Modelling the potential impact of adherence technologies on tuberculosis in India.

BACKGROUND: For patients taking standard first-line tuberculosis treatment, missing 10% or more of their doses increases the risk of relapse six-fold. Digital technologies offer new approaches to adherence support for TB patients. We estimated the potential impact of new adherence technologies in India.METHOD: We developed a mathematical model of TB transmission dynamics in India, capturing the independent effects of missed doses and treatment default on post-treatment recurrence. We simulated the impact of interventions to address both missed doses and treatment default in the public and private healthcare sector.RESULTS: Adherence interventions, if deployed optimally in the public sector alone, would reduce cumulative TB incidence by 7.3% (95% credible intervals [CrI] 4.7-11) between 2020 and 2030, and by 16% (95% CrI 11-23) if also deployed in the private sector. This impact is roughly proportional to the effectiveness of the interventions. Reducing missed doses reduced incidence by 12% (95% CrI 7.0-18), while reducing treatment default reduced incidence by 7.9% (95% CrI 3.2-13).CONCLUSION: Minimising missed doses is at least as important as promoting treatment completion. Our results suggest that emerging technologies to improve treatment adherence could have a substantial impact on TB incidence and mortality in India.

The affordability for patients of a new universal MDR-TB coverage model in China.

BACKGROUND: China has piloted a new model of universal coverage for multidrug-resistant tuberculosis (MDR-TB), designed to rationalize hospital use of drugs and tests and move away from fee-for-service payment towards a standard package with financial protection against catastrophic health costs. OBJECTIVE: To evaluate the affordability to patients of this new model. DESIGN: This was an observational study of 243 MDR-TB cases eligible for enrolment on treatment under the project. We assessed the affordability of the project from the perspective of households, with a focus on catastrophic costs. RESULTS: Of the 243 eligible cases, 172 (71%) were enrolled on treatment; of the 71 cases not enrolled, 26 (37%) cited economic reasons. The 73 surveyed cases paid an average of RMB 5977 (US$920) out-of-pocket in search costs incurred outside the pilot model. Within the pilot, they paid another RMB 2094 (US$322) in medical fees and RMB 5230 (US$805) in direct non-medical costs. Despite 90% reimbursement of medical fees, 78% of households experienced catastrophic costs, including indirect costs. CONCLUSION: The objectives of the pilot model are aligned with health reform in China and universal health coverage globally. Enrollment would almost certainly be higher with 100% reimbursement of medical fees, but patient enablers will be required to truly eliminate catastrophic costs.

Diagnostic dilemma: treatment outcomes of tuberculosis patients with inconsistent rifampicin susceptibility.

OBJECTIVE: A retrospective clinical trial to evaluate treatment outcomes in adults with smear-positive tuberculosis (TB) and discordant rifampicin (RMP) resistance results. DESIGN: A total of 2156 smear-positive TB patients underwent both conventional and Genechip drug susceptibility testing (DST) for RMP resistance. All 49 patients with discordant results treated with either a first-line or second-line regimen were analysed. RESULTS: Of 30 Type I cases (Genechip-resistant, conventional DST-susceptible) receiving the first-line regimen, 4 had a favourable outcome and 5 failed treatment. The 21 remaining Type I cases were treated with the second-line regimen, of whom 18 had a favourable outcome. Second-line regimen thus resulted in significantly more favourable outcomes than first-line treatment (P = 0.032). Among Type II cases (Genechip-susceptible, conventional DST-resistant), 13/19 received the first-line regimen, and 7 had a favourable outcome. The six Type II cases treated with the second-line regimen all had favourable outcomes. CONCLUSION: Patients with discordant RMP DST results who receive second-line regimens may have a better clinical response than those treated with the first-line regimen. Patients infected with fluoroquinolone-resistant Mycobacterium tuberculosis strains were observed to have a significantly higher treatment failure rate.

Model collaboration between hospitals and public health system to improve tuberculosis control in China.

OBJECTIVE: Hospitals provide clinical care to many tuberculosis (TB) patients, but limited linkage with public health programmes is contributing to low TB case detection and rising TB drug resistance. We evaluated a hospital-public health collaboration to improve the follow-up of TB patients initially seen in hospitals. DESIGN: In nine counties in eastern China, we evaluated a collaboration with three interventions: hospitals carried out internet-based reporting and patient referral to the local Center for Disease Control (CDC). The CDC regularly checked on hospital reporting and referrals and performed active follow-up of reported patients, and a government coordinating group facilitated implementation of collaborative activities. RESULTS: Compared to the pre-intervention period, the percentage of TB suspects and patients needing referral from the hospitals who arrived in the CDC increased from 59.3% to 83.2% (P < 0.001). This increase was a result of improved hospital reporting (42.5% to 95.3%, P < 0.001), improved referral from hospitals (48.1% to 83.3%, P < 0.001), active CDC follow-up of 82.5% of reported patients who did not attend CDC by themselves, and successful tracing of 60.8% of these patients. This contributed to a 33% increase in reported smear-positive pulmonary TB cases. CONCLUSION: This model collaboration successfully improved the follow-up of TB patients seen by hospitals, and contributed to an increase in TB case detection.

Importance of co-cultivation medium pH for successful Agrobacterium-mediated transformation of Lilium x formolongi.

An efficient system for Agrobacterium-mediated transformation of Lilium x formolongi was established by preventing the drastic drop of pH in the co-cultivation medium with MES. Meristematic nodular calli were inoculated with an overnight culture of A. tumefaciens strain EHA101 containing the plasmid pIG121-Hm which harbored intron-containing beta-glucuronidase (GUS), hygromycin phosphotransferase (HPT), and neomycin phosphotransfease II (NPTII) genes. After three days of co-cultivation on 2 g/l gellan gum-solidified MS medium containing 100 microM acetosyringone, 30 g/l sucrose, 1 mg/l picloram and different concentrations of MES, they were cultured on the same medium containing 12.5 mg/l meropenem to eliminate Agrobacterium for 2 weeks and then transferred onto medium containing the same concentration of meropenem and 25 mg/l hygromycin for selecting putative transgenic calli. Transient GUS expression was only observed by adding MES to co-cultivation medium. Hygromycin-resistant transgenic calli were obtained only when MES was added to the co-cultivation medium especially at 10 mM. The hygromycin-resistant calli were successfully regenerated into plantlets after transferring onto picloram-free medium. Transformation of plants was confirmed by histochemical GUS assay, PCR analysis and Southern blot analysis.

Use of recommended laboratory testing methods among patients with tuberculosis in California.

This study assessed the extent to which laboratory methods recommended by the Centers for Disease Control and Prevention were used in tuberculosis testing of patients in California in 1998. While recommended methods were used for most patients, there was room for improvement by hospital and independent non-health maintenance organization laboratories.

Adverse impact of cigarette smoking on dimensions of health-related quality of life in persons with HIV infection.

Because effects of cigarette smoking on health-related quality of life (HRQL) have not been well described, we carried out a cross-sectional assessment of HRQL using the Medical Outcomes Survey Scale adapted for patients with human immunodeficiency virus (MOS-HIV questionnaire) in 585 HIV-infected homosexual/bisexual men, injection drug users, and female partners enrolled in a multicenter, prospective study of the pulmonary complications of HIV infection. Mean scores for the following dimensions of HRQL were calculated: general health perception, quality of life, physical functioning, bodily pain, social functioning, role functioning, energy, cognitive functioning, and depression. A multivariate model was used to determine the impact on HRQL of the following factors: smoking, CD4 loss, acquired immune deficiency syndrome (AIDS) diagnoses, number of symptoms, study site, education, injection drug use, gender, and age. Current smoking was independently associated with lower scores for general health perception, physical functioning, bodily pain, energy, role functioning, and cognitive functioning (all with p < 0.05). We conclude that patients with HIV infection who smoke have poorer HRQL than nonsmokers. These results support the use of smoking cessation strategies for HIV-infected persons who smoke cigarettes.

Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis.

Isoniazid taken daily for 12 mo and isoniazid and rifampin taken daily for 4 mo are both recommended options for patients with radiographic evidence of previous tuberculosis and positive tuberculin skin tests who have not had prior treatment. We compared the completion rates, number of adverse effects, and cost effectiveness of these two regimens. Patients were treated at the San Francisco Tuberculosis Clinic from 1993 through 1996. A Markov model was developed to assess impact on life expectancy and costs. One thousand twenty-two patients, with a mean age of 52 yr, and > 90% foreign born, were treated; 545 received isoniazid and 477 received isoniazid and rifampin. For isoniazid, 79.8% completed 12 mo of therapy and 4.9% had adverse effects versus 83.6% completion, 6.1% adverse effects for isoniazid and rifampin (p > 0.05 for all between-group comparisons). Both regimens increased life expectancy by 1.4-1.5 yr. Compared with isoniazid, isoniazid and rifampin produced net incremental savings of $135 per patient treated. In patients with radiographic evidence of prior tuberculosis who have not been previously treated, isoniazid for 12 mo and isoniazid and rifampin for 4 mo have similar rates of completion and adverse effects, and both increase life expectancy compared with no treatment. Isoniazid and rifampin for 4 mo is cost saving compared with isoniazid alone. This advantage was maintained even when compared with 9 mo of isoniazid, the new American Thoracic Society/Centers for Disease Control (ATS/CDC) recommendation for treatment with isoniazid alone.

Progress and problems in achieving the United States national target for completion of antituberculosis treatment.

SETTING: The target for antituberculosis treatment in the United States is for 90% of patients to complete therapy within 12 months. OBJECTIVE: To assess progress in achieving the US national target for tuberculosis treatment. DESIGN: A comparison of treatment outcome in two cohorts of patients with drug-susceptible tuberculosis in California-those reported in 1993-1994 (8488 patients) and 1995-1996 (7823 patients). Risk factors for delay in treatment completion (more than 12 months) were assessed. RESULTS: The percentage of cases completing treatment within 12 months increased in the 1995-1996 cohort (to 68.2%), primarily due to concomitant reductions in delays in treatment completion (to 11.1%) and defaulting (to 2.4%). Disparities in timely treatment completion narrowed over time and in nearly all subpopulations, especially in groups with lowest treatment completion in the 1993-1994 cohort. Remaining risk factors for delay in treatment completion included AIDS and older ages. A substantial percentage of patients died or moved before treatment completion. CONCLUSIONS: Despite recent improvements, completion of antituberculosis treatment in California has not reached the national target. Reaching this target will require further reductions in delays in treatment completion and deaths during treatment, and ensuring that patients who move eventually complete treatment.

Spread of Mycobacterium tuberculosis in a community implementing recommended elements of tuberculosis control.

CONTEXT: Despite improvements in tuberculosis (TB) control during the past decade, Mycobacterium tuberculosis transmission and resulting disease continue to occur in the United States. OBJECTIVE: To determine the primary reasons for disease development from a particular strain of M tuberculosis. DESIGN: Population-based, molecular epidemiological study. SETTING: Urban community in the San Francisco Bay area of California with recommended elements of TB control in place. PATIENTS: Seventy-three TB cases were reported in 1996-1997 that resulted from 1 strain of M tuberculosis as identified by TB genotyping and epidemiological linkage. MAIN OUTCOME MEASURES: Transmission patterns involving source and secondary case-patients; primary reasons for disease development. RESULTS: Seventy-three (33%) of 221 TB case-patients in this community resulted from this strain of M tuberculosis. Thirty-nine (53%) of the 73 case-patients developed TB because they were not identified as contacts of source case-patients; 20 case-patients (27%) developed TB because of delayed diagnosis of their sources; and 13 case-patients (18%) developed TB because of problems associated with the evaluation or treatment of contacts; and 1 case-patient (1%) developed TB because of delay in being elicited as a contact. Of the 51 TB cases identified with sources, 49 (96%) were infected within the 2 years prior to diagnosis. CONCLUSIONS: Our results indicate that in a community that has implemented the essential elements of TB control, TB from ongoing transmission of M tuberculosis will continue to develop unless patients are diagnosed earlier and contacts are more completely identified. JAMA. 2000.

Impact of bacterial pneumonia and Pneumocystis carinii pneumonia on human immunodeficiency virus disease progression. Pulmonary Complications of HIV Study Group.

The course of pneumonia caused by pyogenic bacteria and Pneumocystis carinii was examined in a multicity cohort study of HIV infection. The median duration of survival among 150 individuals following initial bacterial pneumonia was 24 months, compared with 37 months among 299 human immunodeficiency virus (HIV)-infected control subjects matched by study site and CD4 lymphocyte count (P<.001). For 152 subjects with P. carinii pneumonia, median survival was 23 months, compared with 30 months for 280 matched control subjects (P = .002). Median durations of survival associated with the two types of pneumonia differed by only 47 days, despite a higher median CD4 lymphocyte count associated with bacterial pneumonia. These results suggest that both P. carinii pneumonia and bacterial pneumonia are associated with a significantly worse subsequent HIV disease course. The similarity of prognosis after one episode of bacterial pneumonia vs. an AIDS-defining opportunistic infection and the proportion of cases occurring in association with a CD4 lymphocyte count of >200 suggest that measures to prevent bacterial pneumonia should be emphasized.

B notifications and the detection of tuberculosis among foreign-born recent arrivals in California.

OBJECTIVE: To evaluate the effectiveness and limitations of the B notification program for detecting tuberculosis among recent foreign-born arrivals in California. DESIGN: Retrospective cohort study. All foreign-born visa holders with a B notification who arrived in California from January 1992 through September 1995 (n = 27 412) were matched with a listing of foreign-born persons who arrived in the US during the same time period and who were reported to have active tuberculosis in California within one year of their arrival from January 1992 through September 1996 (n = 2547). RESULTS: Overall, 3.5% (95% confidence interval 3.3%, 3.8%) of all persons with a B notification were reported to have active tuberculosis within a year of arrival. Recent arrivals with a B notification and tuberculosis accounted for 38% of all foreign-born cases of tuberculosis reported within one year of arrival. Compared to recent arrivals without a B notification, those with a B notification were more likely to have pulmonary tuberculosis, less likely to have smear-positive pulmonary disease and reported with tuberculosis sooner after their arrival in the US. The B notification program was not able to identify 87% of the smear-positive pulmonary tuberculosis cases in adults, and did not identify 99% of these highly infectious cases among Latin Americans. CONCLUSIONS: Although the evaluation of persons who enter the US with B notifications has a high yield for identifying active tuberculosis cases, it was not able to identify the majority of recent arrivals with the most infectious form of tuberculosis.

Cost-effectiveness analysis of directly observed therapy for patients with tuberculosis at low risk for treatment default.

To determine the incremental cost of directly observed therapy (DOT) for patients with tuberculosis at low risk for treatment default, we applied a model of DOT effectiveness to 1,377 low-risk patients in California during 1995. The default rate for this cohort, which consisted of those with no recent history of substance abuse, homelessness, or incarceration, was 1.7%. The model predicted that DOT and self-administered therapy (SAT) cured 93.1 and 90.8% of these patients, respectively. DOT would initially cost $1.83 million more than SAT, but avert $569,191 in treatment cost for relapse cases and their contacts, for a net incremental cost of $1.27 million ($919 per patient treated), or $40,620 per additional case cured. The cost-effectiveness of DOT was sensitive to the default rate and relapse rate after completing SAT. DOT would generate cost savings only when the default and relapse rates were more than 32.2 and 9.2%, respectively. Given the low default rate and resulting high incremental cost of DOT, provision of DOT to low-risk patients in California should be evaluated in the context of resource availability, competing program priorities, and program success in completing self-administered therapy with a low relapse rate.

Tuberculosis prevention in methadone maintenance clinics. Effectiveness and cost-effectiveness.

To determine the effectiveness and cost-effectiveness of a program to provide screening for tuberculosis infection and directly observed preventive therapy (DOPT) in methadone maintenance clinics, we determined completion rates of screening for tuberculosis infection, medical evaluation, and preventive therapy, as well as the number of active tuberculosis cases and tuberculosis-related deaths prevented, in five clinics in San Francisco, California. Between 1990 and 1995, a total of 2,689 clients (of whom 18% were HIV-seropositive) were screened at least once. Of eligible clients, 99% received tuberculin skin tests, 96% received a medical examination, 91% began isoniazid preventive therapy, and 82% completed preventive therapy. Program effectiveness was enhanced by close collaboration between public health and methadone maintenance programs and the use of incentives and enablers. Over a 3-yr follow-up period, only one verified case of tuberculosis was reported among clients with a positive tuberculin skin test, thereby preventing as much as 95% of expected tuberculosis cases. Over 10 yr, we estimate the program would prevent 30.0 (52%) of 57.7 expected cases of tuberculosis, and 7.6 (57%) of 13.4 expected tuberculosis-related deaths. The program cost $771,569, but averted an estimated $876,229, for a net savings of $104,660 (average of $3, 724 per case prevented). Our study demonstrates that when effectively implemented, screening for tuberculosis infection and DOPT in methadone maintenance clinics is a highly cost-effective approach to prevent tuberculosis.

Differences in contributing factors to tuberculosis incidence in U.S. -born and foreign-born persons.

To determine the factors contributing to tuberculosis incidence in the U.S.-born and foreign-born populations in San Francisco, California, and to assess the effectiveness of tuberculosis control efforts in these populations, we performed a population-based molecular epidemiologic study using 367 patients with strains of Mycobacterium tuberculosis recently introduced into the city. IS6110-based and PGRS-based restriction fragment length polymorphism (RFLP) analyses were performed on M. tuberculosis isolates. Patients whose isolates had identical RFLP patterns were considered a cluster. Review of public health and medical records, plus patient interviews, were used to determine the likelihood of transmission between clustered patients. None of the 252 foreign-born cases was recently infected (within 2 yr) in the city. Nineteen (17%) of 115 U. S.-born cases occurred after recent infection in the city; only two were infected by a foreign-born patient. Disease from recent infection in the city involved either a source or a secondary case with human immunodeficiency virus (HIV) infection, homelessness, or drug abuse. Failure to identify contacts accounted for the majority of secondary cases. In San Francisco, disease from recent transmission of M. tuberculosis has been virtually eliminated from the foreign-born but not from the U.S.-born population. An intensification of contact tracing and screening activities among HIV-infected, homeless, and drug-abusing persons is needed to further control tuberculosis in the U.S.-born population. Elimination of tuberculosis in both the foreign-born and the U.S. -born populations will require widespread use of preventive therapy.

Two-year follow-up of directly-observed intermittent regimens for smear-positive pulmonary tuberculosis in China.

SETTING: The tuberculosis component of the Infectious and Endemic Disease Control Project in the People's Republic of China is the largest single tuberculosis control project in the world using directly-observed therapy and standardized intermittent regimens. OBJECTIVE: To determine the two-year relapse and mortality rates following completion of treatment. DESIGN: A prospective cohort study of 649 cases cured in this project. The 306 new and 343 retreatment cases were treated under field conditions with 2H3R3Z3S3/4H3R3 and 2H3R3Z3E3S3/6H3R3E3, respectively. Following treatment completion, two sputum samples were collected every six months for two years and examined for acid-fast bacilli. Causes of death were identified. RESULTS: The two-year relapse rates for new and retreatment cases were 3.3% and 5.6%, respectively. Retreatment cases with delayed sputum conversion had a greater risk for subsequent relapse. The two-year mortality rate for new and retreatment cases was 3.3% and 8.5%, respectively. The higher mortality rate in retreatment cases was not attributable to relapse of disease, but rather to non-infectious sequelae of tuberculosis. CONCLUSION: The use of directly-observed intermittent regimens is effective in permanently removing infectious tuberculosis cases from the community.

Movement of tuberculosis patients and the failure to complete antituberculosis treatment.

The outcomes of tuberculosis (TB) patients who move before completing antituberculosis treatment have not been described. We studied a population-based cohort of 2,576 adult patients reported as having TB in California during 1993, including 147 patients who moved from one local health jurisdiction to another within California. We determined treatment outcomes (completed, defaulted, died, other) for 131 (89%) of these 147 patients. Patients who moved defaulted more often (relative risk [RR] = 5.5, 95% confidence interval [CI] = 4.1 to 7.4) than patients who did not move. Including these patients' treatment outcomes increased the known number of defaulters by 30%, from 141 to 183 persons. Additionally, diagnosis of TB in a state prison emerged as the strongest risk factor for defaulting from treatment. Patients who moved or defaulted were more likely to abuse drugs or alcohol, to be homeless or to be associated with congregate settings such as jails and prisons. On average, patients who defaulted after moving received less than three-quarters of their recommended treatment regimens. These patients may remain infectious or become infectious again. Our findings highlight the importance of ensuring complete treatment for TB patients who move; failure to do so will adversely affect patient health and TB control, especially in many high-risk populations and settings.

Tuberculosis among immigrants and refugees.

BACKGROUND: Overseas screening of immigrants and refugees applying for a visa to the United States identifies foreign-born individuals who are at high risk for tuberculosis (TB) or who have active TB. The system's effectiveness relies on further medical evaluation and follow-up of foreign-born individuals after their arrival in the United States. METHODS: Retrospective cohort study of 893 immigrants and refugees who arrived in the United States from July 1, 1992, through December 31, 1993, with a destination of San Francisco, Calif, and a referral for further medical evaluation. MAIN OUTCOME MEASURES: Time to report to the local health department after arrival and the yield of active and preventable cases of TB from follow-up medical evaluations. RESULTS: Median time from arrival in the United States to seeking care in San Francisco was 9 days (range, 1-920 days). Of 745 immigrants and refugees (83.4%) who sought further medical evaluation, 51 (6.9%) had active TB and 296 (39.7%) were candidates for preventive therapy. Being a refugee was an independent predictor of failure to seek further medical evaluation in the United States. Class B-1 disease status based on overseas TB screening (odds ratio, 3.5; 95% confidence interval, 2.0-6.2) and being from mainland China (odds ratio, 4.4; 95% confidence interval, 1.9-9.9) were independent predictors of TB diagnosed in San Francisco. CONCLUSIONS: Timely, adequate medical evaluation and follow-up care of immigrants and refugees has a relatively high yield and should be a high priority for TB prevention and control programs.

Genetic similarity among Mycobacterium avium isolates from blood, stool, and sputum of persons with AIDS.

Large-restriction-fragment pattern comparison of Mycobacterium avium from 85 blood, stool, and respiratory specimens from 25 human immunodeficiency virus-infected San Francisco patients revealed 4 strains that infected multiple people (3 groups of 2 patients and 1 group of 3 patients). Most patients harbored a single M. avium strain, but 2 strains were recovered from 8 patients. The significance of recovering 2 strains is not clear, since the second strain was seldom recovered more than once. The strain recovered from blood was recovered from stool of 4 patients and respiratory secretions of 6 patients >4 weeks before detection of bacteremia, indicating that the intestinal and respiratory tracts are entry portals from which M. avium can disseminate. M. avium from 21 cities outside of California served as controls. Thus, a single M. avium strain can cause disseminated infection in multiple patients. This may represent infection from a common environmental source or person-to-person spread.

Mycobacterial complications of HIV infection.

Tuberculosis is the most common opportunistic infection worldwide and is caused by the only readily transmissible pathogen among persons with HIV infection. If treatment is initiated promptly and is supervised appropriately, cure, fortunately, is highly likely. Isoniazid preventive therapy substantially reduces the risk of tuberculosis in persons with HIV infection. Of the nontuberculous mycobacteria, Mycobacterium avium complex (MAC) is the most frequent cause of disease; however, disseminated MAC disease usually is not seen until the CD4+ cell count is less than 50 cells/L. Newer agents, such as the macrolides and rifabutin, form the nucleus of treatment regimens and also are effective in preventing the disease.