Cost and cost-effectiveness analysis of pre-exposure prophylaxis among men who have sex with men in two hospitals in Thailand.

INTRODUCTION: In 2014, the Government of Thailand recommended pre-exposure prophylaxis (PrEP) as an additional HIV prevention programme within Thailand's National Guidelines on HIV/AIDS Treatment Prevention. However, to date implementation and uptake of PrEP programmes have been limited, and evidence on the costs and the epidemiological and economic impact is not available. METHODS: We estimated the costs associated with PrEP provision among men having sex with men (MSM) participating in a facility-based, prospective observational cohort study: the Test, Treat and Prevent HIV Programme in Thailand. We created a suite of scenarios to estimate the cost-effectiveness of PrEP and sensitivity of the results to the model input parameters, including PrEP programme effectiveness, PrEP uptake among high-risk and low-risk MSM, baseline and future antiretroviral therapy (ART) coverage, condom use, unit cost of delivering PrEP, and the discount rate. RESULTS: Drug costs accounted for 82.5% of the total cost of providing PrEP, followed by lab testing (8.2%) and personnel costs (7.8%). The estimated costs of providing the PrEP package in accordance with the national recommendation ranges from US$223 to US$311 per person per year. Based on our modelling results, we estimate that PrEP would be cost-effective when provided to either high-risk or all MSM. However, we found that the programme would be approximately 32% more cost-effective if offered to high-risk MSM than it would be if offered to all MSM, with an incremental cost-effectiveness ratio of US$4,836 per disability-adjusted life years (DALY) averted and US$7,089 per DALY averted respectively. Cost-effectiveness acceptability curves demonstrate that 80% of scenarios would be cost-effective when PrEP is provided solely to higher-risk MSM. CONCLUSION: We provide the first estimates on cost and cost-effectiveness of PrEP in the Asia-Pacific region, and offer insights on how to deliver PrEP in combination with ART. While the high drug cost poses a budgeting challenge, incorporating PrEP delivery into an existing ART programme could be a cost-effective strategy to prevent HIV infections among MSM in Thailand.

Programmatic Evaluation of an Algorithm for Intensified Tuberculosis Case Finding and Isoniazid Preventive Therapy for People Living With HIV in Thailand and Vietnam.

BACKGROUND: Tuberculosis (TB) screening affords clinicians the opportunity to diagnose or exclude TB disease and initiate isoniazid preventive therapy (IPT) for people living with HIV (PLHIV). METHODS: We implemented an algorithm to diagnose or rule out TB among PLHIV in 11 HIV clinics in Thailand and Vietnam. We assessed algorithm yield and uptake of IPT and factors associated with TB disease among PLHIV. RESULTS: A total of 1448 PLHIV not yet on antiretroviral therapy (ART) were enrolled and screened for TB. Overall, 634 (44%) screened positive and 119 (8%) were diagnosed with TB; of these, 40% (48/119) were diagnosed by a positive culture following a negative sputum smear microscopy. In total, 55% of those eligible (263/477) started on IPT and of those, 75% (196/263) completed therapy. The prevalence of TB disease we observed in this study was 8.2% (8218 per 100,000 persons): 46 and 25 times the prevalence of TB in the general population in Thailand and Vietnam, respectively. Several factors were independently associated with TB disease including being underweight [aOR (95% CI): 2.3 (1.2 to 2.6)] and using injection drugs [aOR (95% CI): 2.9 (1.3 to 6.3)]. CONCLUSIONS: The high yield of TB disease diagnosed among PLHIV screened with the algorithm, and higher burden among PLHIV who inject drugs, underscores the need for innovative, tailored approaches to TB screening and prevention. As countries adopt test-and-start for antiretroviral therapy, TB screening, sensitive TB diagnostics, and IPT should be included in differentiated-care models for HIV to improve diagnosis and prevention of TB among PLHIV.

Implementing an isoniazid preventive therapy program for people living with HIV in Thailand.

Treatment of people living with HIV (PLHIV) with latent tuberculosis (TB) infection using isoniazid preventive therapy (IPT) can reduce the risk of TB disease, however, the scale-up of IPT among PLHIV in Thailand and worldwide has been slow. To hasten the implementation of IPT in Thailand, we developed IPT implementation training curricula and tools for health care providers and implemented IPT services in seven large government hospitals. Of the 659 PLHIV enrolled, 272 (41.3%) reported symptoms of TB and 39 (14.3% of those with TB symptoms) were diagnosed with TB. A total of 346 (52.4%) participants were eligible for IPT; 318 (91.9%) of these participants opted to have a tuberculin skin test (TST) and 52 (16.3% of those who had a TST) had a positive TST result. Among the 52 participants with a positive TST, 46 (88.5%) initiated and 39 (75.0%) completed 9 months of IPT: physicians instructed three participants to stop IPT, two participants were lost to follow-up, one chose to stop therapy, and one developed TB. IPT can be implemented among PLHIV in Thailand and could reduce the burden of TB in the country.

Use of drug-susceptibility testing for management of drug-resistant tuberculosis, Thailand, 2004-2008.

In 2004, routine use of culture and drug-susceptibility testing (DST) was implemented for persons in 5 Thailand provinces with a diagnosis of tuberculosis (TB). To determine if DST results were being used to guide treatment, we conducted a retrospective chart review for patients with rifampin-resistant or multidrug-resistant (MDR) TB during 2004-2008. A total of 208 patients were identified. Median time from clinical sample collection to physician review of DST results was 114 days. Only 5.8% of patients with MDR TB were empirically prescribed an appropriate regimen; an additional 31.3% received an appropriate regimen after DST results were reviewed. Most patients with rifampin -resistant or MDR TB had successful treatment outcomes. Patients with HIV co-infection and patients who were unmarried or had received category II treatment before DST results were reviewed had less successful outcomes. Overall, review of available DST results was delayed, and results were rarely used to improve treatment.

Nontuberculous mycobacterial disease in patients with HIV in Southeast Asia.

RATIONALE: Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare. OBJECTIVES: To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia. METHODS: We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories. MEASUREMENTS AND MAIN RESULTS: In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART. CONCLUSIONS: Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Bloodstream infections among HIV-infected outpatients, Southeast Asia.

Bloodstream infections (BSIs) are a major cause of illness in HIV-infected persons. To evaluate prevalence of and risk factors for BSIs in 2,009 HIV-infected outpatients in Cambodia, Thailand, and Vietnam, we performed a single Myco/F Lytic blood culture. Fifty-eight (2.9%) had a clinically significant BSI (i.e., a blood culture positive for an organism known to be a pathogen). Mycobacterium tuberculosis accounted for 31 (54%) of all BSIs, followed by fungi (13 [22%]) and bacteria (9 [16%]). Of patients for whom data were recorded about antiretroviral therapy, 0 of 119 who had received antiretroviral therapy for ≥14 days had a BSI, compared with 3% of 1,801 patients who had not. In multivariate analysis, factors consistently associated with BSI were fever, low CD4+ T-lymphocyte count, abnormalities on chest radiograph, and signs or symptoms of abdominal illness. For HIV-infected outpatients with these risk factors, clinicians should place their highest priority on diagnosing tuberculosis.

An algorithm for tuberculosis screening and diagnosis in people with HIV.

BACKGROUND: Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS: We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS: Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS: In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Multidrug-resistant TB and HIV in Thailand: overlapping, but not independently associated, risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

Yield of acid-fast smear and mycobacterial culture for tuberculosis diagnosis in people with human immunodeficiency virus.

RATIONALE: The World Health Organization recently revised its recommendations for tuberculosis (TB) diagnosis in people with HIV. Most studies cited to support these policies involved HIV-uninfected patients and only evaluated sputum specimens. OBJECTIVES: To evaluate the performance of acid-fast bacilli smear and mycobacterial culture on sputum and nonsputum specimens for TB diagnosis in a cross-sectional survey of HIV-infected patients. METHODS: In Thailand and Vietnam, we enrolled people with HIV regardless of signs or symptoms. Enrolled patients provided three sputum, one urine, one stool, one blood, and, for patients with palpable peripheral adenopathy, one lymph node aspirate specimen for acid-fast bacilli microscopy and mycobacterial culture on solid and broth-based media. We classified any patient with at least one specimen culture positive for Mycobacterium tuberculosis as having TB. MEASUREMENTS AND MAIN RESULTS: Of 1,060 patients enrolled, 147 (14%) had TB. Of 126 with pulmonary TB, the incremental yield of performing a third sputum smear over two smears was 2% (95% confidence interval, 0-6), 90 (71%) patients were detected on broth-based culture of the first sputum specimen, and an additional 21 (17%) and 12 (10%) patients were diagnosed with the second and third specimens cultured. Of 82 lymph nodes cultured, 34 (42%) grew M. tuberculosis. In patients with two negative sputum smears, broth-based culture of three sputum specimens had the highest yield of any testing strategy. CONCLUSIONS: In people with HIV living in settings where mycobacterial culture is not routinely available to all patients, a third sputum smear adds little to the diagnosis of TB. Broth-based culture of three sputum specimens diagnoses most TB cases, and lymph node aspiration provides the highest incremental yield of any nonpulmonary specimen test for TB.

HIV care and treatment factors associated with improved survival during TB treatment in Thailand: an observational study.

BACKGROUND: In Southeast Asia, HIV-infected patients frequently die during TB treatment. Many physicians are reluctant to treat HIV-infected TB patients with anti-retroviral therapy (ART) and have questions about the added value of opportunistic infection prophylaxis to ART, the optimum ART regimen, and the benefit of initiating ART early during TB treatment. METHODS: We conducted a multi-center observational study of HIV-infected patients newly diagnosed with TB in Thailand. Clinical data was collected from the beginning to the end of TB treatment. We conducted multivariable proportional hazards analysis to identify factors associated with death. RESULTS: Of 667 HIV-infected TB patients enrolled, 450 (68%) were smear and/or culture positive. Death during TB treatment occurred in 112 (17%). In proportional hazards analysis, factors strongly associated with reduced risk of death were ART use (Hazard Ratio [HR] 0.16; 95% confidence interval [CI] 0.07-0.36), fluconazole use (HR 0.34; CI 0.18-0.64), and co-trimoxazole use (HR 0.41; CI 0.20-0.83). Among 126 patients that initiated ART after TB diagnosis, the risk of death increased the longer that ART was delayed during TB treatment. Efavirenz- and nevirapine-containing ART regimens were associated with similar rates of adverse events and death. CONCLUSION: Among HIV-infected patients living in Thailand, the single most important determinant of survival during TB treatment was use of ART. Controlled clinical trials are needed to confirm our findings that early ART initiation improves survival and that the choice of non-nucleoside reverse transcriptase inhibitor does not.

Diagnostic performance and costs of Capilia TB for Mycobacterium tuberculosis complex identification from broth-based culture in Bangkok, Thailand.

OBJECTIVES: Broth-based culture (BBC) systems are increasingly being used to detect Mycobacterium tuberculosis complex (MTBC) in resource-limited. We evaluated the performance, time to detection and cost of the Capilia TB identification test from broth cultures positive for acid-fast bacilli (AFB) in Thailand. METHODS: From October-December 2007, broth cultures that grew AFB from specimens submitted by district TB clinics to the Bangkok city laboratory were tested for MTBC using Capilia TB and standard biochemical tests. Isolates that were identified as MTBC by biochemical tests but not by Capilia TB underwent repeat testing using Capilia TB, Accuprobe (Gen-Probe, San Diego, CA, USA) and sequencing. Costs of time, labour, infrastructure and consumables for all procedures were measured. RESULTS: Of 247 isolates evaluated, the sensitivity of Capilia TB was 97% and its true specificity 100% compared with biochemical testing. The median time from specimen receipt to confirmed MTBC identification was 20 days (range 7-53 days) for Capilia TB and 45 days (range 35-79 days) for biochemical testing (P < 0.01). Six isolates that were Capilia TB negative but positive by biochemical testing were confirmed as MTBC and mutations in the mpb64 gene were detected in all. The unit cost of using Capilia TB was 2.67 USD that of biochemical testing was 8.78 USD. CONCLUSIONS: In Thailand, Capilia TB had acceptable sensitivity and specificity, was lower in cost and had shorter turn-around times. Laboratories investing in BBC should consider Capilia TB for identification of MTBC, after validation of performance in their setting.

HIV-associated extrapulmonary tuberculosis in Thailand: epidemiology and risk factors for death.

BACKGROUND: We conducted a prospective, multicenter observational cohort study in Thailand to characterize the epidemiology of extrapulmonary tuberculosis (TB) in HIV-infected persons and to identify risk factors for death. METHODS: From May 2005 to September 2006, we enrolled, interviewed, examined, and performed laboratory tests on HIV-infected adult TB patients and followed them from TB treatment initiation until the end of TB treatment. We conducted multivariate proportional hazards analysis to identify factors associated with death. RESULTS: Of the 769 patients, pulmonary TB only was diagnosed in 461 (60%), both pulmonary and extrapulmonary TB in 78 (10%), extrapulmonary TB at one site in 223 (29%), and extrapulmonary TB at more than one site in seven (1%) patients. Death during TB treatment occurred in 59 of 308 patients (19%) with any extrapulmonary involvement. In a proportional hazards model, patients with extrapulmonary TB had an increased risk of death if they had meningitis, and a CD4+ T-lymphocyte count <200 cells/microl. Patients who received co-trimoxazole, fluconazole, and antiretroviral therapy during TB treatment had a lower risk of death. CONCLUSIONS: Among HIV-infected patients with TB, extrapulmonary disease occurred in 40% of the patients, particularly in those with advanced immune suppression. Death during TB treatment was common, but the risk of death was reduced in patients who took co-trimoxazole, fluconazole, and antiretroviral therapy.

Multi-drug resistant TB and HIV in Thailand: overlapping, but not independently associated risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

Performance of the BACTEC MGIT 960 compared with solid media for detection of Mycobacterium in Bangkok, Thailand.

Controlled trials have demonstrated that liquid media culture (LMC) is superior to solid media culture for diagnosis of Mycobacterium tuberculosis (MTB), but there is limited evidence about its performance in resource-limited settings. We evaluated the performance of LMC in a demonstration project in Bangkok, Thailand. Sputum specimens from persons with suspected or clinically diagnosed tuberculosis were inoculated in parallel on solid (Lowenstein-Jensen [LJ]) and liquid (mycobacterial growth indicator tube [MGIT 960]) media. Biochemical tests identified isolates as MTB or nontuberculosis mycobacteria (NTM). Of 2566 specimens received from October 2004 to September 2006, 1355 (53%) were culture positive by MGIT compared with 1013 (39%) by LJ. Median time to growth for MGIT was significantly less than LJ: 11 versus 27 days. Of 1417 isolates detected by at least 1 media, 1255 (86%) were identified as MTB and 162 (11%) NTM. MGIT improved speed and sensitivity of MTB isolation and drug susceptibility testing, regardless of HIV status.

Evaluating the potential impact of the new Global Plan to Stop TB: Thailand, 2004-2005.

OBJECTIVE: WHO's new Global Plan to Stop TB 2006-2015 advises countries with a high burden of tuberculosis (TB) to expand case-finding in the private sector as well as services for patients with HIV and multidrug-resistant TB (MDR-TB). The objective of this study was to evaluate these strategies in Thailand using data from the Thailand TB Active Surveillance Network, a demonstration project begun in 2004. METHODS: In October 2004, we began contacting public and private health-care facilities monthly to record data about people diagnosed with TB, assist with patient care, provide HIV counselling and testing, and obtain sputum samples for culture and susceptibility testing. The catchment area included 3.6 million people in four provinces. We compared results from October 2004-September 2005 (referred to as 2005) to baseline data from October 2002-September 2003 (referred to as 2003). FINDINGS: In 2005, we ascertained 5841 TB cases (164/100 000), including 2320 new smear-positive cases (65/100 000). Compared with routine passive surveillance in 2003, active surveillance increased reporting of all TB cases by 19% and of new smear-positive cases by 13%. Private facilities diagnosed 634 (11%) of all TB cases. In 2005, 1392 (24%) cases were known to be HIV positive. The proportion of cases with an unknown HIV status decreased from 66% (3226/4904) in 2003 to 23% (1329/5841) in 2005 (P< 0.01). Of 4656 pulmonary cases, mycobacterial culture was performed in 3024 (65%) and MDR-TB diagnosed in 60 (1%). CONCLUSION: In Thailand, piloting the new WHO strategy increased case-finding and collaboration with the private sector, and improved HIV services for TB patients and the diagnosis of MDR-TB. Further analysis of treatment outcomes and costs is needed to assess this programme's impact and cost effectiveness.

Antiretroviral therapy during tuberculosis treatment and marked reduction in death rate of HIV-infected patients, Thailand.

Antiretroviral therapy (ART) is lifesaving in patients with advanced HIV infection, but the magnitude of benefit in HIV-infected patients receiving tuberculosis (TB) treatment remains uncertain, and population-based data from developing countries are limited. We prospectively collected data about HIV-infected TB patients from February 2003 through January 2004 in Ubon-ratchathani, Thailand. During 12 months, HIV was diagnosed in 329 (14%) of 2,342 patients registered for TB treatment. Of patients with known outcomes, death during TB treatment occurred in 5 (7%) of 71 who received ART and 94 (43%) of 219 who did not. Using multivariate analysis, we found a large reduction in the odds of death for patients receiving ART before or during TB treatment (odds ratio, 0.2; 95% confidence interval, 0.1-0.5), adjusting for CD4 count, smear status, co-trimoxazole use, and treatment facility. ART is associated with a substantial reduction in deaths during TB treatment for HIV-infected TB patients in Thailand.

Clade replacements in dengue virus serotypes 1 and 3 are associated with changing serotype prevalence.

The evolution of dengue virus (DENV) is characterized by phylogenetic trees that have a strong temporal structure punctuated by dramatic changes in clade frequency. To determine the cause of these large-scale phylogenetic patterns, we examined the evolutionary history of DENV serotype 1 (DENV-1) and DENV-3 in Thailand, where gene sequence and epidemiological data are relatively abundant over a 30-year period. We found evidence for the turnover of viral clades in both serotypes, most notably in DENV-1, where a major clade replacement event took place in genotype I during the mid-1990s. Further, when this clade replacement event was placed in the context of changes in serotype prevalence in Thailand, a striking pattern emerged; an increase in DENV-1 clade diversity was associated with an increase in the abundance of this serotype and a concomitant decrease in DENV-4 prevalence, while clade replacement was associated with a decline in DENV-1 prevalence and a rise of DENV-4. We postulate that intraserotypic genetic diversification proceeds at times of relative serotype abundance and that replacement events can result from differential susceptibility to cross-reactive immune responses.