Low level of efavirenz in HIV-1-infected Thai adults is associated with the CYP2B6 polymorphism.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infections with a plasma efavirenz concentration of <1,000 ng/mL appear to have a high risk for the emergence of drug resistance. In the present study, we assessed the influence of the CYP2B6 polymorphism on the plasma efavirenz level. METHODS: CYP2B6 T18492C (rs2279345) in 149 HIV-infected Thai adults were genotyped. Plasma efavirenz concentrations 12 h after dosing were measured using a validated high-performance liquid chromatography. The relationship between the plasma efavirenz level and the CYP2B6 T18492C polymorphism were analysed. RESULTS: Among the 149 patients, the frequency of T18492C heterozygous (T/C) and homozygous mutant (C/C) was 38.26 % (n = 57) and 6.04 % (n = 9), respectively. In the entire cohort, the median efavirenz plasma concentration was 2,410 ng/mL [interquartile range (IQR) 1,460-4,120 ng/mL]. The plasma efavirenz concentration for patients with 18492CC (1,200 ng/mL, IQR 1,050-1,990 ng/mL) or 18492TC (1,900 ng/mL, IQR 1,320-2,510 ng/mL) genotypes were significantly lower than those with homozygous wild type (3,380 ng/mL, IQR 2,040-5,660 ng/mL), P-value < 0.001. CONCLUSIONS: The CYP2B6 T18492C polymorphism was significantly associated with lower efavirenz concentrations compared to those with homozygous wild type in HIV-1 infections. The genetic polymorphism CYP2B6 T18492C may be useful for the optimised efavirenz dose. Further studies in the clinical setting will need to be conducted before such an approach can be recommended for widespread use.

Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis.

Chromosome 5q31 spans the T helper (Th) 2-related cytokine gene cluster, which is potentially important in Th1/Th2 immune responses. The chromosome 5q23.2-31.3 has been recently identified as a region with suggestive evidence of linkage to tuberculosis in the Asian population. With the aim of fine-mapping a putative tuberculosis susceptibility locus, we investigated a family-based association test between the dense single nucleotide polymorphism (SNP) markers within chromosome 5q31 and tuberculosis in 205 Thai trio families. Of these, 75 SNPs located within candidate genes covering SLC22A4, SLC22A5, IRF1, IL5, RAD50, IL13, IL4, KIF3A and SEPT8 were genotyped using the DigiTag2 assay. Association analysis revealed the most significant association with tuberculosis in haplotypes comprising SNPs rs274559, rs274554 and rs274553 of SLC22A5 gene (P(Global)=2.02 x 10(-6)), which remained significant after multiple testing correction. In addition, two haplotypes within the SLC22A4 and KIF3A region were associated with tuberculosis. Haplotypes of SLC22A5 were significantly associated with the expression levels of RAD50 and IL13. The results show that the variants carried by the haplotypes of SLC22A4, SLC22A5 and KIF3A region potentially contribute to tuberculosis susceptibility among the Thai population.

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. METHODS: A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography. RESULTS: Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively). CONCLUSION: High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.

Economic Burden of Influenza in Thailand: A Systematic Review.

Thailand has a high incidence and high mortality rates of influenza. This study summarizes the evidence on economic burden or costs of influenza subsequent to the occurrence of influenza illness in the Thai population by specific characteristics such as population demographics, health conditions, healthcare facilities, and/or cost types from published literature. A systematic search was conducted in six electronic databases. All costs were extracted and adjusted to 2018 US dollar value. Out of 581 records, 11 articles (1 with macroeconomic analysis and 10 with microeconomic analyses) were included. Direct medical costs per episode for outpatients and inpatients ranged from US$4.21 to US$212.17 and from US$163.62 to US$4577.83, respectively, across distinct influenza illnesses. The overall burden of influenza was between US$31.1 and US$83.6 million per year and 50-53% of these estimates referred to lost productivity. Costs of screening for an outbreak of influenza at an 8-bed-intensive-care-unit hospital was US$38242.75 per year. Labor-sensitive sectors such as services were the most affected part of the Thai economy. High economic burden tended to occur among children and older adults with co-morbidities and to be related to complications, non-vaccinated status, and severe influenza illness. Strategies involving prevention, limit of transmission, and treatment focusing on aforementioned patients' factors, containment of hospitalization expenses and quarantine process, and assistance on labor-sensitive economy sectors are likely to reduce the economic burden of influenza. However, a research gap exists regarding knowledge about the economic burden of influenza in Thailand.

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.

Impact of drug-resistant tuberculosis on the survival of HIV-infected patients.

OBJECTIVE: To determine the effect of drug-resistant tuberculosis (TB) on the survival of human immunodeficiency virus (HIV) infected patients in an area with a high prevalence of TB. DESIGN: Retrospective cohort study. RESULTS: Of 225 HIV-TB patients with a mean age of 35.8 years, 72.4% were male. The median CD4 cell count at TB diagnosis was 44 cells/mm3. Sixty per cent presented with extra-pulmonary TB (EPTB). Sixty-three (28%) patients were infected with Mycobacterium tuberculosis resistant to at least one drug; respectively 16.4%, 9.3%, 5.3% and 12.9% were resistant to isoniazid (INH), rifampicin (RMP), ethambutol and streptomycin, and 14 (6.2%) had multidrug-resistant TB (MDR-TB). During a median follow-up of 11.5 months, 4% died. From Kaplan-Meier analysis, INH resistance, RMP resistance and MDR-TB were associated with shorter survival (log-rank test, P < 0.005). Cox's proportional hazard model showed that MDR-TB (hazard ratio [HR] 11.7; 95% CI 2.1-64.9), not receiving antiretroviral therapy (ART) (HR 7.9; 95% CI 1.5-43.1) and EPTB (HR 5.1; 95% CI 1.9-25.9) were significant risk factors for death. CONCLUSION: MDR-TB and EPTB substantially reduce survival among patients co-infected with HIV and TB. Early detection and optimal treatment of MDR-TB are crucial. ART significantly prolongs survival and should be initiated in HIV-TB co-infected patients.

Significant intolerability of efavirenz in HIV occupational postexposure prophylaxis.

BACKGROUND: Completion of human immunodeficiency virus (HIV) occupational postexposure prophylaxis (PEP) is important for successful prophylaxis. AIM: To determine factors associated with failure to complete the four-week HIV PEP. METHODS: A retrospective study was conducted among healthcare workers (HCWs) accidentally exposed to blood or body fluids of patients at the Bamrasnaradura Infectious Diseases Institute, Thailand, between March 1996 and June 2014. Logistic regression analysis was used to determine factors associated with failure to complete the four-week HIV PEP. FINDINGS: In total, 225 exposure episodes were reported. The mean age of HCWs was 33.1 (standard deviation 9.9) years, and 189 (84%) were female. Nurses (43%) were exposed most frequently. The HIV status of the source was defined in 149 (66%) episodes, and 101 (68%) of these were positive. Of 225 exposures, PEP was prescribed in 155 (69%) cases, with intentional discontinuation in 26 cases. Ninety-one of 129 (71%) HCWs completed the four-week regimen. Multi-variate analysis showed that a regimen of two nucleotide reverse transcriptase inhibitors (NRTI) + efavirenz (EFV) was the only significant factor associated with non-completion of the four-week course (odds ratio 37.8, 95% confidence interval 4.2-342.3; P < 0.01). Other factors including age, sex, staff position, status of the source and other PEP regimens were not associated with non-completion of the four-week course (P > 0.05). None of the HCWs were documented to have HIV seroconversion. CONCLUSION: A regimen of two NRTIs + EFV was significantly associated with premature discontinuation of occupational PEP. This regimen should not be used for HIV prophylaxis following occupational exposure.

Isoniazid preventive therapy and 4-year incidence of pulmonary tuberculosis among HIV-infected Thai patients.

SETTING: Human immunodeficiency virus (HIV) clinics at two Thai tertiary care medical centres. OBJECTIVES: To evaluate the efficacy of tuberculin skin test (TST) guided isoniazid preventive therapy (IPT) in combination with antiretroviral therapy (ART) in the prevention of tuberculosis (TB). DESIGN: A 4-year prospective comparative study of patients at two HIV clinics: one performed TST at enrolment and, if positive, prescribed IPT (IPT group), while the other did not perform TST (non-IPT group). RESULTS: There were 200 patients included in each group. Baseline characteristics and drop-out rates were similar in both groups. The incidence of pulmonary TB over 4 years was not significantly different between the IPT and non-IPT groups (0.80 cases vs. 1.76 per 100 person-years [py], P = 0.13). However, the incidence of pulmonary TB in the non-IPT group was significantly higher during the first 6 months (8.60 vs. 0 cases/100 py, P = 0.01) and among patients with initial CD4 < 200 cells/l (9.41 vs. 0 cases/100 py, P = 0.02). The survival analyses demonstrated a protective effect of IPT (x(2) = 3.66, P = 0.04) for early TB. CONCLUSIONS: Benefit of IPT plus ART was evident only in the first 6 months of care. These findings suggest that TST-guided IPT should be routinely provided for HIV-infected patients after initial entry into medical care.

Hypogonadism among HIV-infected men in Thailand.

This study assessed prevalence and associated factors of hypogonadism among 491 HIV-infected Thai men who visited the HIV outpatient clinic. All participants were interviewed and data were collected from medical records, including demographic and HIV-related illness characteristics. They also completed questionnaires relevant to hypogonadal symptoms, sexual function and depression. All participants' blood samples were obtained to check for total testosterone, sex hormone-binding globulin (SHBG) and albumin levels, and free testosterone (cFT) was calculated. Hypogonadism was diagnosed if a cFT level of <0.225 nmol/L was detected. The median age of the participants was 37 years old (ranging from 34 to 44 years old). HIV infection was diagnosed for a median of 77 (47-99) months. Eight of 491 participants (2%) had hypertension and 1% had diabetes mellitus (DM). Fourteen (3%) used methadone and 23% had SHBG level over 70 nmol/L. Of the 491 participants, 123 (25%) men were diagnosed with hypogonadism. The univariate analyses indicated that DM, hypertension, methadone use, SHBG level >70 nmol/L group and lack of antiretroviral therapy were associated with hypogonadism. In multivariate analysis, a SHBG level >70 nmol/L was the only factor that was significantly associated with hypogonadism (odds ratio [OR] = 1.922, P = 0.007).

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.

Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin.

BACKGROUND: There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day-based antiretroviral therapy (ART) among HIV-1 patients with tuberculosis (TB) and receiving rifampicin. METHODS: A retrospective cohort study was conducted in all ART-naïve patients who were receiving rifampicin between January 2002 and December 2005. RESULTS: Of 188 patients, 77 and 111 patients were initiated on EFV-based ART (EFV group) and NVP-based ART (NVP group), respectively. Overall, median [interquartile range (IQR)] CD4 count was 36 (15-77) cells/microL and median (IQR) viral load was 5.6 (5.2-5.9) HIV-1 RNA log copies/mL. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV-1 RNA <50 copies/mL (P=0.140, odds ratio=0.590, 95% confidence interval=0.302-1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/muL in the EFV group and 156 and 218 cells/microL in the NVP group (P>0.05). By binary logistic regression, treatment group was not associated with HIV-1 RNA <50 copies/mL (P>0.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P=0.084). CONCLUSIONS: For HIV-TB co-infected patients who receive rifampicin, efficacy of 600 mg EFV-based and 400 mg NVP-based ART may be similar, although adverse events tend to be higher in NVP-based ART.

Initiation of antiretroviral therapy in advanced AIDS with active tuberculosis: clinical experiences from Thailand.

OBJECTIVES: To study treatment outcomes of antiretroviral therapy (ART) initiated in advanced HIV-infected patients with active tuberculosis (TB). METHODS: A retrospective cohort study was conducted in ART-naïve HIV-infected patients who presented with active TB, CD4<200 cells/microl, and had been initiated ART. ART, TB treatment and treatment outcomes of both HIV and TB were studied. RESULTS: There were 29 patients (19 males) with a median age of 37 (range 26-65) years. Site of TB were: lung (70%), lymph node (27.6%), and gastrointestinal tract (3.4%). At the time of TB diagnosis, median (range) CD4 cell count and HIV RNA were 74 (23-178) cells/microl and 229,000 (26,100-750,000) copies/ml, respectively. All patients received isoniazid, rifampin, ethambutol, and pyrazinamide in the first 2 months of TB therapy but the continuation phase was different depending on whether efavirenz (EFV) or nevirapine (NVP) was used. ART was initiated at a median of 8 weeks of TB treatment. All patients received NNRTI-based regimens (EFV 62.1%, NVP 37.9%). Percentage of patients with HIV RNA<50 copies/ml at 24 and 48 weeks of ART was 65.5 and 75.9%. Median CD4 cell count at 24, 48, and 72 weeks were 156, 186, and 227 cells/microl, respectively. Eighteen patients were cure; eight were treatment completed; two were treatment interrupted; and one died from CMV encephalitis. There was neither occurrence of new OI or relapse of TB in 26 patients who completed 72-week follow-up. CONCLUSIONS: Initiation of ART with NNRTI-based regimens at 4-12 weeks of TB treatment in advanced AIDS may be safe and effective, and may not be delayed. Further, prospective clinical studies for the optimal timing of ART initiation and ART regimen are needed.

Incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash.

OBJECTIVE: To determine the incidence and risk factors of rash associated with efavirenz in HIV-infected patients with preceding nevirapine-associated rash. METHODS: A retrospective cohort study was conducted in HIV-infected patients diagnosed with nevirapine-associated rash who subsequently received efavirenz between July 2003 and January 2005. Patients were followed up for 3 months after receiving efavirenz. Possible risk factors, including demographics, previous opportunistic infections, CD4 cell count, viral load, severity of nevirapine-associated rash and concurrent drugs, were studied and compared between those who had (group A) and did not have (group B) rash associated with efavirenz. RESULTS: A total of 122 patients (52.5% male) were included in the study, with a mean age of 38.2 years. Median (and interquartile range) CD4 cell count and viral load were 55 (20-167) cells/microL and 86,150 (35,321-700,750) HIV-1 RNA copies/mL, respectively. Of the 122 patients, 10 (8.2%) developed rash associated with efavirenz and all required discontinuation of efavirenz. The baseline characteristics of group A (10 patients) and group B (112 patients) were similar. Median (and interquartile range) time from nevirapine discontinuation to efavirenz initiation was 12 (9-21) days in group A and 11 (7-21) days in group B (P=0.765). None of the risk factors investigated was associated with developing rash associated with efavirenz. The preceding development of severe nevirapine-associated rash had a trend towards a higher rate in group A than in group B (20.0% vs 10.7%; odds ratio=2.08; 95% confidence interval 0.39-10.97; P=0.322). CONCLUSIONS: The majority (>90%) of HIV-infected patients with CD4 counts <200 cells/muL who had preceding nevirapine-associated rash could tolerate efavirenz well. Efavirenz may be an option for subsequent use in these patients, particularly in those who had preceding nevirapine-associated rash.

Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens in antiretroviral-naïve patients with advanced HIV infection.

OBJECTIVE: To compare virological and immunological responses to nevirapine (NVP)-based and efavirenz (EFV)-based highly active antiretroviral therapy (HAART) regimens in antiretroviral-naïve patients with advanced HIV infection. METHODS: A retrospective observational cohort study was conducted on antiretroviral-naïve HIV-infected patients whose pretreatment CD4 cell counts were less than 100 cells/microL or whose viral loads were greater than 100,000 HIV-1 RNA copies/mL. RESULTS: Baseline characteristics of patients in the NVP (n=24) and EFV (n=29) groups were not different. The proportion of patients with viral loads >100,000 copies/mL was higher in the EFV group. The probability of virological success estimated by the Kaplan-Meier method showed that 3- and 6-month success rates were 30.8% [95% confidence interval (CI): 16.7-52.2%] and 63.1% (95% CI: 44.7-81.3%) for the NVP group. The corresponding values were 41.2% (95% CI: 25.8-61.0%) and 62.9% (95% CI: 45.7-80.1%) for the EFV-based group. The median success times of the two groups were about 4 and 3 months (P=0.678), respectively, for NVP and EFV. Cox's proportional hazard was used after adjusting for age, previous opportunistic infections (OIs), and viral load at baseline, and showed that patients who received the NVP-based regimen had about 25% [hazard ratio (HR)=0.75, 95% CI: 0.37-1.51] less chance of virological success than patients who received the EFV-based regimen (P=0.415). The median times to CD4 > or =100 cells/microL were 5.6 and 4.4 months for the NVP- and EFV-based regimens, respectively (log-rank test, P=0.144). CONCLUSIONS: NVP- and EFV-based HAART regimens as initial regimens in patients with advanced HIV infection are effective and comparable, in term of virological and immunological responses. However, further large-scale randomized controlled clinical trials in this group of patients with advanced HIV infection are needed.