Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy

BACKGROUND Enterocytozoon bieneusi and Cryptosporidium parvum cause chronic antimicrobial-resistant gastrointestinal infections in HIV-1-infected individuals. HIV-1 reverse transcriptase inhibitors delay the onset of opportunistic infections, but are not known to reverse established infections. HIV-1 protease inhibitors are more effective across a broader range of HIV-1-infected immune cells. Combination antiretroviral therapy that includes a protease inhibitor could improve immunity to E bieneusi and C parvum. METHODS HIV-1 infected patients with chronic microsporidiosis (five), cryptosporidiosis (three), or dual infection (one), were treated with combination therapy that included at least one HIV-1 protease inhibitor. Outcome measures were symptoms, weight, use of antidiarrhoeal and antimicrobial drugs, T-lymphocyte subsets, HIV-1 viraemia, stool microscopy, and biopsy by endoscopy. FINDINGS All patients had complete clinical responses, gained a median 15 kg in weight, and ceased all antidiarrhoeal and antimicrobial therapies. Biliary cryptosporidiosis responded in both affected patients. Neither pathogen was detected in follow-up stool microscopy (eight of eight patients) or in biopsy samples by endoscopy (five of five). Intestinal architecture returned to normal in three patients. There was a dense CD8 lymphocyte and macrophage infiltrate and staining of intraepithelial E bieneusi with interferon-gamma before and after treatment, but little staining for CD4 or B lymphocytes, interleukin 10, or HIV-1 gp41. Five patients remained symptom-free after a median 13 months follow-up. Four patients had recurrent diarrhoea at 7-13 months (one with positive stool microscopy), associated with declining CD4 counts. INTERPRETATION Combination antiretroviral therapy that includes a protease inhibitor can restore immunity to E bieneusi or C parvum in HIV-1 infected individuals, and result in complete clinical, microbiological, and histological responses. The persistent CD8 cell and macrophage infiltrate, and the rapid time to relapse in patients with declining CD4 lymphocyte counts, suggest that neither infection was eradicated.

[1]  D. Cooper,et al.  Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. , 1996, The Journal of infectious diseases.

[2]  S. Kent,et al.  HIV-1 infection of human macrophages impairs phagocytosis and killing of Toxoplasma gondii. , 1995, Journal of immunology.

[3]  J. Rose,et al.  The infectivity of Cryptosporidium parvum in healthy volunteers. , 1995, The New England journal of medicine.

[4]  J. Moffett,et al.  Localization of quinolinic acid in the murine AIDS model of retrovirus-induced immunodeficiency: implications for neurotoxicity and dendritic cell immunopathogenesis , 1996, AIDS.

[5]  J. Revillard,et al.  Secretory IgA antibodies to Cryptosporidium parvum in AIDS patients with chronic cryptosporidiosis. , 1994, The Journal of infectious diseases.

[6]  T. Waldmann,et al.  Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. , 1985, The New England journal of medicine.

[7]  J. Maclean,et al.  A Phase I study of letrazuril in AIDS‐related Cryptosporidiosis , 1994, AIDS.

[8]  C. Fox,et al.  Macrophages as a source of HIV during opportunistic infections. , 1997, Science.

[9]  G Slavin,et al.  Chronic malabsorption due to cryptosporidiosis in a child with immunoglobulin deficiency , 1982, Gut.

[10]  R. Sacco,et al.  In vitro proliferation and production of gamma interferon by murine CD4+ cells in response to Cryptosporidium parvum antigen. , 1994, The Journal of parasitology.

[11]  D. Schwartz,et al.  Atovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in HIV‐1‐infected patients , 1996, AIDS.

[12]  J. Spencer,et al.  Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine , 1988, The Journal of experimental medicine.

[13]  J M Taylor,et al.  The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. , 1990, The New England journal of medicine.

[14]  D. Jewell,et al.  Cytokine gene expression in HIV‐infected intestinal mucosa , 1994, AIDS.

[15]  F. Carnot,et al.  Microsporidia infection in patients with the human immunodeficiency virus and unexplained cholangitis. , 1993, The New England journal of medicine.

[16]  F. Lemonnier,et al.  Differential requirements for survival and proliferation of CD8 naïve or memory T cells. , 1997, Science.

[17]  P. Rougier,et al.  Paromomycin: an effective treatment for cryptosporidial diarrhea in patients with AIDS. , 1994, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  S. Schwartz,et al.  Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. , 1996, The New England journal of medicine.

[19]  F. Finkelman,et al.  Cryptosporidium infection in an adult mouse model. Independent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity. , 1991, Journal of immunology.

[20]  L. M. Lehman,et al.  A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. , 1995, The New England journal of medicine.

[21]  T. Flanigan,et al.  Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial. , 1994, The Journal of infectious diseases.

[22]  M. Zupancic,et al.  Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. , 1997, Science.

[23]  D. Havlir,et al.  Cryptosporidium infection and CD4 counts. , 1992, Annals of internal medicine.

[24]  J. Orenstein,et al.  Small intestinal injury and parasitic diseases in AIDS. , 1990, Annals of internal medicine.

[25]  C. Rubin,et al.  Overwhelming watery diarrhea associated with a cryptosporidium in an immunosuppressed patient. , 1976, Gastroenterology.

[26]  F. Wit,et al.  Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial , 1997 .

[27]  D. Cooper,et al.  CD8+ lymphocyte responses to antiretroviral therapy of HIV infection. , 1996, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[28]  H. Clifford Lane,et al.  HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies , 1997, Nature Medicine.

[29]  J. Rehg.  Effect of Interferon-γ in Experimental Cryptosporidium parvum Infection , 1996 .

[30]  A. Saxon,et al.  Oral administration of bovine colostrum anti-cryptosporidia antibody fails to alter the course of human cryptosporidiosis. , 1987, The Journal of parasitology.

[31]  C. Ponticelli,et al.  Clinical features and course of Kaposi's sarcoma in kidney transplant patients: report of 13 cases. , 1994, American journal of nephrology.