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1.  Tuberculosis Risk Before and After Highly Active Antiretroviral Therapy Initiation: Does HAART Increase the Short-term TB Risk in a Low Incidence TB Setting? 
Objective
To evaluate the short- and long-term effects of highly active antiretroviral therapy (HAART) on tuberculosis (TB) risk, compared to risk without HAART in a low TB incidence setting.
Design
An observational cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between January 1998 and December 2008.
Methods
A marginal structural model was used to estimate the effect of HAART on short- (≤180 days) and long-term (>180 days) TB risk, with CD4+ lymphocyte count incorporated as a time-updated covariate.
Results
Of 4,534 HIV-infected patients, 34 developed TB (165/100,000 p-y; 20,581 person-years [p-y] of follow-up). Seventeen cases occurred among persons not on HAART or >30 days after HAART discontinuation (212/100,000 p-y; 8,019 p-y of follow-up). Seventeen occurred among persons on HAART (135/100,000 p-y; 12,562 p-y of follow-up); ten in the first 180 days (402/100,000 p-y; 2,489 p-y of follow-up) and 7 after more than 180 days (69/100,000 p-y; 10,073 p-y of follow-up). After adjusting for the most recent CD4+ lymphocyte count, the risk of TB in the first 180 days of HAART exposure relative to no HAART was 0.68 (0.14–3.22, p=0.63).
Conclusions
In this low TB incidence setting, the TB rate in the first 180 days of HAART was almost twice as high as persons not on HAART. However, after adjusting for most recent CD4+ count there was no significant difference in TB risk between these two groups. This suggests that low recent CD4+ lymphocyte count influences TB risk during the first 180 days of HAART.
doi:10.1097/QAI.0b013e3182182e2d
PMCID: PMC3141096  PMID: 21423024
tuberculosis; M. tuberculosis infection; tuberculosis risk; human immunodeficiency virus; highly active antiretroviral therapy
2.  Incidence, risk factors and mortality of tuberculosis in Danish HIV patients 1995-2007 
Background
Human Immunodeficiency Virus (HIV) infection predisposes to tuberculosis (TB). We described incidence, risk factors and prognosis of TB in HIV-1 infected patients during pre (1995-1996), early (1997-1999), and late Highly Active Antiretroviral Therapy (HAART) (2000-2007) periods.
Methods
We included patients from a population-based, multicenter, nationwide cohort. We calculated incidence rates (IRs) and mortality rates (MRs). Cox's regression analysis was used to estimate risk factors for TB infection with HAART initiation included as time updated variable. Kaplan-Meier was used to estimate mortality after TB.
Results
Among 2,668 patients identified, 120 patients developed TB during the follow-up period. The overall IR was 8.2 cases of TB/1,000 person-years of follow-up (PYR). IRs decreased during the pre-, early and late-HAART periods (37.1/1000 PYR, 12.9/1000 PYR and 6.5/1000 PYR respectively). African and Asian origin, low CD4 cell count and heterosexual and injection drug user route of HIV transmission were risk factors for TB and start of HAART reduced the risk substantially. The overall MR in TB patients was 34.4 deaths per 1,000 PYR (95% Confidence Interval: 22.0-54.0) and was highest in the first two years after the diagnosis of TB.
Conclusions
Incidence of TB still associated with conventional risk factors as country of birth, low CD4 count and route of HIV infection while HAART reduces the risk substantially. The mortality in this patient population is high in the first two years after TB diagnosis.
doi:10.1186/1471-2466-11-26
PMCID: PMC3115926  PMID: 21605366
3.  Tuberculosis treatment and risk of stavudine substitution in first line antiretroviral therapy 
Background
Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART.
Methods
We evaluated a cohort of 7,066 patients who initiated HAART between April 2004 and March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation; concurrent initiation of TB treatment and HAART; incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks.
Results
Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dose. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI] 1.82-5.56) in the first two months of HAART, 2.51 (95% CI 1.77-3.54) in months 3-6, and 1.19 (95% CI 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI 3.03-14.37) in the first two months,1.88 (95% CI 0.87-4.09) in months 3-6, and 1.07 (95% CI 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk.
Conclusions
Risk of stavudine substitution was increased among patients receiving TB treatment, especially soon after HAART initiation. In settings where alternative antiretroviral drugs are available, initiation of stavudine in patients receiving TB treatment may need to be reconsidered.
doi:10.1086/598977
PMCID: PMC2787193  PMID: 19385733
Tuberculosis treatment; HIV; stavudine; highly active antiretroviral therapy (HAART); drug interactions
4.  Antiretroviral therapy at a district hospital in Ethiopia prevents death and tuberculosis in a cohort of HIV patients 
Background
Although highly active antiretroviral therapy (HAART) reduces mortality in the developed world, it remains undocumented in resource-poor settings. We assessed the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in Ethiopia. The objective of this study was to assess the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in a resource-limited setting in south Ethiopia. Starting in January 2003, we followed all consecutive adult HIV infected patients who visited the HIV clinic. Since August 2003, we treated patients with HAART. Only basic laboratory services were available.
Results
We followed 185 patients in the pre-HAART cohort and 180 patients in the HAART cohort. The mortality rate was 15.4 per 100 person-years of observation (PYO) in the HAART group and tuberculosis incidence rate was 3.7 per 100 PYO. In the pre-HAART group, the mortality rate was 58.1 per 100 PYO and the tuberculosis incidence rate was 11.1 per 100 PYO. HAART resulted in a 65% decline in mortality (adjusted hazard ratio [95%CI] = 0.35 [0.19–0.63]; P < 0.001). Tuberculosis incidence rate was lower in the HAART group (adjusted hazard ratio [95%CI] = 0.11 [0.03–0.48]; P < 0.01). Most of the deaths occurred during the first three months of treatment.
Conclusion
HAART improved survival and decreased tuberculosis incidence to a level similar to that achieved in the developed countries during the early years of HAART. However, both the mortality and the tuberculosis incidence rate were much higher in terms of absolute figures in this resource-limited setting. Attention should be paid to the early weeks of treatment when mortality is high. The high tuberculosis incidence rate, when coupled with the improved survival, may lead to increased tuberculosis transmission. This highlights the need for strengthening tuberculosis prevention efforts with the scale-up of treatment programmes
doi:10.1186/1742-6405-3-10
PMCID: PMC1475602  PMID: 16600050
5.  Clinical presentation and outcome of Tuberculosis in Human Immunodeficiency Virus infected children on anti-retroviral therapy 
BMC Pediatrics  2008;8:1.
Background
The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART.
Methods
We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005.
Results
Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%).
Conclusion
We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.
doi:10.1186/1471-2431-8-1
PMCID: PMC2246130  PMID: 18186944
6.  Clinicopathological correlates in HIV seropositive tuberculosis cases presenting with jaundice after initiating antiretroviral therapy with a structured review of the literature 
BMC Infectious Diseases  2012;12:257.
Background
The development of jaundice after initiation of HAART in HIV-TB co-infected patients is a challenging presentation in resource constrained settings, and is often attributed to drug induced liver injury (DILI).Some investigators have described hepatic tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) as a cause of liver disease in patients initiating HAART, which could also cause jaundice.
Case presentations
We report the clinical and histopathological features of five HIV-TB co-infected patients presenting with a syndrome of jaundice, tender hepatomegaly, bile canalicular enzyme rise and return of constitutional symptoms within 8 weeks of initiation of highly active antiretroviral therapy (HAART) for advanced HIV infection at a rural clinic in KwaZulu Natal, South Africa.
All five patients had been diagnosed with tuberculosis infection prior to HAART initiation and were on antituberculous medication at time of developing jaundice. There was evidence of multiple aetiologies of liver injury in all patients. However, based on clinical course and pathological findings, predominant hepatic injury was thought to be drug induced in one case and hepatic tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in the other four.
In these later 4 patients, liver biopsy findings included necrotising and non-necrotising granulomatous inflammation in the lobules and portal tracts. The granulomas demonstrated – in addition to epithelioid histiocytes and Langhans giant cells – neutrophils, plasma cells and large numbers of lymphocytes, which are not features of a conventional untreated tuberculous response.
Conclusion
In this high TB prevalent, low resource setting, TB-IRIS may be an important cause of jaundice post-HAART initiation. Clinicopathological correlation is essential for optimal diagnosis. Further multi-organ based histopathological studies in the context of immune reconstitution would be useful to clinicians in low resource settings dealing with this challenging presentation.
doi:10.1186/1471-2334-12-257
PMCID: PMC3526386  PMID: 23061403
Human immunodeficiency virus; Tuberculosis; Immune reconstitution inflammatory syndrome; Drug induced liver injury; Jaundice; Low resource setting; Liver biopsy
7.  Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort 
AIDS (London, England)  2009;23(5):631-636.
Background
The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa.
Methods
Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk.
Results
Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78).
Conclusion
Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.
doi:10.1097/QAD.0b013e328327964f
PMCID: PMC3063949  PMID: 19525621
HAART; isoniazid; preventive treatment; sub-Saharan Africa; tuberculosis
8.  Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment 
BMC Infectious Diseases  2012;12:168.
Background
For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events.
Methods
In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART.
Findings
A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar.
Interpretation
Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability.
Trial registration
CTRI/2011/12/002260
doi:10.1186/1471-2334-12-168
PMCID: PMC3457866  PMID: 22846195
Antiretroviral; Early; Delayed; HIV; Tuberculosis
9.  Antiretroviral Program Associated with Reduction in Untreated Prevalent Tuberculosis in a South African Township 
Rationale: In 2005, we reported high prevalence of untreated pulmonary tuberculosis (TB) in a South African community. Prevalent untreated TB is the main source of transmission. In settings with large burdens of human immunodeficiency virus (HIV) and TB, highly active antiretroviral therapy (HAART) may contribute to TB control.
Objectives: To assess the community-level impact of HAART on TB prevalence, we repeated a community-based TB prevalence cross-sectional survey in 2008 following HAART roll-out.
Methods: A random 10% adult population sample was identified from the community. Participants provided two sputum specimens for acid-fast bacilli microscopy and TB culture. Oral transudate specimen was collected for anonymous HIV testing, linked to TB diagnosis. An interviewer-administered, structured questionnaire identified TB and HIV history and risk factors.
Measurements and Main Results: In the 2008 survey, 1,250 adults participated (90% response rate); 306 (25%) tested HIV positive, of which 60 (20%) were receiving HAART. A total of 20 TB cases were identified (12 receiving TB treatment), representing a significant decline in prevalence from 3.2 to 1.6% (P = 0.02) between the surveys. TB prevalence in participants not infected with HIV was unchanged (P = 0.90). The decline occurred among participants not infected with HIV, decreasing from 9.2 to 3.6% in 2005 to 2008, respectively (P = 0.003). In participants infected with HIV, prevalence of treated TB declined from 4 to 2.3% (P = 0.06), and untreated TB prevalence from 5.2 to 1.3% (P = 0.02). The proportion of untreated TB in patients receiving HAART decreased significantly, from 22 to 0% (P < 0.001).
Conclusions: Prevalence of undiagnosed TB declined significantly over a period of increasing HAART availability. The decline was predominantly in individuals infected with HIV receiving HAART.
doi:10.1164/rccm.201004-0598OC
PMCID: PMC2970849  PMID: 20558626
tuberculosis; prevalence; human immunodeficiency virus; antiretroviral therapy
10.  Tuberculosis IRIS : a mediastinal problem 
F1000Research  2013;2:54.
We present a case of a 39 years old male patient with Acquired Immune Deficiency Syndrome (AIDS) who developed Mycobacterium tuberculosis related Immune Reconstitution Inflammatory Syndrome (IRIS) after initiation of Highly Active Antiretroviral Therapy (HAART) treatment. The inflammatory response resulted in mediastinal necrotic lymphadenopathy and subsequent perforation of the esophageal wall.
doi:10.12688/f1000research.2-54.v1
PMCID: PMC3799548  PMID: 24358876
11.  Tuberculosis IRIS: a mediastinal problem 
F1000Research  2013;2:54.
We present a case of a 39 year old male patient with Acquired Immune Deficiency Syndrome (AIDS) who developed Mycobacterium tuberculosis related Immune Reconstitution Inflammatory Syndrome (IRIS) after initiation of Highly Active Antiretroviral Therapy (HAART) treatment. The inflammatory response resulted in mediastinal necrotic lymphadenopathy and subsequent perforation of the esophageal wall.
doi:10.12688/f1000research.2-54.v2
PMCID: PMC3799548  PMID: 24358876
12.  Tuberculosis chemoprophylaxis. 
Western Journal of Medicine  1992;157(4):421-424.
The incidence of tuberculosis in the United States, after decreasing for many years, has recently begun to climb at an alarming rate. This rise is due mainly to excess cases in high-risk groups including human immunodeficiency virus-infected patients, the elderly, the foreign born, and the homeless. In the United States tuberculosis has been associated with a 10% mortality despite adequate treatment. The tuberculin skin test is a safe and inexpensive test for detecting tuberculous infection. To improve its predictive value the diagnostic criteria for classifying a positive reaction have recently been revised. High-risk populations should be screened to identify those persons who would most benefit from preventive treatment. Isoniazid therapy taken for 6 to 12 months is a safe and highly effective means of preventing tuberculous infection from developing into active disease. The most worrisome toxicity of isoniazid, fatal hepatitis, is extremely rare; when patients are monitored closely the incidence of death from hepatotoxicity is less than 0.01%.
PMCID: PMC1011301  PMID: 1462535
13.  When Tuberculosis Comes Back: Who Develops Recurrent Tuberculosis in California? 
PLoS ONE  2011;6(11):e26541.
Background
Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California.
Methods
The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode.
Results
Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p = 0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p = 0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p = 0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p = 0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p = 0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p = 0.0171).
Conclusions
The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions.
doi:10.1371/journal.pone.0026541
PMCID: PMC3206026  PMID: 22069456
14.  Safety and effectiveness of HAART in tuberculosis-HIV co-infected patients in Brazil 
SUMMARY
BACKGROUND
Antiretroviral therapy (ART) significantly reduces tuberculosis (TB) incidence among persons with human immunodeficiency virus (HIV), but the safety and effectiveness of concomitant treatment for both diseases remain unclear.
OBJECTIVE
To evaluate the impact of ART and anti-tuberculosis treatment on survival and risk of adverse events (AE) among co-infected individuals.
METHODS
In a retrospective cohort study, clinical data were collected from 618 TB-HIV patients treated with rifampin, isoniazid and pyrazinamide ± ethambutol between 1 January 1995 and 31 December 2003. Patients were categorized into two groups: highly active ART (HAART) or no ART. Different HAART regimens were evaluated. Bivariate analysis, multivariate logistic regression and survival analysis using Cox proportional hazards regression were used.
RESULTS
One-year mortality was lower for patients receiving HAART (adjusted hazard ratio [aHR] 0.17, 95%CI 0.09–0.31) compared to no ART. HAART increased the risk of AE (aHR 2.08, 95%CI 1.29–3.36). The odds of AE when receiving a ritonavir + saquinavir HAART regimen was eight-fold higher compared to no ART (OR 8.31, 95%CI 3.04–22.69), while efavirenz-based HAART was not associated with a significantly increased risk of AE (OR 1.42, 95%CI 0.76–2.65).
CONCLUSION
HIV patients with TB have significantly better survival if they receive HAART during anti-tuberculosis treatment. Efavirenz-based HAART is associated with fewer AEs than protease inhibitor-based HAART.
doi:10.5588/ijtld.11.0831
PMCID: PMC3713776  PMID: 23317954
tuberculosis; AIDS; HAART; adverse events; survival
15.  HIV and tuberculosis coinfection: inextricably linked liaison. 
In sub-Saharan Africa, human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. Sub-Saharan Africa has seen the woeful failure of World Health Organization (WHO) targets of detecting 70% of the infectious cases of tuberculosis and curing > or =85%. Current treatment of Mycobacterium tuberculosis in most resource limited settings is comprised of a four-drug initial antituberculosis regimen for two months, followed by either a two-drug continuation phase of antituberculosis regimen for four months or six months depending on the medications. Many countries in sub-Saharan Africa are scaling up with highly active antiretroviral therapy (HAART), using one of the first-line regimens that consist of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our current HAART regimen and antituberculosis drugs continue to give us a therapeutic challenge in terms of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndromes. Scientific research is needed in the areas of diagnosis, treatment and prevention of tuberculosis in sub-Saharan Africa. Such research could be facilitated due to greater availability of funding than a decade ago.
PMCID: PMC2575925  PMID: 18229780
16.  Potentially preventable tuberculosis among HIV-infected persons in the era of highly active antiretroviral treatment 
SUMMARY
OBJECTIVE
To characterize the proportion of tuberculosis (TB) cases that could have been prevented among human immunodeficiency virus (HIV) infected persons receiving care in the era of highly active antiretroviral treatment (HAART).
DESIGN
We conducted an observational cohort study among HIV-infected patients with ≥2 out-patient visits at the Comprehensive Care Center, Nashville, Tennessee, USA, between 1 January 1998 and 31 December 2005.
METHODS
A potentially preventable TB case was defined as a case in which the patient received no screening tuberculin skin test (TST) prior to TB diagnosis or a case in which a patient with a positive screening TST did not complete treatment for latent infection.
RESULTS
Of 3601 HIV-infected persons in care (13 905 person-years [p-y] of follow-up), 29 developed TB (230/100 000 p-y). Of the 29, 20 (69%) had not had TST performed as part of routine screening. Of the nine patients screened, four had a positive test, three of whom completed treatment for latent TB infection. Of 29 TB cases, 21 (72%) were therefore potentially preventable.
CONCLUSIONS
Most TB cases in this cohort were potentially preventable had the patients undergone a screening TST followed by treatment of latent infection if they had a positive TST.
PMCID: PMC2866056  PMID: 19275796
tuberculosis; M. tuberculosis infection; tuberculin skin testing; human immunodeficiency virus; highly active antiretroviral treatment
17.  Tuberculosis and HIV Co-infection, California, USA, 1993–2008 
Emerging Infectious Diseases  2013;19(3):400-406.
To understand the epidemiology of tuberculosis (TB) and HIV co-infection in California, we cross-matched incident TB cases reported to state surveillance systems during 1993–2008 with cases in the state HIV/AIDS registry. Of 57,527 TB case-patients, 3,904 (7%) had known HIV infection. TB rates for persons with HIV declined from 437 to 126 cases/100,000 persons during 1993–2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co-infected with TB–HIV during 2001–2008 were significantly more likely than those infected before highly active antiretroviral therapy became available to be foreign born, Hispanic, or Asian/Pacific Islander and to have pyrazinamide-monoresistant TB. Death rates decreased after highly active antiretroviral therapy became available but remained twice that for TB patients without HIV infection and higher for women. In California, HIV-associated TB has concentrated among persons from low and middle income countries who often acquire HIV infection in the peri-immigration period.
doi:10.3201/eid1903.121521
PMCID: PMC3648844  PMID: 23622423
Tuberculosis; HIV; TB–HIV co-morbidity; HAART; California; Mycobacterium tuberculosis and other mycobacterial diseases; United States; co-infection; USA; highly active antiretroviral therapy
18.  Prevalent tuberculosis and mortality among HAART initiators 
AIDS (London, England)  2012;26(6):770-773.
The effect of tuberculosis on mortality in people initiating highly active antiretroviral treatment (HAART) remains unclear; here, we strengthened a previous cohort analysis. Multivariate Cox proportional hazards models were used to assess the association of baseline tuberculosis and time to all-cause mortality among HAART initiators. In reanalysis, treatment for tuberculosis at time of HAART initiation remained unassociated with increased risks of all-cause mortality, with adjusted hazard ratios ranging from 1.00 to 1.09.
doi:10.1097/QAD.0b013e328351f6b8
PMCID: PMC3348652  PMID: 22313956
19.  Short and Long-Term Incidence of Tuberculosis and CD4-Cell Count Dynamic on HAART in Senegal 
The Open AIDS Journal  2009;3:63-70.
Objectives:
Estimate tuberculosis (TB) incidence among patients receiving HAART. Compare the dynamic of the CD4-cell count and viral load before notification of the TB with the dynamic among patients remaining free of TB.
Design:
Prospective cohort with ascertainment of TB cases from medical records.
Methods:
The first 404 adults HIV-1 infected patients enrolled in the Senegalese antiretroviral drug access initiative were eligible. CD4-cell and viral load were assessed at baseline and every 6 months. Patients receiving an antituberculosis treatment at HAART initiation were excluded from analysis. Any TB case notified after the first month of HAART was considered as an incident case. Follow-up was censored at death or at the last visit before March 31, 2008. CD4-cell trajectories until TB notification were compared to non-TB developers within two distinct periods: from HAART initiation to 24 months and after.
Results:
Over 404 eligible patients, 352 were included in this analysis. Median follow-up reached 73 months and 1821 person-years were accrued. Half of the 42 incident cases were notified before month 19 of HAART yielding to an overall incident rate of 2.3/100 PY [1.7-3.1]. Annual incidence decreased with duration of HAART (trend in incidence: RR=0.26, p<10-4). During the first period, CD4-cell count dynamic of most TB patients was identical to the dynamic among patients remaining free of TB. Most cases of the second period occurred in a context of an immunological failure.
Conclusions:
This study provides an estimate of TB incidence among patients on HAART in Senegal and supports two underlying mechanisms.
doi:10.2174/1874613600903010063
PMCID: PMC2812839  PMID: 20148061
20.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Background
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
Methods
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Results
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Conclusions
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
doi:10.1186/1742-6405-9-4
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
21.  Trends of Mortality and Cause of Death among HIV-Infected Patients in Korea, 1990-2011 
Although a decrease in acquired immunodeficiency syndrome (AIDS)-related mortality has been documented in highly active antiretroviral therapy (HAART) era, there are no published data comparing specific causes of death between pre-HAART and HAART era in Korea. Mortality and cause of death were analyzed in three treatment periods; pre-HAART (1990-1997), early-HAART (1998-2001), and late-HAART period (2002-2011). The patients were retrospectively classified according to the treatment period in which they were recruited. Although mortality rate per 100 person-year declined from 8.7 in pre-HAART to 4.9 in late-HAART period, the proportion of deaths within 3 months of initial visit to study hospital significantly increased from 15.9% in pre-HAART to 55.1% in late-HAART period (P < 0.001). Overall, 59% of deaths were attributable to AIDS-related conditions, and Pneumocystis pneumonia (PCP) was the most common cause of death (20.3%). The proportion of PCP as cause of death significantly increased from 8.7% in pre-HAART to 31.8% in late-HAART period (P < 0.001). Despite of significant improvement of survival, there was still a high risk of early death in patients presenting in HAART era, mainly due to late human immunodeficiency virus (HIV) diagnosis and late presentation to care.
doi:10.3346/jkms.2013.28.1.67
PMCID: PMC3546107  PMID: 23341714
HIV; Antiretroviral Therapy; Mortality; Cause of Death
22.  Influenza-Related Mortality Among Adults Aged 25–54 Years With AIDS in South Africa and the United States of America 
In the absence of highly active therapy antiretroviral (HAART), adults with AIDS experience substantially elevated influenza-associated mortality in South Africa and the United States. This elevated mortality risk declined with widespread HAART introduction in the United States but did not disappear entirely. These data support increased access to HAART and influenza vaccination for human immunodeficiency virus–infected adults globally.
Background. Data are limited on human immunodeficiency virus (HIV)–associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States.
Methods. Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25–54 years in South Africa (1998–2005) and the United States (pre-HAART era, 1987–1994; HAART era, 1997–2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults ≥65 years old.
Results. In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49–460) and 208 (95% CI, 74–583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9–7.2) and 4.1 (95% CI, 1.4–13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16–121]); P&I RR, 73 [95% CI, 47–113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era.
Conclusions. Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults.
doi:10.1093/cid/cis549
PMCID: PMC3657519  PMID: 22715173
23.  Essentials of tuberculosis control for the practising physician. Tuberculosis Committee, Canadian Thoracic Society. 
OBJECTIVE: To recommend guidelines for the management of tuberculosis (TB), particularly in high-risk groups including poor and homeless people, aboriginal Canadians, immigrants from countries where TB is highly prevalent and people with HIV infection. OPTIONS: Diagnosis, pharmacotherapy, vaccination and chemoprophylaxis. OUTCOMES: Prevention of infection and diagnosis and cure of TB. EVIDENCE: The evidence was gathered in late 1992 from previous guidelines, recommendations by specialist societies and new studies. VALUES: Evidence was categorized into four levels: I, randomized clinical trials of therapeutic interventions or prospective studies of diagnostic strategies; II, case-control studies; III, retrospective descriptive studies; and IV, consensus of the committee members and published statements. The Tuberculosis Committee of the Canadian Thoracic Society comprises experts in TB from across Canada. BENEFITS, HARM AND COSTS: The benefits of early diagnosis and prompt initiation of therapy are well documented. The cost effectiveness of antituberculous therapy in developing countries is well documented. In developed countries chemoprophylaxis has been shown to be cost effective, and directly observed chemotherapy has recently been hypothesized to have economic benefits. RECOMMENDATIONS: In the appropriate clinical setting, particularly when patients are known to be at high risk of TB, clinicians should consider TB, reserve body secretions for mycobacteriologic tests and conduct other investigations such as chest radiography. Furthermore, if TB is strongly suspected or confirmed by appropriate investigation the early initiation of multi-drug therapy, including at least three first-line drugs, is strongly recommended. If drug resistance is suspected a regimen of four to five drugs, including at least two drugs with which the patient has not been treated, should be started. If the strain is found to be resistant to any of the drugs in the regimen appropriate changes should be made. Chemoprophylaxis should be considered especially in contacts with a recent significant reaction to the purified protein derivative (PPD) skin test and in people known to be at risk of reactivated TB infection, particularly those with HIV infection and a significant PPD skin-test result. Vaccination with bacillus Calmette-Guérin should be limited to high-risk groups, particularly aboriginal Canadians living on reserves. VALIDATION: These recommendations are based on a consensus of Canadian experts supported by other specialist societies and reference groups. They have been reviewed by the Standards Committee of the Canadian Thoracic Society. SPONSOR: The Canadian Lung Association and the Tuberculosis Committee of the Canadian Thoracic Society.
PMCID: PMC1336959  PMID: 8174026
24.  Factors Impacting Early Mortality in Tuberculosis/HIV Patients: Differences between Subjects Naïve to and Previously Started on HAART 
PLoS ONE  2012;7(9):e45704.
Background
Mortality among patients with tuberculosis (TB)/HIV is highest during the first few months of antituberculous therapy. The objective of this study was to assess the factors associated with early mortality among TB/HIV patients and whether these factors are similar for HAART naïve and those with prior HAART initiation.
Methods
Prospective cohort study including HIV patients with tuberculosis confirmed by culture, cared for at a referral center in Rio de Janeiro, Brazil. Multivariable Cox analysis was used to assess predictors of mortality within 3 months of antituberculous therapy.
Results
Among 227 patients included, 90 (40%) started HAART before TB diagnosis. The median time to TB diagnosis after ARV initiation was 5.9 months (interquartile range [IQR] 3.0–8.9 months). Fourteen patients (6%) died within the first 3 months. Mortality was not different between patients previously started on HAART and those who were naïve to it. In the overall adjusted analysis, HAART use during TB treatment (hazard ratio [HR] = 0.21, 95% confidential interval [CI] = 0.06–0.72) and CD4 lymphocyte count >100 cells/mm3 (HR = 0.21, 95% CI = 0.04–0.99) were associated with lower mortality, while subjects with unknown baseline CD4 lymphocyte count (HR = 9.39, 95% CI = 2.56–34.5) had higher mortality. In subgroup analysis, among HAART naïve subjects, disseminated TB (HR = 5.32, 95% CI = 1.09–25.8) and unknown baseline CD4 lymphocyte count (HR = 13.2, 95% CI = 2.71–64.5) were associated with significantly higher mortality, while HAART (HR = 0.14, 95% CI = 0.03–0.69) predicted a better outcome. Among subjects previously started on HAART, mortality was significantly associated with duration of TB symptoms >120 days (HR = 6.15, 95% CI = 1.15–32.9).
Conclusions
Predictors of early mortality among TB/HIV patients may vary according to the timing of HAART initiation. Among HAART naïve patients, mortality was influenced by baseline clinical severity, HAART use and, possibly, the quality of care preceding TB diagnosis. For patients with prior HAART initiation, longer delays in TB diagnosis predicted a significantly higher mortality.
doi:10.1371/journal.pone.0045704
PMCID: PMC3458068  PMID: 23049842
25.  Effect of Free Treatment and Surveillance on HIV-Infected Persons Who Have Tuberculosis, Taiwan, 1993–2006 
Emerging Infectious Diseases  2009;15(2):332-334.
In 1997, Taiwan made highly active antiretroviral therapy (HAART) available without cost to HIV-infected persons; in 2001, a national web-based surveillance system was implemented. Healthcare workers use the system to monitor patients' conditions and can intervene when necessary. Free HAART, coupled with the surveillance system, appears to have increased survival rates of HIV-infected persons with tuberculosis in Taiwan.
doi:10.3201/eid1502.081000
PMCID: PMC2657632  PMID: 19193288
HIV/TB coinfection; HAART; surveillance system; mortality; influenza A (H5N1); AZT

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