Sasisopin Kiertiburanakul

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.).

CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial.

BACKGROUND Stopping antiretroviral therapy in patients with HIV-1 infection can reduce costs and side-effects, but carries the risk of increased immune suppression and emergence of resistance. METHODS 430 patients with CD4-positive T-lymphocyte (CD4) counts greater than 350 cells per muL, and viral load less than 50 copies per mL were randomised to continued therapy (n=146) or scheduled treatment interruptions (n=284). Median time on randomised treatment was 21.9 months (range 16.4-25.3). Primary endpoints were proportion of patients with viral load less than 50 copies per mL at the end of the trial, and amount of drugs used. Analysis was intention-to-treat. This study is registered at ClinicalTrials.gov with the identifier NCT00113126. FINDINGS Drug savings in the scheduled treatment interruption group, compared with continuous treatment, amounted to 61.5%. 257 of 284 (90.5%) patients in the scheduled treatment interruption group reached a viral load less than 50 copies per mL, compared with 134 of 146 (91.8%) in the continued treatment group (difference 1.3%, 95% CI-4.3 to 6.9, p=0.90). No AIDS-defining events occurred. Diarrhoea and neuropathy were more frequent with continuous treatment; candidiasis was more frequent with scheduled treatment interruption. Ten patients (2.3%) had resistance mutations, with no significant differences between groups. INTERPRETATION Drug savings with scheduled treatment interruption were substantial, and no evidence of increased treatment resistance emerged. Treatment-related adverse events were more frequent with continuous treatment, but low CD4 counts and minor manifestations of HIV infection were more frequent with scheduled treatment interruption.

Options for a Second-Line Antiretroviral Regimen for HIV Type 1-Infected Patients Whose Initial Regimen of a Fixed-Dose Combination of Stavudine, Lamivudine, and Nevirapine Fails

BACKGROUND A fixed-dose combination of stavudine, lamivudine, and nevirapine is extensively used as an antiretroviral regimen in developing countries because of its affordability. Virological failure with this regimen has become more common, and a second-line regimen needs to be prepared in the national program. METHODS Genotypic resistance testing was conducted among human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced treatment failure with their first antiretroviral regimen (a fixed-dose combination of stavudine, lamivudine, and nevirapine) during 2003-2005. Patterns of resistance mutations and options for a second-line regimen were studied. RESULTS We studied 98 patients (mean age, 35.2 years), of whom, 63% were male. The median duration of antiretroviral therapy was 20 months. The median HIV-1 RNA load at the time of virological failure detection was 4.1 log copies/mL. The prevalences of patients with > or =1 major mutation conferring drug resistance to nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors were 95% and 92%, respectively. M184V was the most common nucleoside reverse-transcriptase inhibitor resistance mutation (observed in 89% of patients). Thymidine analogue mutations, K65R, and Q151M were observed in 37%, 6%, and 8% of patients, respectively. Patients with an HIV-1 RNA load of >4 log copies/mL at the time of treatment failure had higher prevalence of thymidine analogue mutations (P=.041), K65R (P=.031), and Q151M (P=.008) mutations. The second-line regimen was determined in a resource-limited setting where tenofovir and enfuvirtide are not available; the options were limited for 48% of patients. CONCLUSIONS After experiencing treatment failure with a fixed-dose combination of stavudine, lamivudine, and nevirapine, almost all patients have lamivudine and nonnucleoside reverse-transcriptase inhibitor resistance. The options for a second-line regimen are limited for one-half of these patients. In resource-limited settings where availability of antiretroviral agents is limited, strategies for prevention of HIV-1 resistance are crucial. Early detection of virological failure may provide more options and better treatment outcomes.

HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients.

Objective Investigation of a possible involvement of differences in human leukocyte antigens (HLA) in the risk of nevirapine (NVP)-induced skin rash among HIV-infected patients. Methods A step-wise case–control association study was conducted. The first set of samples consisted of 80 samples from patients with NVP-induced skin rash and 80 samples from NVP-tolerant patients. These patients were genotyped for the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 by a sequence-based HLA typing method. Subsequently, we verified HLA alleles that showed a possible association in the first screening using an additional set of samples consisting of 67 cases with NVP-induced skin rash and 105 controls. Results An HLA-B*3505 allele revealed a significant association with NVP-induced skin rash in the first and second screenings. In the combined data set, the HLA-B*3505 allele was observed in 17.5% of the patients with NVP-induced skin rash compared with only 1.1% observed in NVP-tolerant patients [odds ratio (OR)=18.96; 95% confidence interval (CI)=4.87–73.44, Pc=4.6×10−6] and 0.7% in general Thai population (OR=29.87; 95% CI=5.04–175.86, Pc=2.6×10−5). The logistic regression analysis also indicated HLA-B*3505 to be significantly associated with skin rash with OR of 49.15 (95% CI=6.45–374.41, P=0.00017). Conclusion A strong association between the HLA-B*3505 and NVP-induced skin rash provides a novel insight into the pathogenesis of drug-induced rash in the HIV-infected population. On account of its high specificity (98.9%) in identifying NVP-induced rash, it is possible to utilize the HLA-B*3505 as a marker to avoid a subset of NVP-induced rash, at least in Thai population.

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results.

The potential of drug–drug interaction between efavirenz and rifampicin is a major concern in the treatment of HIV and tuberculosis. The optimal efavirenz dosage is still unclear. Our randomized control trial study recently reported the similar efavirenz level between efavirenz 600 and 800 mg/day in HIV-infected patients receiving rifampicin. We report the similar virological and immunological outcomes at 48 weeks between the two groups. Efavirenz 600 mg/day should be sufficient for concurrent use with rifamipicin.

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.

Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin

Background:Concomitant use of efavirenz and rifampicin is common for treatment of HIV and tuberculosis. Plasma efavirenz levels can be reduced by rifampicin, but the appropriate daily dosage of efavirenz is unclear. Methods:HIV-infected patients with active tuberculosis, receiving rifampicin > 1 month, were randomized to receive stavudine and lamivudine plus efavirenz 600 or 800 mg daily. Plasma efavirenz levels were measured (at 12 h after dosing and on day 14) by high-performance liquid chromatography. Plasma HIV RNA was assessed at 16 and 24 weeks after antiretroviral therapy. Results:Baseline characteristics were comparable in the 84 patients (two groups of 42). Median plasma efavirenz levels were 3.02 mg/l (range, 0.07–12.21) in the 600 mg group and 3.39 mg/l (range, 1.03–21.31) in the 800 mg group (P = 0.632). Plasma efavirenz levels were < 1 mg/l in 3 of 38 (7.9%) patients in the 600 mg group and in none of the 800 mg group (P = 0.274). Approximately 40 and 45% of patients had efavirenz levels > 4 mg/l, respectively. There was no significant difference in time to HIV RNA < 50 copies/ml (P = 0.848). Conclusions:Median plasma efavirenz levels were comparable among both groups. Efavirenz 600 mg/day should be sufficient for most Thai HIV-infected patients receiving rifampicin with body weight approximately 50 kg. These results may not be applicable to other ethic populations who have higher body weights. However, the study of long-term virological and immunological outcomes is needed and under further investigation.

Long-term Virological Outcomes of First-Line Antiretroviral Therapy for HIV-1 in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

BACKGROUND More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. METHODS We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. RESULTS Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. CONCLUSIONS Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.

Genome-wide Association Study Identifies Variations in 6p21.3 Associated With Nevirapine-Induced Rash

BACKGROUND We aimed to identify disease-predisposing variations with nevirapine-induced rash using genome-wide single-nucleotide polymorphisms (SNPs) as genetic markers. METHODS A genome-wide association study (GWAS) was performed using ∼550000 markers in 72 human immunodeficiency virus (HIV)-infected Thai patients with nevirapine-induced rash and 77 nevirapine-tolerant patients, and then candidate SNPs were further evaluated in a replication set (88 patients with nevirapine-induced rash and 145 nevirapine-tolerant patients). RESULTS The genome-wide association analysis and replication studies of candidate SNPs identified significant associations of nevirapine-induced rash with 2 SNPs (rs1265112 and rs746647) within CCHCR1 on chromosome 6p21.3 (P(GWAS) = 1.6 × 10(-4); P(replication) = 2.6 × 10(-5); P(combined) = 1.2 × 10(-8)). The odds ratio (OR) of the risk genotypes under a dominant model was 4.36 (95% confidence interval [CI], 2.58-7.36). The noncoding SNPs rs1265112 and rs746647 were in complete linkage disequilibrium with the nonsynonymous SNP rs1576 (r(2) = 1.00), which has been associated with psoriasis. The logistic regression analysis also indicated genetic variations in CCHCR1 to be significantly associated with rash, with an OR of 2.59 (95% CI, 1.82-3.68; P = .007). The receiver operating characteristic curve showed that the algorithm had an area under the curve of 76.4%, which was developed with 5 factors: rs1576*G status, HLA-B*3505 status, not receiving prescribed lead-in of nevirapine, history of drug allergy, and CD4 cell count prior to the nevirapine treatment. CONCLUSIONS We demonstrated that genetic variations in CCHCR1 are strongly associated with nevirapine-induced rash. A predictive model that includes genetic and clinical risk factors for nevirapine-associated rash might be useful in lowering the incidence of rash associated with nevirapine initiation among HIV-infected patients.