Experience with the use of a first-line regimen of stavudine, lamivudine and nevirapine in patients in the TREAT Asia HIV Observational Database.

BACKGROUND: The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region. METHODS: We selected patients from the TREAT Asia HIV Observational Database (TAHOD) who started their first ART regimen with d4T/3TC/NVP. Treatment change was defined as cessation of therapy or the addition or change of one or more drugs. Clinical failure was defined as diagnosis with an AIDS-defining illness, or death while on d4T/3TC/NVP treatment. RESULTS: The rate of treatment change among TAHOD patients starting d4T/3TC/NVP as their first antiretroviral treatment was 22.3 per 100 person-years, with lower baseline haemoglobin (i.e. anaemia) associated with slower rate of treatment change. The rate of clinical failure while on d4T/3TC/NVP treatment was 7.3 per 100 person-years, with baseline CD4 cell count significantly associated with clinical failure. After d4T/3TC/NVP was stopped, nearly 40% of patients did not restart any treatment and, of those who changed to other treatment, the majority changed to zidovudine (ZDV)/3TC/NVP and less than 3% of patients changed to a protease inhibitor (PI)-containing regimen. The rates of disease progression on the second-line regimen were similar to those on the first-line regimen. CONCLUSION: These real-life data provide an insight into clinical practice in Asia and the Pacific region. d4T/3TC/NVP is maintained longer than other first-line regimens and change is mainly as a result of adverse effects rather than clinical failure. There is a need to develop affordable second-line antiretroviral treatment options for patients with HIV infection in developing countries.

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.

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.

Spontaneous cryptococcal peritonitis in cirrhotic patients.

Spontaneous bacterial peritonitis is a common complication in patients with cirrhosis and ascites. However, spontaneous peritonitis caused by Cryptococcus neoformans is uncommon. Delayed diagnosis of cryptococcal peritonitis often results in death. We describe three cases of spontaneous cryptococcal peritonitis in patients with decompensated cirrhosis. One case had associated symptomatic human immunodeficiency virus infection. Clinical awareness of this entity may lead to the early diagnosis and proper treatment.

Antimicrobial resistance among respiratory pathogens collected in Thailand during 1999-2000.

A multi-center surveillance study was conducted in Thailand during 1999-2000 to determine antimicrobial susceptibilities among the respiratory pathogens Streptococcus pneumoniae (n = 206), Haemophilus influenzae (n = 305), and Moraxella catarrhalis (n = 39). Of the S. pneumoniae isolates collected, 33.5% were penicillin-susceptible, 27.2% intermediate and 39.3% resistant. Expectedly, resistance rates to beta-lactams were higher among penicillin-resistant (ceftriaxone, 14.8%; amoxicillin-clavulanate, 42.0%; cefuroxime, 100%) than penicillin-susceptible (ceftriaxone, 0%; amoxicillin-clavulanate, 0%; cefuroxime, 0%) isolates. Likewise, azithromycin and clarithromycin resistances were 4.3% and 5.8% among penicillin-susceptible isolates, and 77.8% and 95.1% among penicillin-resistant isolates. All S. pneumoniae remained susceptible to vancomycin and 99.5% were susceptible to levofloxacin. Multidrug resistance (resistance to >3 antimicrobial classes) was present in 25.2% of pneumococcal isolates (n = 52), with resistance to azithromycin, penicillin and trimethoprim-sulfamethoxazole the most common phenotype (40/52 isolates; 77.0%). Among the isolates of H. influenzae, the prevalence of beta-lactamase production was 45.2%. All isolates of H. influenzae were susceptible to amoxicillin-clavulanate, azithromycin, ceftriaxone, cefuroxime and levofloxacin while 49.5% were resistant to trimethoprim-sulfamethoxazole. All 39 isolates of M. catarrhalis produced beta-lactamase. Azithromycin (MIC90, < or = 0.03 microg/ml) and levofloxacin (MIC90, 0.03 microg/ml) were the most active agents tested against M. catarrhalis. The results of this study may serve as a baseline for future studies to monitor antimicrobial susceptibilities among respiratory pathogens in Thailand.

Genotypic subtyping of the HIV-1 polymerase gene in 30 naåve patients from Thailand.

To investigate the subtype classification of the circulating virus strains among infected Thai patients with human immunodeficiency virus type 1 (HIV-1). A random population of patients who were HIV-1 antibody positive after two independent screening assays was selected. HIV RNA from plasma samples was reverse-transcribed and amplified with specific primers that annealed to conserve regions of the HIV-1 pol gene. Amplified products were sequenced directly by using an automated sequencer. The sequencing products represent about 1.2 kb of the pol gene from each patient and they were phylogenetically analyzed and compared to the corresponding pol sequences of the published HIV-1 sequences of known genotypes. Genotype E was found in 25 of 30 patients (83.3%), and 5 patients (16.7%) were HIV-1 genotype B. The result confirmed that HIV-1 subtype E is still predominant in Thailand. Genotype B is found frequently, but there have been no examples of genotype A. In concordance with the serotypic assay, which was previously reported using the V3-peptide enzyme immunoassay (V3-PEIA), the genotypic assay of subtype E was high, at 80% and 83.3% in serotyping and genotyping, respectively. These findings of two subtypes with low heterogeneity indicate that Thailand may be a desirable site for evaluating candidate HIV-1 antiretroviral drugs and vaccines. The mixture of subtype E and B' strains also offers the opportunity to study phenotypic differences between the two subtypes.

In vitro susceptibility testing of levofloxacin and ofloxacin by microtiter plate Alamar blue against multidrug and non multidrug resistant Mycobacterium tuberculosis in Thailand.

Antituberculous drugs for current therapy of multidrugs resistant tuberculosis (MDR-TB) are limited. The in vitro susceptibility of Mycobacterium tuberculosis (MTB) as well as MDR-TB with other antibiotic drugs were determined in order to find alternative drugs for the treatment of MDR-TB. Forty-seven MDR-TB and 62 MTB of clinical isolates were tested against levofloxacin and ofloxacin. The MDR-TB at the MIC90 of levofloxacin and ofloxcain were 1 microg/ml and 2 microg/ml, respectively. Of these MTB, the MIC90 of both drugs were 0.5 microg/ml and 1 microg/ml, respectively. It seemed that levofloxacin MICs of both MDR-TB and MTB were one dilution less than ofloxcin. The promising activity of ofloxacin and levofloxacin against MDR-TB and MTB suggest that both drugs could be used as second-line drugs for MDR-TB or as a good alternative antituberculous drug for patients who have intolerance to the first line drug.

Preliminary report for the application of nucleic acid sequence-based amplification in detection of human cytomegalovirus (HCMV) late pp67 mRNA for diagnosis of HCMV infection.

Human cytomegalovirus (HCMV) late pp67 mRNA expression by nucleic acid sequence-based amplification (NASBA) in patients, clinically diagnosed as possible HCMV, probable HCMV disease, and no disease, was evaluated. The RNAs were isolated from 11 whole-blood samples of 11 patients for the specific amplification of the pp67 mRNA. NASBA results were compared to results from PCR assay and serological assay. The HCMV pp67 mRNA could be found in 3 of 11 patients, whereas, HCMV-DNA PCR was positive in 6 of 11 patients. PCR assay for HCMV-DNA in plasma has proved to correlate with clinical diagnosis of HCMV infection. Only 2 patient samples of NASBA positive results coincided with HCMV-DNA PCR. However, the diagnosis of clinically relevant HCMV infection by NASBA was seen. Anti-CMV IgG titers of 1:1,600 or over 1:1,600 were found in 2 of 3 NASBA positive cases and 5 of 6 HCMV-DNA positive cases, whereas, anti-CMV IgM were all negative. These results showed the correlation of HCMV infection detected by NASBA, PCR assay and anti-CMV IgG of the titers up to 1:1,600. Additionally, a low antibody titer of the HIV patient could be diagnosed by NASBA or PCR. In conclusion, pp67 mRNA NASBA appears to be a promising diagnostic tool in analysis of HCMV infection and/or disease. Its diagnostic value should be defined in the specific group for the follow-up of immunocompromised patients, such as organ transplant recipients in future prospective studies.

Risk factors for penicillin-resistant Streptococcus pneumoniae acquisition in patients in Bangkok.

To identify risk factors for acquisition of penicillin-resistant Streptococcus pneumoniae (PRSP) in patients in Bangkok, using a case-control study, the study included patients with clinical specimens which grew S. pneumoniae during January to December 1997, treated at a teaching hospital in Bangkok. Penicillin susceptibility was determined by E-test and strains with MIC of > 0.1 microg/ml were considered resistant. Cases were the patients who had PRSP, and patients who had penicillin-susceptible S. pneumoniae (PSSP) were controls. The study variables included age 15 years or younger, immunocompromised status, ventilatory support, and antibiotic use or hospitalization within the previous 3 months. There were 73 cases and 51 controls. Their ages were 0 to 87 years, with median age of cases 4 and controls 49 years. Pneumonia was the most common type of infection, being 47% in cases and 45% in controls. Univariate analysis revealed significant association of PRSP acquisition with previous antibiotic use (p<0.0001), age < or = 15 years (p=0.001) and previous hospitalization (p=0.002). Logistic regression analysis in order to adjust for confounding effects showed that the only significant risk factor was previous antibiotic use (OR 18.4; 95% CI 6.2-54.6). The major risk factor for acquisition of PRSP in this study population is recent antibiotic use. Decreased antibiotic use would reduce risk of acquisition of PRSP.

Pharmacokinetics of levofloxacin in healthy Thai male volunteers.

The pharmacokinetics of levofloxacin, a new fluoroquinolone, were investigated in 12 healthy Thai male volunteers with an average age (SD) of 22.92 (2.50) years. A single oral dose of 300 mg or 500 mg levofloxacin was given to subjects following an 8- hour overnight fast. The drug was given in a controlled, randomized, 2 x 2 crossover design with a 1 week washout period. Venous blood samples were drawn prior to and from 0.25 up to 48 hours after dosing. Plasma levofloxacin concentrations were determined by HPLC assay. The pharmacokinetics of levofloxacin were well described by a linear, 2-compartment open model with first-order absorption with lag time and first-order elimination. Mean +/- SEM of Cmax after 300 mg and 500 mg dose was 4.83 +/- 0.33 and 7.75 +/- 0.71 micrograms/mL, respectively. Tmax ranged from 0.7 to 0.8 hours for both doses. Mean +/- SEM of AUC0-infinity was 35.77 +/- 2.06 micrograms x h/mL for 300 mg dose and 61.57 +/- 2.84 micrograms x h/mL for 500 mg dose. High distribution with VSS/F value of approximately 1.5 L/kg was demonstrated after both doses. Mean +/- SEM of CL/F value was 8.64 +/- 0.41 L/h and 8.31 +/- 0.37 L/h for a 300-mg and a 500-mg dose, respectively. Long t1/2 beta of 7 to 8 hours with the mean residence time of 10.43 +/- 0.43 hours and 10.49 +/- 0.38 hours after 300 mg and 500 mg dose, respectively, was observed. The results suggested that an oral 300 mg dose once daily provides sufficient Cmax to cover most Gram-negative and atypical bacteria (median MIC90 0.032-0.5 microgram/mL) common in mild to moderate respiratory tract infections or complicated urinary tract infections and Gram-positive bacteria (median MIC90 0.5 microgram/mL) common in skin and soft tissue infections. For severe cases or Streptococcus pneumoniae (MIC90 2 micrograms/mL) infection, a 500-mg dose should be recommended.

Susceptibility of human cytomegalovirus to two-drug combinations in vitro.

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality for immunocompromised hosts. We sought to determine the in vitro susceptibility of HCMV reference laboratory strains, clinical isolates and strains with known resistance to currently available anticytomegaloviral drugs to two-drug combinations of the following compounds: ganciclovir, foscarnet, cidofovir and its cyclic congener, cyclic HPMPC (cHPMPC), and lobucavir. Cytotoxicity was determined by Trypan Blue exclusion of cells exposed both when proliferating (non-confluent) and once confluent. Antiviral effect was determined by a plaque-reduction assay in MRC-5 human embryonic lung cells. Drug interactions were determined by median-dose effect analysis with the combination index calculated at 50, 75, 90 and 95% inhibitory concentrations. No drug, either alone or in combination, reached a 50% cytotoxicity concentration in the dose ranges tested. Overall, 252/280 (90.0%) of the two-drug combinations demonstrated additive or synergistic interactive effects towards the panel of HCMV isolates tested. No combination demonstrated antagonism at all inhibitory concentrations to more than one isolate. Interestingly, the clinical isolate tested demonstrated the highest frequency of antagonistic combinations (3/10), as well as marked differences from pan-susceptible laboratory strains. The combinations of ganciclovir + foscarnet and cHPMPC + foscarnet demonstrated additive to synergistic effects against all isolates tested. In vitro combination drug studies could help in the rational choice of therapeutic regimens for use in clinical trials, potentially resulting in decreased toxicity, increased efficacy and delayed onset of drug resistance.

High-pressure liquid chromatography and microbiological assay of serum ofloxacin levels in adults receiving intravenous and oral therapy for skin infections.

Thirty-two adults hospitalized with skin and skin structure infections received intravenous ofloxacin followed by oral ofloxacin. The standard treatment was 400 mg every 12 h. One patient with renal failure received 400 mg every 24 h. Serum ofloxacin levels were measured (1.5 h postdose and 1 h predose) during intravenous (32 patients) and oral (30 patients) therapy. Levels were assayed by high-pressure liquid chromatography (HPLC) and microbiological assay (MBA). Mean levels +/- standard deviation (in micrograms per milliliter) when measured by MBA after intravenous dosing were (postdose versus predose) 6.23 +/- 2.49 versus 2.42 +/- 1.56, and those after oral dosing were 6.17 +/- 3.25 versus 3.49 +/- 2.77. When measured by HPLC, mean levels +/- standard deviation after intravenous dosing were 5.81 +/- 2.08 versus 2.14 +/- 1.26 and those after oral dosing were 5.63 +/- 2.92 versus 3.41 +/- 2.98. There were no significant differences between levels achieved with oral or intravenous dosing when measured by either MBA or HPLC. Levels in serum did not correlate with side effects. The MICs for 50 and 90% of the 40 aerobic pathogens isolated from 21 patients were 0.5 and 2.0 micrograms/ml, respectively. Cure or improvement was achieved in 30 patients. Intravenous and oral administration of ofloxacin yielded similar levels in serum which were safe and effective in the therapy of skin infections in adult patients.

Monokine production by malnourished nursing home patients.

Protein malnutrition is associated with a decreased febrile and acute phase response to infection and increased mortality. To elucidate a cause for this poor response, we assessed the effect of chronic protein malnutrition on monocyte production of the pyrogens interleukin-1 (IL-1) and tumor necrosis factor (TNF). Thirteen malnourished nursing home residents, 11 age-matched controls, and 9 young controls were studied. Production of IL-1 and TNF in vitro was not diminished in the malnourished group when compared with the age-matched and young controls. Causes other than diminished IL-1 or TNF production should be sought to explain decreased resistance to infection in the malnourished nursing home resident.

Monokine secretion in aging and protein malnutrition.

Aged and protein-malnourished hosts have diminished febrile responses and increased morbidity and mortality from infection that could be due to deficiencies in the production of certain monokines. In this study, the ability of peritoneal macrophages from aged and protein-malnourished rats to produce IL-1 and TNF was explored. Aged rats fed a standard diet produced less IL-1 and TNF, as measured by the thymocyte proliferation and L929 cytotoxicity assays, than young and middle-aged rats. Monokine production was not diminished by protein malnutrition in any age group. No synergistic decline in IL-1 or TNF production was seen with increasing age in malnourished rats. Diminished IL-1 and TNF production may partially explain the severity of infection seen in the elderly patient, but not the malnourished host. The role of other cytokines such as IL-6 and cytokine inhibitors in aging and malnutrition should be explored.

Acquired hypertrichosis lanuginosa.

A 32-year-old Thai woman developed acquired hypertrichosis lanuginosa with generalized lanugo hair, deeply furrowed tongue, and keratosis pilaris. She had metastatic adenocarcinoma of the liver. A review of world literature reveals 24 cases of which 22 were associated with proven malignancies. Acquired hypertrichosis lanuginosa is almost always a cutaneous sign of internal cancer.