The prospective evaluation of the TB strain typing service in England: a mixed methods study.

BACKGROUND: In response to rising TB notification rates in England, universal strain typing was introduced in 2010. We evaluated the acceptability, effectiveness and cost-effectiveness of the TB strain typing service (TB-STS). METHODS: We conducted a mixed-methods evaluation using routine laboratory, clinic and public health data. We estimated the effect of the TB-STS on detection of false positive Mycobacterium tuberculosis diagnoses (2010-2012); contact tracing yield (number of infections or active disease per pulmonary TB case); and diagnostic delay. We developed a deterministic age-structured compartmental model to explore the effectiveness of the TB-STS, which informed a cost-effectiveness analysis. RESULTS: Semi-structured interviews explored user experience. Strain typing identified 17 additional false positive diagnoses. The TB-STS had no significant effect on contact tracing yield or diagnostic delay. Mathematical modelling suggested increasing the proportion of infections detected would have little value in reducing TB incidence in the white UK-born population. However, in the non-white UK-born and non-UK-born populations, over 20 years, if detection of latent infection increases from 3% to 13% per year, then TB incidence would decrease by 11%; reducing diagnostic delay by one week could lead to 25% reduction in incidence. The current TB-STS was not predicted to be cost-effective over 20 years (£95 628/quality-adjusted life-years). Interviews found people had mixed experiences, but identified broader benefits, of the TB-STS. CONCLUSIONS: To reduce costs, improve efficiency and increase effectiveness, we recommend changes to the TB-STS, including discontinuing routine cluster investigations and focusing on reducing diagnostic delay across the TB programme. This evaluation of a complex intervention informs the future of strain typing in the era of rapidly advancing technologies.

Health-seeking behaviour among adults with prolonged cough in Vietnam.

OBJECTIVE: To assess health-seeking behaviour among adults with prolonged cough in a population-based, nationally representative sample in Vietnam. METHODS: Cross-sectional survey conducted from September 2006 to July 2007. All inhabitants aged ≥15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X-ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health-seeking behaviour in an in-depth interview. RESULTS: Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty-four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X-ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9-4.4) among cough suspects and 4.0 weeks (95% CI: 3.1-4.9) among TB cases. CONCLUSIONS: In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects.

Progress towards tuberculosis elimination: secular trend, immigration and transmission.

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993-2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Interferon-gamma release assays in immigrant contacts and effect of remote exposure to Mycobacterium tuberculosis.

OBJECTIVE: To assess the association between remote exposure to tuberculosis (TB) and results of the tuberculin skin test (TST), and two interferon-gamma release assays (IGRAs)-QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB-in immigrant contacts of sputum smear-positive TB patients. METHODS: Immigrants aged >or=16 years in close contact with smear-positive TB patients were included. QFT-GIT and T-SPOT.TB were performed if the TST induration size was >or=5 mm. Associations between test results and origin from an endemic country were assessed. RESULTS: Of 433 close contacts, 322 (74%) had TST >or=5 mm, of whom, 282 (88%) had valid test results for all assays. Positive QFT-GIT results were obtained for 152/282 (54%) and positive T-SPOT.TB for 168/282 (60%). After adjustment for age, sex and recent contact, positive IGRA results and TST results >/=10 mm were found to be more frequent among immigrants who originated from Africa, in particular sub-Saharan Africa. CONCLUSION: When IGRAs are used to determine latent TB infection in foreign-born individuals, positive findings not only relate to recent TB infection, but also reflect prior TB exposure in the country of origin. This late reactivity will limit their usefulness in contact investigations among immigrants originating from endemic areas.

The Beijing genotype is associated with young age and multidrug-resistant tuberculosis in rural Vietnam.

BACKGROUND: Associations between multidrug resistance and the Mycobacterium tuberculosis Beijing genotype have been described mainly in populations with poor tuberculosis (TB) control such as prisons and inner cities, and may reflect shared risk factors rather than a biological association. OBJECTIVE: To study the association between genotype and drug resistance among TB patients in a population with adequate TB control. SETTING: Three rural districts in Vietnam. The study was performed at the Pham Ngoc Thach Tuberculosis and Lung Disease Hospital, Ho Chi Minh City, and the Tien Giang Provincial Tuberculosis and Lung Disease Hospital, My Tho, Vietnam. METHODS: Pretreatment sputum specimens were collected for culture, drug susceptibility testing and spoligotyping of all sputum smear-positive pulmonary TB patients consecutively diagnosed over a 3-year period. RESULTS: Beijing genotype infections were observed in 614 of 1744 (35%) patients. Beijing strains were more common among female (adjusted odds ratio [aOR] 1.4, P = 0.005), young (aOR 2.8, P < 0.001) and previously treated patients (aOR 2.4, P < 0.001). The Beijing genotype was associated with any resistance (aOR 3.7, P < 0.001) and multidrug resistance (aOR 6.8, P < 0.001) among new patients, and with any resistance (aOR 2.7, P = 0.005) but not with multidrug resistance (aOR 1.4, P = 0.545) among previously treated patients. CONCLUSION: In Vietnam, Beijing genotype is associated with young age and in new patients with multidrug resistance despite adequate TB control, suggesting a biological association. This potentially undermines the effectiveness of TB control in countries where Beijing genotype infections are common.

Annual meeting of the Tuberculosis Surveillance and Research Unit, 2008.

The Tuberculosis Surveillance and Research Unit (TSRU) held its last annual meeting in Helsinki, Finland, from 1 to 4 April 2008. Several topics of current interest for tuberculosis (TB) research and new research projects were presented and discussed in depth by 60 delegates from Europe, Africa and Asia. This paper summarises some of the highlights of the meeting which may be of interest to epidemiologists and managers active in the field of TB.

Lessons learned from community-based tuberculosis case-finding in western Kenya.

SETTING: Although Kenya has a high burden of tuberculosis (TB), only 46% of cases were diagnosed in 2016. OBJECTIVE: To identify strategies for increasing attendance at community-based mobile screening units. DESIGN: We analysed operational data from a cluster-randomised trial, which included community-based mobile screening implemented during February 2015-April 2016. Community health volunteers (CHVs) recruited individuals with symptoms from the community, who were offered testing for human immunodeficiency virus (HIV) and sputum collection for Xpert® MTB/RIF testing. We compared attendance across different mobile unit sites using Wilcoxon rank-sum test. RESULTS: A total of 1424 adults with symptoms were screened at 25 mobile unit sites. The median total attendance among sites was 54 (range 6-134, interquartile range [IQR] 24-84). The median yields of TB diagnoses and new HIV diagnoses were respectively 2.4% (range 0.0-16.7, IQR 0.0-5.3) and 2.5% (range 0.0-33.3, IQR 1.2-4.2). Attendance at urban sites was variable; attendance at rural sites where CHVs were paid a daily minimum wage was significantly higher than at rural sites where CHVs were paid a nominal monthly stipend (P < 0.001). CONCLUSION: Mobile units were most effective and efficient when implemented as a single event with community health workers who are paid a daily wage.

Optimizing the efficiency of tuberculosis active case-finding in health facilities and communities.

SETTING: Efficient tuberculosis (TB) active case-finding strategies are important in settings with high TB burdens and limited resources, such as those in western Kenya.OBJECTIVE: To guide efforts to optimize screening efficiency, we identified the predictors of TB among people screened in health facilities and communities.DESIGN: During February 2015-June 2016, adults aged ≥15 years reporting any TB symptom were identified in health facilities and community mobile screening units, and evaluated for TB. We assessed the predictors of TB using a modified Poisson regression with generalized estimating equations to account for clustering according to screening site.RESULTS: TB was diagnosed in 484 (20.3%) of 2394 symptomatic adults in health facilities and 39 (3.4%) of 1424 in communities. In health facilities, >10% of symptomatic adults in all demographic groups had TB, and no predictors were associated with a ≥2-fold increased risk. In communities, the independent predictors of TB were male sex (adjusted prevalence ratio [aPR] = 4.26, 95%CI 2.43-7.45), HIV infection (aPR 2.37, 95%CI 1.18-4.77), and household TB contact in the last 2 years (aPR 2.84, 95%CI 1.62-4.96).CONCLUSION: Our findings support the notion of general TB screening in health facilities and evaluation of the adult household contacts of TB patients.

Coverage and yield of entry and follow-up screening for tuberculosis among new immigrants.

The aim of the present study was to determine the effectiveness of entry screening for tuberculosis and biannual follow-up screening among new immigrants in The Netherlands. To achieve this, the present authors analysed screening, prevalence and incidence data of 68,122 immigrants, who were followed for 29 months. Patients diagnosed within 5 months and 6-29 months after entry screening were considered to be detected at entry and during the follow-up period, respectively. Coverage of the second to fifth screening rounds was 59, 46, 36 and 34%, respectively. Yield of entry screening was 119 per 100,000 individuals, and prevalence at entry was 131 per 100,000. Average yield of follow-up screening was highest among immigrants with abnormalities on chest radiography (CXR) at entry (902 per 100,000 individuals). When excluding these, yield of follow-up screening was 9, 37 and 97 per 100,000 screenings for immigrants from countries with tuberculosis incidences of <100, 100-200 and >200 per 100,000, respectively. The incidence during follow-up in individuals with a normal CXR was 11, 58 and 145 per 100,000 person-yrs follow-up in these groups. The proportion of cases detected through screening declined per screening round from 91 to 31%. Yield of entry screening was high. Overall coverage and yield of follow-up screening was low. Follow-up screening of immigrants with a normal chest radiograph from countries with an incidence of <200 per 100,000 individuals was therefore discontinued.

The design effect and cluster samples: optimising tuberculosis prevalence surveys.

Cross-sectional surveys of disease prevalence, including for tuberculosis (TB), often use a two (or more) stage sampling procedure. By choosing clusters of people randomly from all possible clusters, the logistic costs of doing the survey can be reduced. However, this increases the statistical uncertainty in the estimate of prevalence, and we need to balance the reduction in cost against the increase in uncertainty. Here we describe cluster sampling and consider ways to determine the optimal survey design as well as the extent to which deviations from the optimal design matter. We illustrate the results using data from a recent survey in Cambodia in which TB was diagnosed using sputum smears, cultures and X-rays.

How to identify tuberculosis cases in a prevalence survey.

The identification of pulmonary tuberculosis (TB) cases in a prevalence survey is a challenge, as diagnostic methods are labour-intensive and large numbers of individuals need to be screened because the prevalence rate is low (almost never greater than 1,200 per 100,000 population). Three testing methods are used: questionnaires, chest radiography (CXR) and bacteriological tests, including sputum smear microscopy and culture. These methods can be applied in four strategies to identify cases. The most sensitive strategy is to apply all methods to each eligible individual. The next most sensitive option is to apply the questionnaire, CXR and sputum smear microscopy to each eligible individual and obtain sputum for culture from those individuals with symptoms, abnormalities on the CXR or a positive smear. If laboratory capacity is limited, screening using symptom enquiry and CXR can be used to select those individuals at highest risk of TB. These individuals are then requested to submit sputum for smear microscopy and culture. If neither CXR nor culture is available, sputum samples may be collected from all eligible individuals and examined by an enhanced microscopy method such as fluorescence microscopy. Case definitions are ideally based on the combined results of symptom enquiry, CXR and bacteriology.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

[Estimation of the incidence of tuberculosis in The Netherlands in 2030]. / Projectie van het aantal tuberculosepatiënten in Nederland in 2030.

OBJECTIVE: To estimate the number of cases of tuberculosis (TB) in 2030 for the purpose of planning future TB control. DESIGN: Statistical modelling in 5-year intervals until 2030. METHOD: The number of Dutch TB cases infected by a Dutch source was estimated using a survival model. The number ofnon-Dutch patients was estimated by calculating the proportion of culture-positive TB patients among first-generation immigrants in 2005 and applying this proportion to the projected size of the non-Dutch population. It was assumed that each non-Dutch TB patient infected by a non-Dutch source would cause one infection in the population in The Netherlands. RESULTS: The estimated number of TB cases is expected to decrease to 877 in 2010. Only a limited decrease in the number of TB patients is expected after 2010 as the number of non-Dutch TB cases increases due to increased immigration. This increase negates the expected decrease in Dutch TB patients infected by a Dutch source. In 2030, non-Dutch TB cases will account for 85% of all TB cases. The proportion of non-Dutch TB cases is greater in the 4 largest cities, i.e. Amsterdam, Rotterdam, The Hague and Utrecht (89%) than in the rest of The Netherlands (76%). CONCLUSION: The decrease in TB incidence observed over the past several years may cease by 2010 due to an increase in non-Dutch TB patients as a result of increased immigration. However, the confidence intervals associated with these estimates were large. Future TB control efforts must be organised in a flexible way so that they can be adapted to changing epidemiological situations.

[Increase in extrapulmonary tuberculosis in The Netherlands associated with an increase in the number of residents with non-Dutch nationality; observational study of data from 1993-2001]. / Toename van extrapulmonale tuberculose in Nederland door toename van het aantal inwoners met een niet-Nederlandse nationaliteit; observationeel onderzoek over 1993-2001.

OBJECTIVE: To describe the epidemiology of extrapulmonary and pulmonary tuberculosis (TB) in The Netherlands between 1993 and 2001, with special attention given to the relationship between disease site and patient nationality. DESIGN: Retrospective descriptive and comparative study. METHOD: Data were collected from all patients diagnosed with TB and entered in The Netherlands Tuberculosis Register between 1 January 1993 and 31 December 2001. Information on age, sex, nationality, year of diagnosis, culture result, disease site and HIV status was retrieved and compared. RESULTS: Of the total 13,258 TB patients, 8,216 (62%) had pulmonary TB and 5,042 (38%) had extrapulmonary TB. The proportion of extrapulmonary TB cases increased during the study period. The most common types of extrapulmonary TB were lymphatic TB, pleural TB and TB of the bones and/or joints. Patients with a non-Dutch nationality were diagnosed with extrapulmonary TB more often than Dutch patients. CONCLUSION: The proportional increase in extrapulmonary TB was explained by an increase in the number of inhabitants with non-Western ethnic backgrounds in The Netherlands. Physicians must be aware of the changing clinical picture of TB.

Steep increases in tuberculosis notification among young men in the industrialised districts of Danang, Vietnam.

BACKGROUND: Tuberculosis (TB) notification is increasing among young adults in urban provinces in Vietnam, despite having achieved World Health Organization targets for treatment success and case detection. OBJECTIVES: To identify causes for non-declining TB case rates in an urban area of Vietnam, and to describe trends in new smear-positive pulmonary TB notification by age, sex and district in the period 1999-2004 in Danang City, Vietnam. RESULTS: Age and sex-standardised notification rates declined by 1.3% (95%CI -2.3-0.3%) annually. Notification rates among men aged 15-44 in Danang City increased significantly (5%, 95%CI 2.4-7.7 annually), most notably in industrialised districts (>or=12% annually). CONCLUSION: TB notification rates among young men in an urban setting in Vietnam increased most notably in industrialised districts. We hypothesise that this is due to poor living and working conditions and internal migration rather than to an emerging human immunodeficiency virus epidemic.

Survival and relapse rate of tuberculosis patients who successfully completed treatment in Vietnam.

SETTING: Reported tuberculosis (TB) cure rates are high in Vietnam with the 8-month short-course chemotherapy regimen. However, long-term treatment outcomes are unknown. OBJECTIVE: To assess survival and relapse rates among patients successfully treated for new smear-positive pulmonary tuberculosis (PTB). METHODS: A cohort of patients treated in 32 randomly selected districts in northern Vietnam were followed up 12-24 months after reported cure or treatment success for survival and bacteriologically confirmed relapse. Measurements included sputum smear examination, culture and interview for recent treatment history. RESULTS: Of 304 patients included in the study, no information was available for 31 (10%) and 19 (6%) had died. Bacteriology results were available for 244 (80%). The median interval between treatment completion and follow-up was 19 months. Relapse was recorded in 21/244 (8.6%, 95%CI 5.4-13), including 9 (4%) with positive sputum smears, 3 (1%) with negative smears but positive culture and 9 (4%) who had started TB retreatment. Four of 12 culture-positive relapse cases (33%) had multidrug-resistant strains. If the definition of relapse was extended to include death, reportedly due to TB, the relapse proportion was 26/263 (9.9%, 95%CI 6.6-14). CONCLUSION: A substantial proportion of patients (15%) had died or relapsed after being successfully treated for TB in northern Vietnam.

Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey.

BACKGROUND: Studies show that tuberculosis notification declines with increasing altitude. This can be due to declining incidence or declining case detection. In Vietnam notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in Vietnam in general (69/100,000 population). In order to clarify whether this is explained by low incidence or low case detection, we aimed to assess the prevalence of new smear-positive tuberculosis among adults with prolonged cough in three mountainous provinces in central Vietnam. METHODS: A house-to-house survey of persons (> or = 15 years) was carried out in twelve randomly selected districts in 2003. Three sputum specimens were microscopically examined of persons reporting a prolonged cough (> or = 3 weeks). Case detection was assessed by the ratio between notification and prevalence. RESULTS: Of 68,946 included persons (95% response), 1,298 (1.9% 95%CI 1.8-2.2) reported a prolonged cough. Of these, eighteen were sputum smear-positive of whom two had had anti-tuberculosis treatment. The prevalence of new smear-positive tuberculosis was 27/100,000 (95%CI 11-44/100,000) and the notification rate was 44/100,000 among persons > or = 15 years. The estimated case detection rate was 76%. CONCLUSION: Low tuberculosis notification in this mountainous setting is probably a true reflection of low tuberculosis incidence. Possible causes for low incidence in mountainous areas include low transmission rates or altitude-related differences in pathology.

Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands.

A previous limited study demonstrated that Mycobacterium tuberculosis isolates with a mutation at amino-acid position 315 of katG (Delta315) exhibited high-level resistance to isoniazid and were more frequently resistant to streptomycin. In the present study, isoniazid-resistant M. tuberculosis isolates from 8,332 patients in The Netherlands (1993-2002) were screened for the Delta315 mutation. Isoniazid resistance was found in 592 (7%) isolates, of which 323 (55%) carried Delta315. IS6110 restriction fragment length polymorphism analysis showed that Delta315 isolates occurred in clusters, suggesting recent transmission, at the same frequency as isoniazid-susceptible isolates. In contrast, other isoniazid-resistant isolates clustered significantly less frequently. Delta315 isolates were high-level isoniazid-resistant, streptomycin-resistant and multidrug-resistant significantly more often, and may have a greater impact on public health, than other isoniazid-resistant isolates.

Treatment outcomes by drug resistance and HIV status among tuberculosis patients in Ho Chi Minh City, Vietnam.

OBJECTIVE: To assess the combined effects of drug resistance, HIV infection and treatment regimen on treatment outcomes of smear-positive tuberculosis patients in Ho Chi Minh City, Vietnam. METHODS: A representative sample of patients diagnosed in 1998-2000 in 12 urban districts was offered HIV testing and submitted sputum for Mycobacterium tuberculosis culture and drug susceptibility testing. New patients were treated with 2SHRZ/6HE in nine districts and with 2SHRZ/4RH in three districts. RESULTS: The cure rate was 87% (1240/1430) among new patients compared to only 73% (287/391) among previously treated patients. Failure was associated with multidrug resistance (adjusted odds ratios [aOR] 49.6 and 16.6, respectively) and combined resistance to isoniazid (INH) and streptomycin (SM) (aOR 13.4 and 4.8), but not with HIV infection. New patients had an increased risk of failure on treatment with 2SHRZ/4RH compared to 2SHRZ/6HE if the isolate was resistant to INH and SM (aOR 2.8, P = 0.016). Death during treatment occurred in 15 of 50 HIV-infected patients (30%). Mortality was significantly associated with HIV infection (aOR 29.9), multidrug resistance (aOR 4.7) and other resistance to two or more drugs (aOR 2.1). CONCLUSION: In Vietnam, adaptation of treatment regimens should be considered, and interventions are needed to reduce the high mortality among HIV-infected patients.