Prophylaxis of OIs in the Age of Protease Inhibitors
Or: Can I Stop the Bactrim?
It has been recognized for several years that a strategy of aggressive prophylaxis against Pneumocystis carinii pneumonia (PCP) is associated with improved outcome and prolonged life in patients with advanced HIV disease. Indeed, compelling data have established that any survival benefit seen with nucleoside analog monotherapy in AIDS patients is enhanced when the antiretroviral therapy is given concomitantly with PCP prophylaxis (see "Does PCP Prophylaxis Improve Survival in Patients with HIV Infection?," Vol. 2, No. 1, pages 3-8). More recently, it has been shown that prophylaxis against other opportunistic pathogens, notably Mycobacterium avium complex, is likewise associated with improved survival, and consequently clinicians have made these prophylaxis regimens the standard of care for patients with advanced disease.
Improved survival and enhanced quality of life are indisputable benefits, and few question the wisdom of aggressive primary and secondary prophylaxis against the most common AIDS-related opportunistic infections. However, this practice is not without a price, both in financial terms and in terms of the side effects and drug interactions associated with polypharmacy.
These days symptomatic patients are often taking two or even three antiretroviral agents, plus drugs to ward off OIs they might get, plus drugs to prevent recurrences of OIs they have had, plus drugs to alleviate the depression that is nearly ubiquitous in the very ill, plus drugs to combat the side effects of all these other drugs.
For these patients, the opportunity to take fewer drugs has great appeal. One way to achieve that goal, in principle anyway, is by addressing these patients' underlying clinical problem -- which is HIV-induced immunosuppression. In theory, an immune system that has been bolstered by antiretroviral therapy -- to the point where some of its lost function has been restored -- is an immune system that can conquer invading pathogens, rendering prophylaxis against PCP, MAC, and other OIs unnecessary. What is required, obviously, is an antiretroviral agent of sufficient potency to suppress viral reproduction and allow the immune system to rebound.
Enter the protease inhibitors! As concerned clinicians are aware, these agents have produced the most profound viral load reductions yet seen with antiretroviral therapies. These dramatic declines in viral burden are virtually always accompanied by significant increases in CD4 counts, and there are anecdotal accounts of sustained CD4 elevations in the range of 100 or more cells.
The consistent, and gratifying, immunologic improvement seen with protease inhibitor therapy -- especially when these new agents are used in combination with several nucleoside analogs -- has been given a name: highly active antiretroviral therapy, or HAART. The striking success of HAART raises a simple but fundamental question: Are the improvements in immune function seen with protease inhibitor therapy, as measured by CD4 counts, sufficient to offer protection against opportunistic infections in the absence of prophylaxis? Or, to put the question as physicians and patients alike are putting it: "If the CD4 count rises far enough, can I stop the PCP prophylaxis?" And/or the MAC prophylaxis? And/or the CMV prophylaxis?
Is prophylaxis necessary in patients who respond well to therapy?
At first blush this seems a reasonable question. The protease inhibitors do produce very significant rises in CD4 counts -- often in the range of 100-150 cells/mm3, sustained for periods of six months or longer -- and in many treated patients this increase raises their CD4 counts above the thresholds at which prophylaxis is generally initiated.
Significantly, this benefit is also seen in patients with advanced disease. The clinical endpoint trial that contributed to the licensing of ritonavir was conducted in patients who had been heavily pretreated with nucleosides and had CD4 counts well below 100 cells/mm3 -- a very sick population indeed! The mean CD4 count at entry into this trial was only 32 cells/mm3, and after four weeks of treatment patients experienced a mean increase of 40 cells/mm3, a response to therapy that was sustained for at least 12 weeks.(1)
These increases in CD4 counts were associated with a reduction in the incidence of opportunistic infections -- suggesting that there may indeed be a benefit to therapy-induced increases in immune responsiveness. A similar reduction in OIs was seen in a recent trial that used the combination of saquinavir and ddC (personal communication), confirming the benefit of adding saquinavir to nucleosides that was seen in a just-published Phase II study.(2)
Despite these data, there are several questions about the clinical benefits of HAART that must be answered before we can routinely recommend that patients who have responded well to protease inhibitor therapy discontinue prophylaxis. First, the benefit of therapy, in terms of reducing the rate of OIs, is not absolute in these clinical trials. True, the reduction in infections seen in the ritonavir trial cited above was 50%, but we do not yet know if this benefit was the result of CD4 count rises or virologic responses.
Second, the duration of benefit of therapy is still unknown. In the ritonavir trial, for example, virologic responses were waning by Week 12 of therapy, and there is no clear indication as to how long the immunologic protection that was conferred by the protease inhibitor will endure.
Third, we understand very little about the true nature of the immunologic improvement seen with these new agents. We know that CD4 counts rise, but we do not yet know the functional capability of these cells, nor do we know much about other components of the immune system. It has been observed, for instance, that CD8 counts rise dramatically with ritonavir therapy,(1, 3) but the functional significance of this observation is unclear.
Similarly, a small Australian study of the effects of ritonavir therapy found increased proliferative responses to phytohemagglutinin in 6 of 7 study subjects.(4) The Australians also reported increased responses to both recall antigens and HIV-specific proteins in treated patients. These increases correlated with duration of viral load suppression, but here again we do not know if these observations correlate with immunity against common opportunistic infections.
Recommendations for clinicians
Further studies are underway to determine the nature and durability of the immunological responses to HAART. Until those studies are concluded, I would urge clinicians to take a conservative approach to prophylaxis. For patients on secondary prophylaxis -- that is, those receiving maintenance therapy to prevent recurrence of a prior infection -- treatment should be continued indefinitely. Since PCP prophylaxis is relatively inexpensive and easily administered, I would not discontinue this treatment either.
The case for MAC prophylaxis is more complex. The drugs involved are costly, are associated with numerous drug-drug interactions, and offer only partial protection against infection in any case (see "Fine-tuning the medical management of MAC," Vol. 2, No. 2, pages 34-35). MAC prophylaxis is certainly indicated for patients with advanced HIV disease, because these individuals are at high risk of infection and are unlikely to derive extended benefit from HAART. In such patients the benefit of stopping prophylaxis is likely to be outweighed by the need for frequent monitoring and the likelihood of breakthrough. For the present, I would consider stopping prophylaxis only in select cases, those involving highly compliant, highly motivated patients who understand the benefits -- and the risks -- involved in halting protective therapy.
1. Leonard J, Cameron B, Heath-Chiozzi M, Kravcik S, Mills R, Potthoff A, Henry D. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. 3rd Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 28-February 1, 1996. Abstract LB6a.
2. Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med 1996; 334: 1011-7.
3. Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333: 1534-9.
4. Kelleher AD, Carr A, Zaunders J, Cooper DA. Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. J Infect Dis 1996; 173: 321-9.
William G. Powderly, M.D., is with the Division of Infectious Diseases, AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, MO.