Elsevier

The Lancet

Volume 351, Issue 9098, 24 January 1998, Pages 252-255
The Lancet

Early Report
Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease

https://doi.org/10.1016/S0140-6736(97)04352-3Get rights and content

Summary

Background

Inhibitors of HIV-1 protease produce a rapid decrease in plasma HIV-1 RNA, with concomitant increases in CD4 T-helper lymphocyte counts. The main side-effects of the protease inhibitors currently in use include gastrointestinal disturbances, paraesthesias, hyperbilirubinaemia, and nephrolithiasis. The increasing use of these agents in patients with advanced HIV-1 infection and CD4 counts of less than 50 cells/μL may be associated with unforeseen adverse effects not observed in earlier studies of patients with higher CD4 counts.

Methods

Five HIV-infected patients with baseline CD4 lymphocyte counts of less than 50 cells/mL were admitted to the Beth Israel Deaconess Medical Center (Boston, MA, USA) with high fever (>39°C), leucocytosis, and evidence of lymph-node enlargement within 1–3 weeks of starting indinavir therapy. Informed consent was obtained for studies that entailed CD4 lymphocyte counts, immunophenotyping, isolator blood cultures, and radiological scans. Biopsy samples of cervical, paratracheal, or mesenteric lymph nodes were taken for culture and pathology in four patients.

Findings

Lymph-node biopsy samples showed that focal lymphadenitis after initiation of indinavir resulted from unsuspected local or disseminated Mycobacterium avium complex (MAC) infection. The prominent inflammatory response to previously subclinical MAC infection was associated with leucocytosis in all patients and with an increase in the absolute lymphocyte counts in four patients. Three patients with follow-up CD4 counts showed two-fold to 19-fold increases after 1–3 weeks of indinavir therapy. Immunophenotyping after therapy in two patients showed that more than 90% of the CD4 cells were of the memory phenotype.

Interpretation

The initiation of indinavir therapy in patients with CD4 counts of less than 50 cells/mL and subclinical MAC infection may be associated with a severe illness, consisting of fever (>39°C), leucocytosis, and lymphadenitis (cervical, thoracic, or abdominal). The intense inflammatory reactions that make admission to hospital necessary may be secondary to significant numbers of functionally competent immune cells becoming available to respond to a heavy mycobacterial burden. Prophylaxis or screening for subclinical MAC infection, or both, should therefore be done before the beginning of protease-inhibitor therapy in patients with advanced HIV infection.

Introduction

The HIV-1 protease, a 99-aminoacid aspartyl protease homodimer, is esssential for the production of infectious HIV virions by the processing of gag and gag-pol polypeptide precursors.1, 2, 3, 4, 5, 6, 7, 8 In vitro, inhibitors of HIV protease are effective against both HIV-1 and HIV-2 strains.9 At present, three HIV-1 protease inhibitors are in widespread clinical use—saquinavir (Invirase, Roche), ritonavir (Norvir, Abbott), and indinavir (Crixivan, Merck). These agents produce a rapid decrease in plasma HIV-RNA of 10-100-fold or greater, with concomitant increases in CD4-lymphocyte counts, in some cases, of more than 100 cells/μL.10, 11, 12, 13, 14, 15, 16 Although these new antiretroviral therapies hold great promise in the treatment of HIV-1 infection, they are associated with significant drug interactions and cause several adverse effects. We report a distinct clinical syndrome in patients with advanced HIV-1 disease that followed administration of indinavir.

Section snippets

Patients and methods

Between April and December, 1996, five HIV-1-infected patients were identified after admission to the Beth Israel Deaconess Medical Center (Boston, MA, USA) for assessment of fever, leucocytosis, and lymph-node enlargement within 1–3 weeks of starting indinavir therapy. All patients gave informed consent for the studies described below. All patients had baseline (before indinavir) CD4 T-helper lymphocyte counts of less than 50 cells/μL. Routine blood-isolator cultures for mycobacteria and fungi

Results

Clinical and laboratory data of the five patients admitted with fever, leucocytosis, and focal inflammatory lymphadenitis after starting indinavir therapy are shown in the table.

Discussion

We have described a distinct clinical syndrome associated with the initiation of a protease inhibitor, indinavir sulphate, in patients with advanced HIV-1 disease. Each of the five patients in this series was clinically stable and afebrile before indinavir therapy. However, after receiving the protease inhibitor, all five patients required admission to hospital for severe, febrile syndromes of long duration, which were attributable to a previously subclinical MAC infection.

This inflammatory

References (30)

  • C Peng et al.

    Role of human immunodeficiency virus type 1-specific protease in core protein maturation and infectivity

    J Virol

    (1989)
  • A Collier et al.

    Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine: AIDS Clinical Trials Group

    N Engl J Med

    (1996)
  • S Danner et al.

    A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease

    N Engl J Med

    (1995)
  • M Markowitz et al.

    A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection

    N Engl J Med

    (1995)
  • F Massari et al.

    A double-blind, randomized trial of indinavir (MK-639) alone or with zidovudine vs zidovudine alone in zidovudine-naive patients. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy

    American Society for Microbiology: Program Addendum 9

    (1995)
  • Cited by (0)

    View full text