A side effect of protease inhibitors

CMAJ 1998;158:1129-30

The article "Guidelines for antiretroviral therapy for HIV infection" (CMAJ 1998;158(4):496-505 [full text / résumé]), by Dr. Anita R. Rachlis and colleagues, was timely, informative and well written, but it did not mention an adverse effect of the protease inhibitor class of drugs. Some patients with hemophilia have experienced increased frequency or severity (or both) of bleeding episodes while taking these drugs.^1­3 This adverse effect has been associated with all of the protease inhibitors currently available. The bleeding is spontaneous and tends to occur early in the course of treatment. The frequency of this reaction has not yet been established, because these drugs have been introduced only relatively recently; furthermore, patients and their care givers are accustomed to the unpredictable and episodic nature of bleeding in severe hemophilia, so the association with the drug may not be immediately obvious. The bleeding can be severe and can occur in the usual locations (joints and muscles) or at atypical sites. In my experience, the exaggerated bleeding tendency persists until the protease inhibitor is discontinued, at which time the problem resolves rapidly.

The pathophysiology of this adverse effect is unknown; it is not accompanied by laboratory abnormalities in addition to the patient's congenital deficiency of factor VIII or IX. Reports of bleeding in nonhemophilic patients have most commonly consisted of hematuria accompanying nephrolithiasis, which can complicate the use of indinavir.³ Because it is difficult to envision a biochemical basis for the preferential impairment of hemostasis in hemophiliac patients, we might anticipate that patients with acquired bleeding disorders will experience a similar hemorrhagic tendency. Among those infected with HIV, such disorders could include idiopathic thrombocytopenia, chemotherapy-induced thrombocytopenia or the hemostatic deficiencies associated with liver disease.

Hemophiliac patients should be closely questioned for any change in their usual bleeding pattern while they are receiving protease inhibitors, as should any patients with other congenital or acquired hemostatic disorders.

Jerome Teitel, MD
Director
Toronto and Central Ontario
Comprehensive Hemophilia Program
St. Michael's Hospital
Toronto, Ont.
TEITELJ@smh.toronto.on.ca

References

1. Ginsburg C, Salmon-Ceron D, Vassilief D, Rabian C, Rotschild C, Fontenay-Roupie M, et al. Unusual occurrence of spontaneous haematomas in three asymptomatic HIV-infected haemophilia patients a few days after the onset of ritonavir treatment. AIDS 1997;11(3):388-9.
2. Yee TT, Amrolia PJ, Lee CA, Mir N, Giangrande PL. Protease inhibitors and unusual bleeding in haemophiliacs. Haemophilia 1997;3(3):220-1.
3. Racoosin JA, Kessler C. A series of bleeding episodes in HIV-positive hemophiliacs (HEM) taking HIV protease inhibitors [abstract]. Blood 1997;40(10 Suppl 1):34a.

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