Pacharee Kantipong

Hepatic Penicilliosis in Patients Without Skin Lesions

Penicillium marneffei is a common cause of opportunistic fungal infection in patients with AIDS in Thailand. The diagnosis of penicilliosis is easily made when typical skin lesions appear but is frequently missed in their absence. We therefore attempted to identify noncutaneous indicators of P. marneffei infection in order to provide early curative treatment. We recognized a characteristic syndrome in six AIDS patients with penicilliosis involving primarily the liver but not the skin who presented with fever of short duration, hepatomegaly, and markedly elevated serum alkaline phosphatase levels. The diagnosis was confirmed by demonstrating the causative organism in the liver or in the blood. Increased awareness of hepatic penicilliosis and more-rapid diagnostic methods are needed to reduce the high mortality rate associated with this syndrome. P. marneffei is predominantly an Asian pathogen, but as a result of international travel, the need for increased awareness of penicilliosis is worldwide.

Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial.

BACKGROUND Some strains of scrub typhus in northern Thailand are poorly responsive to standard antirickettsial drugs. We therefore did a masked, randomised trial to compare rifampicin with standard doxycycline therapy for patients with scrub typhus. METHODS Adult patients with strictly defined, mild scrub typhus were initially randomly assigned 1 week of daily oral treatment with 200 mg doxycycline (n=40), 600 mg rifampicin (n=38), or doxycycline with rifampicin (n=11). During the first year of treatment, the combined regimen was withdrawn because of lack of efficacy and the regimen was replaced with 900 mg rifampicin (n=37). Treatment outcome was assessed by fever clearance time (the time for oral temperature to fall below 37.3 degrees C). FINDINGS About 12,800 fever patients were screened during the 3-year study to recruit 126 patients with confirmed scrub typhus and no other infection, of whom 86 completed therapy. Eight individuals received the combined regimen that was discontinued after 1 year. The median duration of pyrexia was significantly shorter (p=0.01) in the 24 patients treated with 900 mg daily rifampicin (fever clearance time 22.5 h) and in the 26 patients who received 600 mg rifampicin (fever clearance time 27.5 h) than in the 28 patients given doxycycline monotherapy (fever clearance time 52 h). Fever resolved in a significantly higher proportion of patients within 48 h of starting rifampicin (900 mg=79% [19 of 24], 600 mg=77% [20 of 26]) than in patients treated with doxycycline (46% [13 of 28]; p=0.02). Severe gastrointestinal events warranted exclusion of two patients on doxycyline. There were two relapses after doxycycline therapy, but none after rifampicin therapy. INTERPRETATION Rifampicin is more effective than doxycycline against scrub-typhus infections acquired in northern Thailand, where strains with reduced susceptibility to antibiotics can occur.

HIV-1 suppression during acute scrub-typhus infection.

BACKGROUND In HIV-1-infected individuals, viral load has been reported to rise transiently if an acute infection with another organism occurs. Our study was prompted by the unexpected finding that HIV-1 copy number fell during an acute infection with Orientia tsutsugamushi, the causative agent of scrub typhus. METHODS Serial HIV-1 viral load determinations were made in ten Thai adults with scrub typhus, who were not receiving antiretroviral therapy, and in five HIV-1-infected patients who had other infections (four malaria, one leptospirosis), during and after acute infections. Sera from HIV-1-infected patients with scrub typhus and from mice immunised with O. tsutsugamushi were examined for HIV-1-suppressive activity. FINDINGS Median viral load 3 days after admission was significantly lower in the scrub-typhus group than in patients with other infections (193% vs 376% of day 28 values, p=0.03). In four O. tsutsugamushi-infected patients HIV-1 RNA copy number fell by three-fold or more compared with day 28 values, and HIV-1 copy numbers were below the assay threshold in two patients with scrub typhus. Five of seven HIV-1 isolates from non-typhus patients with CD4 lymphocytes less than 200 cells/microL were syncytia-inducing variants, whereas all ten isolates from O. tsutsugamushi-infected individuals matched by CD4-cell count were non-syncytia inducing (p=0.03). Sera from an HIV-1-negative patient with scrub typhus had potent HIV-1-suppressive activity in vitro. Sera from typhus-infected mice inhibited HIV-1 syncytia formation and bound by immunofluorescence to HIV-1-infected lymphocytes. INTERPRETATION HIV-1-suppressive factors are produced during some scrub-typhus infection and should be investigated further in the search for novel strategies for the treatment and prevention of AIDS.

Cohort profile: The PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring studies to evaluate resistance-HIV drug resistance in sub-Saharan Africa and the Asia-Pacific

This article discusses two multi-centre prospective cohort studies in Africa that assess the prevalence and incidence of HIV in people using the first-line ART treatment. Participants are enrolled in the study for approximately 18 months after which new participants are recruited. The HIV positive people in the study are evaluated during their regular clinic visits. Researchers are collecting information about various HIV subtypes in the affected population incidence of duel infections and disease progression and response to treatment. Due to the various clinics involved in the study the study benefits from a large number of patients with very different backgrounds and disease characteristics.

Decrease in human immunodeficiency virus type 1 load during acute dengue fever.

Rather than the expected increase in human immunodeficiency virus type 1 (HIV-1) load, there was transient suppression of HIV-1 replication during acute dengue infection in a 29-year-old Thai woman. Acute-phase (but not convalescent-phase) serum samples obtained from an HIV-1-uninfected patient with dengue fever reduced HIV-1 infectivity, as determined by a peripheral blood mononuclear cell assay, suggesting the possibility that HIV-1 replication is suppressed during acute dengue fever, as occurs during some cases of scrub typhus infection and measles.

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.

HIV-1 Drug Resistance Mutations Among Antiretroviral-Naive HIV-1–Infected Patients in Asia: Results From the TREAT Asia Studies to Evaluate Resistance-Monitoring Study

Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia.

A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study.

BACKGROUND Data informing the use of boosted protease inhibitor (PI) monotherapy as second-line treatment are limited. There are also no randomized trials addressing treatment options after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimens. METHODS HIV-infected subjects ≥18 years, with HIV RNA≥1,000 copies/ml while using NNRTI plus 2 NRTIs, and naive to PIs were randomized to lopinavir/ritonavir (LPV/r) 400/100 mg twice daily monotherapy (mono-LPV/r) or tenofovir disoproxil fumarate (TDF) once daily plus lamivudine (3TC) twice daily plus LPV/r 400/100 mg twice daily (TDF/3TC/LPV/r) at nine sites in Thailand. The primary outcome was time-weighted area under curve (TWAUC) change in HIV RNA over 48 weeks. The a priori hypothesis was that the mono-LPV/r arm would be considered non-inferior if the upper 95% confidence limit in TWAUC mean difference was ≤0.5 log(10) copies/ml. RESULTS The intention-to-treat (ITT) population comprised 195 patients (mono-LPV/r n=98 and TDF/3TC/LPV/r n=97): male 58%, baseline mean (sd) age of 38 (7) years, CD4(+) T-cell count of 204 (135) cells/mm(3) and HIV RNA of 4.1 (0.6) log(10) copies/ml. The majority had HIV-1 recombinant CRF01_AE infection, and thymidine analogue mutation (TAM)-2 was 3× more common than TAM-1. At 48 weeks, the difference in TWAUC HIV RNA between arms was 0.15 (95% CI -0.04, 0.33) log(10) copies/ml, consistent with our definition of non-inferiority. However, the proportion with HIV RNA<50 copies/ml was significantly lower in the mono-LPV/r arm: 61% versus 83% (ITT, P<0.01). Baseline HIV RNA≥5 log(10) copies/ml (P<0.001) and mono-LPV/r use (P=0.003) were predictors of virological failure. Baseline genotypic sensitivity scores ≥2 and TAM-2 were associated with better virological control in subjects treated with the TDF-containing regimen. CONCLUSIONS In PI-naive patients failing NNRTI-based first-line HAART, mono-LPV/r had a significantly lower proportion of patients with HIV RNA<50 copies/ml compared to the TDF/3TC/LPV/r treatment. Thus, mono-LPV/r should not be recommended as a second-line option.

Trends of CD4 cell count levels at the initiation of antiretroviral therapy over time and factors associated with late initiation of antiretroviral therapy among Asian HIV-positive patients

Although antiretroviral therapy (ART) has been rapidly scaled up in Asia, most HIV‐positive patients in the region still present with late‐stage HIV disease. We aimed to determine trends of pre‐ART CD4 levels over time in Asian HIV‐positive patients and to determine factors associated with late ART initiation.

Transmitted drug resistance and antiretroviral treatment outcomes in non-subtype B HIV-1-infected patients in South East Asia.

Background:We compared treatment outcomes of transmitted drug resistance (TDR) in patients on fully or partially sensitive drug regimens. Methods:Factors associated with survival and failure were analyzed using Cox proportional hazards and discrete time conditional logistic models. Results:TDR, found in 60 (4.1%) of 1471 Asian treatment-naive patients, was one of the significant predictors of failure. Patients with TDR to >1 drug in their regimen were >3 times as likely to fail compared to no TDR. Conclusions:TDR was associated with failure in the context of non-fully sensitive regimens. Efforts are needed to incorporate resistance testing into national treatment programs.