Siriluck Anunnatsiri

Adult-onset immunodeficiency in Thailand and Taiwan

BACKGROUND Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown. METHODS We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained. RESULTS Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering. CONCLUSIONS Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).

Disseminated Nontuberculous Mycobacterial Infection in Patients Who Are Not Infected with HIV in Thailand

BACKGROUND Disseminated nontuberculous mycobacterial (NTM) infection is an emerging infectious disease worldwide that occurs mostly in immunocompromised hosts. Disseminated NTM infection is uncommon in persons who are not infected with human immunodeficiency virus (HIV). Recently, we described a group of non-HIV-infected Thai patients whose disease manifestation was a previously unrecognized clinical entity characterized by chronic bilateral lymphadenopathy due to rapidly growing mycobacteria. Most of the patients had coinfection with other opportunistic pathogens and reactive skin diseases. Therefore, in recognition of the increasing significance of this unique disease due to NTM in our country, we initiated a study to assess the prevalence, clinical characteristics, and geographic variations of this disease. METHODS There were 129 cases of disseminated NTM infection identified from 4 university hospitals located in major areas throughout Thailand. All patients but 1 were adults. Only 12% of patients had underlying diseases. The majority of the patients (81%) lived in the northeast of Thailand. RESULTS The most common organ involved was the lymph node (89%), followed by skin and soft tissue (26%), lung (19%), and others. Fifty-nine patients (46%) had 81 episodes of coinfection with other opportunistic infections (e.g., salmonellosis, 32 cases; cryptococcosis, 8 cases; penicilliosis, 8 cases; histoplasmosis, 5 cases). Seventy-seven patients had 86 episodes of reactive skin diseases (e.g., Sweet syndrome, 60 cases; pustular psoriasis, 6 cases; erythematous pustulosis, 5 cases). CONCLUSIONS These findings suggest a cell-mediated immune defect in these patients that needs to be further investigated. This study strongly suggests that the prevalence of NTM infection in Thailand is increasing. To our knowledge, this is the largest study of disseminated NTM infection among non-HIV-infected patients.

Disseminated Infection Due to Rapidly Growing Mycobacteria in Immunocompetent Hosts Presenting with Chronic Lymphadenopathy: A Previously Unrecognized Clinical Entity

Disseminated infection due to rapidly growing mycobacteria is uncommon and occurs mostly in immunocompromised patients. We report 16 cases of such infection with an unusual presentation seen at Srinagarind Hospital, a university hospital in northeastern Thailand. The clinical features were different from those in previous reports. All of the patients presented with chronic bilateral cervical lymphadenopathy. Twelve had mycobacterial involvement of other organs (sinuses, 6 patients; lungs, 4; liver, 4; spleen, 3; skin, 3; bone and joint, 2; and tonsils, 2). An interesting occurrence in 11 patients was 14 episodes of reactive skin manifestations (Sweets syndrome, 9; generalized pustulosis and erythema nodosum, 2 each; and pustular psoriasis, 1). No identifiable predisposing factors, including human immunodeficiency disease, were found in these patients. However, 8 patients had 11 episodes of prior infection or coinfection with other opportunistic pathogens (salmonellosis, 4; penicilliosis, 3; pulmonary tuberculosis, 2; and melioidosis and cryptococcosis, 1 each). These findings suggest that cell-mediated immunity is defective in these patients.

Two Randomized Controlled Trials of Ceftazidime Alone versus Ceftazidime in Combination with Trimethoprim-Sulfamethoxazole for the Treatment of Severe Melioidosis

BACKGROUND Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime monotherapy. It is not known whether TMP-SMX provides an additional benefit. METHODS Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta-analysis. The primary end point was in-hospital mortality rate. RESULTS The in-hospital mortality rate among all enrolled patients (n=449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P=.73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died > or =48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P=.70) or for deaths that occurred > or =48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P=.73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model. CONCLUSION We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate.

Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial

Summary Background Melioidosis, an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment. Methods For this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ≥15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks (1:1; block size of ten, stratified by study site). We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1·7. This study is registered with www.controlled-trials.com, number ISRCTN86140460. Findings We enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0·81; 95% CI 0·42–1·55). The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]). Interpretation Our findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients. Funding Thailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust.

Randomized, Double-Blind, Controlled Study of Cefoperazone-Sulbactam Plus Cotrimoxazole versus Ceftazidime Plus Cotrimoxazole for the Treatment of Severe Melioidosis

We conducted a prospective randomized, double-blind, controlled study of cefoperazone-sulbactam (ratio, 1:1; cefoperazone 25 mg/kg/day) plus cotrimoxazole (trimethoprim-sulfamethoxazole [TMP-SMZ] at a ratio of 80:400; TMP, 8 mg/kg/day) versus ceftazidime (100 mg/kg/day) plus cotrimoxazole (TMP, 8 mg/kg/day) for the treatment of severe melioidosis. Of 219 patients enrolled in the study, 102 (47%) had culture-proven melioidosis. These patients were assigned randomly to 2 treatment groups, each with 50 patients (2 patients were excluded). Mortality rates were not significantly different between the 2 groups: 18% in the cefoperazone-sulbactam group versus 14% in the ceftazidime group. The crude difference in the mortality rate was 4%, but when adjusted for type of infection the difference was 0.9% (95% confidence interval, -3.6% to 5.4%; P = .696). The duration of defervescence and the bacteriological response of successfully treated patients were similar in both groups, and both treatment regimens were well tolerated. Cefoperazone-sulbactam plus cotrimoxazole might be used as an alternative to ceftazidime plus cotrimoxazole as treatment for severe melioidosis.

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.

Fungemia in non-HIV-infected patients: a five-year review.

OBJECTIVES To investigate the incidence, risk factors, causative fungi, and outcomes of fungemia in adult, non-HIV-infected patients. DESIGN We studied 147 episodes of fungemia due to Candida spp and Trichosporon spp in adult patients admitted to a university hospital in Northeast Thailand between 1999 and 2003. RESULTS The overall incidence of fungemia was 14.1 per 10,000 hospital admissions. Candida was the most common isolate (138 episodes, 93.9%) with non-albicans Candida accounting for 68.7%. The major non-albicans Candida isolates were Candida parapsilosis and Candida tropicalis. Fungemia caused by Trichosporon accounted for 6.1% of the cases, but their clinical features could not be distinguished from fungemia due to Candida. The overall in-hospital mortality rate was 56.1%. The independent factors related to mortality were high APACHE II score (odds ratio (OR) 1.12 per 1-point increments, 95% confidence interval (CI) 1.03-1.23), assisted ventilation (OR 3.49, 95% CI 1.04-11.64), and neutropenia (OR 7.47, 95% CI 1.25-44.74). CONCLUSIONS Candidemia, especially that caused by non-albicans Candida, was an important nosocomial infection in this tertiary care hospital in Northeast Thailand. The mortality rate was high, particularly in patients who were critically ill. Rapid diagnosis and early treatment are therefore important challenges for improving clinical 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.

Low-dose, once-daily atazanavir/ritonavir (200/100): an effective treatment for HIV-infected patients in Thailand.

To the Editors: Atazanavir (ATV) is the first oncedaily protease inhibitor (PI) approved with a recommended dose of 400 or 300 mg and boosted with ritonavir (RTV). Coadministered with RTV, the CYP3A4 isoenzyme inhibitor markedly increases the ATV blood level. ATV/RTV-300/100 results in a 4-fold increase in the trough concentration compared with a dose of 400 mg once daily. ATV has the lowest pill burden and best favorable effects on the lipid profile compared with other PIs; however, ATV has a higher cost compared with other PIs. If a lower dose of ATV/RTV could be used as safely as a low-dose of indinavir/RTV-400/100 twice daily in Thai patients, it would be preferable for more resource-limited settings. We retrospectively reviewed HIVinfected adult patients who were on antiretroviral treatment with a viral load <50 copies/mL and had changed their regimen to ATV/RTV-200/100 mg once daily as boosted PI plus 2 nucleoside reverse transcriptase inhibitors or nonnucleoside reverse transcriptase inhibitor. Their CD4, HIV RNA, and fasting lipid profiles were monitored every 3–6 months. Some of the patients had blood obtained for ATV trough levels. There were 14 HIV-infected patients in this cohort averaging (SD) 47 years of age (±11.4). The demographic and clinical data are presented in Table 1. Most of the patients were female (57%) with a median body weight of 53.5 kg (range = 46–74 kg). The mean (SD) baseline CD4, before switching, was 299.5 (±152.5) cells/mm. The respective median (range) of baseline fasting total cholesterol (TC), triglyceride, lowdensity lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) was 213 (128–307), 224 (85– 497), 121 (33–197), and 42 (29–94) mg/ dL. The median duration of follow-up was 68.1 (range = 12–165) weeks. During the follow-up period, all the patients had viral suppression (<50 copies/ mL). The mean CD4 (SD) count was significantly increased from 299.5 (±152.5) to 420.1 (±135.1) cells/mm (P = 0.001). The respective median (range) change in fasting TC, triglyceride, LDL-C, and HDL-C was 7 ( 98 to 59), 46 ( 226 to 87), 8 ( 79 to 72), and 0 ( 30 to 26) mg/dL; however, the changes were not statistically significant. All the patients tolerated the treatment very well and none discontinued the medication due to any adverse reaction. All 5 cases had their ATV trough levels checked and had levels >150 ng/mL, which is the minimum target trough level required by the Department of Health and Human Service guidelines. In this cohort study, we demonstrated the long-term efficacy of lowdose ATV/RTV-200/100 once daily as part of an antiretroviral therapy regimen. All the patients achieved undetectable HIV RNA (<50 copies/mL) during a median follow-up of 68 weeks. (Five of the patients had been followed up for as long as 2 years.) The finding was confirmed by adequate trough levels in 5 cases for whom blood had been obtained. This might be explained by the relatively low body weight in our cohort (median = 53.5 kg); however, patient no. 3 had an adequate ATV level even though he was taking ATV with efavirenz, which usually results in decreased ATV blood levels. These results provide some evidence that this regimen is adequate in HIV-infected patients in Thailand. It had a minimal effect on lipid profiles, and none of the patients discontinued the medication due to any adverse reaction. In conclusion, the use of ATV/RTV200/100 mg once daily, as a boosted PI, was effective in HIV-infected Thai patients. This combination markedly lowered the cost of treatment. In addition, this regimen is safe, well tolerated, and has a low pill burden compared with other PIs and therefore should be considered as a boosted PI regimen in resource-limited settings. Notwithstanding, a full pharmacokinetic