Deferred modification of antiretroviral regimen following documented treatment failure in Asia: results from the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVE: The aim of the study was to examine the rates and predictors of treatment modification following combination antiretroviral therapy (cART) failure in Asian patients with HIV enrolled in the TREAT Asia HIV Observational Database (TAHOD). METHODS: Treatment failure (immunological, virological and clinical) was defined by World Health Organization criteria. Countries were categorized as high or low income by World Bank criteria. RESULTS: Among 2446 patients who initiated cART, 447 were documented to have developed treatment failure over 5697 person-years (7.8 per 100 person-years). A total of 253 patients changed at least one drug after failure (51.6 per 100 person-years). There was no difference between patients from high- and low-income countries [adjusted hazard ratio (HR) 1.02; P=0.891]. Advanced disease stage [Centers for Disease Control and Prevention (CDC) category C vs. A; adjusted HR 1.38, P=0.040], a lower CD4 count (>or=51 cells/microL vs. or=400 HIV-1 RNA copies/mL vs. <400 copies/mL; adjusted HR 2.69, P<0.001) were associated with a higher rate of treatment modification after failure. Compared with patients from low-income countries, patients from high-income countries were more likely to change two or more drugs (67%vs. 49%; P=0.009) and to change to a protease-inhibitor-containing regimen (48%vs. 16%; P<0.001). CONCLUSIONS: In a cohort of Asian patients with HIV infection, nearly half remained on the failing regimen in the first year following documented treatment failure. This deferred modification is likely to have negative implications for accumulation of drug resistance and response to second-line treatment. There is a need to scale up the availability of second-line regimens and virological monitoring in this region.

Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVES: Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. METHODS: Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (> or = 3, 1-2 or <1) or CD4 (> or = 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. RESULTS: Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and 'Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting 'Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). CONCLUSION: Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.

Low prevalence of insulin resistance among HIV-infected children receiving nonnucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in Thailand.

BACKGROUND: Highly active antiretroviral therapy (HAART) is reported to cause insulin resistance among adults, but effects on children are less clear. We attempted to describe the prevalence of insulin resistance among HIV-infected children receiving HAART. METHODS: Insulin resistance was assessed at 96 weeks of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART (nevirapine or efavirenz with stavudine and lamivudine) among children in Chiang Mai, Thailand. Insulin resistance was defined as homeostasis model assessment for insulin resistance (HOMA-IR) >/=3.16, fasting c-peptide >/=4.40 ng/mL or fasting insulin >/=25.0 muU/mL. Impaired fasting glucose (IFG) was defined as glucose >/=110 mg/dL. Measurements were analysed for associations with age, lipodystrophy, treatment regimen and clinical data. RESULTS: The prevalence of insulin resistance was 6.5%; no child had IFG. Those with insulin resistance were older with higher body mass index. Children >/=10 years had higher HOMA-IR, c-peptide and insulin, but no difference was seen in the frequency of insulin resistance. No associations between insulin resistance and lipodystrophy or treatment regimen were detected. CONCLUSIONS: Insulin resistance is uncommon among children receiving NNRTI-based HAART and is unrelated to lipodystrophy.

Late manifestations of HIV in Asia and the Pacific.

PIP: Late-stage HIV infection is characterized by profound immunodeficiency with a progressive and irreversible decline in the CD4 count, functional impairment of cellular and humoral immunity, and evidence of increased viral replication, with the appearance of p24 antigenemia and increasing levels of beta(2)-microglobulin and neopterin. These changes are associated with increased susceptibility to many infections, the emergence of malignancies, and neurological complications due to the direct infection of neural tissue with HIV. In Australia, opportunistic infections and malignancies account for 75% and 18% of AIDS diagnoses, respectively. Opportunistic infections and neurological involvement usually occur late in the illness and may be associated with disturbances of function of each part of the neuraxis. The detailed clinical nature of the involvement has been described in several recent reviews and is probably not different in the Asia-Pacific region. The most common opportunistic infections in Australia are Pneumocystis carinii pneumonia (PCP), esophageal candidiasis, toxoplasmosis, CMV infection, atypical mycobacteriosis, and cryptococcal meningitis. There are few data from Asian countries, but it seems that the most common opportunistic infections are tuberculosis, PCP, systemic Penicillium marneffei infection, and cryptococcal meningitis. There is little information from Asia on neurological conditions. Tuberculosis is probably the most significant threat to public health in Asia and the Pacific. Its management and prevention require ongoing planning and resources. To that end, a collaborative effort is called for to help resource-poor countries. Mycobacterial, fungal, viral, and protozoal infections are discussed, along with consideration of neurological complications, malignant disease, and late manifestations of HIV infection in children.^ieng

Disseminated Penicillium marneffei infection in human immunodeficiency virus-infected children.

Disseminated infection with the fungus Penicillium marneffei is one of the most common opportunistic infections in human immunodeficiency virus (HIV) disease in northern Thailand. We report the clinical, laboratory and therapeutic features of 21 human immunodeficiency virus-infected children with disseminated P. marneffei who were prospectively followed. Significant clinical and laboratory features included generalized lymphadenopathy (90%), hepatomegaly (90%), body temperature > 38.5 degrees C (81%), papular skin lesions with central umbilication (67%), splenomegaly (67%), failure to thrive (52%), severe anemia (hemoglobin < 60 g/liter) (43%) and thrombocytopenia (platelet count < 0.5 x 10(11)/liter) (21%). The response rate in patients who were treated with appropriate antifungal therapy (amphotericin B, fluconazole or ketoconazole) was 82%. No relapse was observed in patients given ketoconazole prophylactically. Skin lesions, usually papules with central necrotic umbilication, provide the most significant clue to the diagnosis. Early diagnosis based on finding P. marneffei in the skin smear or lymph node provides the basis for prompt administration of antifungal therapy and improved outcome.

PIP: This report describes the epidemiology of Penicillium marneffei infections among HIV infected children who were seen at Chiang Mai University Hospital, Thailand, between April 1989 and January 1995. HIV infections among children 18 months old and older were determined by both enzyme-linked immunosorbent assay and particle agglutination tests. Confirmation of HIV infection was made among younger children by signs and symptoms and repeated reactive serum tests. Diagnosis of P. marneffei infection was determined by isolation of the organism from clinical blood or tissue specimens. Antifungal agents were administered and improvement was recorded. There were 23 cases of P. marneffei among the 362 children diagnosed with HIV infection during the study period. One case was a non-HIV infected girl and another was a thalassemic patient who had received an HIV infected blood transfusion. The remaining 21 children acquired the infection perinatally. All mothers of the 21 children had acquired the HIV infection as prostitutes or from husbands who used prostitutes. All 21 children had clinical cases of HIV infection at the onset of the P. marneffei infection. The median time of presentation was 32 months. Fever was a primary symptom. 67% had skin lesions and most lesions were on the face and extremities. Other laboratory findings are reported. 9 of the 21 children had other HIV-related opportunistic infections diagnosed at the same time as the diagnosis of P. marneffei. There were 4 cases of Salmonella bacteremia, 2 cases of cryptosporidiosis, 1 case of Pseudomonas aeruginosa bacteremia, 1 case of Pneumocystis carinii and cytomegalovirus pneumonia, and 1 case of nontyphoid Salmonella bacteremia and herpes zoster. All 7 culture-proved patients who did not receive antifungal therapy died. 9 culture-proved and 3 other cases responded to antifungal treatment. Findings suggest that P. marneffei infection should be included as another AIDS-defining illness. The case fatality rate of patients with P. marneffei infection was very high, mostly due to late diagnosis.

Serological studies of patients with cutaneous and oral-oropharyngeal anthrax from northern Thailand.

An outbreak of 52 cases of cutaneous anthrax and 24 cases of oral-oropharyngeal anthrax occurred in rural Northern Thailand in 1982, caused by contaminated water buffalo meat. Microbiologic diagnosis of many of these cases was hindered by delayed presentation for care and by prior antibiotic therapy. In a retrospective investigation, we used enzyme-linked immunosorbent assays to measure antibody titers to components of anthrax edema toxin (edema factor [EF] and protective antigen [PA]), lethal toxin (lethal factor [LF] and PA), and poly-D-glutamic acid capsule. Electrophoretic-immunotransblots (EITB, Western blot) were used to detect antibodies to PA and LF. Nine patients with cutaneous anthrax, 10 patients with oral-oropharyngeal anthrax, and 43 healthy unexposed Thai control villagers were studied. Over all, EITB was positive in 13/18 patients (sensitivity 72%) and 0/43 controls (specificity 100%). The sensitivity of the ELISA was 72% for PA, 42% for LF, 26% for EF, and 95-100% for capsule. Although a few control sera had apparent false positive titers to PA, the specificity of the ELISA confirmed by EITB (100%) demonstrated the applicability of these tests for the diagnosis of anthrax.

Outbreak of oral-oropharyngeal anthrax: an unusual manifestation of human infection with Bacillus anthracis.

An oral-oropharyngeal form of human anthrax is described in 24 individuals. The cases occurred as an epidemic in northern Thailand, concurrent with an epidemic of the common cutaneous form. This syndrome is a potentially fatal, febrile illness, characterized by a mucosal lesion in the oral cavity and/or oropharynx which can progress to pseudomembranous necrosis, and to cervical adenopathy and edema. Cattle and water buffaloes, recently arrived from Burma and eaten raw or undercooked, were the probable source of the infection. Determination of etiology was based on both microbiologic and epidemiologic evidence. The clinical syndrome and epidemiology are discussed.

First cases of spotted fever group rickettsiosis in Thailand.

The first three cases of spotted fever group rickettsiosis from Thailand are reported. The patients presented with fever, headache, lymphadenopathy, and petechial maculopapular rash. One patient also had an eschar and overt evidence of confusion. An indirect fluorescent antibody test, an indirect immunoperoxidase test, and an enzyme-linked immunosorbent assay demonstrated a broad, strong reactions of the sera of the patients with spotted fever group rickettsia antigens of many species, but not with antigens of typhus or scrub typhus rickettsiae. All three patients responded to treatment with a single dose of doxycycline.

Epidemiology and management of penicilliosis in human immunodeficiency virus-infected patients.

Penicillium marneffei is a dimorphic fungus that can cause systemic mycosis in humans. It is endemic in Southeast Asia, the Guangxi province of China, Hong Kong, and Taiwan. Prior to the epidemic of human immunodeficiency virus (HIV), penicilliosis was a rare event. The incidence of this fungal infection has increased markedly during the past few years, paralleling the incidence of HIV infection. The patients usually present with fever, anemia, weight loss, skin lesions, generalized lymphadenopathy, and hepatomegaly. The skin lesions are most commonly papules with central necrotic umbilication. The average number of CD4+ T lymphocytes at presentation is 64 cells/mm3. The fungus is usually sensitive to amphotericin B, itraconazole, and ketoconazole. The response to antifungal treatment is good if the treatment is started early. After the initial treatment the patient may need to take an antifungal drug as secondary prophylaxis for life. New tests for the laboratory diagnosis of penicilliosis have been reported. Further studies of these tests, as well as the epidemiology, natural history, and management of this potentially fatal systemic fungal infection are needed.

Oropharyngeal anthrax.

The first bacteriologically confirmed case of oropharyngeal anthrax is described. A 59-year-old male patient presented with sore throat and extensive swelling of the neck and anterior chest wall five hours after the ingestion of uncooked water buffalo meat. Marked inflammation of the oropharynx and a small necrotic area in the left tonsil were found. Culture taken from this area grew Bacillus anthracis. In anthrax-susceptible areas, this acute illness should be added to the differential diagnoses of inflammatory lesion of the oropharynx with extensive neck swelling.

Infection due to Penicillium marneffei.

Penicillium marneffei is endemic in Southeast Asia, the Guangxi province of China, and Hong Kong. Cases of patients infected with P. marneffei have been very rare, but the incidence has increased markedly during the past several years. This increase is exclusively due to infection among patients infected with human immunodeficiency virus (HIV). The patients usually presented with symptoms and signs similar to other patients with late HIV diseases. These included fever (99% of the patients), anaemia (78%), pronounced weight loss (76%), generalised lymphadenopathy (58%) and hepatomegaly (51%). Skin lesions were seen in 71% of our patients. These lesions were most commonly papules with central necrotic umbilication. It was easy to culture P. marneffei from various clinical specimens. Bone marrow culture was the most sensitive (100%), followed by culture of the specimen obtained from skin biopsy (90%) and blood culture (76%). The fungus was sensitive to amphotericin B, itraconazole, and ketoconazole. Our regimen is to give amphotericin B for 2 weeks, followed by itraconazole 400 mg/day orally for the next 10 weeks. After the initial treatment, the patient is given itraconazole 200 mg/day as secondary prophylaxis for life.

PIP: Penicillium marneffei is endemic in Southeast Asia, the Guangxi province of China, and Hong Kong. Cases of patients infected with P. marneffei have been very rare, but the incidence has increased markedly during the past several years. This increase is exclusively due to infection occurring among HIV-infected patients. The patients usually presented with symptoms and signs similar to other patients with late HIV-associated diseases. These included fever (99% of patients), anemia (78%), pronounced weight loss (76%), generalized lymphadenopathy (58%), and hepatomegaly (51%). Skin lesions were seen in 71% of the patients. These lesions were most commonly papules with central necrotic umbilication. It was easy to culture P. marneffei from various clinical specimens. Bone marrow culture was the most sensitive (100%), followed by culture of specimens obtained from skin biopsy (90%) and blood culture (76%). The fungus was sensitive to amphotericin B, itraconazole, and ketoconazole. The authors' regimen is to give amphotericin B for 2 weeks, followed by itraconazole 400 mg/day orally for the next 10 weeks. After the initial treatment, the patient is given itraconazole 200 mg/day as secondary prophylaxis for life.

Flow cytometric analysis of T-lymphocytes subsets in adult Thais.

Flow cytometer (FACScan) was used to determine the range of T lymphocyte subpopulations in normal Thai blood donors at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai. Reference population consisted of 150 healthy HIV seronegative blood donors. T lymphocyte subsets were analysed using two-color immunophenotyping of peripheral blood lymphocytes with a lysed whole blood technique and enumerated. The study showed that the normal values for CD3+ lymphocytes (percent), CD4+ lymphocytes (percent), CD8+ lymphocytes (percent), CD4/CD8 ratio, absolute CD3+ lymphocyte count, absolute CD4+ lymphocyte count and absolute CD8+ lymphocyte count were 64 +/- 8.8, 36.1 +/- 6.4, 25.7 +/- 7.3, 1.5 +/- 0.6, 1,630 +/- 600 cells/microl, 910 +/- 300 cells/microl and 670 +/- 350 cells/microl, respectively. We found that the values of CD3, CD4 and CD4/CD8 ratio were significantly lower than those in the Caucasians but those of CD8 was not significantly different. This observations have important clinical implication for the use of T lymphocyte subsets measurement, especially in the management of HIV infection in Thais. These normal ranges can be used as a reference for the decisions in clinical practice.

Prevalence of HBV infection in nurses and manual workers in Maharaj Nakorn Chiang Mai Hospital.

The prevalence of hepatitis B serologic markers was studied in 1,772 nurses, practical nurses, aides and workers. Results showed: 6.6 per cent of carriers, 3.3 per cent of anti-HBs and 38.4 per cent of contact cases. Higher rates of hepatitis B virus carriers and contact cases were in workers (11.1 and 56.0 per cent) and practical nurses (7.0 and 42.6 per cent) respectively. There were significant differences in each marker among nurses, practical nurses, aides and workers. Furthermore, there were variations of various markers in some ranks of age-groups and working-years. The prevalence of HBV carriers increased with age up to 40 years and was remarkably high in nurses. Higher rates of HBV infection were found in personnel working in the emergency room, operating room and outpatient department.

An efficacy study of itraconazole in the treatment of Penicillium marneffei infection.

OBJECTIVES: to evaluate the efficacy and safety of itraconazole in treating P. marneffei infection. METHODS: Ten patients with previously untreated P. marneffei infection were given oral itraconazole at a dose of 200 mg twice a day for 2 months, followed by a dose of 100 mg once a day for 1 month. Efficacy was determined by the clinical and microbiological cure. RESULTS: All but one patient were seropositive for human immunodeficiency virus (HIV). Two patients died during therapy. Clinical improvement was evident in 8 patients. In 7 of these, the mean duration for becoming culture negative was 57 days. Five patients presented with relapse of P. marneffei infection within four months after completion of treatment. CONCLUSIONS: Itraconazole was shown to be effective in the initial treatment of P. marneffei infection. Relapse after treatment is common and long-term suppressive therapy is recommended.

Predictors of clinical progression in HIV-1-infected adults initiating combination antiretroviral therapy with advanced disease in the Asia-Pacific region: results from the TREAT Asia HIV observational database.

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm(3) in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings.

Causes of first hospitalization among 1121 HIV-infected children: comparison of the pre-Pneumocystis jiroveci pneumonia prophylaxis, pre-antiretroviral therapy and antiretroviral therapy periods.

This study identified causes of first hospitalization among perinatally acquired HIV-infected children at Chiang Mai University Hospital between 1989 and 2009. Data were stratified into three seven-year time periods: pre-Pneumocystis jiroveci pneumonia (PJP) prophylaxis, pre-antiretroviral therapy (ART) and ART period. Over the 21-year study period, 1121 children were hospitalized. The mean age at admission was 2.7 years and had become older over time. Of the 1121 hospitalization causes, 50.6% were AIDS-defining illnesses (ADIs), 48.1% were non-AIDS-defining illnesses (NADIs) and 1.3% were related to immune reconstitution syndrome. Types of ADIs changed over time: PJP and recurrent Salmonella septicaemia decreased, while mycobacterial infection and systemic fungal infection increased. For NADIs, bacterial infections, viral infections and gastrointestinal problems decreased, but haematological problems increased in the third period. Decline in the number of hospitalizations and mortality rate, increase in the mean age of hospitalized children, change in the distribution of specific illnesses and appearance of immune reconstitution syndrome were observed in the ART period.

Treatment outcomes of patients co-infected with tuberculosis and HIV at Chiang Mai University Hospital, Thailand.

Thailand has been greatly affected by the tuberculosis (TB) and HIV syndemic. This study aimed to determine treatment outcomes among HIV/TB co-infected patients. A retrospective cohort study was conducted at Chiang Mai University Hospital from 1 January 2000 to 31 December 2009. Of 171 patients, 100 patients were male (58.5%) and the mean age was 36.8 ± 8.0 years. Seventy-two patients (42.1%) had pulmonary tuberculosis. Median CD4+ count before TB treatment was 69 cells/mm(3) (interquartile range [IQR] 33, 151). The overall mortality was 3.5% (6 patients). Immune reconstitution inflammatory syndrome (IRIS) occurred in eight patients (6.0%). Disseminated TB infections increased risk of death (odds ratio [OR] = 2.55, 95% confidence interval [CI] 1.25, 5.18) and IRIS (OR = 9.16, 95% CI 1.67, 50.07). Initiating combination antiretroviral therapy (cART) within two months after TB treatment increased risk of IRIS (OR = 6.57, 95% CI 1.61-26.86) and physicians caring for HIV/TB co-infected patients should be aware of this condition.