The effectiveness of treatment of newly diagnosed and relapsed tuberculosis with HIV infection in a medical and correctional institution

Herpes Zoster Among HIV-Infected Patients in the Highly Active Antiretroviral Therapy Era: Korean HIV Cohort Study

HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.

Towards addressing questions related to HIV pathogenesis and vaccine design we are fortunate to have the availability of the SIV-infected rhesus macaque model. The strengths of this model which include a rapid rate of progression to AIDS and knowledge of the dose route and strain of the infecting virus complement studies in HIV-infected patients in which the reagents host genetics and access to samples are more extensive and better defined. Unfortunately there is currently still too little known about the antiviral immune responses in either system to directly and accurately compare their similarities and differences and to draw any definitive conclusions. Therefore the data and views presented herein will simply reflect what has recently been discovered in both humans and non-human primate studies. (excerpt)

Simple SummaryDiffuse large B-cell lymphoma (DLBCL) frequently occurs in HIV-infected patients. However, the effect of HIV infection on the outcome of the DLBCL population remains controversial. The aim of the present retrospective study was to compare clinical features, phenotypic markers and outcomes of BLBCL between HIV-infected and HIV-uninfected Chinese patients. Our study indicated HIV-infected DLBCL patients displayed high EBER expression but low CD20 and CD79a expression on histopathology. The overall response rate at end of chemotherapy and 1-year overall survival (OS) were low in HIV-infected patients, which may be associated with the higher incidence of leukopenia, neutropenia, thrombocytopenia and hypoalbuminemia, as well as high involvement of the central nervous system (CNS), gastrointestinal tract and bone marrow. Hypoalbuminemia and CNS involvement were independent risk factors for 1-year OS. HIV-infected DLBCL patients without CNS involvement had a favorable outcome if rituximab was included in the chemotherapy regimen.Background: The effect of HIV infection on the clinicopathological characteristics of diffuse large B-cell lymphoma (DLBCL) remains debatable. Methods: Fifty-three HIV-infected and ninety-three HIV-uninfected DLBCL patients were enrolled in the retrospective study by propensity score matching for sex, age, body mass index and international prognostic index (IPI) at a ratio of 1:2. The clinicopathological characteristics were compared between the two groups. Results: HIV-infected DLBCL patients had lower white blood cell counts [×109/L; 4.4 (3.4–5.6) vs. 6.1 (4.2–8.2), p < 0.001], platelet counts (×109/L; 184.7 ± 89.3 vs. 230.0 ± 113.9, p = 0.014) and serum albumin (g/L; 37.3 ± 6.9 vs. 41.3 ± 6.2, p < 0.001) but higher incidences of central nervous system (CNS) involvement (9.4% vs. 1.1%, p = 0.014), bone marrow involvement (24.5% vs. 11.5%, p = 0.044) and Epstein–Barr viremia (61.1% vs. 26.7%, p = 0.002) than HIV-uninfected patients. In terms of histopathology, HIV-infected patients had higher positivity of Epstein–Barr virus-encoded small RNA (EBER) (41.7% vs. 6.7%, p = 0.002), but lower CD20 (90.2% vs. 98.7%, p= 0.029) and CD79a (23.1% vs. 53.7%, p < 0.001) expression. The overall response rate (ORR) at the end of chemotherapy (70.2% vs. 87.8%, p= 0.012) and 1-year overall survival (OS) (61.7% vs. 84.2%, log-rank p = 0.006) in HIV-infected patients were significantly lower than those in HIV-uninfected patients. Multivariate analysis suggested IPI ≤2.0 [adjusted odds ratio (AOR) (95% confidence interval): 5.0 (1.2–21.2), p = 0.030] was associated with ORR, hypoalbuminemia [AOR: 3.3 (1.3–9.1), p = 0.018] and CNS involvement [AOR: 3.3 (1.0–10.5), p = 0.044] were associated with reduced 1-year OS in HIV-infected patients. Conclusion: HIV-infected DLBCL patients have unique blood profiles and phenotypic markers. Low ORR and 1-year OS were observed in HIV-infected DLBCL patients in our study, even in the HAART era.

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.

The recent publication entitled “serum Albumin for Tuberculosis in HIV Infected Patients Eligible for Antiretroviral Therapy”1 is very interesting. Alvarez-Uria et al. mentioned that “serum albumin can be a useful low-cost diagnostic marker for tuberculosis in HIV infected patients eligible for ART.”1 In fact, this conclusion has to be carefully considered. Albumin is a basic biochemistry parameter in clinical practice. The test is widely used in any clinical setting and the main indication for measuring blood albumin level is to determine the hypoalbuminemia, which can contribute to edema.2 In medical practice, the common conditions that can result in hypoalbuminemia include liver disease, glumerulopathy and protein malnutrition.2 The use of albumin as a biomarker for other conditions is very interesting issue in laboratory medicine. Focusing on infection, the aberration of blood albumin level can be observed.3 Of several infections, tuberculosis is widely discussed about its interrelationship with alteration of blood albumin. Extremely low blood albumin level is a common finding in the death cases of tuberculosis.4 Horita et al. recently proposed blood albumin as an important determinant for prognostic scoring of tuberculosis.5 It was found that low blood albumin could effectively predict a poor outcome.4 However, the use of blood albumin determination in the cases with concurrent morbidity is not well understood and the study in this topic is interesting. Of several clinical problems, the important problematic concurrent infection in the patients with tuberculosis is HIV infection. Due to the deterioration of immunity in the HIV infected patients, the emerging of tuberculosis can be expected. The clinical use of blood albumin determination in the cases with HIV infection is a challenging topic. Alvarez-Uria et al. performed a Cohort Study on this topic in India.1 They focused their interest on the feasibility of using blood albumin determination as biomarker to predict tuberculosis in the HIV infected patients.1 Alvarez-Uria et al. found that “the diagnostic accuracy of serum albumin, measured by the area under the receiver operating characteristic curve, to predict tuberculosis was 0.81.”1 As Alvarez-Uria et al. reported, the diagnostic property of the albumin was only fair and it could not be used for ruling out tuberculosis. In fact, the hypoalbuminemia can be seen in several conditions that have the problem of protein malnutrition. Both tuberculosis and HIV infection can contribute to the problem of hypoalbuminemia. Focusing on laboratory parameters, hypoalbuminemia is very common in the HIV infected patients.6,7 Graham et al. mentioned that “each 1 g/liter decrease in albumin with HIV-1 acquisition was associated with a 13% increase (p = 0.01) in the risk of progressing to a CD4 count <200 cells/mul.”6 Altice et al. also mentioned that low blood albumin level suggested “increased risk for HIV, particularly in settings where HIV testing resources are scarce.”8 It is no doubt that Alvarez-Uria et al. could not be able to discriminate between the cases with and without tuberculosis. Focusing on the observation that hypoalbuminemia was relating to the poor outcome, it has ever been reported in previous studies. Sudfeld et al. found that this relationship is dependent to CD4+ count; hence, this reflects the nutritional not the immunological problem.9 Dao also found a similar observation that hypoalbuminemia could help predict mortality in HIV infected cases, especially for the first year of initiating ART.10 Conclusively, with or without tuberculosis, hypoalbuminemia could be a good biomarker for predicting poor outcome of HIV infection. On the other hand, with or without HIV infection, hypoalbuminemia could be a good biomarker for predicting poor outcome of tuberculosis. However, the conclusion on the concurrent HIV and tuberculosis infection, the value of hypoalbuminemia in predicting requires further systematic investigation to clarify.

Metabolic complications of HIV therapy in children.

Galectin-9 (Gal-9) and osteopontin (OPN) play immunomodulatory roles in tuberculosis and HIV infections. Evaluation of their levels as well as their interplay with different pro-inflammatory cytokines is critical to understand their role in immunopathogenesis of HIV/tuberculosis co-infection considering the complexity of the disease. Plasma levels of these proteins were measured by ELISAs in HIV-negative individuals with pulmonary (n = 21), extrapulmonary (n = 33), and latent tuberculosis (n = 22) and in HIV infected patients with pulmonary (n = 14), latent tuberculosis (n = 17), and without tuberculosis (n = 41). Levels of pro-inflammatory cytokines were estimated by Luminex assay. Receiver operated characteristic curve analysis was performed to evaluate discriminatory roles of these proteins. Spearman’s correlation analysis was performed with the markers of HIV and tuberculosis disease progression to evaluate their immunopathogenic roles. Gal-9 and OPN levels were higher in HIV uninfected patients with active tuberculosis than with latent tuberculosis. Gal-9 but not OPN levels were higher in HIV infected patients with active tuberculosis than with latent tuberculosis. Area under curve for Galectin-9 was >0.9 in HIV/tuberculosis co-infection and extrapulmonary tuberculosis. OPN and IL-6 levels were higher in patients with severe chest X-ray grade indicating its association with severity of the disease and positively correlated with each other. Stronger positive and negative correlations of Gal-9 levels, respectively, with viral loads and CD4 cell counts in HIV infected patients were observed than OPN levels indicating their association with HIV disease progression. Thus, significantly elevated Gal-9 levels were reported for the first time in HIV/tuberculosis co-infection and extrapulmonary tuberculosis in our study than single infections with HIV and tuberculosis. The study indicated a need for further evaluation of monitoring role of Gal-9 for detection of developing tuberculosis in HIV infected individuals. The findings also indicated differential roles of Gal-9 and OPN in the pathogenesis of tuberculosis and HIV infections.

A Mycobacterium tuberculosis complex organism was isolated unexpectedly from blood cultures obtained from a 3-year-old child succumbing to HIV-associated cardiomyopathy at our hospital. Biochemical studies speciated the isolate as Mycobacterium bovis. Because the child had been immunized with Bacillus Calmette-Guérin (BCG) at birth, we sought to determine whether the isolate recovered from the blood before death was BCG or a pathogenic strain of M. bovis. Our report focuses on three issues: the methods of differentiation of the M. tuberculosis complex strains; the factors contributing to possible underdiagnosis of disseminated infections; and the need for additional studies to determine the true incidence of dissemination in BCG-vaccinated HIV-infected children. Case report. A Brazilian child, immunized with BCG at birth, was adopted by an American expatriate family at 1 week of age. Medical history included developmental delay, recurrent otitis media and failure to thrive. At 15 months of age he was found to be infected with HIV by serologic testing in Brazil (not repeated at our hospital). Zidovudine therapy was begun at the time of diagnosis. Approximately 1 month before arrival in the United States for parental job relocation at 3 years of age, the patient developed increasing dyspnea and signs of cardiac failure. Physical examination on admission to Vanderbilt Children's Hospital in 1993 revealed an afebrile child with a heart rate of 160 and a respiratory rate of 32, accompanied by intercostal retractions and nasal flaring. Pulmonary congestion, cardiomegaly, hepatomegaly and generalized adenopathey were present. No cutaneous lesions or splenomegaly were seen. Chest roentgenogram revealed massive cardiomegaly, severe pulmonary congestion and bilateral pleural effusions. Despite vigorous diuresis and digitalization, the child expired. Request for autopsy was denied. Postmortem Bactec® blood cultures were obtained to evaluate the possibility of disseminated Mycobacterium avium-intracellulare infection. These cultures grew a mycobacterial organism confirmed by DNA probe (Gen-Probe, San Diego, CA) to be M. tuberculosis complex. The rarity of this observation led the clinicians to pursue vigorously a more complete identification of the organism. Conventional phenotypic studies performed in the laboratories of the Tennessee State Health Department revealed the organism to be niacin- and nitrate reduction-negative, findings consistent with M. bovis or BCG. Mycolic acid characterization by high performance liquid chromatography (HPLC) at the Centers for Disease Control, Atlanta, GA, revealed a distinctive chromatogram unique to TMC 1022, a Russian BCG strain.1 Molecular characterization was also performed (by Richard Frothingham, Duke University) by a recently described method of sequence-based strain differentiation.2 The patient strain, like those of other BCG strains, belonged to the MEDIUM-C® sequevar. Strains of M. tuberculosis and non-BCG M. bovis isolates belong to other sequevars. Discussion. With improved methods to isolate mycobacteria from the blood, disseminated infections in HIV-infected patients are more commonly recognized. Although the majority of mycobacterial isolates in the United States are M. avium-intracellulare strains, M. tuberculosis complex strains are also recovered and are confirmed by gene probe technology. Because the M. tuberculosis complex contains the four species, M. tuberculosis, Mycobacterium bovis, Mycobacterium microti and Mycobacterium africanum, which are closely related genetically, strain differentiation can be difficult. Biochemical methods can be suggestive but are not definitive. Antimicrobial susceptibility testing can offer some assistance since BCG is resistant to PZA and M. tuberculosis is generally susceptible. Separation of BCG from M. tuberculosis and M. bovis by HPLC of mycolic acids has been very useful.1 Molecular markers, such as the insertion sequence, IS6110, have been extremely important in differentiating strains of M. tuberculosis for epidemiologic purposes, but have not been as useful for other members of the M. tuberculosis complex since they share common IS6110 patterns.3 Another insertion sequence, IS1081, has been used successfully to differentiate M. bovis strains of BCG and non-BCG origin and may be used more commonly in the future to distinguish between these strains.4 Finally sequence-based analysis has been helpful in distinguishing these strains.2 Biochemical, HPLC and sequence-based analysis confirmed that the strain isolated from our patient was BCG. BCG vaccines are live attenuated mycobacterial strains originating directly or indirectly at different times from the original Institut Pasteur strain which was itself derived from a virulent bovine tubercle bacillus by 230 passages on glycerol-bile-potato medium in the years between 1908 and 1921. The earliest daughter strains were the Brazilian, Russian, Romanian and Swedish strains which were all derived between 1925 and 1928. The descendants of these four strains are similar in their mycolic acid profiles, in their pattern of protein synthesis and in the possession of two copies of IS6110.5 After that time other BCG strains were derived, such as the Japanese, Danish, Pasteur and Tice strains, having different HPLC patterns, different secreted proteins and a single copy of IS6110. The HPLC pattern obtained from our patient immunized in Brazil appeared identical with that of a Russian BCG strain, suggesting a common ancestry of both strains. Attempts to more fully characterize the lineage of the BCG strain administered to our patient were unsuccessful. Live BCG vaccine is given to newborn infants throughout the developing world. Many of these areas have high rates of tuberculosis and HIV infection. It is remarkable that only 14 cases of disseminated BCG in HIV-infected patients had been reported previously in the literature,6-17 with 7 of the previously reported cases in children (Table 1).6, 7, 11, 13, 15, 16 Symptoms seen in these patients included fever, adenopathy, weight loss and organomegaly, although some of the reports provided few clinical details. Before our report definitive biochemical and molecular confirmation of the BCG strain had been made in only one patient.6 Because our patient was afebrile and had symptoms that could all be explained by HIV cardiomyopathy, we had no clinical suspicion of disseminated BCG infection. It was fortuitous that the blood culture was done. However, it is likely that many patients receiving BCG, whether infected with HIV or not, have transient bacteremia with BCG. In fact in a report of autopsy findings in 26 BCG-vaccinated non-HIV-infected individuals dying of causes not related to BCG, granulomas were seen in distant organs at least 2 to 3 years after vaccination without any clinical signs.18 These data suggest that hematogenous spread of BCG from the site of vaccination is common. It is also possible that some of the cases reported as disseminated BCG might actually be infections with other species of the M. tuberculosis complex, such as M. bovis or M. tuberculosis. In a large series of patients with M. bovis infections, Danker et al.19 described eight cases of disseminated M. bovis infections in HIV-infected patients. Isolation of M. tuberculosis from blood cultures from HIV-infected patients has also be shown in 26 to 41% of patients with clinical tuberculosis, a rate much higher than reported for non-HIV-infected patients.20, 21 This case clearly demonstrates the need for definitive identification of mycobacterial isolates obtained from HIV-infected individuals with the most sophisticated methods of HPLC, molecular markers and sequence-based analysis. In areas of the world where such techniques are unavailable, isolates should be sent to reference laboratories for this purpose. Finally larger prospective studies utilizing mycobacterial blood cultures obtained at regular intervals in BCG-immunized HIV-infected infants appear warranted. Only in this way can the true incidence of disseminated BCG infection and its impact on HIV-infected infants and children be determined. Currently the World Health Organization and UNICEF policies support the routine immunization of asymptomatic infants in countries with high rates of both HIV and tuberculosis infection.22 For children living in the United States a joint communication from two Centers for Disease Control and Prevention advisory groups, the Advisory Council for the Elimination of Tuberculosis and the Advisory Council for Immunization Practices, has recommended that BCG vaccination should not be given to HIV-seropositive or known infected infants and children, even if the risk of tuberculosis is high. While additional studies are in progress, we endorse both of these policies. Acknowledgment. Work was supported by NIH Grants AI37871 (KME) and AI-35250 (DSK). Kathryn M. Edwards, M.D.; Douglas S. Kernodle, M.D. Division of Infectious Diseases Departments of Pediatrics and Medicine Vanderbilt University Medical Center Nashville, TN

In this paper we will present an overview of what is known about prevention of HIV associated infections in sub-Saharan Africa. We will focus on primary prophylaxis aiming to prevent first episodes of infections as feasibility and access to secondary prophylaxis cannot be separated from the treatment of opportunistic infections. (excerpt)

DI-fusion, le Dépôt institutionnel numérique de l'ULB, est l'outil de référencementde la production scientifique de l'ULB.L'interface de recherche DI-fusion permet de consulter les publications des chercheurs de l'ULB et les thèses qui y ont été défendues.

HIV-infected adults display increased cardiovascular disease, probably driven by inflammation and immune activation. These relationships have not been addressed in vertically HIV-infected children and adolescents, a population at very high risk for long-term non-AIDS complications. Carotid intima media thickness (IMT) was measured in a cohort of HIV-infected children and adolescents and healthy controls. C-reactive protein and markers of immune activation (CD38⁺HLA-DR⁺) and immune senescence (CD28⁻CD57⁺) were determined. One hundred fifty HIV-infected patients and 150 controls were included, 64.8% female. IMT was thicker in HIV-infected patients (0.434 mm ± 0.025 vs. 0.424 mm ± 0.018, P < 0.001). After adjustment by age, sex, body mass index, and smoking status, HIV infection was independently associated with thicker IMT (odds ratio, 2.28; 95% confidence interval: 1.25 to 4.13; P = 0.007). Among HIV-related variables, a low CD4 nadir was related to an increased IMT. Although HIV-infected subjects presented higher frequencies of activated CD4⁺ and CD8⁺ T cells (P = 0.002 and P = 0.087, respectively), no relation was found between IMT and inflammation, immune activation, or senescence. Structural changes of the vasculature present early in vertically HIV-infected subjects as well as immune activation and senescence. These patients should be carefully monitored for the prompt detection and early treatment of cardiovascular disease.

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Epidemic of Lung Cancer in Patients With HIV Infection

Relevance. Today, there are controversies regarding the influence of hepatitis B and C viruses on the course of HIV infection. Objective assess the course and outcomes of chronic hepatitis B and C in HIV-infected patients, as well as to analyze the causes of death of such patients. Materials and methods. A retrospective pseudorandomized study was conducted with a depth of 5 years. 114 medical records of inpatients (HIV infection in association with hepatitis B and C) were selected. The analysis of the causes of death in patients with HIV infection was carried out based on the study of autopsy materials of 21 patients. Results. It was established that the frequency of CHV exacerbation in III-IV clinical stages of HIV infection is significantly higher, and remission is lower than in I-II stages - (36.8±4.5) versus (7.0±2.4)% and (35.1±4.5) and (7.9±2.5)%, respectively (p&lt;0.001). The frequency of liver cirrhosis was characterized by a clear tendency to increase with the deepening of immunodeficiency. The calculation of the frequency of findings in liver cirrhosis showed that in the I-II clinical stage of HIV infection, this value was equal to 0.17, and in the III-IV stage - 0.33. The relative risk of developing liver cirrhosis in HIV-infected patients was 0.52. Moreover, the probability of a fatal outcome in cirrhosis of the liver in HIV-infected patients in the I-II clinical stage was equal to 0.16, and in the III-IV stage - 0.29, with a relative risk of 0.63. The reduction in the relative risk of a fatal outcome taking into account the stage of HIV infection is 0.32. The average life expectancy of patients from the moment of detection of HIV antibodies was (3.4±0.6) years (from 4 months to 9 years). Such a short average life expectancy of HIV-infected patients was caused by a large number of patients diagnosed for the first time already in the IV clinical stage. In more than half (13 out of 21) the causes of death were AIDS-related diseases (61.9 %). Conclusions. A retrospective pseudorandomized study showed that cirrhosis of the liver in the early stages of HIV infection was registered 2.7 times less often than in patients with HIV infection in the stage of secondary diseases. Exacerbation of chronic hepatitis B and C is significantly more often established in the III-IV clinical stage of concomitant HIV infection. Under the same circumstances, signs of cirrhosis of the liver are more often registered, and fatal outcomes occupy one of the leading places in patients with HIV infection. This indicates the need to revise the tactics of clinical management of this category of patients. In 61.9 % of cases, the causes of death were AIDS-indicative diseases. Tuberculosis turned out to be the leading cause of death (46.1 %) of HIV-infected patients and was mainly in a generalized form. Toxoplasmosis (30.8 %) with damage to the brain and other organs takes the second place in terms of the frequency of fatal AIDS-indicative diseases. Meningoencephalitis of unspecified (probably herpetic) etiology was found in 23.1 % of the deceased. An important place in the structure of fatal outcomes in HIV-infected patients is occupied by the terminal stage of cirrhosis of the liver of mixed etiology - viral and alcoholic (38.1 %).