Tuberculosis Then and Now: Perspectives on the History of an Infectious Disease

The global pandemic of drug sensitive tuberculosis (TB) as well as the increasing threat from various multidrug resistant forms of TB drives the quest for newer, safer, more effective TB treatment options. The general lack of success in progressing novel chemical matter from high throughput screens of Mycobacterium tuberculosis (M.tb) biochemical targets has prompted resurgence in interest and efforts in prosecuting mycobacterial phenotypic screens. Whole cell active compounds identified from such screens offer significant intrinsic advantages over biochemical screening hits, and derivatives of many of these have proven invaluable in helping to fill the current TB drug development pipeline. Modern techniques for "de-orphaning" such screening hits (i.e., determining their specific biological mechanism of action) offer the possibility of ultimately identifying improved next-generation chemical series by screening these essential, pharmacologically validated biochemical targets as well.

Tuberculosis (TB) represents the largest cause of death in human immunodeficiency virus (HIV)-infected individuals in part due to HIV-related CD4+ T cell loss, rendering patients immunocompromised and susceptible to a loss of Mycobacterium tuberculosis control. However, in light of increasing data pointing to a role for humoral immunity in controlling M. tuberculosis infection, here, we aimed to define whether HIV infection also alters the humoral immune response in subjects with active and latent TB. We show that in the setting of active TB, HIV-positive individuals have significantly lower IgG responses to LAM and Ag85 than HIV-negative individuals. Furthermore, significant isotype/subclass-specific differences were frequently observed, with active TB, HIV-positive individuals demonstrating compromised antigen-specific IgM titers. HIV-infected individuals with active TB also exhibited a significant loss of influenza hemagglutinin- and tetanus toxoid-specific antibody titers at the isotype/subclass level, a symptom of broad humoral immune dysfunction likely precipitated by HIV infection. Finally, we illustrated that despite the influence of HIV infection, differences in M. tuberculosis-specific antibody profiles persist between latent and active TB disease. Taken together, these findings reveal significant HIV-associated disruptions of the humoral immune response in HIV/TB-coinfected individuals.IMPORTANCE TB is the leading cause of death from a single infectious agent globally, followed by HIV. Furthermore, TB represents the leading cause of death among people with HIV. HIV is known to cause severe defects in T cell immunity, rendering HIV/TB-coinfected individuals more susceptible to TB disease progression and complicating accurate TB disease diagnosis. Here, we demonstrate that HIV infection is additionally associated with severely compromised antibody responses, particularly in individuals with active TB. Moreover, despite the influence of HIV infection, antibody profiles still allow accurate classification of individuals with active versus latent TB. These findings reveal novel immunologic challenges associated with HIV/TB coinfection and additionally provide a basis with which to leverage the key antibody features identified to potentially combat TB globally via next-generation therapeutic or diagnostic design.

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.

Current Concepts in the Management of Tuberculosis

(See the article by Gupta et al, on pages 358–362) Tuberculosis (TB) is the most important infectious cause of disease and death in women residing in areas where TB is endemic, such as sub-Saharan Africa and Asia [1]. Traditionally, the majority of TB cases reported were in men, but the global human immunodeficiency virus (HIV) epidemic induced major changes in TB epidemiology. The preponderance of HIV-infected women (women account for up to 70% of HIV-infected adults in areas where heterosexual HIV transmission is dominant) may explain why more women than men receive a diagnosis of TB in countries where HIV infections prevalence is high [2]. TB and TB-HIV coinfection are associated with poor pregnancy outcomes, including intrauterine growth retardation, prematurity and fetal death, and infant and maternal disease and death [3]. Although there is general awareness regarding the greatly increased TB risk experienced by immunocompromised individuals, the risk that TB may enhance HIV transmission and/or disease progression is less appreciated. Animal models that explore possible TB-HIV interactions include macaques coinfected with simian immunodeficiency virus and Mycobacterium bovis bacille Calmette-Guerin (BCG). M.bovis BCG infection causes marked T lymphocyte activation with increased plasma viral loads, reduced CD4 cell counts, and accelerated HIV disease progression [4, 5]. Studies evaluating TB-HIV interactions in humans have also demonstrated immune activation, with resultant increases in viral load [6, 7]. Its clinical and epidemiological relevance is less well defined [8], but its potential contribution to HIV pathogenesis and transmission has been recognized [7, 8]. In this issue of the Journal, Gupta et al study the contribution of maternal TB as a risk factor for mother-to-child transmission (MTCT) of HIV infection [9]. Limiting MTCT of HIV infection is a major public health priority, because every infant infected with HIV represents a preventable event. Early initiation of life-long antiretroviral therapy saves lives and improves the outcomes in HIV-infected infants [10], but this comes at a huge cost to the health care system and a multitude of long-term adverse effects. The study by Gupta et al, conducted in India, used data from 783 mother–infant pairs enrolled in the prospective, randomized, placebo-controlled six week extended-dose nevirapine trial [11]. The primary aim of the trial was to compare rates of MTCT with use of a single dose, compared with daily nevirapine for 6 weeks, in breastfed infants. Although TB cases were limited (only 33), the rate of MTCT was significantly higher (30% vs 12%) in mothers with TB. Excluding the 3 cases with prevalent TB, the number of mothers with incident TB (30 of 780) equates to a TB incidence of 3846 cases/100,000 population/year, which is exceptionally high, compared with the expected background TB incidence. Maternal viral load and CD4 cell count were strongly associated with HIV MTCT. Increased viral load resulting from chronic immune stimulation in patients with TB probably accounts for much of the increased HIV MTCT risk observed; however, a significantly increased risk persisted in multivariate analysis despite correcting for maternal viral load, CD4 cell count, and other relevant factors. Potential mechanistic explanations for this phenomenon are of interest. One of the reasons why pregnant women are thought to be more vulnerable to developing TB is Th-1 down regulation to accommodate the growing fetus. The strong Th-1 stimulus provided by TB may increase placental inflammation, explaining some of the adverse fetal outcomes observed and the increased risk of in utero HIV MTCT. In fact, the majority of infant HIV infections were detected at delivery (indicating in utero transmission) and in very close proximity to the maternal TB diagnosis. Apart from the significant independent association demonstrated between maternal TB and infant HIV infection, the clustering of the 2 events (maternal TB diagnosis and infant HIV infection diagnosis) also suggests a possible causal relationship. It demonstrates that prevention of TB among HIV-infected mothers should be considered as part of a well-functioning prevention of HIV MTCT program. The exceptionally high TB disease and transmission risk provides additional motivation to carefully monitor all HIV-infected women for TB during and after pregnancy [12]. More operational research is required to clearly define the feasibility, benefits, and risks of providing routine TB preventive therapy to HIV-infected pregnant mothers in areas where TB is endemic [13]. In 2000, world leaders signed the United Nations Millennium Declaration and agreed to meet 8 Millennium Development Goals by 2015. These included a strong focus on maternal and child health, control of major infectious diseases, and other issues of global importance, such a poverty alleviation, environmental sustainability, and biodiversity protection. From 1995 through 2008, 43 million patients with TB were treated and 36 million were cured through TB control efforts. Despite this achievement, an estimated 9.4 million new cases of TB occurred in 2008, with 1.7 million TB-related deaths (more than half among women) [14]. Although the burden of childhood TB remains poorly quantified, TB clearly has a major impact on child health and under-5 mortality in areas where TB is endemic [1]. A prospective pediatric surveillance study from South Africa demonstrated that TB is a major cause of community-acquired pneumonia not responding to first-line antibiotics [15], and a Zambian autopsy study confirmed TB to be a common cause of death in children, irrespective of their HIV status [16]. These deaths are frequently misclassified as pneumonia-related deaths, because diagnostic facilities and expertise to diagnose childhood TB are limited [17]. There is huge opportunity to improve the provision of preventive therapy and TB diagnostic services to young and vulnerable children, irrespective of their HIV status [13]. It is evident that TB has a major impact on maternal and child health in areas where TB is endemic, with HIV-infected mothers and their young children being particularly vulnerable. This includes direct effects on morbidity and mortality, but also multiple indirect effects that trap people in a vicious circle of poverty and vulnerability [14], even facilitating vertical transmission of HIV, as demonstrated by Gupta et al (9). The renewed global focus on maternal and child health as key components of a healthy society is welcomed with enthusiasm, but adequate recognition must be given to the importance of TB control and prevention in areas where TB is endemic.

TB ALERT

TB ALERT: Author's response

Downwards trends in adolescent risk-taking behaviours in New Zealand: Exploring driving forces for change.

To determine the treatment success rate among TB patients and associated factors in Anambra and Oyo, the two states with the largest burden of tuberculosis in Nigeria. A health facility record review for 2016 was conducted in the two states (Anambra and Oyo). A checklist was used to extract relevant information from the records kept in each of the selected DOTS facilities to determine TB treatment success rates. Treatment success rate was defined as the proportion of new smear-positive TB cases registered under DOTS in a given year that successfully completed treatment, whether with bacteriologic evidence of success ('cured') or without ('treatment completed'). Treatment success rate was classified into good (≥85%) and poor (<85%) success rates using the 85% national target for TB treatment outcome. Data were analysed using descriptive statistics and chi-square at P<0.05. There were 1281TB treatment enrollees in 2016 in Anambra and 3809 in Oyo (total=4835). An overall treatment success rate of 75.8% was achieved (Anambra-57.5%; Oyo-82.0%). The percentage cure rates were 61.5% for Anambra and 85.2% for Oyo. Overall, only 28.6% of the facilities in both states (Anambra-0.0%; Oyo-60.0%) had a good treatment success rate. More facilities in Anambra (100.0%) than Oyo (40.0%) had a poor treatment success rate (p<0.001), as did more private/FBO (100.0%) than public health facilities (60.0%) (p=0.009). All tertiary facilities had a poor treatment success rate followed by 87.5% of secondary health facilities and 56.5% of primary healthcare facilities (P=0.035). Treatment success and cure rates in Anambra state were below the 85.0% of the recommended target set by the WHO. Geographical location, and level/tier and type of facility were factors associated with this. Interventions are recommended to address these problems.

Introduction The HIV/AIDS pandemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection in many developing countries. Treatment of Mycobacterium tuberculosis in persons with HIV infection presents several challenges to the clinician, particularly in resource-poor countries. As will be discussed in this paper, diagnosis of latent tuberculosis relies on tuberculin skin testing, which has poor sensitivity and reproducibility in immunocompromised patients. The World Health Organization (WHO) recommends treatment of active tuberculosis as the primary means of global tuberculosis control. In practice, treatment of active tuberculosis typically requires that a symptomatic patient self-report to a health service for evaluation and management. Even if this approach to tuberculosis control were sufficient, many logistic and clinical problems remain involving tuberculosis diagnosis and therapy in the patient with HIV/AIDS. Recognizing the significant clinical and public health challenges surrounding the treatment of tuberculosis in patients with HIV infection, this paper will address a number of issues relevant to the care of co-infected patients. These include current guidelines for the treatment of active tuberculosis, as well as the diagnosis and treatment of latent tuberculosis in HIV-positive patients. The paper concludes with a discussion of promising new drugs for tuberculosis treatment. Epidemiology of tuberculosis and HIV co-infection It is estimated that one-third of the world population is infected with M. tuberculosis, the large majority of whom live in the developing world. The HIV pandemic of the past two decades has led to a rise in the incidence of tuberculosis, particularly in sub-Saharan Africa. There is now an emerging pandemic of patients with HIV infection who are co-infected with tuberculosis. As of December 2000, the WHO estimated that approximately 36.1 million persons worldwide are living with HIV and nearly one-third of these persons are co-infected with M. tuberculosis[1]. Approximately 68% of persons co-infected with HIV and tuberculosis live in sub-Saharan Africa, while 22% live in Southeast Asia. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that approximately 40% of new tuberculosis cases among persons aged 15-44 years occur among individuals with HIV infection or AIDS. Tuberculosis rates among HIV-infected individuals in the United States, however, vary significantly among different groups, with highest rates among intravenous drug users and those who are foreign-born. Today, the burden of tuberculosis and HIV infections largely impacts the developing world, as well as the minority and low socio-economic individuals within industrialized countries. This paper will discuss issues in the treatment of M. tuberculosis in patients with HIV/AIDS; however, it is important to recognize that many patients co-infected with HIV and M. tuberculosis have limited or no access to essential diagnostic and therapeutic strategies. Escalating tuberculosis case rates over the past decade are largely attributable to HIV. Immunity to M. tuberculosis is partly under the control of the MHC class II restricted CD4 cells. With the progressive loss of CD4 cells, patients with HIV infection are at increased risk of reactivation of latent tuberculosis, as well as primary tuberculosis infection [2]. In turn, active tuberculosis infection appears to upregulate HIV replication, resulting in further immune compromise and accelerated HIV disease progression [3,4]. As a result, patients with HIV infection and active tuberculosis are at increased risk of opportunistic infections and associated mortality. The case fatality rate by the end of tuberculosis treatment is approximately 20% for new sputum smear-positive cases and up to 50% for new smear-negative cases [5]. Tuberculosis is the leading cause of death among persons with HIV/AIDS worldwide [6]. Guidelines for the treatment of active tuberculosis This section will review recent guidelines for the treatment of tuberculosis published by the Tuberculosis Committee of the Infectious Disease Society of America (IDSA) in conjunction with the American Thoracic Society (ATS) and the CDC [7,8]. In addition, we will review the Directly Observed Treatment Short-course (DOTS) strategy of the WHO for tuberculosis control worldwide. These published guidelines pertain to the treatment of tuberculosis without respect to the patient's HIV status. Modified recommendations for the treatment of tuberculosis in HIV-seropositive patients will be discussed in the following section. In April 2000, the IDSA published practice guidelines for the treatment of tuberculosis [7]. Table 1, adapted from the IDSA publication, lists the 10 essential recommendations for the treatment of patients with tuberculosis. Readers are referred to the original publication for detailed comments pertaining to these recommendations, as well as performance indicators. It should be noted that the IDSA recommendations were developed for use in industrialized nations such as the United States and are currently not feasible in many countries of the world. In Table 1, therefore, we have juxtaposed the WHO DOTS strategy guidelines for management of patients with tuberculosis.Table 1: Infectious Disease Society of America (IDSA) recommendations and World Health Organization Directly Observed Treatment Shortcourse (WHO DOTS) strategy for the management of patients with tuberculosis (TB).In geographic areas where ≥ 4% of the M. tuberculosis isolates are resistant to isoniazid, the IDSA, ATS, and CDC recommend that the usual three-drug regimen of isoniazid, rifampin and pyrazinamide be augmented with a fourth drug, either ethambutol or streptomycin. Clinicians will therefore need to be aware of the susceptibility patterns in their geographic area. In 1997, approximately 84% of the US population lived in states that had ≥ 4% of tuberculosis isolates resistant to isoniazid. Therefore, most patients in the United States should be started on an initial four-drug regimen. This is followed by isoniazid and rifampin for 18 weeks. Although a 6-month course of treatment is recommended, this should be extended to 9 months if there is a delay in AFB, culture conversion or clinical improvement for 8 weeks. The WHO Global Tuberculosis Programme (WHO/GTP) assists over 60 countries with national tuberculosis control and prevention. The priority of the WHO program has been active case finding and cure of infectious tuberculosis cases. In 1993, the WHO/GTP declared tuberculosis a global emergency and began promoting the DOTS strategy. The DOTS strategy consists of five key components: "1) Government commitment to sustained TB control activities; 2) Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services; 3) Standardized treatment regimen of six to eight months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial two months; 4) A regular, uninterrupted supply of all essential anti-tuberculosis drugs; and 5) A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control programme performance overall" [9] (see Table 1). According to the WHO/GTP, as of 1999, 127 countries had accepted the DOTS strategy and were implementing it to varying degrees [10]. Nevertheless, the WHO/GTP estimate that, in 1999, only 45% of the world population had access to DOTS and 23% of new smear-positive cases were referred to DOTS programs. In addition, there are often a complex array of political, financial, and infrastructure problems that impede local DOTS programs. The current WHO DOTS strategy does not incorporate the diagnosis and treatment of latent tuberculosis. Some experts believe that the DOTS strategy, which focuses exclusively on the treatment of active cases, is insufficient for the control and elimination of tuberculosis, particularly in the HIV/AIDS era [11]. It has been recommended that targeted diagnosis and treatment of latent tuberculosis infection among specific populations be added to national tuberculosis control programs. At present, WHO recommends treatment of latent tuberculosis in HIV-positive patients; but only in settings where it is possible to provide HIV testing and counseling, and where it is possible to exclude cases of active tuberculosis and ensure proper follow-up. The DOTS strategy also employs empiric anti-tuberculous therapy without mycobacterial cultures and drug susceptibility testing. Without drug susceptibility information, it is impossible to identify cases of drug-resistant tuberculosis and to avoid treatment failure and further transmission of drug-resistant strains. The WHO recognizes the threat of multidrug-resistant tuberculosis (MDR-TB) and, in July 1999, convened a working group on DOTS-Plus for the treatment of MDR-TB [12]. DOTS-Plus is a pilot program to provide second-line drugs (i.e., fluoroquinolones, amikacin, kanamycin, capreomycin, cycloserine, para-aminosalicylic acid, and ethionamide) to manage MDR-TB in resource-limited countries. This strategy does not, however, address the role of mycobacterial cultures and drug susceptibility testing for individualized drug therapy and the prevention of drug-resistant tuberculosis. Finally, because DOTS relies on patients self-reporting to health services, additional tuberculosis transmission can take place before the patient is evaluated and receives appropriate therapy. Modeling of the tuberculosis epidemic in Tanzania suggests that DOTS may slow the incidence rate, but in the face of the HIV epidemic is unlikely to reverse the upward trend [13]. Again, some experts advocate targeted case finding, particularly among high-risk groups [11,14]. Diagnosis and treatment of active tuberculosis infection in patients with HIV infection This section deals specifically with the treatment of active tuberculosis in HIV-infected individuals as recommended by the CDC [15,16]. Again, many people co-infected with HIV and tuberculosis in the developing world do not have access to the relevant diagnostic tests and anti-tuberculosis and antiretroviral therapies. To impact tuberculosis-associated morbidity and mortality worldwide, developing countries will require both the skills and commodities to diagnose and treat individuals effectively. At present, tuberculosis treatment for the HIV-positive patient as recommended by the CDC is not applicable in most resource-poor countries. Treatment of active and latent tuberculosis infection in patients with HIV depends on the application of both clinical judgment and appropriate diagnostic tests. Active tuberculosis can occur at any CD4 cell count but atypical presentations are more likely with advanced HIV disease or AIDS. Clinicians should be alert to the sometimes atypical presentations of pulmonary and extrapulmonary tuberculosis in HIV-infected patients. Sputum acid fast staining, mycobacterial cultures, and drug susceptibility testing are recommended in all patients suspected of having tuberculosis. However, patients with HIV are slightly less likely to have positive sputum smears than non-HIV-infected individuals [17]. Likewise, chest radiographic findings can vary depending on the degree of immunosuppression. Patients with CD4 cell counts greater than 200 are more likely to have classic findings of upper lobe infiltrates with cavitary lesions, while those patients with AIDS may more likely have hilar adenopathy and pleural effusions without cavitations [18]. Mycobacteremia and extrapulmonary tuberculosis, especially meningitis and adenopathy, also correlate with diminishing numbers of CD4 cells and degree of immunosuppression. Thus, for patients with HIV infection, the diagnosis of active tuberculosis is more challenging. Clinical suspicion of tuberculosis in a patient known or suspected of being HIV-infected should result in prompt initiation of anti-tuberculosis therapy regardless of sputum staining or radiograph findings. The 1998 CDC recommendations for the treatment of tuberculosis among patients infected with HIV are summarized in Table 2[15]. The treatment of tuberculosis in the HIV-seropositive patient may differ from the standard treatment in the following ways: (i) choice of anti-tubercular regimen and dose adjustments; (ii) duration of treatment (ideally with directly observed therapy); (iii) promotion of antiretroviral therapy; and (iv) monitoring requirements. Due to rapid advances in the management of HIV disease, it is recommended that all patients co-infected with HIV and tuberculosis should be evaluated by a specialist to ensure optimal management.Table 2: Tuberculosis (TB) treatment recommendations for the HIV-seropositive patient.The treatment algorithm begins with establishing the patient's HIV status and whether the patient is on optimal antiretroviral therapy. All patients diagnosed with active tuberculosis should be HIV tested and, if seropositive, evaluated for antiretroviral therapy. It was previously felt that the diagnosis of active tuberculosis should result in the deferral of antiretroviral therapy. Early initiation of antiretroviral therapy is now recommended. While being treated for tuberculosis, the HIV-positive patient not receiving concurrent HIV therapy should be reassessed every 3 months for initiation of antiretroviral therapy. Known or suspected HIV-positive patients should receive prompt initiation of effective anti-tuberculosis therapy. If antiretroviral therapy is not started, the patient can typically receive standard anti-tuberculosis therapy: isoniazid, rifampin, pyrazinamide, and ethambutol. If the patient is to receive simultaneous anti-tuberculosis and antiretroviral therapy, the selected regimens and doses must account for significant drug-drug interactions between the rifamycins (rifampin, rifabutin, rifapentine) and the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI). Rifamycins, particularly rifampin, induce the hepatic cytochrome P-450 (CYP450) and reduce the serum levels of protease inhibitors, NNRTI, and other drugs metabolized by the CYP450 system. The CDC generally recommends the substitution of rifabutin, a less potent CYP450 inducer, for rifampin to allow simultaneous use of protease inhibitors and NNRTI. The use of rifampin with protease inhibitors or NNRTI is contraindicated, except in three antiretroviral combinations: (i) the NNRTI efavirenz and two nucleoside reverse transcriptase inhibitors (NRTI); (ii) the protease inhibitor ritonavir and one or more NRTI; and (iii) the combination of ritonavir and saquinavir, either hard-gel or soft-gel capsules [16]. Table 3 lists the recommended anti-tubercular drug doses, depending on frequency of administration and concurrent antiretroviral use.Table 3: Anti-tubercular drug doses.If the HIV-positive patient is already on an effective anti-retroviral regimen at the time of tuberculosis diagnosis, it is desirable to continue the patient on the same antiretroviral regimen with appropriate dose adjustments. If the patient is starting a new antiretroviral regimen, options include: (i) a rifabutin-based regimen with the necessary protease inhibitor or NNRTI dose adjustments; (ii) a non-rifamycin-containing regimen such as isoniazid, streptomycin, pyrazinamide, ethambutol for 2 months, then isoniazid, streptomycin, ethambutol for 7 months; or (iii) a regimen that does not contain a protease inhibitor or NNRTI. Table 4 lists the recommended dose adjustments for rifabutin-based regimens. Given the complexity of these drug interactions, it is recommended that the selection of dual anti-tubercular and antiretroviral therapies be made following consultation with a specialist.Table 4: Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) dose adjustments with rifabutin.Among the protease inhibitors, ritonavir has the highest potency in inhibiting the CYP450 pathway. With any dose of ritonavir, including low-dose ritonavir 100 mg twice a day, a reduced dose of rifabutin (150 mg two or three times per week) is recommended. According to the 2000 CDC guidelines for the use of rifabutin or rifampin among patients taking protease inhibitors or NNRTI, co-administration of ritonavir with the usual dose of rifampin (600 mg daily or two or three times per week) may be an option but pharmokinetic and clinical data are limited [16]. As previously stated, a patient taking the combination of saquinavir (either the soft-gel or hard-gel capsule) and ritonavir should take the reduced dose of rifabutin (150 mg two or three times per week). The saquinavir-ritonavir combination may possibly be given with the usual dose of rifampin but, again, limited pharmacokinetic and clinical data are available. Saquinavir, as a sole protease inhibitor, is generally not recommended in combination with rifabutin because the serum levels of saquinavir may be decreased as much as 45%. Indinavir, nelfinavir, and amprenavir should not be used in combination with rifampin, but all three protease inhibitors can be administered with a reduced daily dose of rifabutin (150 mg daily) or the usual dose of rifabutin (300 mg two or three times per week). Efavirenz induces CYP450 and accelerates rifamycin metabolism; therefore, efavirenz should be co-administered with an increased dose of rifabutin (450 or 600 mg daily, or 600 mg two or three times per week). According to the recent CDC guidelines, efavirenz may be combined with the usual dose of rifampin (600 mg daily or two or three times per week). The NNRTI nevirapine should typically be given with the usual dose of rifabutin (300 mg daily or two or three times per week). If co-administration of nevirapine with rifampin is clearly indicated, careful monitoring is recommended. The use of delavirdine is contraindicated during the treatment of tuberculosis because the drug levels are markedly decreased with both rifampin and rifabutin. HIV-infected patients have a higher incidence of drug-resistant tuberculosis isolates than non-HIV-infected patients. There have been several reports of increased risk of rifampin resistance among HIV-positive patients [19-21]. Higher rates of drug-resistant tuberculosis in HIV-infected patients may be associated with biological, behavioral, and societal factors including drug malabsorption, non-adherence, nosocomial outbreaks, and inadequate drug therapy in countries with high rates of co-infection. Directly observed therapy, regarded as the best strategy for ensuring adherence and limiting drug-resistant tuberculosis, is recommended for all patients with HIV infection [15]. In a randomized, controlled trial of anti-tuberculosis therapy among HIV-positive patients in Baltimore, Maryland, patients who received supervised therapy for tuberculosis had better survival than those who self-administered therapy [22]. Treatment of drug-resistant tuberculosis involves initiation of a multi-drug regimen tailored to the susceptibility profile of the organism. Due to the diversity of resistance patterns, it is not possible to recommend standardized protocols for therapy. Any regimen should include two or more drugs to which the isolate is susceptible. For HIV-positive patients at risk of MDR-TB, defined as resistance to both isoniazid and rifampin, initial empiric treatment should include second-line tuberculosis drugs to which resistance is uncommon. The 1999 WHO Essential Drug List was to include the following second-line tuberculosis amikacin, kanamycin, capreomycin, cycloserine, acid, and and drug susceptibility testing should be on all tuberculosis isolates and the anti-tuberculosis regimens Although MDR-TB is associated with a high mortality rate especially in resource-poor countries where the detection of drug resistance to months, if at and the second-line drugs are often months is the duration of treatment for pulmonary tuberculosis among HIV-positive patients in the United States a regimen is used [15]. treatment is for patients with a clinical or conversion of sputum cultures from positive to Some experts recommend the use of treatment regimens in all patients with HIV infection, especially among patients with advanced [17]. duration of treatment is clearly recommended in patients with slow clinical or with or HIV-positive individuals with active tuberculosis to be at increased risk of tuberculosis of a 6-month regimen. A trial of isoniazid was among HIV-positive patients in who a 6-month regimen of isoniazid decreased the risk of a of tuberculosis among HIV-positive patients. This not whether these were to M. tuberculosis or both of which have previously been The recommend of isoniazid for HIV-positive patients of tuberculosis therapy. At present, the WHO and the CDC recommend a months of directly observed tuberculosis therapy without Treatment of latent tuberculosis infection in patients with HIV infection It is estimated that 2 people worldwide are infected with latent tuberculosis. Patients with HIV infection are at increased risk of to active disease [2]. In 2000, the and the CDC new guidelines for the diagnosis and treatment of latent tuberculosis infection This public health strategy both prevention by the latent infection before it to active infection and primary prevention by further tuberculosis In addition, the use of active antiretroviral therapy has been to reduce the incidence of tuberculosis among persons with HIV infection The new guidelines recommend targeted of populations and patients at increased risk of tuberculosis infection who from treatment to active for targeted include drug health care of and all patients with HIV Diagnosis of latent tuberculosis infection is on the tuberculin skin new including detection are being developed A has with tuberculin skin testing in are to the diagnostic of this in the United States and in populations with varying degrees of risk for latent tuberculosis. There be two significant of developing tests for the detection of latent M. tuberculosis tests the need for a health service at and their be less than tuberculin skin testing. of latent tuberculosis in an HIV-infected patient can be a diagnostic It has been that the sensitivity of tuberculin skin testing may be in patients with to as well as to and can in persons with HIV infection and of the is associated with higher CD4 cell For these testing is no recommended for the diagnosis of latent tuberculosis. guidelines are to treat latent tuberculosis infection in HIV-infected persons with at high-risk of latent tuberculosis or with recent to a case of active tuberculosis should receive therapy regardless of tuberculin has been the of treatment of latent tuberculosis clinical have a in the risk of to active tuberculosis following months of isoniazid therapy. The optimal duration of isoniazid therapy has also been including the trial of the Tuberculosis and in in the and this or months of isoniazid therapy months of isoniazid therapy reduced the tuberculosis incidence by with for months and 20% for 3 months; however, with months therapy was than for of therapy A recent of isoniazid therapy in that from isoniazid therapy 9 months, with no additional associated with therapy The new and CDC guidelines recommend isoniazid therapy for 9 months (300 mg isoniazid daily mg with months of therapy as a less The to isoniazid therapy include and poor Directly observed therapy has been to adherence but is not important in the treatment of latent tuberculosis has been the of regimens that may adherence and reduce have the of regimens for the treatment of latent tuberculosis in individuals A trial that daily rifampin and pyrazinamide for 2 months was to isoniazid for months for the treatment of latent tuberculosis in HIV-infected persons the of these the new guidelines regimens for the treatment of latent tuberculosis as summarized in Table from their publication rifampin and pyrazinamide for 2 months (600 mg rifampin daily pyrazinamide daily) is the regimen for HIV-infected patients and be for suspected cases of tuberculosis. should be for rifampin in patients receiving protease inhibitors or NNRTI, further is to in the treatment of latent tuberculosis. The same drug-drug interactions and dose adjustments for antiretroviral drugs and rifamycins It is that the also recommends the regimen for individuals the the clinical for this combination have been only in HIV-positive patients. If MDR-TB is the recommended therapy is pyrazinamide and ethambutol or pyrazinamide and a (i.e., or for Treatment for suspected to MDR-TB should be extended to months for HIV-positive American Thoracic Society and Centers for Disease Control and Prevention guidelines for the treatment of latent tuberculosis the use of rifampin pyrazinamide therapy in infected patients has been associated with a rate of patients with resulting from the use of therapy have been to the five of these patients on these CDC and have their 2000 recommendations The (i) that be used with particularly in patients with disease, on or those taking drugs; and (ii) that patients who are treated with be by a health care at and for a of tests and evaluation with a at 8 to treatment therapy with the regimen should be for significant rates of have not been observed in HIV-infected patients treated with this regimen, either in clinical or to the use of the regimen in For HIV-infected patients to persons with active tuberculosis, treatment for latent tuberculosis should be a tuberculin In addition, some experts advocate HIV-infected individuals who in high-risk evaluation for latent tuberculosis treatment should include a careful and and, chest radiograph to exclude active tuberculosis. anti-tubercular drugs in treatment of tuberculosis, particularly for MDR-TB, will on the of new anti-tubercular there are several drugs under that have in M. tuberculosis. In some cases the drug has also in a of tuberculosis, and some have received and Drug for other under include and other and is a rifamycin the serum of which is three times than that of the rifampin The of M. tuberculosis is to or one to that of Given the between and other rifamycin the of over rifampin pharmokinetic In the infected with tuberculosis and in tuberculosis a regimen is less active than a daily regimen, both rifamycins being given at 10 In tuberculosis however, the regimen is significantly less active than the daily regimen In the regimens during the of tuberculosis therapy may provide increased to as well as to health care programs. is an for and other infections that has in M. tuberculosis, to that of and in in a of tuberculosis that at 100 is as as isoniazid at and more than clinical are being to the role of in combination therapy active tuberculosis. and also promising in a of tuberculosis are a class of inhibitors with and The of at 100 is with isoniazid at per an by the and Drug for the treatment of appears to be less active M. tuberculosis than It has been recommended, however, for further at higher is a new to that has been to potent in M. in were also to be to this with of In a administration of this drug at a dose of per led to of disease burden in and with that with isoniazid per and issues in the treatment of tuberculosis in patients with HIV have previously to some of the and issues that the treatment of tuberculosis in resource-poor countries. At the and there may also some important and to effective tuberculosis treatment. A among tuberculosis patients in Tanzania that only of the patients had of the disease and treatment In a recent from people were generally well HIV but tuberculosis of and were to AIDS than tuberculosis. patients with tuberculosis were often as having AIDS. Due to the associated with the that patients with tuberculosis may not or to appropriate These the important impact that the HIV epidemic may have on the public and to tuberculosis. a epidemic of tuberculosis and HIV co-infection in many of the developing world. The increased of tuberculosis and HIV/AIDS and the rise of MDR-TB a health threat to all While significant have been made in developing regimens for the treatment of active and latent tuberculosis, therapy is and second-line drugs are drug resistance is for are the anti-tuberculosis of drugs such as and and the of which may treatment. The optimal use of these drugs in combination therapy is a promising of active In addition, we advocate the of new and tuberculosis drugs that will be made to patients in developing countries.

More than 50 years after the introduction of chemotherapy for the treatment of tuberculosis (TB), the disease is far from being under control. Among curable infectious diseases, TB remains the number‐one killer—each year, 2 million people still die of the disease and 8.4 million more fall ill (World Health Organization (WHO), 2002a). And future projections are grim. Fewer than half of all TB cases are diagnosed, and of those that are, fewer than 30% have access to the care recommended by the WHO (WHO, 2002a). The increase in TB worldwide is due, in part, to the expansion of the HIV/AIDS pandemic (WHO, 2001): at least one‐third of people with HIV die of TB (WHO, 2002a). HIV/AIDS now causes more than 3 million deaths per year (UNAIDS, 2002). More than 90% of HIV/AIDS deaths and new infections occur in poor countries where less than 5% of those who need antiretroviral treatment have access to these therapies (WHO, 2002b). If we consider that, on average, 10% of people with HIV need antiretroviral treatment, the 5% figure comes down to less than 1% in sub‐Saharan Africa, the region most affected by the pandemic. > The social contexts in which our patients became infected are an integral part of their stories Large‐scale social forces, such as racism, sexism, political violence, poverty and other social inequalities, are rooted in historical and economic processes and sculpt the distribution and outcome of HIV/AIDS and TB. We refer to these social forces as ‘structural violence’ (Castro & Farmer, 2002, 2003a,b; Farmer, 2003), which predisposes the human body to pathogenic vulnerability by shaping the risk of infection and subsequent disease reactivation. After infection, structural violence also determines who has access to diagnostics and effective therapy. Drugs that could stop or slow down these epidemics, such as …

A review of 162 patients with active tuberculosis seen at the King Faisal Specialist Hospital and Research Centre between January 1979 and April 1981 was carried out. Patients with classic...

Introduction. According to the literature, HIV infection increases the risk of tuberculosis, and tuberculosis causes an adverse effect on the course of HIV infection. Tuberculosis is the direct cause of death of patients up to 30.0% with HIV infection and in 90.0% of cases at AIDS. That’s why studying the clinical course of HIV/AIDS-associated tuberculosis and analysis of causes of death in these patients is highly actual today. The aim of the study. To determine the clinical course and causes of death in patients with primarily diagnosed HIV/AIDS-associated tuberculosis. Materials and methods. 22 patients cards who died of primarily diagnosed HIV/AIDS-associated tuberculosis were analyzed in this article. The results of research. Among patients with primarily diagnosed HIV/AIDS-associated tuberculosis there were 12 men (54.6%), and 10 (45.4%) women. The average age was 39.5 ± 1.5 years. There were 90.9% of unemployed patients (20 patients), 4 patients (18.2%) were former prisoners, 1(4.5%) – shelterless person, 5 patients (22.7%) suffered from drug addiction and alcoholism. 9 (40.9%) patients lived antisocial life. HIV-infection had started after tuberculosis in 1 patient (4.5%), before tuberculosis - in 15 (68.2%), the simultaneous detection of co-infection was found in 6 cases (27.3%). Prevailed disseminated (60 %) and infiltrative forms of lung tuberculosis (33,3 %) were significantly (P <0.05) more often registered among patients with co-infection of primarily diagnosed HIV/AIDS-associated tuberculosis. 5 (33.3%) patients had pulmonary tuberculosis combined with extrapulmonary, that significantly complicated the course of co-infection. There were 3 patients (13.6%), who interrupted treatment, 1 patient refused treatment completely. 6 patients had received antiretroviral therapy (27.3%), 5 patients (22.7%) renounced, in 11 (50.0%) - antiretroviral therapy was not intended. The autopsy determined that 14 (63.6%) patients died from progressive worsening of tuberculosis (8 (57.1%) - pulmonary, 6 (42.9%) - extrapulmonary) and 8 (36.4%) - due to progression of HIV infection. It was found, that late diagnosis of HIV infection occurred in 4.5% of cases, late diagnosis of tuberculosis (TB was established only at autopsy) - in 5 patients (22.7%). It was found, that all of these patients died from progression of a specific process. Conclusion. It was determined that most of the patients lived the anti-social way of life, and suffered from alcoholism or drug addiction, tuberculosis more often had started after HIV-infection. Disseminative and infiltrative forms of pulmonary tuberculosis were more often determined in patients who died of co-infection. In one-third of patients combined pulmonary and extrapulmonary localization of tuberculosis were determined, most patients had noncompliance with a specific anti-TB and antiretroviral treatment and had a significant immunodeficiency. Death came more often from progression of tuberculosis.

In Taiwan in 2003, the incidence of tuberculosis (TB) was 66.67 per 100,000 residents, with a mortality rate of 5.80 per 100,000 residents; this is still a very high mortality rate. A retrospective analysis of the causes of death of reported TB patients who died from 2000-2004 was performed; 102 patients with definitely active TB died during this period: 64 (63%) died of TB while on treatment, and 38 (37%) had a postmortem diagnosis of TB, based on positive culture reports. TB was considered to be the principal cause of death in 31 (30%) of the 102 patients, a contributing cause in 45 (44%), and unrelated in 26 (26%). Among the 38 patients with whom a postmortem diagnosis of TB was made, the mean hospital stay was 14.2 (range, 2 to 38) days. Severe pneumonia (53%) was the most commonly diagnosed cause of death in these patients, and multiple lobar infiltrates were the most common chest X-ray findings (67%). In conclusion, TB was the principal cause of death in only 30% of TB patients who died, though TB was a contributory factor in most patients. One-third of patients had a postmortem diagnosis of TB. The presence of multiple lobar infiltrates should alert clinicians to the possibility of TB. More rapid and reliable diagnostic methods for TB are urgently needed.

Objectives:Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy studies to determine the true burden of TB at death.Methods:We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence.Results:We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0–64.4%), but was markedly higher in adults [pooled prevalence 39.7%, 95% confidence interval (CI) 32.4–47.0%] compared to children (pooled prevalence 4.5%, 95% CI 1.7–7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7–68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0–48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0–38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2–93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8–97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7–48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6–59.1%) of TB cases.Conclusions:In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.