ceftazidime followed by co-trimoxazole plus doxycycline had a good clinical outcome.
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