Tuberculosis Co-infected Patients Research Articles

Causes of mortality among tuberculosis and HIV co-infected patients in Chiang Rai, Northern Thailand.

BackgroundThe case fatality rate in patients with tuberculosis (TB) associated with human immunodeficiency virus (HIV) has been particularly high in Chiang Rai, Northern Thailand. It was almost 50% before the introduction of antiretroviral therapy in the last decade, and was still at 28% in 2008, despite expanding access to antiretroviral therapy. Reviewing the causes of death may lead to further understanding of the timeline and natural history of TB-HIV coinfection, and in so doing help to devise an effective prevention strategy in Chiang Rai. In this study, we aimed to investigate the distribution of confirmed causes of death in patients coinfected with TB and HIV in Chiang Rai, describe the causes of such deaths along the timeline of TB treatment, and identify predictors of each cause of death.MethodsIn this retrospective study, we reviewed the causes of death for 331 patients who died of TB-HIV coinfection at Chiang Rai Prachanukroh Hospital from 2005 to 2008. Causes of death were confirmed by reviewing medical records, vital registration, and the TB register in the province, as well as obtaining reconfirmation by two experienced HIV physicians.ResultsThe confirmed causes of death were TB (39%), acquired immune deficiency syndrome (AIDS)-related opportunistic infections other than TB (AOI) (29%), and other systemic diseases which were neither TB nor AIDS-related opportunistic infections (nonTB-nonAOI) (16%). The definitive cause could not be confirmed in the remaining 16% of deaths. After starting the TB treatment, deaths caused by TB occurred earlier compared with deaths caused by AOI, which occurred steadily throughout the course of TB treatment, whilst deaths caused by non-TB-nonAOI increased gradually in later months. Further analysis by multivariate multinomial regression analysis showed that deaths in the first month (adjusted odds ratio [aOR] 4.64, 95% confidence interval [CI] 2.49–8.63), CD4 count ≥ 200 cells/mm3 (aOR 5.33, CI 1.05–26.10), non-category 1 TB treatment regimens (aOR 5.23, CI 1.04–9.77), and TB meningitis (aOR 3.27, CI 1.37–7.82) were significant predictors of confirmed TB deaths. Moreover, age over 45 years (aOR 3, CI 1.32–6.84) and admission as an inpatient were predictors of death caused by neither TB nor AIDS-related opportunistic infections (aOR 3.08, CI 1.39–6.80). Additional analysis showed that non-Thai patients (aOR 0.35, CI 0.12–0.99), those with an unknown CD4 count at TB diagnosis (aOR 0.16, CI 0.08–0.33), and those without an HIV diagnosis before TB treatment (aOR 0.32, CI 0.18–0.59) were less able to access antiretroviral therapy.ConclusionThe timeline and predictors of causes of death may assist in devising an intervention strategy for further reduction of the TB-HIV case fatality rate.

The impact of asymptomatic helminth co-infection in patients with newly diagnosed tuberculosis in north-west Ethiopia.

BackgroundAreas endemic of helminth infection, tuberculosis (TB) and HIV are to a large extent overlapping. The aim of this study was to assess the impact of asymptomatic helminth infection on the immunological response among TB patients with and without HIV, their house hold contacts and community controls.MethodologyConsecutive smear positive TB patients (n = 112), their household contacts (n = 71) and community controls (n = 112) were recruited in Gondar town, Ethiopia. Stool microscopy, HIV serology, serum IgE level, eosinophil and CD4 counts were performed and tuberculosis patients were followed up for 3 months after initiation of anti-TB treatment.ResultsHelminth co-infection rate was 29% in TB patients and 21% in both community control and household contacts (p = 0.3) where Ascaris lumbricoides was the most prevalent parasite. In TB patients the seroprevalence of HIV was 47% (53/112). Eosinophilia and elevated IgE level were significantly associated with asymptomatic helminth infection. During TB treatment, the worm infection rate of HIV+/TB patients declined from 31% (10/32) at week 0 to 9% (3/32) at week 2 of TB treatment, whereas HIV−/TB patients showed no change from baseline to week 2, 29% (13/45) vs. 22.2% (10/45). This trend was stable at week 8 and 12 as well.ConclusionOne third of smear positive TB patients were infected with helminths. Eosinophilia and elevated IgE level correlated with asymptomatic worm infection, indicating an effect on host immunity. The rate of worm infection declined during TB treatment in HIV+/TB co-infected patients whereas no decline was seen in HIV−/TB group.

Mortality and loss to follow-up among tuberculosis and HIV co-infected patients in rural southwestern Uganda

We describe the presentation and outcome of care among patients with tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection from a prospective observational cohort in Uganda. We analysed basic demographics, CD4+ counts, time of initiating antiretroviral therapy (ART), clinical and haematological parameters and outcome of care of 386 patients enrolled between February 2007 and March 2010. At presentation, 56.7% of the patients were sputum-positive, 89.9% had new TB infection, 62.7% had wasting, 78.7% were anaemic, 72.1% had a CD4+ count of <200 cells/mm(3), 20.2% had pneumonia, 50.3% had oral thrush and 1.3% had Kaposi's sarcoma. Patients developing TB within 3 months of starting ART were less likely to have wasting, to be anaemic or to have a CD4+ count of <100 cells/mm(3). The cure, default and death rates were respectively 54.3%, 24% and 16%. At 8 months, 53 (13.7%) were confirmed dead, 119 (30.8%) were lost to follow-up, 28 (7.3%) were transferred out and 1 (0.3%) had treatment failure. Mortality and loss to follow-up were associated with failure to start ART and having a CD4+ count of <200 cells/mm(3). In Uganda, TB-HIV patients present with severe immune suppression and are at increased risk of death and loss to follow-up, particularly those not on ART. There is need for early identification and improved follow-up of TB-HIV co-infected patients.

Quality of life among tuberculosis (TB), TB retreatment and/or TB-HIV co-infected primary public health care patients in three districts in South Africa

IntroductionTB and HIV co-morbidity amount to a massive burden on healthcare systems in many countries. This study investigates health related quality of life among tuberculosis (TB), TB retreatment and TB-HIV co-infected public primary health care patients in three districts in South Africa.MethodsA cross sectional study was conducted among 4900 TB patients who were in the first month of anti-TB treatment in primary public health care clinics in three districts in South Africa. Quality of life was assessed using the social functioning (SF)-12 Health Survey through face to face interviews. Associations of physical health (Physical health Component Summary = PCS) and mental health (Mental health Component Summary = MCS) were identified using logistic regression analyses.ResultsThe overall physical and mental health scores were 42.5 and 40.7, respectively. Emotional role, general health and bodily pain had the lowest sub-scale scores, while energy and fatigue and mental health had the highest domain scores. Independent Kruskal–Wallis tests found significant positive effects of being TB-HIV co-infected on the domains of mental health functioning, emotional role, energy and fatigue, social function and physical role, while significant negative effects were observed on general health, bodily pain and physical function. In multivariable analysis higher educational, lower psychological distress, having fewer chronic conditions and being HIV negative were significantly positively associated with PCS, and low poverty, low psychological distress and being HIV positive were positively significantly associated with MCS.ConclusionTB and HIV weaken patients’ physical functioning and impair their quality of life. It is imperative that TB control programmes at public health clinics design strategies to improve the quality of health of TB and HIV co-infected patients.

Proportion of multidrug-resistant tuberculosis in human immunodeficiency virus/mycobacterium tuberculosis co-infected patients in Korea.

Much controversy surrounds the issue of whether HIV infection is a risk factor for developing multidrug-resistant tuberculosis (MDR-TB). In this study, we evaluated the prevalence of and risk factors for MDR-TB in HIV-infected patients at the National Medical Center of Korea. We reviewed the medical records of HIV/TB co-infected patients from January 2005 to May 2011; the drug susceptibility profiles were available for 55 patients. Of these, 32.7% had MDR-TB, which was approximately 3.6 times higher than the prevalence among the general population. Additionally, there were more additional AIDS-defining clinical illnesses in the MDR-TB group than in the non-MDR-TB group (27.8% vs 5.4%, P = 0.032). These results suggest that HIV infection and HIV-related immunosuppresion may contribute to the development of MDR-TB.

Pharmacogenetic &amp; Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based Anti-TB Drug Induced Liver Injury in TB-HIV Infected Patients

BackgroundImplication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients.Methods and FindingsNewly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001).ConclusionWe report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

Antiretroviral treatment uptake and attrition among HIV-positive patients with tuberculosis in Kibera, Kenya

Using data of human immunodeficiency virus-positive patients with tuberculosis from three primary care clinics in Kibera slums, Nairobi, Kenya, we report on the proportion that started antiretroviral treatment (ART) and attrition (deaths, lost to follow-up and stopped treatment) before and while on ART. Of 427 ART eligible patients, enrolled between January 2004 and December 2008, 70% started ART, 19% were lost to attrition and 11% had not initiated ART. Of those who started ART, 14% were lost to attrition, making a cumulative pre-ART and ART attrition of 33%. ART uptake among patients with TB was relatively good, but programme attrition was high and needs urgent addressing.

The antiretroviral efficacy of highly active antiretroviral therapy and plasma nevirapine concentrations in HIV-TB co-infected Indian patients receiving rifampicin based antituberculosis treatment

BackgroundRifampicin reduces the plasma concentrations of nevirapine in human immunodeficiency virus (HIV) and tuberculosis (TB) co-infected patients, who are administered these drugs concomitantly. We conducted a prospective interventional study to assess the efficacy of nevirapine-containing highly active antiretroviral treatment (HAART) when co-administered with rifampicin-containing antituberculosis treatment (ATT) and also measured plasma nevirapine concentrations in patients receiving such a nevirapine-containing HAART regimen.Methods63 cases included antiretroviral treatment naïve HIV-TB co-infected patients with CD4 counts less than 200 cells/mm3 started on rifampicin-containing ATT followed by nevirapine-containing HAART. In control group we included 51 HIV patients without tuberculosis and on nevirapine-containing HAART. They were assessed for clinical and immunological response at the end of 24 and 48 weeks. Plasma nevirapine concentrations were measured at days 14, 28, 42 and 180 of starting HAART.Results97 out of 114 (85.1%) patients were alive at the end of 48 weeks. The CD4 cell count showed a mean increase of 108 vs.113 cells/mm3 (p=0.83) at 24 weeks of HAART in cases and controls respectively. Overall, 58.73% patients in cases had viral loads of less than 400 copies/ml at the end of 48 weeks. The mean (± SD) Nevirapine concentrations of cases and control at 14, 28, 42 and 180 days were 2.19 ± 1.49 vs. 3.27 ± 4.95 (p = 0.10), 2.78 ± 1.60 vs. 3.67 ± 3.59 (p = 0.08), 3.06 ± 3.32 vs. 4.04 ± 2.55 (p = 0.10) respectively and 3.04 μg/ml (in cases).ConclusionsGood immunological and clinical response can be obtained in HIV-TB co-infected patients receiving rifampicin and nevirapine concomitantly despite somewhat lower nevirapine trough concentrations. This suggests that rifampicin-containing ATT may be co administered in resource limited setting with nevirapine-containing HAART regimen without substantial reduction in antiretroviral effectiveness. Larger sample sized studies and longer follow-up are required to identify populations of individuals where the reduction in nevirapine concentration may result in lower ART response or shorter response duration.

High Incidence of Hospital Admissions With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Among South African Health Care Workers

Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. Hospital admission rates and hospital admission incidence rate ratios. Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Barriers and outcomes: TB patients co-infected with HIV accessing antiretroviral therapy in rural Zambia

The vulnerabilities that underlie barriers faced by the rural poor whilst trying to access and adhere to “free” antiretroviral treatment (ART) demand more attention. This paper highlights barriers that poor rural Zambians co-infected with tuberculosis (TB) and HIV and their households faced in accessing ART between September 2006 and July 2007, and accounts for patient outcomes by the end of TB treatment and (more sporadically) beyond October 2009. The analysis draws on findings from wider anthropological fieldwork on the converging impact of TB, HIV and food insecurity, focusing for the purpose of this paper on ethnographic case-studies of seven newly diagnosed TB patients co-infected with HIV and their six households (one household had two TB patients). Economic barriers included being pushed into deeper poverty by managing TB, rural location, absence of any external assistance, and mustering time and extended funds for transport and “special food” during and beyond the end of TB. In the case of death, funeral costs were astronomical. Social barriers included translocation, broken marriages, a sub-ordinate household position, gender relations, denial, TB/HIV stigma and the difficulty of disclosure. Health facility barriers involved understaffing, many steps, lengthy procedures and inefficiencies (lost blood samples, electricity cuts). By the end of TB treatment, outcomes were mixed; two co-infected patients had died, three had started ART and two had yet to start ART. The three on ART underwent a striking transformation in the short term. By October 2009, two more had died and three were doing well. The study advocates nutritional support and other material support (especially transport funds) for co-infected TB patients until ART is accessed and livelihood regained. More prompt diagnosis of TB and reducing steps and increasing the reach of the ART programme in rural areas are also recommended.

Management of individuals requiring antiretroviral therapy and TB treatment.

Globally, tuberculosis (TB) is the commonest opportunistic infection in people living with HIV. Many co-infected patients first present with advanced immunosuppression and require antiretroviral therapy (ART) initiation during TB treatment. The incidence of TB in patients established on ART remains high. Co-treatment presents several management challenges. Recent data on these management issues are reviewed. Efavirenz concentrations at standard doses are similar with and without concomitant rifampicin-based TB treatment. Nevirapine concentrations are frequently subtherapeutic during lead-in dosing at 200 mg daily in patients on rifampicin-based TB treatment, which may result in inferior virological outcomes. Hepatotoxicity occurred in three pharmacokinetic studies (conducted in healthy volunteers) of boosted protease inhibitors initiated in participants on rifampicin. Results of a clinical trial comparing efavirenz-based and nevirapine-based ART in patients on TB treatment, with no lead-in dosing of nevirapine, are awaited. Concurrent TB treatment increases the need for stavudine substitutions, mainly related to neuropathy. Consensus case definitions for TB immune reconstitution inflammatory syndrome (TB-IRIS) have been published. It is important to exclude TB drug resistance in patients with suspected TB-IRIS. A clinical trial demonstrated benefit of prednisone for treating TB-IRIS, reducing a combined endpoint of days of hospitalization and outpatient therapeutic procedures. Starting ART during TB treatment improved survival in patients with CD4 cell count less than 500 cells/mul, but the optimal interval between starting TB treatment and starting ART remains to be determined in several ongoing trials. ART improves survival in co-infected TB patients, but is complicated by several management challenges that compromise programmatic implementation in resource-limited settings. Recent findings and the findings of ongoing studies will assist clinicians in dealing with these challenges.

Tuberculosis and HIV co-infection: its impact on quality of life

Background-Very little is known about the quality of life of tuberculosis (TB) and HIV co-infected patients. In this study in Ethiopia, we compared the quality of life HIV positive patients with and without TB.Methods-A cross sectional study was conducted from February to April, 2009 in selected hospitals in Oromiya Regional state, Ethiopia. The study population consisted of 467 HIV patients and 124 TB/HIV co-infected patients. Data on quality of life was collected by trained nurses through face to face interviews using the short Amharic version of the World Health Organization Quality of Life Instrument for HIV clients (WHOQOL HIV). Depression was assessed using a validated version of the Kessler scale. Data was collected by trained nurses and analyzed using SPSS 15.0 statistical software.ResultsTB/HIV co-infected patients had a lower quality of life in all domains as compared to HIV infected patients without active TB. Depression, having a source of income and family support were strongly associated with most of the Quality of life domains. In co-infected patients, individuals who had depression were 8.8 times more likely to have poor physical health as compared to individuals who had no depression, OR = 8.8(95%CI: 3.2, 23). Self-stigma was associated with a poor quality of life in the psychological domain.Conclusion-The TB control program should design strategies to improve the quality of life of TB/HIV co-infected patients. Depression and self-stigma should be targeted for intervention to improve the quality of life of patients.

Antiretroviral Drug-Resistant Mutations at Baseline and at Time of Failure of Antiretroviral Therapy in HIV Type 1-Coinfected TB Patients

There is limited information on the prevalence and pattern of HIV drug-resistant mutations (DRMs) among HIV-1-coinfected tuberculosis (TB) patients before and after antiretroviral treatment. Patients with HIV-1 and TB were recruited into a clinical trial from two different once-daily antiretroviral regimens and followed for a period of 6 months after ART initiation. Patients were treated with standard short-course anti-TB treatment (2EHRZ3/4RH3) and were randomized to receive ddI/3TC with either nevirapine or efavirenz, once daily. Genotypic drug resistance (DR) testing was carried out for the pol gene at baseline and at the time of virological failure. At baseline, major DRMs with respect to NNRTIs (G190GA) and TAMs (T215S and I) were observed in 3 out of 107 patients. Of 15 treatment failures, 14 had more than one major NRTI and NNRTI mutation. V106M was the major NNRTI mutation that emerged in EFZ and Y181C in the NVP group. Among NRTI mutations, M184V was the commonest followed by L74I/V. Primary drug resistance to antiretroviral drugs was low among HIV-1 co-infected TB patients in south India. A once-daily regimen of ddI/3TC/EFZ or NVP results in a specific pattern of NNRTI mutations and negligible thymidine analog mutations (TAMs).

The association between HIV and antituberculosis drug resistance

In the UK, HIV is considered to be a risk factor for antituberculosis drug resistance. Evidence of the association is, however, inconclusive and there are few population-level data. The present study investigated the association in England and Wales during the period 1999-2005. National tuberculosis surveillance data for adults were matched to HIV/AIDS reports. Unmatched cases were assumed to be HIV-negative. Separate analyses were conducted on new tuberculosis cases and those with a previous diagnosis. Logistic regression was used for univariable and multivariable analyses. There were 1,657 previously diagnosed cases (80 HIV-positive) and 18,130 new cases (1,156 HIV-positive). Isoniazid resistance was found in 8.1% of previously diagnosed cases and 6.6% of new cases, and multidrug resistance in 2.8% and 0.7%, respectively. There was no evidence of an association between HIV and antituberculosis drug resistance among previously diagnosed cases. Among new cases, there was no overall association between HIV and isoniazid or multidrug resistance after adjusting for confounding factors. White HIV-positive patients were more likely to have multidrug resistance, but numbers were small. In contrast to some previous studies, this large, up-to-date study provides little evidence that HIV co-infected tuberculosis patients in England and Wales are at increased risk of firstline antituberculosis drug resistance.

Cytokine pattern in Kaposi's sarcoma associated with immune restoration disease in HIV and tuberculosis co-infected patients

We analysed the evolution of different cytokines (IL-4, IL-6, tumour necrosis factor alpha and vascular endothelial growth factor; VEGF) involved in the development of Kaposi's sarcoma in two patients in whom HIV infection presented with disseminated Mycobacterium tuberculosis infection. They simultaneously developed tuberculosis-associated immune restoration disease and Kaposi's sarcoma shortly after the initiation of HAART. Analysis of VEGF and pro-inflammatory cytokines led us to hypothesize that Kaposi's sarcoma could be promoted by the tuberculosis immune response.

Association between ABO, Rheus blood group systems and haemoglobin genotype among confirmed HIV/AIDS-TB co-infected patients in Enugu urban, Nigeria

The distribution of ABO, Rhesus blood group and haemoglobin (Hb) genotypes was investigated among 320 confirmed human immunodeficiency virus I & II (HIV)/acquired immunodeficiency syndrome (AIDS) with tuberculosis (TB) co-infected patients. One Hundred and Sixty (160) healthy HIV I & II negative age and sex-matched population were used as controls for this study. Patients and controls were from the same environment and their blood groups and Hb genotypes were determined by the standard tube and electrophoresis methods respectively. The statistical analysis of the results revealed statistically significant association (P<0.01) between Hb-genotype among female patients and female controls chi-squared = 6.099, P<0.01, and also between patient and control groups of both sexes chi-squared = 7.4561, p<0.01 only. We conclude that HIV I & II/AIDs with TB co-infection among Nigerians so far studied appear to show no association in the distribution of ABO, Rhesus blood group and Hb-genotype prevalence. Hence they cannot be said to have either protective nor predisposing characteristics.

Immune reconstitution syndrome in tuberculosis and HIV-co-infected patients: Th1 explosion or cytokine storm?

The article ‘Explosion of tuberculin-specific Th1 responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients’ by Bourgarit and colleagues [1] explores the immunological changes underlying the immune reconstitution syndrome (IRS). The paper is the first to apply a broad proteomic approach, and highlights very important aspects of this complex immunological phenomenon. The authors analyse the in-vitro production of 25 inflammatory and immunomodulatory cytokines, chemokines and soluble cytokine receptors in supernatants of purified protein derivative-stimulated peripheral blood mononuclear cells from four patients (three undergoing IRS, one not undergoing IRS). The authors classify the immune molecules in the following fashion: T helper cell (Th) type 1-related cytokines/chemokines (IFN-γ, IL-2, IL-12, IFN-γ-inducible protein 10 and monokine induced by IFN-γ); Th2 cytokines (IL-4, IL-5, IL-13 and IL-15); inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1b, IL-10, regulated upon activation: normal T cell expressed/secreted and monocyte chemoattractant protein 1). The markers IL-1 receptor antagonist (IL-1RA), IL-2 receptor, IL-7, IL-8, IL-17, granulocyte macrophage colony-stimulating factor, macrophage inflammatory proteins 1α and 1β are measured, but data are not presented. On the basis of this classification of cytokines, the authors propose ‘that an excessive restoration of purified protein derivative-specific Th1 response with no Th2 balance is responsible for the enlargement of TB granuloma lesions and is associated with an acute release of non-specific pro-inflammatory cytokines and chemokines inducing the systemic inflammatory syndrome’. In the present study, however, IL-10 is classified as a non-specific inflammatory cytokine, and IL-15 as a Th2 cytokine. IL-10 is well established as a classic Th2 and anti-inflammatory cytokine [2]. IL-15 is a pro-inflammatory cytokine sharing many functions with IL-2 [3]. With the correct classification of the presented cytokine measurements, the results are an increase in purified protein derivative-specific Th1 cytokines/chemokines (IFN-γ, IL-2, IL-12, IFN-γ-inducible protein 10 and monokine induced by IFN-γ), in non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, regulated upon activation: normal T cell expressed/secreted and monocyte chemoattractant protein 1), and in the Th2/anti-inflammatory cytokine IL-10, coinciding with the development of IRS symptoms. Therefore, on the basis of the data presented in the article, the IRS seems more likely to be induced by an explosion of Th1, Th2, and non-specific inflammatory mediators simultaneously, i.e. a cytokine storm [4]. Although measured, the authors fail to comment on the production of the two non-specific anti-inflammatory immune effectors IL-1RA and soluble IL-2 receptor. As non-specific anti-inflammatory cytokine and soluble receptor production represent naturally occurring inflammation inhibitors, the study of markers from this class is essential for the understanding of IRS. We have recently found high levels of IL-1RA in 1: 8 diluted plasma of whole blood culture stimulated with the tuberculosis specific antigens ESAT-6, CFP-10 and TB7.7 (unpublished observations). Patients with active tuberculosis produced antigen-specific IL-1RA responses of a median 2282 pg/ml (range 162–4432 pg/ml; Fig. 1), equivalent to 18 256 pg/ml in undiluted sample. Future studies are needed to elucidate the effects of these immune mediators during IRS, and should compare whole blood with peripheral blood mononuclear cell culture and take cytokine kinetics into consideration [5].Fig. 1: Antigen-specific IL-1 receptor antagonist production in whole blood culture. Whole blood of eight Quantiferon In Tube-positive, culture or sputum-positive tuberculosis (TB) patients and seven healthy tuberculosis-unexposed controls was stimulated for 20–24 h with either saline or Mycobacterim tuberculosis-specific antigens in the Quantiferon In Tube system. IL-1 receptor antagonist (IL-1RA) production was measured in 1: 8 diluted plasma by multiplex technology on the Luminex platform (Luminex, Riverside, California, USA) using Biosource reagents (Biosource, Camarillo, California, USA). Antigen-specific production represent the antigen-stimulated sample subtracted from the saline sample. Straight lines represent median values. Differences between healthy controls and patients were significant at P < 0.0006 (Kruskal–Wallis test).On the basis of current knowledge it is tempting to hypothesize that the immunological basis of IRS is a HAART-induced rapid clonal expansion and redistribution of Mycobacterium tuberculosis-specific memory T cells [6], which drives a deregulated immune activation [7] and a cytokine storm [1]. The deregulated immune function could be the consequence of the fact that an HIV-induced loss of thymic-derived cell populations (naive T cells [8] and natural regulatory T cells [9,10]) are restored at much slower kinetics compared with the peripheral memory T-cell population after HAART [6,8]. Tuberculosis-specific regulatory T cells have recently been demonstrated [11], and murine data have shown that regulatory T cells dampen the symptoms of IRS [12]. Therefore, because of a lack of naturally occurring regulatory T cells in the first months of HAART treatment, there is a basis of deregulated memory T-cell expansion leading to a cytokine storm and the development of IRS. Acknowledgements The authors would like to thank Kristian Kofoed, MD, for helpful comments. Sponsorship: MR is a PhD student holding a Scholarship from Copenhagen University Hospital; PR is supported by the Thorvald Madsen, Custer of International Health.

Mechanisms of Polymorphonuclear Neutrophil–Mediated Induction of HIV‐1 Replication in Macrophages during Pulmonary Tuberculosis

Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBP beta ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta . Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBP beta expression. PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis

To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs). Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients

To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV-tuberculosis (TB) coinfected patients. Prospective, multicenter study of 19 consecutive untreated HIV-TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS- if no IRS occurred within 3 months after HAART initiation. Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-gamma quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-gamma-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6- but no 85B-specific responses. IRS- patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-gamma, IP10 and monokine-induced by IFN-gamma] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-alpha, IL-6, IL-1beta, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.