Highly Active Antiretroviral Therapy for HIV With Tuberculosis
2002; Elsevier BV; Volume: 122; Issue: 2 Linguagem: Inglês
10.1378/chest.122.2.399
ISSN1931-3543
Autores Tópico(s)HIV/AIDS drug development and treatment
ResumoHighly active antiretroviral therapy (HAART) has changed the landscape of HIV infection. HIV-infected individuals are living longer,1Mocroft A Vella S Benfield TL et al.Changing patterns of mortality across Europe in patients infected with HIV-1: EuroSIDA Study Group.Lancet. 1998; 352: 1725-1730Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar2Palella FJ Delaney KM Moorman AC et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8475) Google Scholar opportunistic infections are being delayed,2Palella FJ Delaney KM Moorman AC et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8475) Google Scholar3Ives NJ Gazzard BG Easterbrook PJ The changing pattern of AIDS-defining illness with the introduction of highly active antiretroviral therapy (HAART) in a London clinic.J Infect. 2001; 42: 134-139Abstract Full Text PDF PubMed Scopus (143) Google Scholar and in many instances patients are being liberated from prophylaxis against opportunistic infections.4Ledergerber B Mocroft A Reiss P et al.Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy.N Engl J Med. 2001; 344: 168-174Crossref PubMed Scopus (160) Google Scholar5Whitcup SM Fortin E Linblad AS et al.Discontinuation of anti-cytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis.JAMA. 1999; 282: 1633-1637Crossref PubMed Scopus (162) Google Scholar It has been proposed that HAART-induced restoration in the number and function of CD4+ T lymphocytes is responsible for these clinical observations.6Shen Y Shen L Sehgal P et al.Antiretroviral agents restore mycobacterium-specific T-cell immune responses and facilitate controlling a fatal tuberculosis-like disease in macaques coinfected with simian immunodeficiency virus and Mycobacterium bovis BCG.J Virol. 2001; 75: 8690-8696Crossref PubMed Scopus (36) Google ScholarIt is logical that HAART affects the natural course of tuberculosis in HIV infection because the CD4+ T lymphocyte, especially the T-helper type 1 (Th1) subclass, is undoubtedly the major effector cell in cell-mediated immunity of tuberculosis.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar8Boom WH The role of T-cell subsets in Mycobacterium tuberculosis infection.Infect Agents Dis. 1996; 5: 73-81PubMed Google Scholar Th1 cells are characterized by their ability to produce the cytokines interferon (INF)-γ and interleukin (IL)-2, whereas T-helper type 2 (Th2) cells, another subclass of CD4+ lymphocytes, produce cytokines such as IL-4, IL-5, and IL-10. A Th1/Th2 paradigm has been proposed whereby Th1 cells secrete cytokines (“the Th1 response”) that enhance immunity, whereas Th2 cells secrete cytokines (“the Th2 response”) that impair immunity.9Romagnami S The Th1/Th2 paradigm.Immunol Today. 1997; 18: 263-266Abstract Full Text PDF PubMed Scopus (1010) Google ScholarA classic example of this paradigm is leprosy. In tuberculoid leprosy, well-formed granulomas are seen and a paucity of organisms is identified. These tuberculoid lesions contain cells expressing the cytokine genes INF-γ and IL-2 and, therefore, are of the Th1 class. This in contrast to lepromatous leprosy, which is characterized by extensive skin lesions that demonstrate poorly defined lesions, abundant organisms when normal skin is stained,10Modlin RL Th1-Th2 paradigm: insights form leprosy.J Invest Dermatol. 1994; 102: 828-832Abstract Full Text PDF PubMed Scopus (203) Google Scholar11Yamamura M Uyemura K Deans RJ et al.Defining protective responses to pathogens: cytokine profiles in leprosy lesions.Science. 1991; 254: 277-279Crossref PubMed Scopus (1050) Google Scholar and cells expressing the genes of the Th2 cytokines IL-4, IL-5, and IL-10. Therefore, the Th1 cytokines promote an immunologic granulomatous response that is capable of clearing organisms, whereas the Th2 response impairs granuloma formation and immunity.When Mycobacterium tuberculosis reaches the lower respiratory tract, the initial defense against infection is the alveolar macrophage. Once the organism is engulfed by the macrophage through a complicated process of phagocytosis,7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google ScholarM tuberculosis can be killed by several different mechanisms involving interactions between lymphocytes and phagocytes. These cellular interactions are mediated by Th1 cytokines similar to tuberculoid leprosy.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google ScholarMacrophage-lymphocyte interactions in tuberculosis involve Th1 and natural killer lymphocytes that secrete INF-γ in response to mycobacterial antigens, which activates alveolar macrophages to produce a variety of substances including reactive oxygen and nitrogen species that are involved in growth inhibition and killing of mycobacteria.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar Macrophages can also secrete IL-12, another Th1 cytokine, in a positive feedback loop to amplify this process.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google ScholarTherefore, HAART therapy would be expected to improve immunity vs M tuberculosis by increasing the function and number of CD4+ lymphocytes, thereby augmenting the Th1 response to mycobacterial antigens and improving the granulomatous response to the organism. Although an increase in CD4+ cells might also increase lymphocytes of the Th2 class, INF-γ suppresses Th2 cell function.In this issue of CHEST (see page 597), Schluger and colleagues examine the time course of restoration of secretion of Th1 cytokines in response to mycobacterial antigens in HIV-infected individuals who began HAART. The study involved a small number of patients, but demonstrated a HAART-induced increase in proliferation of peripheral blood mononuclear cells and INF-γ in response to specific mycobacterial antigens. These increases occurred over several months and did not reach levels seen in healthy control subjects. These data suggest that HAART can improve immunity against M tuberculosis in HIV-infected individuals and heighten the granulomatous response to the organism, although it takes several months for a maximum effect and a normal level of response is not attained.However, there is a potential downside to HAART-induced improved immunity against M tuberculosis. Although the heightened granulomatous response may help clear mycobacterial organisms, the granulomatous inflammation itself may do significant damage. Such “paradoxical reactions” have been defined as transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis that occur after initiation of treatment, and are not the result of treatment failure or a second process.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar In HIV-infected individuals, paradoxical reactions are common after the initiation of HAART,13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar and have been called “HAART attacks.”14Kunimoto DY Chui L Norbert E et al.Immune mediated ‘HAART’ attack during treatment for tuberculosis.Int J Tuberc Lung Dis. 1999; 3: 944-947PubMed Google Scholar Paradoxical reactions may be as subtle as isolated fever or as serious as acute respiratory failure or expanding brain masses.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar14Kunimoto DY Chui L Norbert E et al.Immune mediated ‘HAART’ attack during treatment for tuberculosis.Int J Tuberc Lung Dis. 1999; 3: 944-947PubMed Google Scholar15Crump JA Tyrer MJ Lloyd-Owen SJ et al.Miliary tuberculosis with paradoxical response of intracranial tuberculosis complicating human immunodeficiency virus infection in a patient receiving highly active retroviral therapy.Clin Infect Dis. 1998; 26: 1008-1009Crossref PubMed Scopus (109) Google ScholarEvidence that HAART induces paradoxical reactions is consistent with the proposed pathogenesis of restoration of the Th1 granulomatous immune response.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar Paradoxical responses have been shown to be more temporally related to initiation of HAART than antituberculosis therapy.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar Most HIV-infected patients who experience paradoxical reactions convert their tuberculin skin tests from negative to strongly positive,13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar which is a sign of improved CD4+ cell number and function. Paradoxical reactions have been reported in 12 of 33 patients (36%) receiving HAART.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar Most reactions occurred within days to weeks after starting HAART, with a median of 15 days.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar This is more rapid than the improvement in Th1 cytokine secretion found in the group of Schluger et al, although some reports of paradoxical reactions that occur months after initiation of HAART16Orlovic D Smego RA Paradoxical tuberculosis reactions in HIV-infected patients.Int J Tuberc Lung Dis. 2001; 5: 370-374PubMed Google Scholar are more consistent with their data.Similarly, numerous cases have been reported of sarcoidosis developing in HIV-infected patients who has been started on HAART.17Haramati LB Lee G Singh A et al.Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.Radiology. 2001; 218: 242-246Crossref PubMed Scopus (54) Google Scholar18Naccache J Antoine M Wislez M et al.Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients receiving antiretroviral therapy.Am J Respir Crit care Med. 1999; 159: 2009-2013Crossref PubMed Scopus (97) Google Scholar19Mirmirani P Maurer TA Herndier B et al.Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome.J Am Acad Dermatol. 1999; 41: 285-286Abstract Full Text Full Text PDF PubMed Google Scholar20Lenner R Bregman Z Teirstein AS Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy.Chest. 2001; 119: 978-981Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar21Gomez V Smith PR Burack J et al.Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome.Clin Infect Dis. 2000; 31: 1278-1280Crossref PubMed Scopus (63) Google Scholar Such patients develop thoracic adenopathy, pulmonary nodules, and reticular opacities after beginning HAART. Noncaseating granulomas consistent with sarcoidosis are found on tissue biopsy. As with the tuberculosis-treated paradoxical reactions, the sarcoidosis paradoxical reaction usually occurs with evidence of increases in CD4+ cell number induced by HAART. The pathogenesis of this condition is likely to be very similar to the paradoxical reactions seen in HAART-treated, HIV-infected tuberculosis patients. It is likely the antigen(s) that cause sarcoidosis are present in the HIV-infected individual with a low CD4+ count. However, CD4+ lymphocyte number and function is inadequate to mount a significant Th1-induced granulomatous response until HAART therapy is administered.The management of paradoxical reactions has not been well studied, but mild-to-moderate reactions can be managed with nonsteroidal anti-inflammatory agents.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar Severe reactions may require corticosteroids or temporary discontinuation of HAART.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google ScholarThe study of Schluger and colleagues reminds us that HAART improves host immunity in specific ways. One of these is the granulomatous Th1 response. Although the granulomatous response can cause tissue damage and destruction, when it comes to HAART therapy, I think that we can pardon the granuloma. The benefits outweigh the risks. Highly active antiretroviral therapy (HAART) has changed the landscape of HIV infection. HIV-infected individuals are living longer,1Mocroft A Vella S Benfield TL et al.Changing patterns of mortality across Europe in patients infected with HIV-1: EuroSIDA Study Group.Lancet. 1998; 352: 1725-1730Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar2Palella FJ Delaney KM Moorman AC et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8475) Google Scholar opportunistic infections are being delayed,2Palella FJ Delaney KM Moorman AC et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8475) Google Scholar3Ives NJ Gazzard BG Easterbrook PJ The changing pattern of AIDS-defining illness with the introduction of highly active antiretroviral therapy (HAART) in a London clinic.J Infect. 2001; 42: 134-139Abstract Full Text PDF PubMed Scopus (143) Google Scholar and in many instances patients are being liberated from prophylaxis against opportunistic infections.4Ledergerber B Mocroft A Reiss P et al.Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy.N Engl J Med. 2001; 344: 168-174Crossref PubMed Scopus (160) Google Scholar5Whitcup SM Fortin E Linblad AS et al.Discontinuation of anti-cytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis.JAMA. 1999; 282: 1633-1637Crossref PubMed Scopus (162) Google Scholar It has been proposed that HAART-induced restoration in the number and function of CD4+ T lymphocytes is responsible for these clinical observations.6Shen Y Shen L Sehgal P et al.Antiretroviral agents restore mycobacterium-specific T-cell immune responses and facilitate controlling a fatal tuberculosis-like disease in macaques coinfected with simian immunodeficiency virus and Mycobacterium bovis BCG.J Virol. 2001; 75: 8690-8696Crossref PubMed Scopus (36) Google Scholar It is logical that HAART affects the natural course of tuberculosis in HIV infection because the CD4+ T lymphocyte, especially the T-helper type 1 (Th1) subclass, is undoubtedly the major effector cell in cell-mediated immunity of tuberculosis.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar8Boom WH The role of T-cell subsets in Mycobacterium tuberculosis infection.Infect Agents Dis. 1996; 5: 73-81PubMed Google Scholar Th1 cells are characterized by their ability to produce the cytokines interferon (INF)-γ and interleukin (IL)-2, whereas T-helper type 2 (Th2) cells, another subclass of CD4+ lymphocytes, produce cytokines such as IL-4, IL-5, and IL-10. A Th1/Th2 paradigm has been proposed whereby Th1 cells secrete cytokines (“the Th1 response”) that enhance immunity, whereas Th2 cells secrete cytokines (“the Th2 response”) that impair immunity.9Romagnami S The Th1/Th2 paradigm.Immunol Today. 1997; 18: 263-266Abstract Full Text PDF PubMed Scopus (1010) Google Scholar A classic example of this paradigm is leprosy. In tuberculoid leprosy, well-formed granulomas are seen and a paucity of organisms is identified. These tuberculoid lesions contain cells expressing the cytokine genes INF-γ and IL-2 and, therefore, are of the Th1 class. This in contrast to lepromatous leprosy, which is characterized by extensive skin lesions that demonstrate poorly defined lesions, abundant organisms when normal skin is stained,10Modlin RL Th1-Th2 paradigm: insights form leprosy.J Invest Dermatol. 1994; 102: 828-832Abstract Full Text PDF PubMed Scopus (203) Google Scholar11Yamamura M Uyemura K Deans RJ et al.Defining protective responses to pathogens: cytokine profiles in leprosy lesions.Science. 1991; 254: 277-279Crossref PubMed Scopus (1050) Google Scholar and cells expressing the genes of the Th2 cytokines IL-4, IL-5, and IL-10. Therefore, the Th1 cytokines promote an immunologic granulomatous response that is capable of clearing organisms, whereas the Th2 response impairs granuloma formation and immunity. When Mycobacterium tuberculosis reaches the lower respiratory tract, the initial defense against infection is the alveolar macrophage. Once the organism is engulfed by the macrophage through a complicated process of phagocytosis,7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google ScholarM tuberculosis can be killed by several different mechanisms involving interactions between lymphocytes and phagocytes. These cellular interactions are mediated by Th1 cytokines similar to tuberculoid leprosy.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar Macrophage-lymphocyte interactions in tuberculosis involve Th1 and natural killer lymphocytes that secrete INF-γ in response to mycobacterial antigens, which activates alveolar macrophages to produce a variety of substances including reactive oxygen and nitrogen species that are involved in growth inhibition and killing of mycobacteria.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar Macrophages can also secrete IL-12, another Th1 cytokine, in a positive feedback loop to amplify this process.7Schluger NW Rom WN The host immune response to tuberculosis.Am J Respir Crit Care Med. 1998; 157: 679-691Crossref PubMed Scopus (355) Google Scholar Therefore, HAART therapy would be expected to improve immunity vs M tuberculosis by increasing the function and number of CD4+ lymphocytes, thereby augmenting the Th1 response to mycobacterial antigens and improving the granulomatous response to the organism. Although an increase in CD4+ cells might also increase lymphocytes of the Th2 class, INF-γ suppresses Th2 cell function. In this issue of CHEST (see page 597), Schluger and colleagues examine the time course of restoration of secretion of Th1 cytokines in response to mycobacterial antigens in HIV-infected individuals who began HAART. The study involved a small number of patients, but demonstrated a HAART-induced increase in proliferation of peripheral blood mononuclear cells and INF-γ in response to specific mycobacterial antigens. These increases occurred over several months and did not reach levels seen in healthy control subjects. These data suggest that HAART can improve immunity against M tuberculosis in HIV-infected individuals and heighten the granulomatous response to the organism, although it takes several months for a maximum effect and a normal level of response is not attained. However, there is a potential downside to HAART-induced improved immunity against M tuberculosis. Although the heightened granulomatous response may help clear mycobacterial organisms, the granulomatous inflammation itself may do significant damage. Such “paradoxical reactions” have been defined as transient worsening or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis that occur after initiation of treatment, and are not the result of treatment failure or a second process.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar In HIV-infected individuals, paradoxical reactions are common after the initiation of HAART,13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar and have been called “HAART attacks.”14Kunimoto DY Chui L Norbert E et al.Immune mediated ‘HAART’ attack during treatment for tuberculosis.Int J Tuberc Lung Dis. 1999; 3: 944-947PubMed Google Scholar Paradoxical reactions may be as subtle as isolated fever or as serious as acute respiratory failure or expanding brain masses.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar14Kunimoto DY Chui L Norbert E et al.Immune mediated ‘HAART’ attack during treatment for tuberculosis.Int J Tuberc Lung Dis. 1999; 3: 944-947PubMed Google Scholar15Crump JA Tyrer MJ Lloyd-Owen SJ et al.Miliary tuberculosis with paradoxical response of intracranial tuberculosis complicating human immunodeficiency virus infection in a patient receiving highly active retroviral therapy.Clin Infect Dis. 1998; 26: 1008-1009Crossref PubMed Scopus (109) Google Scholar Evidence that HAART induces paradoxical reactions is consistent with the proposed pathogenesis of restoration of the Th1 granulomatous immune response.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar Paradoxical responses have been shown to be more temporally related to initiation of HAART than antituberculosis therapy.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar Most HIV-infected patients who experience paradoxical reactions convert their tuberculin skin tests from negative to strongly positive,13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar which is a sign of improved CD4+ cell number and function. Paradoxical reactions have been reported in 12 of 33 patients (36%) receiving HAART.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar Most reactions occurred within days to weeks after starting HAART, with a median of 15 days.13Narita M Ashkin D Hollender ES et al.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med. 1998; 158: 157-161Crossref PubMed Scopus (548) Google Scholar This is more rapid than the improvement in Th1 cytokine secretion found in the group of Schluger et al, although some reports of paradoxical reactions that occur months after initiation of HAART16Orlovic D Smego RA Paradoxical tuberculosis reactions in HIV-infected patients.Int J Tuberc Lung Dis. 2001; 5: 370-374PubMed Google Scholar are more consistent with their data. Similarly, numerous cases have been reported of sarcoidosis developing in HIV-infected patients who has been started on HAART.17Haramati LB Lee G Singh A et al.Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.Radiology. 2001; 218: 242-246Crossref PubMed Scopus (54) Google Scholar18Naccache J Antoine M Wislez M et al.Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients receiving antiretroviral therapy.Am J Respir Crit care Med. 1999; 159: 2009-2013Crossref PubMed Scopus (97) Google Scholar19Mirmirani P Maurer TA Herndier B et al.Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome.J Am Acad Dermatol. 1999; 41: 285-286Abstract Full Text Full Text PDF PubMed Google Scholar20Lenner R Bregman Z Teirstein AS Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy.Chest. 2001; 119: 978-981Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar21Gomez V Smith PR Burack J et al.Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome.Clin Infect Dis. 2000; 31: 1278-1280Crossref PubMed Scopus (63) Google Scholar Such patients develop thoracic adenopathy, pulmonary nodules, and reticular opacities after beginning HAART. Noncaseating granulomas consistent with sarcoidosis are found on tissue biopsy. As with the tuberculosis-treated paradoxical reactions, the sarcoidosis paradoxical reaction usually occurs with evidence of increases in CD4+ cell number induced by HAART. The pathogenesis of this condition is likely to be very similar to the paradoxical reactions seen in HAART-treated, HIV-infected tuberculosis patients. It is likely the antigen(s) that cause sarcoidosis are present in the HIV-infected individual with a low CD4+ count. However, CD4+ lymphocyte number and function is inadequate to mount a significant Th1-induced granulomatous response until HAART therapy is administered. The management of paradoxical reactions has not been well studied, but mild-to-moderate reactions can be managed with nonsteroidal anti-inflammatory agents.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar Severe reactions may require corticosteroids or temporary discontinuation of HAART.12Burman WJ Jones BE Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy.Am J Respir Crit Care Med. 2001; 164: 7-12Crossref PubMed Scopus (181) Google Scholar The study of Schluger and colleagues reminds us that HAART improves host immunity in specific ways. One of these is the granulomatous Th1 response. Although the granulomatous response can cause tissue damage and destruction, when it comes to HAART therapy, I think that we can pardon the granuloma. The benefits outweigh the risks.
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