Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India.
Methods and Findings
We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy.
Citation: Uhler LM, Kumarasamy N, Mayer KH, Saxena A, Losina E, Muniyandi M, et al. (2010) Cost-Effectiveness of HIV Testing Referral Strategies among Tuberculosis Patients in India. PLoS ONE 5(9): e12747. https://doi.org/10.1371/journal.pone.0012747
Editor: Madhukar Pai, McGill University, Canada
Received: April 29, 2010; Accepted: August 20, 2010; Published: September 16, 2010
Copyright: © 2010 Uhler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported in part by the U.S. National Institute of Allergy and Infectious Disease (R01 AI058736 and K24 AI062476), the Doris Duke Charitable Foundation (Operations Research on AIDS Care and Treatment in Africa (ORACTA) Award 2007015), and the Indian Council of Medical Research and Central TB Division, Ministry of Health, Government of India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
India accounts for one fifth of the global burden of tuberculosis (TB), with 1.8 million new cases of active TB each year—more new cases than any other country . The Revised National Tuberculosis Control Programme (RNTCP) in India reports that two in five Indians are infected with latent TB . India also has a substantial burden of HIV; recent estimates from the World Health Organization (WHO) and India's National AIDS Control Organization (NACO) report 2.5 million people living with HIV in India (an overall population HIV prevalence of 0.36%) , . HIV co-infection substantially increases the risk of progression from latent TB infection to active TB, and TB is the leading cause of mortality in HIV-infected persons in India , . However, recent studies have shown substantial improvement in CD4 counts and decreased mortality among HIV-infected patients who received ART during TB treatment compared to HIV-infected patients without access to antiretrovirals , .
The RNTCP and NACO addressed the intersection of TB and HIV disease by establishing cross-referral mechanisms between facilities providing TB services and HIV integrated counseling and testing centers . NACO guidelines recommend that all patients with active TB and HIV risk factors be referred for HIV counseling and testing . Yet current estimates show that less than 6% of TB patients are tested for HIV infection . In 2007, the Indian government reported that over 12% of the 77,000 TB patients referred for HIV testing were diagnosed with HIV . National TB/HIV policy in India is evolving. In 2007, NACO and the Central TB Division established the first National Framework of Joint TB/HIV Collaborative Activities, expanding basic TB/HIV activities to all states . In October 2008, guidelines were changed to implement an Intensified TB/HIV Package in the nine states with the highest HIV prevalence, including referral to HIV counseling and testing sites for HIV tests free of charge for all TB patients, with continued selective referral in the other 26 states , . The National Framework for Joint TB/HIV Collaborative Activities was further revised in 2009 to establish uniform guidelines at counseling and testing centers and ART centers nationwide, to standardize monitoring and evaluation, and to expand the Intensified TB/HIV Package to all states by 2012 . The TB/HIV Collaborative Activities also include routine TB screening for patients attending HIV testing centers and ART centers; however, the current analysis addresses HIV testing referral for TB patients. Our objective was to project the clinical and economic outcomes of alternative referral strategies for HIV testing among TB patients in India.
We use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model, a state-transition simulation model of HIV and TB disease in resource-limited settings, to project the life expectancy, cost, and cost-effectiveness of HIV testing for patients with active TB in India. Details of the model are published elsewhere , , , , , . Input parameters for the model include data on both TB and HIV natural history, treatment efficacy, and costs of care from India; model outputs include projected per-person life expectancy, lifetime cost, and cost-effectiveness. Life expectancy and cost are discounted at 3% per year .
We estimate life expectancy and costs for three different HIV testing referral strategies for TB patients: 1) selective referral of patients considered to be at high risk for HIV, hereafter referred to as “selective referral,” 2) routine referral of patients in the nine highest HIV prevalence states with selective referral in the other 26 states (the “current standard”), and 3) routine referral of all patients for HIV testing, hereafter “routine referral.” Patients at “high-risk” for HIV—those targeted for HIV testing under the “selective referral” strategy—include those who report a history of high-risk behavior, who have a history of sexually transmitted infection, and/or who have signs and symptoms suggestive of HIV-related opportunistic infections . For each HIV testing referral strategy, patients who are referred for HIV testing, offered a test, and accept testing, receive one rapid HIV test; those with reactive tests receive a confirmatory rapid test. For each strategy, the overall probability that a patient is referred for HIV testing and receives the test is referred to as the “probability of offer/accept” , . There are three HIV testing-related outcomes: 1) HIV-negative, 2) HIV-infected, but not tested or linked to HIV care and therefore not treated, and 3) HIV-infected, tested, linked to care, and treated (Figure S1). Patients with HIV infection who are not tested initially enter HIV care later in the course of disease, upon the occurrence of a severe opportunistic infection (excluding bacterial infections and recurrent TB). HIV-infected patients who are tested and linked to care, but not yet eligible for antiretroviral therapy (CD4 count>350/µl), are monitored with regular clinic visits every 3 months and receive treatment for acute opportunistic infections. They also have CD4 counts every 6 months, and are initiated on antiretroviral therapy (ART) once their CD4 count falls below 350/µl.
We were guided by the Commission on Macroeconomics and Health, sponsored by the WHO, in determining if a particular HIV testing strategy is considered “cost-effective.” Strategies with incremental cost-effectiveness ratios <3 times the per capita Gross Domestic Product (GDP) in India (3x per capita GDP = $3,050) are considered “cost-effective,” while strategies with incremental cost-effectiveness ratios <1 times the per capita GDP (1x per capita GDP = $1,015) are considered “very cost-effective” , .
Tuberculosis Disease States
The CEPAC International model incorporates detailed data with respect to both TB and TB/HIV co-infection. There are five mutually exclusive TB health states considered: no TB exposure, latent TB infection, active TB disease without treatment, active TB disease with treatment, and history of active TB. Patients transition among health states if they experience a primary latent or active TB infection, re-infection, relapse of an active infection, or spontaneous resolution, or if they complete treatment successfully or fail treatment. The four TB outcomes considered are: cured, failed TB treatment, defaulted (TB treatment interrupted for at least two consecutive months), or died.
HIV Disease and Treatment
The natural history of HIV disease is determined by CD4 count decline, the rate of which depends on HIV RNA level . HIV morbidity and mortality are CD4 count-dependent, with higher morbidity and mortality at lower CD4 counts . ART reduces HIV RNA levels, increases CD4 counts, and thus decreases HIV-related morbidity and mortality . Data on virologic efficacy and CD4 count increases due to ART are from a published trial . ART regimens and treatment policies follow recommendations from NACO and the WHO , . First-line ART is a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen consisting of nevirapine and two nucleoside reverse transcriptase inhibitors (NRTIs), usually stavudine and lamivudine. HIV co-infected patients in care have CD4 count tests every 6 months and are treated with co-trimoxazole and two sequential ART regimens once their CD4 count falls to <350 cells/µl, per NACO guidelines , . All TB-related outcomes are worse for HIV-infected patients than for HIV-negative patients and for HIV-infected patients who do not receive ART compared to those on ART . All HIV-infected patients are subject to a monthly risk of mortality from both TB and HIV.
Model Input Data
Baseline characteristics reflect the composition of patients enrolled in a study of short-course anti-TB treatment at the Tuberculosis Research Centre in Chennai, India . Mean age at initial HIV test is 33.50 years (SD 7.20 years), and 83% are male (Table 1). The overall prevalence of HIV disease in TB patients is 4.9% and among those with TB/HIV co-infection, mean CD4 count is 169/µl (SD 126/µl) , . Additional cohort characteristics are shown in Table S1.
The proportion of each TB treatment outcome in the HIV-negative and HIV-infected patients is from the WHO . For HIV-negative patients at six months, 83% are cured of TB, 3% fail TB treatment, 8% default from TB treatment, and 6% die (Table 1) . Of the TB patients with HIV co-infection, at six months 61% are cured of TB, 3% fail TB treatment, 14% default from TB treatment, and 22% die . Mean survival and cost of each TB treatment outcome are weighted according to the proportion of those outcomes as reported by WHO to determine the overall survival and cost for the simulated cohort (Table 1; Tables S2, S3, S4). Mortality rates for each TB outcome are midpoint assumptions on survival for HIV-negative TB patients in India (Table 2).
HIV Disease and Treatment.
Data on HIV natural history are from the Y.R. Gaitonde Center for AIDS Research and Education (YRG CARE) in Chennai, India . The efficacy of a first-line NNRTI-based ART regimen is 73% virologic suppression (HIV RNA <50 copies/ml) at 24 weeks with a mean CD4 increase of 148/µl at 24 weeks (Table 2) , . Second-line ART, consisting of ritonavir-boosted lopinavir, zidovudine and emtricitabine, was assumed to have similar efficacy as first-line ART. Additional details on the clinical input data have been published elsewhere , , .
HIV Testing Offer/Acceptance and Outcomes.
Selective referral (Strategy 1) has a test offer/accept probability of 5.2% and detects 13.2% of those with HIV (Table 3) . The current standard (routine referral in the nine highest HIV prevalence states, with selective referral elsewhere; Strategy 2), has a test offer/accept probability of 22.7% and detects 44.7% of those with HIV. Routine referral for all TB patients (Strategy 3) has a test offer/accept probability of 66.2% and detects 66.2% of those with HIV , . The Technical Appendix (Text S1) contains a detailed description of calculations for HIV test offer/accept and the proportion of HIV among TB patients detected. Of ART-eligible patients newly identified as HIV-infected under Strategy 3, 26.0% link to HIV care, defined as starting ART if eligible . We assumed the same linkage to care rates for Strategies 1 and 2, but varied this assumption in sensitivity analysis.
Costs of Testing and Care.
Resource utilization data are from the YRG CARE database, as well as from a daily cost analysis of YRG CARE conducted by Family Health International . Input parameters include the number of inpatient and outpatient days associated with routine HIV care, acute HIV-associated opportunistic infections, and death. ART drug costs are from India's National AIDS Control Organisation . Annual per-person costs of first- and second-line ART are $108 and $690, and the annual cost of co-trimoxazole prophylaxis is $4 (Table 4) , . The cost of TB treatment, consisting of ethambutol, isoniazid, rifampicin and pyrazinamide three times weekly for two months, followed by rifampicin and isoniazid three times weekly for four months, is $34 . The cost of an HIV test is $3, including the salary of the counselor but excluding infrastructure costs related to scale-up of HIV testing . All costs are standardized to 2008 US dollars using India's 2008 GDP deflator .
Univariate sensitivity analyses are performed on key model parameters to assess how changes in these parameters affect the results. We also performed two-way sensitivity analyses on parameters with the greatest impact on the results. HIV-related parameters examined include HIV prevalence, percent of patients tested for HIV, linkage to HIV care after a positive HIV test, and HIV test cost. ART parameters examined in sensitivity analyses include efficacy, availability, and cost of both first- and second-line ART, and TB parameters examined include TB treatment outcomes, rates of TB mortality and cost of TB treatment.
Survival and Cost for HIV-Negative and HIV-Infected Patients
Among HIV-negative patients, those who were cured of TB, failed TB treatment, or defaulted, had mean undiscounted life expectancies, beginning at age 33.50, ranging from 33.89 years down to 18.38 years (Table 5). Mean per person lifetime TB-related costs ranged from $20–$75.
TB patients who were HIV-infected, but not tested or treated for HIV, and who survived 6 months with TB, had projected undiscounted mean life expectancies ranging from 1.33 years to 4.71 years, and costs ranging from $440-$1,990, depending on their TB outcomes. For those tested and treated for HIV, both mean undiscounted life expectancy and lifetime costs increased substantially compared to those with untreated HIV. HIV-infected patients on ART who survived 6 months with TB had projected life expectancies ranging from 2.03 years to 13.87 years, depending on TB outcomes. Lifetime costs for those tested and treated for HIV and who survived 6 months with TB, ranged from $985–$7,840. Across all TB outcomes, HIV-infected patients treated for HIV had a projected mean life expectancy of 9.04 years, compared to 3.21 years for those HIV-infected but not treated for HIV.
Base Case Analysis
The mean life expectancy and costs for each of the 12 subgroups of TB and HIV patients were weighted by the frequency of their occurrence to determine the overall projected mean life expectancy and cost for each HIV testing referral strategy (Tables S2, S3, S4). For Strategy 1 (selective referral), discounted mean life expectancy was projected to be 16.88 years with a mean discounted lifetime cost of $100 (Table 6). Strategy 2 increased survival by 0.02 years at an additional cost of $10, for an incremental cost-effectiveness ratio of $650/year of life saved (YLS) compared to Strategy 1. Strategy 3 (routine referral), further increased discounted life expectancy by 0.01 years and costs by $10 compared to Strategy 2, with an incremental cost-effectiveness ratio of $730/YLS.
Sensitivity analyses showed that results were most sensitive to the prevalence of HIV in patients receiving TB treatment. However, until the prevalence dropped below 0.5%, substantially below the reported HIV prevalence among TB patients in any setting in India, the cost-effectiveness ratio for Strategy 3 (routine referral) remained less than 3x the per capita GDP in India, $3,050/YLS (Figure 1). In multivariate sensitivity analysis, we varied HIV test cost simultaneously with HIV prevalence; even if the HIV test cost was increased 10-fold, to $30/test, Strategy 3 still had a cost-effectiveness ratio below $3,050/YLS, unless the HIV prevalence among TB patients was also less than 2.5% (Figure 1, dotted line).
The cost-effectiveness of routine referral for HIV testing for all TB patients (Strategy 3) compared to the current standard of referral for HIV testing for TB patients in the nine states with the highest HIV prevalence and selective referral elsewhere (Strategy 2), as a function of HIV prevalence and HIV test cost. The 3x and 1x per capita GDP for India represent thresholds for “cost-effective” and “very cost-effective” health care interventions, as recommended by the WHO (See Methods). GDP: Gross Domestic Product; YLS: Year of life saved.
Although TB treatment outcomes affected projected survival substantially, they did not have an important effect on cost-effectiveness results. If the proportion of patients cured of TB increased an absolute 10%—to 93% for HIV-negative patients and to 71% for HIV-infected patients—and the proportion of patients defaulting, failing treatment, or dying decreased, the projected life expectancy for Strategy 2 increased from 16.90 years to 18.07 years, while the life expectancy for Strategy 3 increased from 16.91 years to 18.08 years. The cost-effectiveness of Strategy 3 compared to Strategy 2 decreased to $720/YLS. If the proportion of patients cured of TB decreased an absolute 10%—to 73% for HIV-negative patients and to 51% for HIV-infected patients—and the proportion of other TB outcomes increased, the projected life expectancy decreased to 15.83 years for Strategy 2 and 15.84 years for Strategy 3, while the cost-effectiveness ratio of Strategy 3 compared to Strategy 2 increased to $760/YLS. We also decreased the rates of death to 13% for HIV-infected patients not receiving ART and 8% for HIV-infected patients receiving ART to match the results of a recent meta-analysis by Khan et al. on TB treatment among HIV-infected patients . This change did not affect the policy results.
The cost of second-line ART had an important impact on the cost-effectiveness results. As costs decreased from the baseline of $690/year, HIV testing in all strategies became more cost-effective. Decreasing the cost of second-line ART to $300/year, the cost-effectiveness ratio of Strategy 3 compared to Strategy 2 improved from $730/YLS to $350/YLS. Increasing the cost of second-line ART to $1,200/year increased the cost-effectiveness ratio of Strategy 3 to $950/YLS. If second-line ART was not available, then routine referral for HIV testing led to lower life expectancy, but its cost-effectiveness ratio was $430/YLS, still less than 1x the per capita GDP in India.
Results were not sensitive to initial age, CD4 count at diagnosis, TB mortality rates, rates of virologic suppression on first- or second-line ART, cost of TB treatment, or HIV test cost. The rates of test offer/accept and linkage to care also had little effect on the results. Higher rates of test offer/accept and linkage to care improved survival and increased costs, but had little impact on cost-effectiveness.
The Revised National TB Control Programme in India currently recommends referral for voluntary HIV counseling and testing of all TB patients in the nine highest HIV prevalence states, with risk-based referral elsewhere . While full implementation of this policy would make major progress in HIV case identification, it is still a program of selective referral and likely misses many additional patients who could also benefit from HIV testing and ART. Using a detailed simulation model of HIV and TB disease, we found that a strategy of routine referral for HIV testing in all TB patients in India compared to HIV testing referral in only the nine highest HIV prevalence states (the current standard) may lead to substantial individual survival benefits. HIV-infected TB patients who were treated for HIV disease had an undiscounted per-person mean life expectancy increase of 5.83 years compared to those not treated for HIV, regardless of TB outcome. For those who remained in TB care, and were cured of TB, referral for HIV testing and linkage to care had the greatest impact on survival. Patients cured of TB who linked to care and received ART had an undiscounted mean life expectancy of 13.87 years, or an increase of 9.16 years over those cured of TB but not treated for HIV.
Referral for HIV testing of all TB patients in India compared to HIV testing referral in only the nine highest HIV prevalence states had an incremental cost-effectiveness ratio of $730/YLS. Routine referral for HIV testing of all TB patients in India would be considered very cost-effective (cost-effectiveness ratio <1x per capita GDP) . In fact, NACO and the RNTCP have recently proposed routine HIV counseling and testing for all TB patients nationwide by 2012. The current study supports this policy decision and highlights that the policy will be very cost-effective. Our findings also support the current WHO recommendation of routine referral for HIV testing for TB patients in all settings . Our analysis examined HIV testing referral for TB patients, so an analysis of screening HIV-infected patients for TB or of cross-referral services would provide additional important policy information.
In 2009, NACO and the RNTCP revised the “National Framework for Joint TB/HIV Collaborative Activities” to strengthen NACO and RNTCP coordination, as well as coordination between HIV counseling and testing centers and ART centers . The revised framework also establishes mechanisms for better reporting, monitoring, and evaluation of the programs, and provides additional training on TB and HIV for staff. A commitment to screen for HIV infection must be coupled with a commitment to HIV care. Although ART scale-up has led to 272 treatment centers and 10 Regional Centers of Excellence nationally, with integrated counseling and testing services available in every district in India, whether they would be able to accommodate the increased patient burden resulting from routine HIV testing referral is unclear . Successfully implementing a routine HIV testing referral program for the approximately 1.8 million people starting TB treatment each year in India will require a major commitment. One recent pilot study of routine referral for HIV testing in India found that patients identified as HIV-infected had low rates of ART initiation, even when they met immunological starting criteria . Further expansion and decentralization of HIV diagnostic and treatment services is underway to prepare for the expanded implementation of the Intensified TB/HIV Package and to provide access to HIV services closer to patients' homes , .
Routine testing can detect HIV infection among individuals in an earlier disease stage, before their CD4 count falls to low levels associated with high morbidity and mortality. Currently, 85% of people living with HIV and registered for ART in India registered when their CD4 count was already <250/µl . With earlier HIV diagnosis, patients can initiate ART at higher CD4 counts, and prevent much of the morbidity and mortality that occurs in lower CD4 strata . TB morbidity and mortality in India is a major driver of global TB outcomes, given the size of India's population. The Millennium Development Goals include halving TB prevalence and death rates between 1990 and 2015. Reducing mortality among HIV-infected TB patients has been identified as an important target for India to reach the Millennium Development Goals; identifying and treating HIV-infected TB patients with ART could contribute substantially toward reaching this target . ART has also been demonstrated to reduce the risk of TB for HIV-infected patients, by lowering HIV RNA levels and increasing CD4 counts , . However, in order for the clinical benefits and cost-effectiveness of routine HIV testing to be realized, linkage to HIV care and treatment must be maximized . One potential strategy to maximize patient retention between the TB center and HIV counseling and testing center would be to integrate HIV testing and treatment into TB services.
The results of this analysis were robust across a wide range of sensitivity analyses. Results depended on HIV prevalence, but the policy implications did not change unless the prevalence was substantially below that reported anywhere in India . Neither outcomes nor cost from TB or HIV disease, including TB-related mortality rates, had a major impact on the results. Even decentralized HIV testing in India, in areas with relatively low HIV prevalence, will be both effective and cost-effective. Since HIV is common in patients with TB, routine referral for voluntary HIV testing of all TB patients will lead to substantial survival benefits, since effective HIV treatment is now widely available in India . Even if the likelihood of patients linking to HIV care was decreased by 40% with routine referral, HIV testing of all patients remained very cost-effective. Although lower linkage rates did adversely affect survival, the impact of linkage on cost-effectiveness is minimal, because as fewer people link to HIV care, both costs and survival decrease. The cost of second-line ART had an impact on the cost-effectiveness of HIV testing, since the cost-effectiveness is highly dependent on the lifetime cost of HIV care, which in turn depends crucially on the cost of second-line therapy. If second-line ART was not available, the survival benefits of HIV testing were less, but the cost-effectiveness results were robust.
HIV testing of TB patients may also confer further benefits in India through its impact on HIV prevention. Although not directly evaluated in the current study, many studies from resource-limited settings have shown that patients testing positive for HIV significantly decrease high-risk behaviors , , , , . The impact of testing negative for HIV on risk-taking behavior is less clear . However, evidence suggests that HIV testing and referral programs will improve HIV prevention, with benefits extending beyond the individual survival benefits highlighted in the current analysis.
The other highest TB burden countries in the world—China, Indonesia, Nigeria, and South Africa—had estimated HIV prevalence in incident TB cases for 2008 ranging from 2.8% (Indonesia) to 71% (South Africa). However, only 22% of TB patients worldwide were tested for HIV in 2008 . Because providing ART is essential to decreasing mortality from TB for HIV-infected persons, detecting HIV earlier, through routine referral for HIV testing for all patients receiving TB treatment, will substantially increase their survival, and likely be cost-effective in other high TB burden countries. HIV testing and earlier initiation of ART may also have prevention benefits by decreasing HIV transmission , , .
There are several limitations to this study. First, data on long-term outcomes for HIV-infected patients cured from TB disease remain scarce. We used the best available data and conducted both univariate and multivariate sensitivity analyses to test the robustness of the results given this uncertainty. While probabilistic sensitivity analysis to simultaneously address uncertainty among all input parameters would be additionally informative, this was not feasible in this Monte Carlo microsimulation. We also assumed in the base case that all patients have an equal probability of linking to HIV care, regardless of disease stage. We did not include the additional benefits of decreasing both HIV transmission and TB transmission by identifying, counseling, and treating HIV disease in TB patients , , , , . Including these benefits would render routine HIV testing even more cost-effective . We also did not include disability-adjusted life years (DALYs) in the analysis. Even for those who do not die from TB, the disease may result in substantial disability . Thus, if DALYs were included in the analysis, routine HIV testing might be even more cost-effective. We also used HIV natural history data from a private clinic in Chennai rather than from government facilities. However, since the main determinant of the cost-effectiveness results is HIV prevalence, these results are likely generalizable to other regions of India. While the new WHO recommendations include ART for any HIV-infected patient with TB, regardless of CD4 count, in this analysis only patients with CD4<350/µl were treated with ART . Since all patients in this analysis had active TB, we did not include the new WHO recommendation for isoniazid preventive therapy in patients with HIV in whom TB disease is excluded .
Among people with HIV infection in India, TB is the most common opportunistic infection and cause of death , . However, the majority of TB patients are not tested for HIV. Our findings suggest that in a country with low overall HIV prevalence, routine voluntary HIV testing of all TB patients would be both clinically effective and very cost-effective. The intersection of the dual epidemics of HIV and TB requires effective HIV and TB case detection and linkage to care to ensure the best possible outcomes for co-infected individuals. Routine voluntary HIV testing for all TB patients in India should be widely implemented.
Baseline cohort characteristics and model inputs for an analysis of HIV testing for TB patients in India.
(0.10 MB DOC)
Weighted cost and life expectancy by TB outcomes.
(0.05 MB DOC)
Weighted cost and life expectancy by TB outcomes (continued).
(0.05 MB DOC)
Weighted cost and life expectancy by TB outcomes (continued).
(0.03 MB DOC)
The authors thank Mai Pho, MD, Callie Scott, MSc, and Sarah Lorenzana, BA, for assistance with the analysis.
The CEPAC-International investigators include:
Massachusetts General Hospital, Harvard Medical School (Boston, Massachusetts, USA): Jessica Becker, John Chiosi, Jennifer Chu, Andrea Ciaranello, Kenneth A. Freedberg, Julie Levison, Sarah Lorenzana, Zhigang Lu, Bethany Morris, June Park, Mai Pho, Erin Rhode, Caroline Sloan, Callie A. Scott, Adam Stoler, Lauren Uhler, Rochelle P. Walensky, Bingxia Wang, Angela Wong.
Brigham and Women's Hospital (Boston, Massachusetts, USA): Elena Losina.
Harvard School of Public Health (Boston, Massachusetts, USA): Sue J. Goldie, April D. Kimmel, Marc Lipsitch, Alethea McCormick, George R. Seage III, Milton C. Weinstein.
Y.R. Gaitonde Centre for AIDS Research & Education (Chennai, India): Nagalingeswaran Kumarasamy, A.K. Ganesh.
Centre Hospitalier de Tourcoing (Tourcoing, France): Yazdan Yazdanpanah.
INSERM U897 (Bordeaux, France): Xavier Anglaret, Delphine Gabillard.
Programme PAC-CI (Abidjan, Côte d'Ivoire): Christine Danel, Eugène Messou, Raoul Moh, Eric Ouattara, Siaka Touré, Catherine Seyler.
University of Cape Town (Cape Town, South Africa): Robin Wood.
Perinatal HIV Research Unit, WITS Health Consortium (Johannesburg, South Africa): Neil A. Martinson, Lerato Mohapi.
Miriam Hospital (Providence, Rhode Island, USA): Timothy Flanigan, Kenneth Mayer.
Yale University (New Haven, Connecticut, USA): A. David Paltiel.
New York University (New York, New York, USA): Melissa A. Bender.
Conceived and designed the experiments: EL MM KAF. Performed the experiments: LMU AS. Analyzed the data: LMU KHM EL ZL RPW TF MAB KAF SS. Wrote the paper: LMU AS KAF. Collected and contributed data: NK. Collected data: MM SS. Contributed model programming and development: AWS. Contributed to writing the paper: RPW SS. Co-developed the model: KAF.
- 1. Steinbrook R (2007) Tuberculosis and HIV in India. N Engl J Med 356: 1198–1199.R. Steinbrook2007Tuberculosis and HIV in India.N Engl J Med35611981199
- 2. RNTCP TB India 2009: RNTCP Status Report. RNTCP TB India 2009: RNTCP Status Report.In: Central TB Division DGoHS, editor. New Delhi.
- 3. UNAIDS/WHO (2007) 2007 AIDS Epidemic Update. UNAIDS. UNAIDS/WHO20072007 AIDS Epidemic Update.UNAIDS
- 4. Reid A, Scano F, Getahun H, Williams B, Dye C, et al. (2006) Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration. Lancet Infect Dis 6: 483–495.A. ReidF. ScanoH. GetahunB. WilliamsC. Dye2006Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration.Lancet Infect Dis6483495
- 5. Raizada N, Chauhan LS, Babu BS, Thakur R, Khera A, et al. (2009) Linking HIV-infected TB patients to cotrimoxazole prophylaxis and antiretroviral treatment in India. PLoS ONE 4: e5999.N. RaizadaLS ChauhanBS BabuR. ThakurA. Khera2009Linking HIV-infected TB patients to cotrimoxazole prophylaxis and antiretroviral treatment in India.PLoS ONE4e5999
- 6. Sharma A, Wanchu A, Bansal V, Singh S, Varma S (2007) Improvement in CD 4 counts in HIV positive patients treated with HAART and antitubercular drugs: an observational study from North India. Indian J Pathol Microbiol 50: 905–907.A. SharmaA. WanchuV. BansalS. SinghS. Varma2007Improvement in CD 4 counts in HIV positive patients treated with HAART and antitubercular drugs: an observational study from North India.Indian J Pathol Microbiol50905907
- 7. NACO (October 2009) National Framework for Joint HIV/TB Collaborative Activities. New Dehli: Ministry of Health and Family Welfare, Government of India. NACOOctober 2009National Framework for Joint HIV/TB Collaborative Activities.New DehliMinistry of Health and Family Welfare, Government of IndiaIn: Organization CTDaNAC, editor.
- 8. WHO (2009) WHO Report 2009 - Global Tuberculosis Control 2009: Epidemiology, Strategy, Financing. WHO2009WHO Report 2009 - Global Tuberculosis Control 2009: Epidemiology, Strategy, Financing
- 9. RNTCP TB India 2008: RNTCP Status Report. RNTCP TB India 2008: RNTCP Status Report.In: Central TB Division DGoHS, editor. New Delhi.
- 10. Raizada N, Chauhan LS, Khera A, Sokhey J, Wares DF, et al. (2008) HIV seroprevalence among tuberculosis patients in India, 2006-2007. PLoS ONE 3: e2970.N. RaizadaLS ChauhanA. KheraJ. SokheyDF Wares2008HIV seroprevalence among tuberculosis patients in India, 2006-2007.PLoS ONE3e2970
- 11. RNTCP (2010) TB India 2010: RNTCP Status Report. RNTCP2010TB India 2010: RNTCP Status Report
- 12. Freedberg KA, Kumarasamy N, Losina E, Cecelia AJ, Scott CA, et al. (2007) Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy. AIDS 21: Suppl 4S117–128.KA FreedbergN. KumarasamyE. LosinaAJ CeceliaCA Scott2007Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy.AIDS21Suppl 4S117128
- 13. Bender MA, Kumarasamy N, Mayer KH, Wang B, Walensky RP, et al. (2010) Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India. Clin Infect Dis 50: 416–425.MA BenderN. KumarasamyKH MayerB. WangRP Walensky2010Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India.Clin Infect Dis50416425
- 14. Goldie SJ, Yazdanpanah Y, Losina E, Weinstein MC, Anglaret X, et al. (2006) Cost-effectiveness of HIV treatment in resource-poor settings–the case of Côte d'Ivoire. N Engl J Med 355: 1141–1153.SJ GoldieY. YazdanpanahE. LosinaMC WeinsteinX. Anglaret2006Cost-effectiveness of HIV treatment in resource-poor settings–the case of Côte d'Ivoire.N Engl J Med35511411153
- 15. Yazdanpanah Y, Losina E, Anglaret X, Goldie SJ, Walensky RP, et al. (2005) Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Cote d'Ivoire: a trial-based analysis. AIDS 19: 1299–1308.Y. YazdanpanahE. LosinaX. AnglaretSJ GoldieRP Walensky2005Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Cote d'Ivoire: a trial-based analysis.AIDS1912991308
- 16. Walensky RP, Wood R, Weinstein MC, Martinson NA, Losina E, et al. (2008) Scaling up antiretroviral therapy in South Africa: the impact of speed on survival. J Infect Dis 197: 1324–1332.RP WalenskyR. WoodMC WeinsteinNA MartinsonE. Losina2008Scaling up antiretroviral therapy in South Africa: the impact of speed on survival.J Infect Dis19713241332
- 17. Walensky RP, Wolf LL, Wood R, Fofana MO, Freedberg KA, et al. (2009) When to start antiretroviral therapy in resource-limited settings. Ann Intern Med 151: 157–166.RP WalenskyLL WolfR. WoodMO FofanaKA Freedberg2009When to start antiretroviral therapy in resource-limited settings.Ann Intern Med151157166
- 18. Gold RM, Siegel EJ, Russell BL, Weinstein CM (1996) Cost-Effectiveness in Health and Medicine. New York, , NY: Oxford University Press. RM GoldEJ SiegelBL RussellCM Weinstein1996Cost-Effectiveness in Health and Medicine.New York, , NYOxford University Press
- 19. Vijay S, Swaminathan S, Vaidyanathan P, Thomas A, Chauhan LS, et al. (2009) Feasibility of provider-initiated HIV testing and counselling of tuberculosis patients under the TB control programme in two districts of South India. PLoS ONE 4: e7899.S. VijayS. SwaminathanP. VaidyanathanA. ThomasLS Chauhan2009Feasibility of provider-initiated HIV testing and counselling of tuberculosis patients under the TB control programme in two districts of South India.PLoS ONE4e7899
- 20. WHO (2001) Macroeconomics and health: investing in health for economic development. Geneva: World Health Organization. WHO2001Macroeconomics and health: investing in health for economic development.GenevaWorld Health Organization
- 21. IMF (October 2009) World Economic Outlook Database. International Monetary Fund. IMFOctober 2009World Economic Outlook Database.International Monetary Fund
- 22. Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, et al. (1997) Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126: 946–954.JW MellorsA. MuñozJV GiorgiJB MargolickCJ Tassoni1997Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection.Ann Intern Med126946954
- 23. Wang B, Kumarasamy N, Divi N, Cecelia AJ, Mayer KH, et al. (2006) Incidence of opportunistic infections (OIs) within specific CD4 strata in HIV-infected patients in Southern India [abstract WePe0279]. Toronto, Canada: XVI International AIDS Conference. B. WangN. KumarasamyN. DiviAJ CeceliaKH Mayer2006Incidence of opportunistic infections (OIs) within specific CD4 strata in HIV-infected patients in Southern India [abstract WePe0279].Toronto, CanadaXVI International AIDS Conference
- 24. Zhou J, Kumarasamy N, Ditangco R, Kamarulzaman A, Lee CK, et al. (2005) The TREAT Asia HIV Observational Database: baseline and retrospective data. J Acquir Immune Defic Syndr 38: 174–179.J. ZhouN. KumarasamyR. DitangcoA. KamarulzamanCK Lee2005The TREAT Asia HIV Observational Database: baseline and retrospective data.J Acquir Immune Defic Syndr38174179
- 25. NACO (2007) Antiretroviral therapy guidelines for adults and adolescents including post-exposure prophylaxis. New Delhi: Ministry of Health & Family Welfare, Government of India. NACO2007Antiretroviral therapy guidelines for adults and adolescents including post-exposure prophylaxis.New DelhiMinistry of Health & Family Welfare, Government of India
- 26. WHO (2006) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. WHO2006Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach
- 27. National AIDS Control Organization (2007) Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV-Infected Adult and Adolescent. National AIDS Control Organization2007Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV-Infected Adult and Adolescent.In: Ministry of Health & Family Welfare GoI, editor. New Delhi.
- 28. WHO (2008) Global Tuberculosis Control: Surveillance, Planning, Financing. WHO2008Global Tuberculosis Control: Surveillance, Planning, Financing.In: Organization WH, editor. Geneva.
- 29. Swaminathan S, Deivanayagam CN, Rajasekaran S, Venkatesan P, Padmapriyadarsini C, et al. (2008) Long term follow up of HIV-infected patients with tuberculosis treated with 6-month intermittent short course chemotherapy. Natl Med J India 21: 3–8.S. SwaminathanCN DeivanayagamS. RajasekaranP. VenkatesanC. Padmapriyadarsini2008Long term follow up of HIV-infected patients with tuberculosis treated with 6-month intermittent short course chemotherapy.Natl Med J India2138
- 30. Dewan PK, Gupta D, Williams BG, Thakur R, Bachani D, et al. (2010) National estimate of HIV seroprevalence among tuberculosis patients in India. Int J Tuberc Lung Dis 14: 247–249.PK DewanD. GuptaBG WilliamsR. ThakurD. Bachani2010National estimate of HIV seroprevalence among tuberculosis patients in India.Int J Tuberc Lung Dis14247249
- 31. WHO (2008) Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva. WHO2008Global Tuberculosis Control: Surveillance, Planning, Financing.Geneva
- 32. Tuboi SH, Brinkhof MW, Egger M, Stone RA, Braitstein P, et al. (2007) Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (ART-LINC) collaboration. J Acquir Immune Defic Syndr 45: 52–59.SH TuboiMW BrinkhofM. EggerRA StoneP. Braitstein2007Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (ART-LINC) collaboration.J Acquir Immune Defic Syndr455259
- 33. Anglaret X, Chêne G, Attia A, Touré S, Lafont S, et al. (1999) Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet 353: 1463–1468.X. AnglaretG. ChêneA. AttiaS. TouréS. Lafont1999Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial. Cotrimo-CI Study Group.Lancet35314631468
- 34. Homan RK, Ganesh AK, Duraisamy P, Castle C, Sripriya M, et al. (2000) Economic Analyses of YRG CARE Services: implications for program sustainability. Research Triangle Park, , NC, USA: Family Health International. RK HomanAK GaneshP. DuraisamyC. CastleM. Sripriya2000Economic Analyses of YRG CARE Services: implications for program sustainability.Research Triangle Park, , NC, USAFamily Health International
- 35. NACO (2010) Care, Support, and Treatment: National AIDS Control Programme, Phase-III, India. NACO2010Care, Support, and Treatment: National AIDS Control Programme, Phase-III, India
- 36. Management Sciences for Health (2009) The International Drug Price Indicator Guide. Management Sciences for Health2009The International Drug Price Indicator Guide
- 37. Muniyandi M, Rajeswari R, Balasubramanian R (2006) Estimating provider cost for treating patients with tuberculosis under Revised National Tuberculosis Control Programme (RNTCP). Indian J Tuberc. pp. 12–17.M. MuniyandiR. RajeswariR. Balasubramanian2006Estimating provider cost for treating patients with tuberculosis under Revised National Tuberculosis Control Programme (RNTCP).Indian J Tuberc1217
- 38. Tamil Nadu State AIDS Control Society (2010) Health & Family Welfare Department, Government of Tamil Nadu. Tamil Nadu State AIDS Control Society2010Health & Family Welfare Department, Government of Tamil Nadu
- 39. Khan FA, Minion J, Pai M, Royce S, Burman W, et al. (2010) Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis. Clin Infect Dis 50: 1288–1299.FA KhanJ. MinionM. PaiS. RoyceW. Burman2010Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis.Clin Infect Dis5012881299
- 40. WHO (2007) Guidance on provider-initiated HIV testing and counselling in health facilities. HIV/AIDS Programme. Geneva: World Health Organization. WHO2007Guidance on provider-initiated HIV testing and counselling in health facilities.HIV/AIDS ProgrammeGenevaWorld Health Organization
- 41. NACO (2010) National AIDS Control Programme: Response to the HIV Epidemic in India. NACO2010National AIDS Control Programme: Response to the HIV Epidemic in India
- 42. Sogarwal R, Bachani D (2009) Are persons living with HIV timely accessing ART services in India? J Indian Med Assoc 107: 228–290,307.R. SogarwalD. Bachani2009Are persons living with HIV timely accessing ART services in India?J Indian Med Assoc107228290,307
- 43. Williams BG, Granich R, Chauhan LS, Dharmshaktu NS, Dye C (2005) The impact of HIV/AIDS on the control of tuberculosis in India. Proc Natl Acad Sci U S A 102: 9619–9624.BG WilliamsR. GranichLS ChauhanNS DharmshaktuC. Dye2005The impact of HIV/AIDS on the control of tuberculosis in India.Proc Natl Acad Sci U S A10296199624
- 44. Lawn SD, Myer L, Edwards D, Bekker LG, Wood R (2009) Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. Aids 23: 1717–1725.SD LawnL. MyerD. EdwardsLG BekkerR. Wood2009Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa.Aids2317171725
- 45. Lawn SD, Kranzer K, Wood R (2009) Antiretroviral therapy for control of the HIV-associated tuberculosis epidemic in resource-limited settings. Clin Chest Med 30: 685–699,viii.SD LawnK. KranzerR. Wood2009Antiretroviral therapy for control of the HIV-associated tuberculosis epidemic in resource-limited settings.Clin Chest Med30685699,viii
- 46. Bassett IV, Regan S, Chetty S, Giddy J, Uhler LMWho starts antiretroviral therapy in Durban, South Africa? … not everyone who should. AIDS 24: Suppl 1S37–44.IV BassettS. ReganS. ChettyJ. GiddyLM UhlerWho starts antiretroviral therapy in Durban, South Africa? … not everyone who should.AIDS24Suppl 1S3744
- 47. Liechty CA (2005) The evolving role of HIV counseling and testing in resource-limited settings: HIV prevention and linkage to expanding HIV care access. Curr Infect Dis Rep 7: 154–158.CA Liechty2005The evolving role of HIV counseling and testing in resource-limited settings: HIV prevention and linkage to expanding HIV care access.Curr Infect Dis Rep7154158
- 48. Sri Krishnan AK, Hendriksen E, Vallabhaneni S, Johnson SL, Raminani S, et al. (2007) Sexual behaviors of individuals with HIV living in South India: a qualitative study. AIDS Education and Prevention 19: 334–345.AK Sri KrishnanE. HendriksenS. VallabhaneniSL JohnsonS. Raminani2007Sexual behaviors of individuals with HIV living in South India: a qualitative study.AIDS Education and Prevention19334345
- 49. The Voluntary HIV-1 Counseling and Testing Efficacy Study Group (2000) Efficacy of voluntary HIV-1 counselling and testing in individuals and couples in Kenya, Tanzania, and Trinidad: a randomised trial. Lancet 356: 103–112.The Voluntary HIV-1 Counseling and Testing Efficacy Study Group2000Efficacy of voluntary HIV-1 counselling and testing in individuals and couples in Kenya, Tanzania, and Trinidad: a randomised trial.Lancet356103112
- 50. Allen S, Meinzen-Derr J, Kautzman M, Zulu I, Trask S, et al. (2003) Sexual behavior of HIV discordant couples after HIV counseling and testing. Aids 17: 733–740.S. AllenJ. Meinzen-DerrM. KautzmanI. ZuluS. Trask2003Sexual behavior of HIV discordant couples after HIV counseling and testing.Aids17733740
- 51. Denison JA, O'Reilly KR, Schmid GP, Kennedy CE, Sweat MD (2008) HIV voluntary counseling and testing and behavioral risk reduction in developing countries: a meta-analysis, 1990–2005. AIDS Behav 12: 363–373.JA DenisonKR O'ReillyGP SchmidCE KennedyMD Sweat2008HIV voluntary counseling and testing and behavioral risk reduction in developing countries: a meta-analysis, 1990–2005.AIDS Behav12363373
- 52. WHO (2009) Global Tuberculosis Control: a short update to the 2009 report. WHO2009Global Tuberculosis Control: a short update to the 2009 report.In: Organization WH, editor.
- 53. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, et al. (2000) Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 342: 921–929.TC QuinnMJ WawerN. SewankamboD. SerwaddaC. Li2000Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group.N Engl J Med342921929
- 54. Marks G, Crepaz N, Senterfitt JW, Janssen RS (2005) Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. J Acquir Immune Defic Syndr 39: 446–453.G. MarksN. CrepazJW SenterfittRS Janssen2005Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs.J Acquir Immune Defic Syndr39446453
- 55. Bunnell R, Ekwaru JP, Solberg P, Wamai N, Bikaako-Kajura W, et al. (2006) Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. Aids 20: 85–92.R. BunnellJP EkwaruP. SolbergN. WamaiW. Bikaako-Kajura2006Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda.Aids208592
- 56. Rajeswari R, Balasubramanian R, Muniyandi M, Geetharamani S, Thresa X, et al. (1999) Socio-economic impact of tuberculosis on patients and family in India. Int J Tuberc Lung Dis 3: 869–877.R. RajeswariR. BalasubramanianM. MuniyandiS. GeetharamaniX. Thresa1999Socio-economic impact of tuberculosis on patients and family in India.Int J Tuberc Lung Dis3869877
- 57. WHO (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010 revision. WHO2010Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010 revision
- 58. WHO (2008) WHO Three I's Meeting: Intensified Case Finding (ICF), Isoniazid Preventive Therapy (IPT), and TB Infection Control (IC) for people living with HIV. Genevea: WHO HIV/AIDS and TB Department. WHO2008WHO Three I's Meeting: Intensified Case Finding (ICF), Isoniazid Preventive Therapy (IPT), and TB Infection Control (IC) for people living with HIV.GeneveaWHO HIV/AIDS and TB Department
- 59. Sadacharam K, Gopi PG, Chandrasekaran V, Eusuff SI, Subramani R, et al. (2007) Status of smear-positive TB patients at 2-3 years after initiation of treatment under a DOTS programme. Indian J Tuberc 54: 199–203.K. SadacharamPG GopiV. ChandrasekaranSI EusuffR. Subramani2007Status of smear-positive TB patients at 2-3 years after initiation of treatment under a DOTS programme.Indian J Tuberc54199203