Correspondence AIDS 2013, 27:2169–2172
The effect of efavirenz versus nevirapine-containing regimens in the HIV-CAUSAL Collaboration: reply to Llibre and Podzamczer and additional results We recently reported a mortality hazard ratio of 1.59 [95% confidence interval (CI) 1.27–1.98] for nevirapine versus efavirenz non-nucleoside reverse transcriptase inhibitor (NRTI)-based first-line regimens [1]. Llibre and Podzamczer [2] refer to our findings as ‘unanticipated’. However, as we reported in our article, our findings were in line with those of a recent Cochrane Collaboration meta-analysis of randomized clinical trials [3], including the 2NN study [4] referenced by Llibre and Podzamczer [2], which found an increased risk of death comparing nevirapine 400 mg once daily with efavirenz 600 mg. After we excluded one trial that included patients
who were also receiving a protease inhibitor [5], the mortality risk ratio was 1.97 (95% CI 0.95–4.07) for nevirapine (all doses) versus efavirenz. Llibre and Podzamczer [2] question our decision to increase statistical efficiency by including patients with any baseline CD4 cell count in our main analysis and allowing 6 months to complete a regimen. Neither decision seems critical as our results did not change appreciably when we restricted to patients with baseline CD4 cell counts for which nevirapine is recommended and required patients to initiate all of the drugs in their
Table 1. Definition and distribution of categories of chronic hepatitis C infection, HIV-CAUSAL Collaboration. Number of replicates (%) Chronic HCV infection
Efavirenz (n ¼ 26 368)
Definition
Definite Probable
2 or more positive HCV RNA test results at least 6 months apart 1 positive HCV RNA test result, 2 positive HCV RNA test results less than 6 months apart 1 or more positive HCV antibody test result, 1 or more positive HCV result (test unknown), No positive HCV RNA tests No positive HCV tests of any variety Unknown or not measured in that cohort
Possible None Unknown
Nevirapine (n ¼ 15 004)
19 127
0.1 0.5
2 45
0.0 0.3
1519
5.8
1164
7.8
22 621 2082
85.8 7.9
12 613 1180
84.1 7.9
HCV, hepatitis C virus. Table 2. Clinical, immunologic and virologic outcomes for regimens based on efavirenz (24 286 individuals) versus nevirapine (13 824 individuals) in the subset of the population with hepatitis C data, HIV-CAUSAL Collaboration. Outcome
Treatment
Death
Efavirenz Nevirapine
AIDS or death
Efavirenz Nevirapine
CD4 cell count
Efavirenz Nevirapine
Hazard ratioa; 95% CI
Model
Without adjustment for HCV With adjustment for HCV
1 (ref.) 1.44 1.43 1 (ref.) 1.41 1.40
Without adjustment for HCV With adjustment for HCV
Change from baseline (cells/ml)a,b; 95% CI 0 (ref.) 14.78 21.84 to 7.73 13.66 20.71 to 6.62
Without adjustment for HCV With adjustment for HCV
1 (ref.) 1.90 1.89
Without adjustment for HCV With adjustment for HCV
1.06–1.95 1.06–1.94 1.02–1.94 1.02–1.94
Risk ratioa,c; 95% CI Virologic failure (HIV-RNA >50)
Efavirenz Nevirapine
1.42–2.53 1.42–2.52
CI, confidence interval; HCV, hepatitis C virus. a All models are adjusted for the baseline covariates (sex, age, race, geographic origin, mode of transmission, CD4 cell count, HIV RNA, calendar year, years since HIV diagnosis and an indicator for starting only nucleoside reverse transcriptase inhibitors at baseline) and the time-varying covariates (CD4 cell count, HIV RNA, AIDS-defining illness, time since last laboratory measurement) during the first 6 months of follow-up via unstabilized weights trimmed at 100. b Based on 9621 and 3552 individuals with CD4 cell count measurements at 12 2 months in the efavirenz and nevirapine arms, respectively. c Based on 9641 and 3508 individuals with HIV RNA measurements at 12 2 months in the efavirenz and nevirapine arms, respectively.
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
2169
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2170
AIDS
2013, Vol 27 No 13
regimen simultaneously. Details were provided in our article. Llibre and Podzamczer [2] suggest that our description of analyses involving hepatitis C coinfection is incomplete. We agree so we are providing additional information here. Table 1 shows the definition and distribution of categories of chronic hepatitis C virus infection for our mortality analysis (the table shows the most recently available data in the HIV-CAUSAL Collaboration). Table 2 shows the updated effect estimates, with and without adjustment for hepatitis C coinfection (we collapsed the definite/probable and none/unknown categories), in the subset of the population with hepatitis C data. These estimates suggest that adjustment for hepatitis C coinfection in the full study population would not result in appreciable reductions in our reported effect estimates. We did not have sufficient data to adjust for NRTI backbone in our analyses or to repeat our analyses in subsets defined by NRTI backbone. As we acknowledge in our article, the fact that we may not be able to completely adjust for this and other potential confounding factors is a limitation of our analysis. It is therefore reassuring that our estimates are in the same direction as – but more precise than – those from randomized clinical trials.
Acknowledgements Conflicts of interest There are no conflicts of interest.
Lauren E. Caina, Miguel A. Herna´nb, on behalf of the HIV-CAUSAL Collaboration, aDepartment of Epidemiology, Harvard School of Public Health, Boston, MA, USA, and bDepartment of Epidemiology, Harvard School of Public Health and Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA. Correspondence to Lauren E. Cain, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. Tel: +1 617 432 6921; fax: +1 617 432 1884; e-mail: [email protected]
References 1. The HIV-CAUSAL Collaboration. The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study. AIDS 2012; 26:1691–1705. 2. Llibre JM, Podzamczer D. Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL Collaboration Cohort. AIDS 2012; 26:2117–2118. 3. Mbuagbaw LCE, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naı¨ve individuals. Cochrane Database Syst Rev 2010:CD004246. 4. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263. 5. van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenzbased versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. HIV Clin Trials 2008; 9:324– 336.
DOI:10.1097/01.aids.0000432446.15061.27
A case of immune reconstitution inflammatory syndrome related to a disseminated histoplasmosis in an HIV-1 infected patient The immune reconstitution inflammatory syndrome (IRIS) is a set of clinical and laboratory findings, related to the expression of opportunistic infections or of cancers. IRIS occurs in two ways: revelation (unmasked disease) or deterioration of a known infection or neoplasic disease (paradoxical reaction) [1]. It may be associated with many different opportunistic pathogens such as Mycobacterium tuberculosis, Cryptococci, JC polyomavirus, and hepatitis C and B virus [2]. This syndrome is usually characterized by an increased CD4 cell count and a rapid decrease in viral load [1]. The pathogenesis is speculative and seems to be caused by a recovery of pathogen-specific T cells responses and perturbations of innate immune responses [2]. Histoplasma capsulatum var. capsulatum is endemic in central regions of sub-Saharian Africa and in the USA
(Ohiao and Mississipi River valley) [3], and is an opportunistic fungal infection in HIV-infected patients with a CD4 low cell count of less than 50 cells/ml [3]. The pathogenesis remains unclear and seems to be related to airborne contamination from the soil (bird ant bat excrements) [4]. We report a case of IRIS related to a disseminated histoplasmosis infection in an African HIV-1-infected patient living in France. A 28-year-old woman with a history of tuberculosis was diagnosed with HIV-1 after her childbirth in 2002 in Ivory Coast, and then she was lost to follow-up. In October 2011, she consulted for weight loss and fatigue. Her physical examination was unremarkable, her CD4 cell count was 3 cells/ml and viral load was 62 976 copies/ml (4.8 log).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
The patient started her antiretroviral therapy (ART) with tenofovir/emtricitabine, atazanavir and ritonavir, but she stopped it 1 month later because of a digestive intolerance and came back to the hospital. Abdominal computed tomography (CT) scan found mesenteric and retroperitoneal adenopathies without necrosis (the largest one measured 23 12 mm). The patient refused further investigations and a new ART regimen was started in November with abacavir/ lamivudine, darunavir and ritonavir. Two months later, she presented with fever, night sweats and multiple cervical adenopathies. CD4 cell count was 10 cells/ml, viral load was 235 copies/ml (3.37 log) and C-reactive protein was less than 5. Sputum and blood testing did not find any fungal, bacterial or viral infection. The second tomography revealed multiple mesenteric, cervical and retroperitoneal adenopathies with central necrosis, with an increase of the latero aortic one, which measured 36 mm. The biopsy of a cervical adenopathy revealed a necrotizing lymphadenitis with typical yeast bodies of Histoplasma sp. (Fig. 1). Liposomal Amphotericin B treatment (3 mg/kg) has been infused for 3 weeks and switched to itraconazole (200 mg 2) for several weeks. The patient slowly felt well. Histoplasmosis was considered cured as the patient continued ART with a favourable immunovirological status. We described a disseminated histoplasmosis after reintroduction of ART, probably related to an unmasked IRIS because of a more than 50% increase in CD4 cell count and a more than 1 log10 decrease in viral load. This is rarely described in the literature [5], and histoplasmosis is rare outside disease-endemic areas [6], although our patient was born in the Ivory Coast but did not return to Africa since 2000. Because of the lack of compliance of this patient, the diagnosis of IRIS could be discussed. Marc De Lavaissie`re et al. [5] reported a case of IRIS
2171
related to H. capsulatum in an HIV-infected patient born in French Guyana, who did not travel to South America or Africa. This case was associated with a haemophagocytic syndrome, which was not the case of our patient. Breton et al. [7] have already reported four cases of patients infected with HIV-1 from Surinam, Ivory Coast, Congo and French Guyana who were showing different clinical signs due to disseminated histoplasmosis (Histoplasma variety capsulatum and duboisii), after initiation of ART. They found granulomas with caseation in the three cases, which are typically associated with immunocompetent patients and attributed to IRIS [7]. In our patient, the histological analysis revealed a necrotizing lymphadenitis, which had been described in a immunocompetent patient with a cervical localization as an unusual presentation in chronicdisseminated histoplasmosis [8]. Finally, histoplasmosis is a differential diagnosis of tuberculosis [9] and even lymphoma, in an immunocompromized patient coming from endemic areas, and presenting with fever, asthenia, weight loss, sweats and lymph nodes such as in our patient [10]. In conclusion, histoplasmosis is an opportunistic infection that can be revealed by an unmasked IRIS in HIVinfected patients on ART and should be suspected in case of fever, alteration of general conditions and lymphadenitis, even outside disease-endemic areas.
Acknowledgements Conflicts of interest There are no conflicts of interest. Adeline Mambiea, Armelle Pasqueta, Hugues Mellieza, Severine Bonnea, Anne-Laure Blanca, Pierre Patozb and Faiza Ajanaa, aService des maladies infectieuses, and b Laboratoire de microbiologie, Hospital Dron, Tourcoing, France. Correspondence to Adeline Mambie, Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing (Faculte´ de Me´decine de Lille), 59200 Tourcoing, France. Tel: +33 3 20 69 46 16; fax: +33 3 20 69 46 15
References
Fig. 1. Numerous clusters of Histoplasma capsulatum cells in macrophages (arrow: periodic acid-Schiff stain).
1. Immune reconstitution inflammatory syndrome (IRIS) in HIVinfected patients. New York State Department of Health AIDS Institute, New York, August 2009. http://www.hivguidelines. org. 2. Martyn AH. Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on. MJA 2012; 196:318– 321.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2172
AIDS
2013, Vol 27 No 13
3. Loulergue P, Bastides F, Baudouin V, Chandenier J, MarianiKurkdjian P, Dupont B, et al. Literature review and case histories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients. Emerg Infect Dis 2007; 13:1647– 1652. 4. Wheat LJ, Freifeld AG, Kleiman MN, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000; 30:688– 695. 5. De Lavaissie`re M, Manceron V, Boure´e P, Garc¸on L, Bisaro F, Delfraissy J-F, et al. Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection. J Infect 2009; 58:245–247. 6. Peigne V, Dromer F, Elie C, Lidove O, Lortholary O, the French Mycosis Study Group. Imported acquired immunodeficiency syndrome-related histoplasmosis in metropolitan France: a comparison of pre-highly active anti-retroviral therapy and highly active anti-retroviral therapy eras. Am J Trop Med Hyg 2011; 85:934–941.
7. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006; 20:119–132. 8. Meijer JA, Sjo¨gren EV, Kuijper E, Verbist BM, Visser LG. Necrotizing cervical lymphadenitis due to disseminated Histoplasma capsulatum infection. Eur J Clin Microbiol Infect Dis 2005; 248:574–576. 9. Mandengue CE, Lindou J, Mandeng N, Takuefou B, Nouedoui C, Atangana P, Fonkoua MC. Fatal military tuberculosis in an HIV-infected Cameroon woman: disseminated histoplasmosis due to Histoplasma capsulatum capsulatum. Med Trop 2011; 71:615–617. 10. Pervez MM, Cobb B, Matin N, Shahrin L, Ford ER, Pietroni M. Disseminated histoplasmosis in a patient with advanced HIV disease: lessons learnt from Bangladesh. J Health Popul Nutr 2010; 28:305–307.
DOI:10.1097/01.aids.0000432448.53110.e3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The effect of efavirenz versus nevirapine-containing regimens in the HIV-CAUSAL Collaboration: reply to Llibre and Podzamczer and additional results We recently reported a mortality hazard ratio of 1.59 [95% confidence interval (CI) 1.27–1.98] for nevirapine versus efavirenz non-nucleoside reverse transcriptase inhibitor (NRTI)-based first-line regimens [1]. Llibre and Podzamczer [2] refer to our findings as ‘unanticipated’. However, as we reported in our article, our findings were in line with those of a recent Cochrane Collaboration meta-analysis of randomized clinical trials [3], including the 2NN study [4] referenced by Llibre and Podzamczer [2], which found an increased risk of death comparing nevirapine 400 mg once daily with efavirenz 600 mg. After we excluded one trial that included patients
who were also receiving a protease inhibitor [5], the mortality risk ratio was 1.97 (95% CI 0.95–4.07) for nevirapine (all doses) versus efavirenz. Llibre and Podzamczer [2] question our decision to increase statistical efficiency by including patients with any baseline CD4 cell count in our main analysis and allowing 6 months to complete a regimen. Neither decision seems critical as our results did not change appreciably when we restricted to patients with baseline CD4 cell counts for which nevirapine is recommended and required patients to initiate all of the drugs in their
Table 1. Definition and distribution of categories of chronic hepatitis C infection, HIV-CAUSAL Collaboration. Number of replicates (%) Chronic HCV infection
Efavirenz (n ¼ 26 368)
Definition
Definite Probable
2 or more positive HCV RNA test results at least 6 months apart 1 positive HCV RNA test result, 2 positive HCV RNA test results less than 6 months apart 1 or more positive HCV antibody test result, 1 or more positive HCV result (test unknown), No positive HCV RNA tests No positive HCV tests of any variety Unknown or not measured in that cohort
Possible None Unknown
Nevirapine (n ¼ 15 004)
19 127
0.1 0.5
2 45
0.0 0.3
1519
5.8
1164
7.8
22 621 2082
85.8 7.9
12 613 1180
84.1 7.9
HCV, hepatitis C virus. Table 2. Clinical, immunologic and virologic outcomes for regimens based on efavirenz (24 286 individuals) versus nevirapine (13 824 individuals) in the subset of the population with hepatitis C data, HIV-CAUSAL Collaboration. Outcome
Treatment
Death
Efavirenz Nevirapine
AIDS or death
Efavirenz Nevirapine
CD4 cell count
Efavirenz Nevirapine
Hazard ratioa; 95% CI
Model
Without adjustment for HCV With adjustment for HCV
1 (ref.) 1.44 1.43 1 (ref.) 1.41 1.40
Without adjustment for HCV With adjustment for HCV
Change from baseline (cells/ml)a,b; 95% CI 0 (ref.) 14.78 21.84 to 7.73 13.66 20.71 to 6.62
Without adjustment for HCV With adjustment for HCV
1 (ref.) 1.90 1.89
Without adjustment for HCV With adjustment for HCV
1.06–1.95 1.06–1.94 1.02–1.94 1.02–1.94
Risk ratioa,c; 95% CI Virologic failure (HIV-RNA >50)
Efavirenz Nevirapine
1.42–2.53 1.42–2.52
CI, confidence interval; HCV, hepatitis C virus. a All models are adjusted for the baseline covariates (sex, age, race, geographic origin, mode of transmission, CD4 cell count, HIV RNA, calendar year, years since HIV diagnosis and an indicator for starting only nucleoside reverse transcriptase inhibitors at baseline) and the time-varying covariates (CD4 cell count, HIV RNA, AIDS-defining illness, time since last laboratory measurement) during the first 6 months of follow-up via unstabilized weights trimmed at 100. b Based on 9621 and 3552 individuals with CD4 cell count measurements at 12 2 months in the efavirenz and nevirapine arms, respectively. c Based on 9641 and 3508 individuals with HIV RNA measurements at 12 2 months in the efavirenz and nevirapine arms, respectively.
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
2169
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2170
AIDS
2013, Vol 27 No 13
regimen simultaneously. Details were provided in our article. Llibre and Podzamczer [2] suggest that our description of analyses involving hepatitis C coinfection is incomplete. We agree so we are providing additional information here. Table 1 shows the definition and distribution of categories of chronic hepatitis C virus infection for our mortality analysis (the table shows the most recently available data in the HIV-CAUSAL Collaboration). Table 2 shows the updated effect estimates, with and without adjustment for hepatitis C coinfection (we collapsed the definite/probable and none/unknown categories), in the subset of the population with hepatitis C data. These estimates suggest that adjustment for hepatitis C coinfection in the full study population would not result in appreciable reductions in our reported effect estimates. We did not have sufficient data to adjust for NRTI backbone in our analyses or to repeat our analyses in subsets defined by NRTI backbone. As we acknowledge in our article, the fact that we may not be able to completely adjust for this and other potential confounding factors is a limitation of our analysis. It is therefore reassuring that our estimates are in the same direction as – but more precise than – those from randomized clinical trials.
Acknowledgements Conflicts of interest There are no conflicts of interest.
Lauren E. Caina, Miguel A. Herna´nb, on behalf of the HIV-CAUSAL Collaboration, aDepartment of Epidemiology, Harvard School of Public Health, Boston, MA, USA, and bDepartment of Epidemiology, Harvard School of Public Health and Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA. Correspondence to Lauren E. Cain, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. Tel: +1 617 432 6921; fax: +1 617 432 1884; e-mail: [email protected]
References 1. The HIV-CAUSAL Collaboration. The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study. AIDS 2012; 26:1691–1705. 2. Llibre JM, Podzamczer D. Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL Collaboration Cohort. AIDS 2012; 26:2117–2118. 3. Mbuagbaw LCE, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naı¨ve individuals. Cochrane Database Syst Rev 2010:CD004246. 4. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263. 5. van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenzbased versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. HIV Clin Trials 2008; 9:324– 336.
DOI:10.1097/01.aids.0000432446.15061.27
A case of immune reconstitution inflammatory syndrome related to a disseminated histoplasmosis in an HIV-1 infected patient The immune reconstitution inflammatory syndrome (IRIS) is a set of clinical and laboratory findings, related to the expression of opportunistic infections or of cancers. IRIS occurs in two ways: revelation (unmasked disease) or deterioration of a known infection or neoplasic disease (paradoxical reaction) [1]. It may be associated with many different opportunistic pathogens such as Mycobacterium tuberculosis, Cryptococci, JC polyomavirus, and hepatitis C and B virus [2]. This syndrome is usually characterized by an increased CD4 cell count and a rapid decrease in viral load [1]. The pathogenesis is speculative and seems to be caused by a recovery of pathogen-specific T cells responses and perturbations of innate immune responses [2]. Histoplasma capsulatum var. capsulatum is endemic in central regions of sub-Saharian Africa and in the USA
(Ohiao and Mississipi River valley) [3], and is an opportunistic fungal infection in HIV-infected patients with a CD4 low cell count of less than 50 cells/ml [3]. The pathogenesis remains unclear and seems to be related to airborne contamination from the soil (bird ant bat excrements) [4]. We report a case of IRIS related to a disseminated histoplasmosis infection in an African HIV-1-infected patient living in France. A 28-year-old woman with a history of tuberculosis was diagnosed with HIV-1 after her childbirth in 2002 in Ivory Coast, and then she was lost to follow-up. In October 2011, she consulted for weight loss and fatigue. Her physical examination was unremarkable, her CD4 cell count was 3 cells/ml and viral load was 62 976 copies/ml (4.8 log).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
The patient started her antiretroviral therapy (ART) with tenofovir/emtricitabine, atazanavir and ritonavir, but she stopped it 1 month later because of a digestive intolerance and came back to the hospital. Abdominal computed tomography (CT) scan found mesenteric and retroperitoneal adenopathies without necrosis (the largest one measured 23 12 mm). The patient refused further investigations and a new ART regimen was started in November with abacavir/ lamivudine, darunavir and ritonavir. Two months later, she presented with fever, night sweats and multiple cervical adenopathies. CD4 cell count was 10 cells/ml, viral load was 235 copies/ml (3.37 log) and C-reactive protein was less than 5. Sputum and blood testing did not find any fungal, bacterial or viral infection. The second tomography revealed multiple mesenteric, cervical and retroperitoneal adenopathies with central necrosis, with an increase of the latero aortic one, which measured 36 mm. The biopsy of a cervical adenopathy revealed a necrotizing lymphadenitis with typical yeast bodies of Histoplasma sp. (Fig. 1). Liposomal Amphotericin B treatment (3 mg/kg) has been infused for 3 weeks and switched to itraconazole (200 mg 2) for several weeks. The patient slowly felt well. Histoplasmosis was considered cured as the patient continued ART with a favourable immunovirological status. We described a disseminated histoplasmosis after reintroduction of ART, probably related to an unmasked IRIS because of a more than 50% increase in CD4 cell count and a more than 1 log10 decrease in viral load. This is rarely described in the literature [5], and histoplasmosis is rare outside disease-endemic areas [6], although our patient was born in the Ivory Coast but did not return to Africa since 2000. Because of the lack of compliance of this patient, the diagnosis of IRIS could be discussed. Marc De Lavaissie`re et al. [5] reported a case of IRIS
2171
related to H. capsulatum in an HIV-infected patient born in French Guyana, who did not travel to South America or Africa. This case was associated with a haemophagocytic syndrome, which was not the case of our patient. Breton et al. [7] have already reported four cases of patients infected with HIV-1 from Surinam, Ivory Coast, Congo and French Guyana who were showing different clinical signs due to disseminated histoplasmosis (Histoplasma variety capsulatum and duboisii), after initiation of ART. They found granulomas with caseation in the three cases, which are typically associated with immunocompetent patients and attributed to IRIS [7]. In our patient, the histological analysis revealed a necrotizing lymphadenitis, which had been described in a immunocompetent patient with a cervical localization as an unusual presentation in chronicdisseminated histoplasmosis [8]. Finally, histoplasmosis is a differential diagnosis of tuberculosis [9] and even lymphoma, in an immunocompromized patient coming from endemic areas, and presenting with fever, asthenia, weight loss, sweats and lymph nodes such as in our patient [10]. In conclusion, histoplasmosis is an opportunistic infection that can be revealed by an unmasked IRIS in HIVinfected patients on ART and should be suspected in case of fever, alteration of general conditions and lymphadenitis, even outside disease-endemic areas.
Acknowledgements Conflicts of interest There are no conflicts of interest. Adeline Mambiea, Armelle Pasqueta, Hugues Mellieza, Severine Bonnea, Anne-Laure Blanca, Pierre Patozb and Faiza Ajanaa, aService des maladies infectieuses, and b Laboratoire de microbiologie, Hospital Dron, Tourcoing, France. Correspondence to Adeline Mambie, Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing (Faculte´ de Me´decine de Lille), 59200 Tourcoing, France. Tel: +33 3 20 69 46 16; fax: +33 3 20 69 46 15
References
Fig. 1. Numerous clusters of Histoplasma capsulatum cells in macrophages (arrow: periodic acid-Schiff stain).
1. Immune reconstitution inflammatory syndrome (IRIS) in HIVinfected patients. New York State Department of Health AIDS Institute, New York, August 2009. http://www.hivguidelines. org. 2. Martyn AH. Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on. MJA 2012; 196:318– 321.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2172
AIDS
2013, Vol 27 No 13
3. Loulergue P, Bastides F, Baudouin V, Chandenier J, MarianiKurkdjian P, Dupont B, et al. Literature review and case histories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients. Emerg Infect Dis 2007; 13:1647– 1652. 4. Wheat LJ, Freifeld AG, Kleiman MN, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000; 30:688– 695. 5. De Lavaissie`re M, Manceron V, Boure´e P, Garc¸on L, Bisaro F, Delfraissy J-F, et al. Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection. J Infect 2009; 58:245–247. 6. Peigne V, Dromer F, Elie C, Lidove O, Lortholary O, the French Mycosis Study Group. Imported acquired immunodeficiency syndrome-related histoplasmosis in metropolitan France: a comparison of pre-highly active anti-retroviral therapy and highly active anti-retroviral therapy eras. Am J Trop Med Hyg 2011; 85:934–941.
7. Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 2006; 20:119–132. 8. Meijer JA, Sjo¨gren EV, Kuijper E, Verbist BM, Visser LG. Necrotizing cervical lymphadenitis due to disseminated Histoplasma capsulatum infection. Eur J Clin Microbiol Infect Dis 2005; 248:574–576. 9. Mandengue CE, Lindou J, Mandeng N, Takuefou B, Nouedoui C, Atangana P, Fonkoua MC. Fatal military tuberculosis in an HIV-infected Cameroon woman: disseminated histoplasmosis due to Histoplasma capsulatum capsulatum. Med Trop 2011; 71:615–617. 10. Pervez MM, Cobb B, Matin N, Shahrin L, Ford ER, Pietroni M. Disseminated histoplasmosis in a patient with advanced HIV disease: lessons learnt from Bangladesh. J Health Popul Nutr 2010; 28:305–307.
DOI:10.1097/01.aids.0000432448.53110.e3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
