Weerawat Manosuthi

Declining Prevalence of Drug-Resistant Tuberculosis among HIV/Tuberculosis Co-Infected Patients Receiving Antiretroviral Therapy

BACKGROUND Drug-resistant tuberculosis (DR-TB) is a serious threat in developing countries where the prevalence of both HIV and TB are high. Antiretroviral therapy (ART) has been more accessible in these countries. The present study aimed to determine the impact of ART on the prevalence of DR-TB among HIV/TB co-infected patients. MATERIAL AND METHOD A retrospective cohort study was conducted among HIV-infected patients with culture-proved TB from 1999 to 2004. Susceptibilities of Mycobacterium tuberculosis to antituberculous drugs and rate ofART use were studied. RESULTS There were 225 patients, mean age 35.8 years, 72.4% male and median CD, 44 cells/mm(3). Patients who had received ART increased from 18.5% in 1999 to 92.1% in 2004 (p<O. 001). The prevalence of DR-TB in the years 1999 and 2004 were 48% and 7.9%, respectively (p<O.001). The prevalence of isoniazid- and rifampicin-resistance significantly declined in 2004 when compared with those in 1999 (p<O. 05). CONCLUSION The declines in the prevalence of DR-TB, INH- and RFP-resistance in HIV/TB co-infected patients are possibly attributable to the use of ART In addition to the survival benefit from ART in HIV-infected patients, increasing use of ART among HIV-infected patients may eliminate DR-TB in this population.

Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy.

Background: The impact of antiretroviral therapy (ART) on survival among patients coinfected with HIV and tuberculosis (TB) has not been well established. Methods: A retrospective cohort study was conducted among HIV-infected patients with TB between January 2000 and December 2004. Patients were categorized into ART+ group (received ART) and ART− group (did not receive ART) and were followed until April 2005. Results: A total of 1003 patients were identified; 411 in ART+ group and 592 in ART− group. Median (interquartile range) CD4 count was 53 (20-129) cells/mm3. Survival rates at 1, 2, and 3 years after TB diagnosis were 96.1%, 94.0%, and 87.7% for ART+ group and 44.4%, 19.2%, and 9.3% for ART− group (log-rank test, P < 0.001). Cox proportional hazard model showed that ART was associated with lower mortality rate; gastrointestinal TB and multidrug resistant TB were associated with higher mortality rate (P < 0.05). Among patients in ART+ group, the patients who delayed ART ≥6 months after TB diagnosis had a higher mortality rate than those who initiated ART <6 months after TB diagnosis (P 0.018, hazard ratio = 2.651, 95% confidence interval = 1.152-6.102). Conclusions: Antiretroviral therapy substantially reduces mortality rate among HIV/TB-coinfected patients. Initiation of ART within 6 months of TB diagnosis is associated with greater survival.

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.

A Randomized Trial Comparing Plasma Drug Concentrations and Efficacies between 2 Nonnucleoside Reverse-Transcriptase Inhibitor-Based Regimens in HIV-Infected Patients Receiving Rifampicin: The N2R Study

BACKGROUND To our knowledge, to date, no prospective, randomized, clinical trial has compared standard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis (TB) who are receiving rifampicin. METHODS Rifampicin recipients with concurrent HIV-1 infection and TB were randomized to receive antiretroviral therapy that included either efavirenz (600 mg per day) or nevirapine (400 mg per day). Efavirenz and nevirapine concentrations at 12 h after dosing (C12) were monitored at weeks 6 and 12. CD4+ cell counts and HIV-1 RNA levels were assessed every 12 weeks. RESULTS One hundred forty-two patients were randomized into 2 groups equally. The mean body weight of patients was 53 kg, the mean CD4+ cell count was 65 cells/mm3, and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12, the mean C12 of efavirenz (+/- standard deviation) were 4.27+/-4.49 and 3.54+/-3.78 mg/L, respectively, and those for nevirapine were 5.59+/-3.48 and 5.6+/-2.65 mg/L, respectively. Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group (coefficient of variation, 107% vs. 47%). At week 12, 3.1% of patients in the efavirenz group and 21.3% in the nevirapine group had C12 values that were less than the recommended minimum concentrations (odds ratio, 8.396; 95% confidence interval, 1.808-38.993; P= .002). Intention-to-treat analysis revealed that 73.2% and 71.8% of patients in the efavirenz and nevirapine groups, respectively, achieved HIV-1 RNA levels <50 copies/mL at week 48, with respective mean CD4+ cell counts of 274 and 252 cells/mm3 (P> .05). Multivariate analysis revealed that patients with low C12 values and those with a body weight <55 kg were 3.6 and 2.4 times more likely, respectively, to develop all-cause treatment failure (P< .05). CONCLUSIONS Antiretroviral therapy regimens containing efavirenz (600 mg per day) were less compromised by concomitant use of rifampicin than were those that contained nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB. Low drug exposure and low body weight are important predictive factors for treatment failure.

A Phase II Randomized Trial of Amphotericin B Alone or Combined with Fluconazole in the Treatment of HIV-Associated Cryptococcal Meningitis

BACKGROUND Cryptococcosis is a life-threatening infection among patients with human immunodeficientcy virus (HIV) infection. Therapeutic options for the treatment of central nervous system cryptococcosis are limited, especially in resource-limited settings. METHODS We conducted a randomized, open-label, phase II trial in Thailand and the United States that compared the safety and efficacy of intravenous amphotericin B deoxycholate (AmB) 0.7 mg/kg (the standard therapy) with that of AmB 0.7 mg/kg plus fluconazole 400 mg (the low-dosage combination) or AmB 0.7 mg/kg plus fluconazole 800 mg (the high-dosage combination) administered daily for 14 days, followed by fluconazole alone at the randomized dosage (400 or 800 mg per day) for 56 days. The primary safety end point was the number of severe or life-threatening treatment-related toxicities; the primary efficacy end point was a composite of survival, neurologic stability, and negative cerebrospinal fluid culture results after 14 days of therapy. RESULTS A total of 143 patients were enrolled. There were no differences in treatment-related toxicities among the 3 arms. Toxicity was predictable and was most often related to AmB, and it included electrolyte abnormalities, anemia, nephrotoxicity, and infusion-related events. At day 14, 41%, 27%, and 54% of patients in the standard therapy, low-dosage combination, and high-dosage combination therapy arms, respectively, demonstrated successful outcomes. A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70. CONCLUSIONS AmB plus fluconazole administered at a dosage of 800 mg for 14 days, followed by fluconazole administered at a dosage of 800 mg daily for 56 days, is well-tolerated and efficacious among HIV-positive patients with central nervous system cryptococcosis. These results have significant treatment implications and should be validated in a randomized phase III trial.

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.

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.

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.

Plasma Nevirapine Levels and 24-Week Efficacy in HIV-Infected Patients Receiving Nevirapine-Based Highly Active Antiretroviral Therapy with or without Rifampicin

Seventy human immunodeficiency virus (HIV)-infected patients receiving rifampicin and 70 HIV-infected patients not receiving rifampicin were enrolled to receive 400 mg of nevirapine-based highly active antiretroviral therapy per day. Mean plasma nevirapine levels at 8 and 12 weeks were lower in patients receiving rifampicin (P=.048). However, virological and immunological outcomes at 24 weeks were not different between the 2 groups (P>.05).

Genome-wide SNP-based linkage analysis of tuberculosis in Thais.

Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics=3.01, logarithm of odds (LOD) score=2.29, empirical P-value=0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score=2.57 and 3.33, permutation P-value=0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.