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Human Immunodeficiency Virus and Leprosy: An Update
Human Immunodeficiency Vi rus and L eprosy: An Update Diana N.J. Lockwood, MD, FRCP*, Saba M. Lambert, MBBS KEYWORDS Human immunodeficiency virus Leprosy Coinfection Antiretroviral treatment
In 2008, 121 countries reported a total of 249,007 new leprosy cases to the World Health Organization (WHO). Most endemic countries for leprosy also have a high HIV prevalence, increasing the possibility of HIVeleprosy coinfection. The few published small studies provide limited data on the course of leprosy in coinfected patients. HIV incidence was not found to be increased among leprosy patients compared with nonleprosy groups.5,6 All types of leprosy can occur in coinfected patients. Two East African studies reporting an increase multibacillary (MB) cases.7,8 However since the introduction of HAART borderline tuberculoid leprosy is the predominant form, as reported in Brazilian studies.9,10 Coinfected patients treated with standard length WHO-multi-drug therapy (MDT), have responded adequately, although there might be a possibility of an increased relapse rate.11 A Ugandan study demonstrated an increased risk of developing type 1 reactions in an MB leprosy patient with HIV,12 and increased recurrence rates of type 1 reactions were seen in an Ethiopian study.13 In general, however, neuritis was not found to be more severe in HIV-positive cases.14 A few case reports of ENL in coinfected patients have been published. Co-infected patients with reactions appear to need very long courses of steroid treatment.13,14 Patients with HIV are also at risk of developing peripheral nerve damage including generalized peripheral neuropathy and mono-neuritis multiplex through several mechanisms, namely, treatment with antiretrovirals and
London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT London, UK * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 125–128 doi:10.1016/j.det.2010.08.016 0733-8635/11/$ e see front matter Ó 2011 Published by Elsevier Inc.
derm.theclinics.com
Co-infection with HIV has a major effect on the natural history of many diseases, particularly mycobacterial diseases. Early in the HIV epidemic it was predicted that HIV infections would worsen outcomes in leprosy patients with more patients developing lepromatous disease and patients having fewer immune reactions. Now that many patients receive HAART tuberculoid leprosy types predominate and reactions are an important clinical feature in co-infected patients.1e4 Leprosy is a chronic infectious disease affecting nerves and skin. It has a long incubation period of 2 to 10 years, and presents with a clinical spectrum depending on the relationship between the host immune system and the bacteria. At one end of the spectrum is tuberculoid leprosy, characterized by strong cell-mediated immunity (CMI) toward M leprae. These patients have few hypopigmented, anesthetic lesions. At the other pole is lepromatous leprosy (LL), which is characterized by the absence of a CMI response. These patients have numerous lesions and high bacillary loads. Most patients have features between these two extreme groups and fall in the categories of borderline tuberculous (BT), borderline borderline (BB) or borderline lepromatous (BL). The borderline cases are immunologically unstable and at greater risk of type 1 reaction, which affects mainly the nerves and skin. The lepromatous types of BL and LL are at higher risk of erythema nodosu leprosum (ENL), a more systemic and severe immunologic complication.
126
Lockwood & Lambert HIV infection per se. In analogy to the situation for tuberculosis in HIV coinfected individuals, it was assumed that HIV coinfection would worsen nerve damage in leprosy patients. There are a few early studies reporting no increase in nerve damage in coinfected patients.12e14 A well controlled study of peripheral nerve function in coinfected patients would be useful. Table 1 summarizes the expected versus actual impact of HIV-1 on coinfected patients.
IMMUNOLOGY OF HIV AND LEPROSY COINFECTION Patients with tuberculoid leprosy have good cellmediated immune response to M leprae, resulting in a few skin lesions, which histologically have well organized lymphocyte (CD681, CD31, CD81, CD41)-rich granulomas with predominantly CD4 T cells. In contrast, patients with LL have a strong humoral response but poor or absent cellmedicated immunity, resulting in uncontrolled growth of bacilli and disseminated skin lesions. Histologic examination of biopsies from their lesions reveals that the granulomas are comprised of macrophages and small numbers of CD8 T cells.10 HIV affects cell-mediated immunity, and it was initially expected that, just as in M. tuberculosis infection, the decrease in CD4 cells would result in decreased capacity for mycobacterial containment and thus an increase in disseminated disease. But studies have shown that HIV coinfected patients with low CD4 count had borderline tuberculoid lesions with well formed granuloma and normal CD4 cells numbers. In contrast, coinfected patients with LL lesions showed loose infiltrates comprised of macrophages and a small number of almost exclusively CD8 lymphocytes.15,16 Carvalho and colleagues16 found that the coinfected group exhibits lower CD4 to CD8 ratios, higher levels of
CD81 activation, increased Vd1 to Vd2 T cell ratios and decreased percentages of plasmacytoid dendritic cells as compared with HIV-1 monoinfected patients. The exact immunopathological mechanism underlying the possible increase in frequency of leprosy reactions is not clear. Dysregulation of the immune system and the heightened state of immune activation in HIV infection may be responsible. In addition, delayed clearance of M.leprae antigen caused by impaired phagocytic function of macrophages also has been implicated.
EFFECT OF ANTIRETROVIRAL THERAPY ON HIV AND LEPROSY COINFECTION Since the introduction of highly active antiretroviral therapy (HAART) in the management of HIV, especially in regions endemic for leprosy, co-infected patients are also developing tuberculoid leprosy with active lesions, and ulceration of lesions is seen in leprosy type 1 reactions. Leprosy is being increasingly reported as part of the immune reconstitution inflammatory syndrome (IRIS). IRIS is a paradoxic deterioration in clinical status after starting HAART, a deterioration that is attributable to the recovery or reactivation of someone’s immune response to a latent or subclinical process. The HAART regimes currently used increase production and redistribution of CD41 cells and improve pathogen-specific immunity, both to HIV and other pathogens. While improved immunity to HIV is the required effect from HAART, improved immunity to other opportunistic pathogens or development of autoimmunity can result in IRIS. The prevalence of IRIS in cohort studies of HIVpositive patients ranges from 3% to more than 50%, varying greatly with the acquired immunodeficiency syndrome (AIDS)- defining illness affecting the patient at the start of HAART therapy.17 Risk factors for the development of IRIS include advanced HIV disease with a CD41 T cell count
Table 1 Summary of impact of human immunodeficiency virus-1 on leprosy: expected versus actual Theory Epidemiologic Clinical
Incidence Tuberculoid leprosy Treatment response Type-1 reactional states Neuritis Novel findings
Histopathological
Granuloma formation Bacterial index
In Practice
Increase in leprosy No change Decreased Increased Worsened No change Fewer Increased Worsened ? Presentation as immune reconstitution inflammatory syndrome Decreased No change Increased No change
HIV and Leprosy: An Update under 50 cells/mm, unrecognized opportunistic infection or high microbial burden, and the number and presence of prior opportunistic infections. HAART triggers overt clinical manifestations of coinfection with tuberculosis, cytomegalovirus, herpes zoster, C and B hepatitis virus, and now leprosy. Since 2003, 23 reports of patients developing leprosy as IRIS have been published.2,3,15e19 Most patients had borderline leprosy, and type 1 reactions frequently occurred. Ulceration, a highly unusual feature in leprosy lesions, was observed in six patients, and four patients also developed neuritis. It may be that the high proportion of borderline tuberculoid leprosy cases among the HIV-infected patients on HAART could shed light on the questions related to the kinetics of M leprae infection and development of disease. Borderline tuberculoid leprosy manifests 2 to 5 years after infection, at which time specific cell-mediated immunity is strong enough to cause tissue damage as well as kill or at least control mycobacterial growth. On the other hand, lepromatous (BL and LL) forms appear in patients after longer periods of incubation (5 to 10 years), during which time a large number of bacilli have accumulated in the tissue due to progressive reduction of CMI. Although HIV patients are typically more aware of their health status and would easily detect small lesions, the high frequency of borderline tuberculoid patients and reactions among HIV-infected individuals and the low bacillary load among the co-infected MB patients strongly suggest an earlier-than-usual detection of the disease in immune-reconstituted patients. To facilitate the recognition and classification of leprosy-associated IRIS, the following case definition has been suggested20: Leprosy or leprosy reaction presenting within 6 months of starting HAART Advanced HIV infection Low CD41 count before starting HAART CD41 count increasing after HAART has been started. Subdividing leprosy-associated IRIS into groups according to data on timing and clinical presentation may help toward defining the causes and mechanisms of this phenomenon. Deps and Lockwood21 recently proposed such a subdivision, attempting to separate unmasking episodes from those of overlap of immune restoration. There are several possible mechanisms for the pathogenesis of leprosy IRIS. Leprosy has a long incubation period, and HAART may provide the immunologic trigger for normal disease. Another
explanation is that leprosy-associated IRIS is similar to a type 1 reaction. Whatever the underlying mechanisms, it is likely that leprosyassociated IRIS will be increasingly reported, especially as access to HAART becomes more widely available. There are also several case reports of patients being diagnosed with leprosy more than 6 months after the initiation of HAART. Although these patients can present with any kind of leprosy, including histoid leprosy,22 the time lag of greater than 6 months since the initiation of HAART excludes the diagnosis of IRIS.
SUMMARY From the available data so far, one can conclude that treatment of leprosy patients with concurrent HIV infection does not differ from that of a seronegative leprosy patient: standard WHO-MDT, in conjunction with HAART if the CD4 count is low. Treatment of reactions can be managed with corticosteroids or thalidomide as appropriate. There are currently no good prospective clinical data on the clinical features of leprosy in HIVinfected patients, particularly the evolution of their skin lesions and progression of nerve damage and response to MDT. The inclusion of HIV testing in sentinel studies of patients relapsing after multidrug therapy treatment would give some indication as to whether HIV infection is an important cofactor in relapse. Response to treatment for neuritis and reaction in coinfected patients needs to be studied carefully in prospective studies. The influence of HIV infection on cell-mediated immune responses to M leprae in the HIVinfected patient needs exploration, especially within the skin. The recognition of leprosy presenting as IRIS warrants immunologic studies, using, for example, immunohistochemistry to delineate cellular phenotypes within the granuloma and mRNA and protein production to assess cytokine expression. Leprosy and HIV coinfection is an evolving situation with ongoing discoveries and further research needs.
REFERENCES 1. Ustianowski AP, Lawn SD, Lockwood DN. Interactions between HIV infection and leprosy: a paradox. Lancet Infect Dis 2006;6(6):350e60. 2. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis 2003;36(1):e5e6.
127
128
Lockwood & Lambert 3. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 2004;140(8):997e1000. 4. Lucas S. Human immunodeficiency virus and leprosy. Lepr Rev 1993;64:97e103. 5. Leonard G, Sangare A, Verdier M, et al. Prevalence of HIV infection among patients with leprosy in African countries and Yemen. J Acquir Immune Defic Syndr 1990;3:1109e13. 6. Ponnighaus JM, Mwanjasi LJ, Fine PE, et al. Is HIV infection risk factor for leprosy? Int J Lepr 1991;59: 221e8. 7. Borgdorff MW, van der Broek J, Chum HJ, et al. HIV-1 infection as a risk factor for leprosy; a case control study in Tanzania. Int J Lepr Other Mycobact Dis 1993;61:556e62. 8. Orege PA, Fine PE, Lucas SB, et al. A case control study on human immunodeficiency virus-1 (HIV-1) infection as a risk for tuberculosis and leprosy in western Kenya. Tuber Lung Dis 1993;74:3777e81. 9. Sarno EN, Illarramendi X, Nery JA, et al. HIVM. leprae interaction: can HAART modify the course of leprosy? Public Health Rep 2008;123:206e12. 10. Pereira GAS, Stefani MMA, Arau´jo Filho JA, et al. Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium leprae coinfection: HIV-1 subtypes and clinical, immunologic and histopathologic profiles in a Brazilian cohort. Am J Trop Med Hyg 2004;71(5):679e84. 11. Rath N, Kar HK. Leprosy in HIV infection: a study of three cases. Indian J Lepr 2003;75:355e9. 12. Birwe R, Kawuma HJ. Type 1 reactions in leprosy, neuritis and steroid therapy: the impact of the human immunodeficiancy virus. Trans R Soc Trop Med Hyg 1994;88:315e6.
13. Talhari C, Mira MT, Massone C, et al. Leprosy and HIV: a clinical, pathological, immunological and therapeutic study of a cohort from a Brazilian referral centre and infectious diseases. J Infect Dis 2010; 202:345e54. 14. Lockwood DN, Lambert S. HIV and leprosy: where are we at? Lepr Rev 2010;81:167e75. 15. Sampaio EP, Caneshi JRT, Nery JA, et al. Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virus-infected individuals. Infect Immun 1995;63:1848e54. 16. Carvalho KL, Maeda S, Marti L, et al. Immune cellular parameters of leprosy and human immunodeficiency virus-1 c-infected subjects. Immunology 2008;124:206e14. 17. Muller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:251e61. 18. Lawn SD, Lockwood DN. Leprosy after starting antiretroviral treatment. BMJ 2007;334(7587):217e8. 19. Vinay K, Smita J, Nikhil G, et al. Human Immunodeficiency virus and leprosy coinfection in Pune, India. J Clin Microbiol 2009;47(9):2998e9. 20. Deps PD, Lockwood DN. Leprosy occurring as immune reconstitution syndrome. Trans R Soc Trop Med Hyg 2008;102(10):966e8. 21. Deps PD, Lockwood DN. Leprosy presenting as immune reconstitution inflammatory syndrome: proposed definitions and classification. Lepr Rev 2010;81:59e68. 22. Bumb RA, Ghiya BC, et al. Histoid leprosy in a patient of acquired immune-deficiency syndrome taking HAART. Lepr Rev 2010.
In 2008, 121 countries reported a total of 249,007 new leprosy cases to the World Health Organization (WHO). Most endemic countries for leprosy also have a high HIV prevalence, increasing the possibility of HIVeleprosy coinfection. The few published small studies provide limited data on the course of leprosy in coinfected patients. HIV incidence was not found to be increased among leprosy patients compared with nonleprosy groups.5,6 All types of leprosy can occur in coinfected patients. Two East African studies reporting an increase multibacillary (MB) cases.7,8 However since the introduction of HAART borderline tuberculoid leprosy is the predominant form, as reported in Brazilian studies.9,10 Coinfected patients treated with standard length WHO-multi-drug therapy (MDT), have responded adequately, although there might be a possibility of an increased relapse rate.11 A Ugandan study demonstrated an increased risk of developing type 1 reactions in an MB leprosy patient with HIV,12 and increased recurrence rates of type 1 reactions were seen in an Ethiopian study.13 In general, however, neuritis was not found to be more severe in HIV-positive cases.14 A few case reports of ENL in coinfected patients have been published. Co-infected patients with reactions appear to need very long courses of steroid treatment.13,14 Patients with HIV are also at risk of developing peripheral nerve damage including generalized peripheral neuropathy and mono-neuritis multiplex through several mechanisms, namely, treatment with antiretrovirals and
London School of Hygiene and Tropical Medicine, Keppel Street, WC1E 7HT London, UK * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 125–128 doi:10.1016/j.det.2010.08.016 0733-8635/11/$ e see front matter Ó 2011 Published by Elsevier Inc.
derm.theclinics.com
Co-infection with HIV has a major effect on the natural history of many diseases, particularly mycobacterial diseases. Early in the HIV epidemic it was predicted that HIV infections would worsen outcomes in leprosy patients with more patients developing lepromatous disease and patients having fewer immune reactions. Now that many patients receive HAART tuberculoid leprosy types predominate and reactions are an important clinical feature in co-infected patients.1e4 Leprosy is a chronic infectious disease affecting nerves and skin. It has a long incubation period of 2 to 10 years, and presents with a clinical spectrum depending on the relationship between the host immune system and the bacteria. At one end of the spectrum is tuberculoid leprosy, characterized by strong cell-mediated immunity (CMI) toward M leprae. These patients have few hypopigmented, anesthetic lesions. At the other pole is lepromatous leprosy (LL), which is characterized by the absence of a CMI response. These patients have numerous lesions and high bacillary loads. Most patients have features between these two extreme groups and fall in the categories of borderline tuberculous (BT), borderline borderline (BB) or borderline lepromatous (BL). The borderline cases are immunologically unstable and at greater risk of type 1 reaction, which affects mainly the nerves and skin. The lepromatous types of BL and LL are at higher risk of erythema nodosu leprosum (ENL), a more systemic and severe immunologic complication.
126
Lockwood & Lambert HIV infection per se. In analogy to the situation for tuberculosis in HIV coinfected individuals, it was assumed that HIV coinfection would worsen nerve damage in leprosy patients. There are a few early studies reporting no increase in nerve damage in coinfected patients.12e14 A well controlled study of peripheral nerve function in coinfected patients would be useful. Table 1 summarizes the expected versus actual impact of HIV-1 on coinfected patients.
IMMUNOLOGY OF HIV AND LEPROSY COINFECTION Patients with tuberculoid leprosy have good cellmediated immune response to M leprae, resulting in a few skin lesions, which histologically have well organized lymphocyte (CD681, CD31, CD81, CD41)-rich granulomas with predominantly CD4 T cells. In contrast, patients with LL have a strong humoral response but poor or absent cellmedicated immunity, resulting in uncontrolled growth of bacilli and disseminated skin lesions. Histologic examination of biopsies from their lesions reveals that the granulomas are comprised of macrophages and small numbers of CD8 T cells.10 HIV affects cell-mediated immunity, and it was initially expected that, just as in M. tuberculosis infection, the decrease in CD4 cells would result in decreased capacity for mycobacterial containment and thus an increase in disseminated disease. But studies have shown that HIV coinfected patients with low CD4 count had borderline tuberculoid lesions with well formed granuloma and normal CD4 cells numbers. In contrast, coinfected patients with LL lesions showed loose infiltrates comprised of macrophages and a small number of almost exclusively CD8 lymphocytes.15,16 Carvalho and colleagues16 found that the coinfected group exhibits lower CD4 to CD8 ratios, higher levels of
CD81 activation, increased Vd1 to Vd2 T cell ratios and decreased percentages of plasmacytoid dendritic cells as compared with HIV-1 monoinfected patients. The exact immunopathological mechanism underlying the possible increase in frequency of leprosy reactions is not clear. Dysregulation of the immune system and the heightened state of immune activation in HIV infection may be responsible. In addition, delayed clearance of M.leprae antigen caused by impaired phagocytic function of macrophages also has been implicated.
EFFECT OF ANTIRETROVIRAL THERAPY ON HIV AND LEPROSY COINFECTION Since the introduction of highly active antiretroviral therapy (HAART) in the management of HIV, especially in regions endemic for leprosy, co-infected patients are also developing tuberculoid leprosy with active lesions, and ulceration of lesions is seen in leprosy type 1 reactions. Leprosy is being increasingly reported as part of the immune reconstitution inflammatory syndrome (IRIS). IRIS is a paradoxic deterioration in clinical status after starting HAART, a deterioration that is attributable to the recovery or reactivation of someone’s immune response to a latent or subclinical process. The HAART regimes currently used increase production and redistribution of CD41 cells and improve pathogen-specific immunity, both to HIV and other pathogens. While improved immunity to HIV is the required effect from HAART, improved immunity to other opportunistic pathogens or development of autoimmunity can result in IRIS. The prevalence of IRIS in cohort studies of HIVpositive patients ranges from 3% to more than 50%, varying greatly with the acquired immunodeficiency syndrome (AIDS)- defining illness affecting the patient at the start of HAART therapy.17 Risk factors for the development of IRIS include advanced HIV disease with a CD41 T cell count
Table 1 Summary of impact of human immunodeficiency virus-1 on leprosy: expected versus actual Theory Epidemiologic Clinical
Incidence Tuberculoid leprosy Treatment response Type-1 reactional states Neuritis Novel findings
Histopathological
Granuloma formation Bacterial index
In Practice
Increase in leprosy No change Decreased Increased Worsened No change Fewer Increased Worsened ? Presentation as immune reconstitution inflammatory syndrome Decreased No change Increased No change
HIV and Leprosy: An Update under 50 cells/mm, unrecognized opportunistic infection or high microbial burden, and the number and presence of prior opportunistic infections. HAART triggers overt clinical manifestations of coinfection with tuberculosis, cytomegalovirus, herpes zoster, C and B hepatitis virus, and now leprosy. Since 2003, 23 reports of patients developing leprosy as IRIS have been published.2,3,15e19 Most patients had borderline leprosy, and type 1 reactions frequently occurred. Ulceration, a highly unusual feature in leprosy lesions, was observed in six patients, and four patients also developed neuritis. It may be that the high proportion of borderline tuberculoid leprosy cases among the HIV-infected patients on HAART could shed light on the questions related to the kinetics of M leprae infection and development of disease. Borderline tuberculoid leprosy manifests 2 to 5 years after infection, at which time specific cell-mediated immunity is strong enough to cause tissue damage as well as kill or at least control mycobacterial growth. On the other hand, lepromatous (BL and LL) forms appear in patients after longer periods of incubation (5 to 10 years), during which time a large number of bacilli have accumulated in the tissue due to progressive reduction of CMI. Although HIV patients are typically more aware of their health status and would easily detect small lesions, the high frequency of borderline tuberculoid patients and reactions among HIV-infected individuals and the low bacillary load among the co-infected MB patients strongly suggest an earlier-than-usual detection of the disease in immune-reconstituted patients. To facilitate the recognition and classification of leprosy-associated IRIS, the following case definition has been suggested20: Leprosy or leprosy reaction presenting within 6 months of starting HAART Advanced HIV infection Low CD41 count before starting HAART CD41 count increasing after HAART has been started. Subdividing leprosy-associated IRIS into groups according to data on timing and clinical presentation may help toward defining the causes and mechanisms of this phenomenon. Deps and Lockwood21 recently proposed such a subdivision, attempting to separate unmasking episodes from those of overlap of immune restoration. There are several possible mechanisms for the pathogenesis of leprosy IRIS. Leprosy has a long incubation period, and HAART may provide the immunologic trigger for normal disease. Another
explanation is that leprosy-associated IRIS is similar to a type 1 reaction. Whatever the underlying mechanisms, it is likely that leprosyassociated IRIS will be increasingly reported, especially as access to HAART becomes more widely available. There are also several case reports of patients being diagnosed with leprosy more than 6 months after the initiation of HAART. Although these patients can present with any kind of leprosy, including histoid leprosy,22 the time lag of greater than 6 months since the initiation of HAART excludes the diagnosis of IRIS.
SUMMARY From the available data so far, one can conclude that treatment of leprosy patients with concurrent HIV infection does not differ from that of a seronegative leprosy patient: standard WHO-MDT, in conjunction with HAART if the CD4 count is low. Treatment of reactions can be managed with corticosteroids or thalidomide as appropriate. There are currently no good prospective clinical data on the clinical features of leprosy in HIVinfected patients, particularly the evolution of their skin lesions and progression of nerve damage and response to MDT. The inclusion of HIV testing in sentinel studies of patients relapsing after multidrug therapy treatment would give some indication as to whether HIV infection is an important cofactor in relapse. Response to treatment for neuritis and reaction in coinfected patients needs to be studied carefully in prospective studies. The influence of HIV infection on cell-mediated immune responses to M leprae in the HIVinfected patient needs exploration, especially within the skin. The recognition of leprosy presenting as IRIS warrants immunologic studies, using, for example, immunohistochemistry to delineate cellular phenotypes within the granuloma and mRNA and protein production to assess cytokine expression. Leprosy and HIV coinfection is an evolving situation with ongoing discoveries and further research needs.
REFERENCES 1. Ustianowski AP, Lawn SD, Lockwood DN. Interactions between HIV infection and leprosy: a paradox. Lancet Infect Dis 2006;6(6):350e60. 2. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis 2003;36(1):e5e6.
127
128
Lockwood & Lambert 3. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 2004;140(8):997e1000. 4. Lucas S. Human immunodeficiency virus and leprosy. Lepr Rev 1993;64:97e103. 5. Leonard G, Sangare A, Verdier M, et al. Prevalence of HIV infection among patients with leprosy in African countries and Yemen. J Acquir Immune Defic Syndr 1990;3:1109e13. 6. Ponnighaus JM, Mwanjasi LJ, Fine PE, et al. Is HIV infection risk factor for leprosy? Int J Lepr 1991;59: 221e8. 7. Borgdorff MW, van der Broek J, Chum HJ, et al. HIV-1 infection as a risk factor for leprosy; a case control study in Tanzania. Int J Lepr Other Mycobact Dis 1993;61:556e62. 8. Orege PA, Fine PE, Lucas SB, et al. A case control study on human immunodeficiency virus-1 (HIV-1) infection as a risk for tuberculosis and leprosy in western Kenya. Tuber Lung Dis 1993;74:3777e81. 9. Sarno EN, Illarramendi X, Nery JA, et al. HIVM. leprae interaction: can HAART modify the course of leprosy? Public Health Rep 2008;123:206e12. 10. Pereira GAS, Stefani MMA, Arau´jo Filho JA, et al. Human immunodeficiency virus type 1 (HIV-1) and Mycobacterium leprae coinfection: HIV-1 subtypes and clinical, immunologic and histopathologic profiles in a Brazilian cohort. Am J Trop Med Hyg 2004;71(5):679e84. 11. Rath N, Kar HK. Leprosy in HIV infection: a study of three cases. Indian J Lepr 2003;75:355e9. 12. Birwe R, Kawuma HJ. Type 1 reactions in leprosy, neuritis and steroid therapy: the impact of the human immunodeficiancy virus. Trans R Soc Trop Med Hyg 1994;88:315e6.
13. Talhari C, Mira MT, Massone C, et al. Leprosy and HIV: a clinical, pathological, immunological and therapeutic study of a cohort from a Brazilian referral centre and infectious diseases. J Infect Dis 2010; 202:345e54. 14. Lockwood DN, Lambert S. HIV and leprosy: where are we at? Lepr Rev 2010;81:167e75. 15. Sampaio EP, Caneshi JRT, Nery JA, et al. Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virus-infected individuals. Infect Immun 1995;63:1848e54. 16. Carvalho KL, Maeda S, Marti L, et al. Immune cellular parameters of leprosy and human immunodeficiency virus-1 c-infected subjects. Immunology 2008;124:206e14. 17. Muller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:251e61. 18. Lawn SD, Lockwood DN. Leprosy after starting antiretroviral treatment. BMJ 2007;334(7587):217e8. 19. Vinay K, Smita J, Nikhil G, et al. Human Immunodeficiency virus and leprosy coinfection in Pune, India. J Clin Microbiol 2009;47(9):2998e9. 20. Deps PD, Lockwood DN. Leprosy occurring as immune reconstitution syndrome. Trans R Soc Trop Med Hyg 2008;102(10):966e8. 21. Deps PD, Lockwood DN. Leprosy presenting as immune reconstitution inflammatory syndrome: proposed definitions and classification. Lepr Rev 2010;81:59e68. 22. Bumb RA, Ghiya BC, et al. Histoid leprosy in a patient of acquired immune-deficiency syndrome taking HAART. Lepr Rev 2010.