Is a 4-month regimen adequate to cure patients with non-cavitary tuberculosis and negative cultures at 2 months?

A recent trial evaluating a 4-month regimen of standard drugs in adults with non-cavitary tuberculosis (TB) and negative cultures at 2 months failed to demonstrate equivalence compared to the same regimen given for 6 months. To contribute further evidence, data from two trials conducted by the British Medical Research Council (BMRC) comparing 4 and 6 month regimens were re-analysed. The results from the BMRC trials in patients with non-cavitary TB and negative cultures at 2 months were consistent with those from the recent trial. However, given that there was no acquired drug resistance, the estimated 6.6% relapse rate (95%CI 4.3-10.1) across all three trials might be considered acceptable for a 4-month regimen in patients with non-cavitary pulmonary TB.

Validation of three-dimensional laser scanning for the assessment of facial fat changes.

OBJECTIVE: We aimed to evaluate the accuracy of three-dimensional laser scanning as an objective method for detecting facial changes. METHODS: Facial laser scanning was performed at baseline and repeated after a median of 10 months in 24 HIV-infected patients, 12 with ongoing lipodystrophy, five with >10% weight loss and seven with >10% weight gain. Surface volume change was estimated using a standardized technique, and compared with change in cheek fat measured by magnetic resonance imaging (MRI). RESULTS: The median laser scanning surface volume changes were -2.1 (range -4.6 to -0.8) mL in the lipoatrophy group, -1.5 (range -6.8 to -1.3) mL in the weight loss group and +3.1 (range -0.2 to +5.4) mL in the weight gain group (the median MRI cheek fat changes were -4.6, -3.7 and +7.0 mL in the three groups, respectively). Laser scanning and MRI measurements were not significantly associated in lipoatrophy patients (r=0.34, P=0.28), but there was a good association in patients who changed weight (r=0.71, P=0.01). CONCLUSIONS: Laser scanning detects changes in the appropriate direction, although it underestimates MRI-measured cheek fat changes. Laser scanning may be useful as an objective measure of cheek surface volume changes, but needs further validation in larger clinical cohorts.

AIDS-defining illness diagnosed within 90 days after starting highly active antiretroviral therapy among patients from the TREAT Asia HIV Observational Database.

Using data from TREAT Asia HIV Observational Database (TAHOD), this paper aims to assess the rate of, and factors associated with the diagnosis of new AIDS-defining illness (ADI) within 90 days after antiretroviral treatment. Patients starting three or more antiretroviral combinations and having subsequent follow-up were included. New ADI cases were checked for evidence of immune reconstitution syndrome (IRS). Among the 1185 patients included, 75 (6.3%) were diagnosed with a new ADI within 90 days, giving a rate of 26.8/100 person-years, compared with a further 3.6% cumulative incidence of new ADI between 90 days to one year (4.2/100 person-years). Of the 75 patients, 21 were judged as definitive or presumptive IRS, giving a rate of 7.3/100 person-years. Patients with new ADI generally had lower CD4 counts before treatment started (median, 43 cells/microL). Lower CD4 count, lower body mass index and starting treatment in the same year as the first HIV-positive test done were associated with developing a new ADI. The higher rate of new ADI within 90 days may be partly explained by IRS occurring shortly after treatment. Although it is difficult to identify IRS from observational data, it appears that in TAHOD setting IRS was relatively uncommon.

Analysis of the role of Mycobacterium tuberculosis kasA gene mutations in isoniazid resistance.

Previous studies have suggested that Mycobacterium tuberculosis kasA G312S and G269S gene mutations may represent sequence polymorphisms of the M. tuberculosis East-African-Indian (EAI) and T families, respectively, rather than relating to isoniazid resistance. The present study examined polymorphisms of these two codons in 98 drug-susceptible M. tuberculosis isolates (68 EAI and 30 T isolates). Twenty-eight isolates belonging to a sub-lineage of the EAI family had the kasA G312S mutation, but none of the 30 T isolates had the G269S mutation. The data suggest that the kasA G312S mutation is not related to isoniazid resistance, but represents a sequence polymorphism in a sub-lineage of the EAI family.

Genotype and phenotype relationships and transmission analysis of drug-resistant tuberculosis in Singapore.

SETTING: The small urban country of Singapore. OBJECTIVES: To investigate the relationships between Mycobacterium tuberculosis genotypes and drug-resistant phenotypes and to analyse the transmission of drug-resistant tuberculosis (DR-TB). DESIGN: A 29-month population-based study comparing drug-resistant and drug-susceptible M. tuberculosis isolates. RESULTS: We found that multidrug-resistant (MDR) isolates (n = 41, OR 2.66, 95%CI 1.28-5.50), rifampicin-resistant isolates (n = 48, OR 2.88, 95%CI 1.44-5.76), and streptomycin (SM) resistant isolates (n = 103, OR 3.35, 95%CI 1.99-5.62) were more common among Beijing genotype strains than among non-Beijing strains, while SM-resistant isolates were less common in East-African-Indian (EAI) genotype strains than in non-EAI strains (OR 0.30, 95%CI 0.14-0.64). Based on clustering analysis and drug-resistant patterns, 22 of 230 drug-resistant isolates were found to have likely resulted from recent transmission. The estimated transmission rate of DR-TB was 9.6% and that of MDR-TB was 7.7%. The transmission rate of DR-TB was significantly higher among Beijing genotype strains than non-Beijing strains (12.9% vs. 4.4%; P = 0.034). CONCLUSIONS: Compared to other genotypes, Beijing genotype strains are associated with a higher frequency of drug resistance, including multidrug resistance, and are more transmissible. However, the overall transmission rate of DR-TB in Singapore is low.

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.

The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy.

BACKGROUND: The impact that malnutrition at the time of starting antiretroviral therapy (ART) has on survival and the CD4 count response is not known. METHODS: A retrospective cohort study of patients attending the national HIV referral centre in Singapore who had a CD4 count less than 250 cells/microL and a measurement of body weight performed at the time of starting ART was carried out. Demographic and clinical variables were extracted from an existing database. Body mass index (BMI) was calculated from the weight in kilograms divided by the square of the height in metres. Moderate to severe malnutrition was defined as BMI less than 17 kg/m(2). Intent-to-treat Cox models were used to determine the predictors of survival. RESULTS: A total of 394 patients were included in the analysis, of whom 79 died during a median study follow-up of 2.4 years. Moderate to severe malnutrition was present in 16% of patients at the time of starting ART, and was found to be a significant independent predictor of death [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.29-3.73, P=0.004 for those with BMI<17 compared with those with BMI>18.5] as were stage of disease (HR 2.47, 95% CI 1.20-5.07, P=0.014 for those who were at stage C compared with those at stage A) and the type of ART [HR 0.50, 95% CI 0.27-0.93, P=0.03 for highly active antiretroviral therapy (HAART) compared with non-HAART treatment]. Malnutrition did not impair the magnitude of the increase in CD4 count at 6 or 12 months. CONCLUSIONS: Malnutrition at the time of starting ART was significantly associated with decreased survival, but the effect appeared not to be mediated by impaired immune reconstitution. Given the increasing access to ART in developing countries and the high frequency of HIV-associated wasting, studies of nutritional therapy as an adjunct to the initiation of HAART are urgently needed.

Association of Mycobacterium tuberculosis Beijing genotype with tuberculosis relapse in Singapore.

The relationship of Mycobacterium tuberculosis Beijing genotype with tuberculosis relapse was examined. Beijing strains were detected from 32 out of 45 (71%) relapsed cases and 148 out of 290 (51%) non-relapsed cases. Multivariate logistic regression analysis revealed that Beijing genotype was significantly associated with tuberculosis relapse (OR 2.64, 95% CI 1.30-5.34, P=0.005).

Laser scanning as a tool for assessment of HIV-related facial lipoatrophy: evaluation of accuracy and reproducibility.

BACKGROUND: Facial lipoatrophy (LA) is a common complication of highly active antiretroviral therapy (HAART). Research into causes and treatment of facial LA is hindered by the lack of an objective measurement tool. OBJECTIVE: To evaluate the accuracy and reproducibility of three-dimensional laser scanning (LS) for estimating cheek volume changes. METHODS: Paired laser scans were performed and the images superimposed using commercial software. The volume difference between images was computed within a circle of radius 25 mm placed in a standardized position over the cheek area. Accuracy was tested by scanning before and after known volumes of plasticine (0.5--5 mL) were applied to the cheek area of a mannequin to simulate volume change. Reproducibility was tested by repeated scanning of the mannequin with and without 2 mL of plasticine, and repeated scanning of 10 healthy subjects over the course of 1 week. RESULTS: The mean difference between actual and estimated volume change was small across the range of volumes tested [mean difference 0.08 mL; 95% confidence interval (CI)-0.36 to 0.20 mL). The coefficient of variation for repeated measurements of 2-mL volume change was 5.8%. The intraclass correlation coefficient for scan-to-scan variability was 0.812 (95% CI 0.515--0.947) and for day-to-day variability it was 0.764 (95% CI 0.332--0.935). Conclusions LS is an accurate and reproducible method for estimating cheek volume changes. It may be useful as an objective tool for assessment of facial LA in clinical research studies.

Hydroxychloroquine, hydroxyurea and didanosine as initial therapy for HIV-infected patients with low viral load: safety, efficacy and resistance profile after 144 weeks.

OBJECTIVES: To evaluate the long-term safety and efficacy of the combination of hydroxychloroquine, hydroxyurea and didanosine. METHODS: We recruited antiretroviral-naive patients with viral loads less than 100 000 HIV-1 RNA copies/mL and CD4 counts greater than 150 cells/microL. All patients received hydroxychloroquine (200 mg), hydroxyurea (500 mg) and didanosine (125-200 mg) twice daily. Clinical and laboratory safety assessments and measurements of viral load and CD4 count were made at regular intervals, and genotypic resistance testing was performed on samples with detectable viral load at 48, 96 and 144 weeks. RESULTS: Fourteen of the 17 patients who commenced therapy remained on treatment at 144 weeks. Treatment was well tolerated but caused neutropenia, usually mild and transient, in 12 patients (71%). Mean viral load was reduced by 1.6 log(10) copies/mL below baseline (P<0.001), eight patients (47%) had undetectable viral load (<400 copies/mL), and two patients (12%) had detectable viral load but no detectable resistance mutations at week 144. Four patients (24%) had detectable viral load together with major resistance mutations (three with both 74 V and 184 V, and one with both 62 V and 65R) at week 144, but still had viral load suppression below baseline. Mean CD4 count was increased by 106 cells/microL above baseline (P=0.07) at week 144. CONCLUSIONS: This novel and well-tolerated combination controls viral replication during long-term follow up, with development of few resistance mutations. With careful monitoring it may be a useful strategy for delaying highly active antiretroviral therapy (HAART) and associated toxicity in selected patients with low initial viral loads.

A randomised controlled trial of oral zinc on the immune response to tuberculosis in HIV-infected patients.

SETTING: The National HIV Unit, Singapore. OBJECTIVE: To test whether zinc supplementation improves the immune response to tuberculosis in HIV-positive patients. DESIGN: A double-blind, randomised, placebo-controlled trial of 28 days of oral zinc sulphate (50 mg of elemental zinc) or placebo in stable adult HIV-positive patients receiving antiretroviral therapy with a CD4 count <200 cells/microl. METHODS: IFN-gamma response to mycobacterial antigen stimulation, CD4/8 cell count, lymphocyte subsets, T-cell receptor excision circle (TREC) levels and viral load were measured at baseline and day 28. RESULTS: Thirty-two patients received zinc and 34 placebo. There was no significant change in the IFN-gamma response to human PPD stimulation in the zinc or placebo groups (placebo baseline: 0.42 +/- 1.03, day 28: 0.84 +/- 1.21 IU/ml, zinc baseline: 1.26 +/- 2.41, day 28: 1.39 +/- 1.88 IU/ml, P = 0.31 between groups), nor any of the other mycobacterial antigens tested. There were no changes in absolute CD4/8 cell levels or other lymphocyte subsets, TREC or viral load. Baseline zinc levels were normal in 62/66 (93.9%) patients. CONCLUSIONS: We found no evidence for recommending pharmacological supplementation with oral zinc in HIV-positive patients without zinc deficiency.

Causes of death among patients with HIV in Singapore from 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS).

OBJECTIVES: To investigate the major primary and contributory causes of death among HIV patients in Singapore. DESIGN: A retrospective observational cohort study of all adult patients seen at the national referral centre for HIV in Singapore between 1985 and 2001. METHODS: Data were extracted from the patients' records by 10 trained health care workers. AIDS-defining conditions were established using predefined criteria. For each case, a single principal cause of death and up to three contributory causes were identified. RESULTS: A total of 1504 patients aged 17 years or over were seen before the end of 2001, of whom 504 have died. The most frequent principal causes of death were Mycobacterium avium (17.5%), Mycobacterium tuberculosis (9.7%), pneumonia (cause unknown) (6.5%) and Cryptococcus neoformans (6.7%). Three hundred and eighteen patients (63.1%) died from an AIDS-defining condition. CONCLUSIONS: The causes of death were similar to those found in Western cohorts, except that disseminated M. avium was a more frequent cause of death.

Prevalence of and risk factors for nasal colonization with Staphylococcus aureus among human immunodeficiency virus-positive outpatients in Singapore.

We studied the prevalence of and risk factors for Staphylococcus aureus nasal colonization in HIV-positive outpatients in Singapore. Overall prevalence was 23% (45 of 195), with 3% (6 of 195) being MRSA. Recent antibiotic use and hospitalization were independent predictors of MRSA colonization. Isolates were genotypically identical to our hospital's inpatient circulating strain.

Importation of seven cases of an unusual helminthic infection into Singapore and assessment of the risk of local transmission.

Singapore remains vulnerable to the introduction of infectious diseases from other countries due to the high traffic of migrant labour and other visitors. We describe seven cases of migrant workers from West Africa who entered Singapore carrying loaisis, a helminthic infection. The clinical presentation, treatment using single dose ivermectin, potential for transmission, and the need for screening of this infection in Singapore are discussed.

A pilot study of the safety and efficacy of thymosin alpha 1 in augmenting immune reconstitution in HIV-infected patients with low CD4 counts taking highly active antiretroviral therapy.

To study the safety and efficacy of thymosin alpha1 in stimulating immune reconstitution in combination with highly active antiretroviral therapy (HAART), a phase II randomized, controlled open-label trial of subcutaneous thymosin alpha1 was undertaken for 12 weeks. Twenty clinically stable patients with viral loads <400 copies/ml and CD4 counts less than 200 cells/microl were randomized to receive 3.2 mg thymosin alpha 1 subcutaneous injections twice weekly or no injections for 12 weeks. CD4 and CD8 counts, CD45 RO+ and RA+ subsets and signal joint T cell receptor excision circles (sjTREC) in peripheral blood mononuclear cells (PBMCs) were measured every 2 weeks. Thirteen patients received thymosin alpha 1 and seven were controls. Thymosin alpha 1 was well tolerated and there were no serious adverse events. There was no significant difference between the thymosin alpha1 and control groups in CD4, CD8 and CD45 lymphocyte subset changes at week 12; however, PBMC sjTREC levels increased significantly in the thymosin alpha 1-treated patients compared to controls at week 12. In conclusion, the increase in PBMC sjTREC levels in patients taking thymosin alpha1 may represent enhanced immune reconstitution; however, the clinical benefits and long-term consequences remain to be determined.

Late clinical and magnetic resonance imaging follow up of Nipah virus infection.

The Nipah virus is a newly identified paramyxovirus responsible for an outbreak of fatal encephalitis in Malaysia and Singapore. This paper reports the follow up clinical and magnetic resonance imaging findings in 22 affected subjects. Of 13 patients with encephalitis, one died, one was lost to follow up, and seven recovered. Among the four remaining patients, one had residual sixth nerve palsy, another suffered from severe clinical depression, and a third patient had evidence of retinal artery occlusion. One patient with delayed onset Horner syndrome had a single lesion in the cervical spinal cord. The brain magnetic resonance findings were stable or improved in nine patients over 18 months of follow up. Among a second group of nine asymptomatic seropositive abattoir workers, magnetic resonance examination in seven subjects revealed discrete small lesions in the brain; similar to those detected in encephalitis patients. These findings suggest that in addition to encephalitis, the newly discovered Nipah virus affects the spinal cord and the retina. Late clinical and radiological findings can occur in Nipah virus infections as with other paramyxoviruses.