Prophylaxis of OIs in the Age of Protease Inhibitors -- an Update

In the June 1996 issue of HIV Newsline we addressed the then-novel notion that it might be possible to stop prophylaxis against certain specific AIDS-related opportunistic infections in situations where maximally suppressive antiretroviral therapy had led to rises in CD4 cell counts (see Vol. 2, No. 3). This hypothesis was based on the observation that patients who responded well to multidrug combination therapy often experienced rebounds in CD4 count of 100 cells or more. In theory, anyway, this response put most patients above the so-called breakthrough points for such common OIs as P. carinii pneumonia, M. avium complex, and CMV infection.

The question we could not answer at that time was whether these observed rises in CD4 cell counts -- some of them quite dramatic -- actually represented some degree of immune reconstitution. We knew that aggressive antiretroviral therapy led to increases in CD4 count, but we knew next to nothing about the functional capability of those cells. We therefore recommended a generally conservative approach to OI prophylaxis, based largely on the lack of reliable data about the degree of immune reconstitution achieved with maximally suppressive antiretroviral therapy and the durability of responses to that therapy.

We therefore suggested that prophylaxis be stopped only in very exceptional circumstances, and only with exceptionally well-informed and highly motivated patients. Indeed, we recommended that, as a general rule, PCP prophylaxis be continued for most patients even if their CD4 counts rose well above the theoretical breakthrough point of 200 cells/mm³. A year later, the U.S. Public Health Service and the Infectious Disease Society of America issued joint guidelines that made essentially the same recommendation.⁽¹⁾ Those guidelines stated that care providers should make decisions about prophylaxis based on a patient's lowest CD4 count, no matter how much of a rebound the patient experienced after being switched to multidrug therapy.

In making this recommendation the authors cited concerns raised by a small study, one of the few that had been published at the time, which suggested that the increases in CD4 counts seen in patients who responded well to maximally suppressive antiretroviral therapy would not confer protection against opportunistic infections.⁽²⁾

A year has passed since the U.S. Public Health Service and the I.D.S.A. made their recommendations concerning prophylaxis in patients receiving potent multidrug antiretroviral therapy. We now know considerably more about immune reconstitution than we did when those guidelines were issued, so it is fair to ask how valid those recommendations are today.

Clinical evidence of immune rebound

There is no longer any doubt that some degree of immune recovery occurs in patients who respond to multidrug therapy. The best evidence that such a rebound occurs comes from our clinical experience. First and foremost, mortality from AIDS and hospitalizations for AIDS-associated opportunistic infections have both decreased dramatically in the United States since the advent of the protease inhibitors (Figure). In most of the cohorts studied to date, the rates of new cases of PCP, disseminated MAC, and CMV infection have been reduced by 75% compared to the incidence of such infections in the years preceding the widespread adoption of protease-inhibitor-containing regimens.

Furthermore, AIDS-related opportunistic infections that were once regarded as virtually impossible to treat -- such as drug-resistant candidiasis, cryptosporidiosis, and even progressive multifocal leucoencephalopathy -- have responded to maximally suppressive therapy (see "Resolution of candidiasis in a patient receiving ddI plus saquinavir," Vol. 2, No. 5, page 112, and "Regression of PML in an aggressively treated patient," Vol. 3, No. 2).

AIDS Deaths Fell Almost 50% Last Year According to the National Center for Health Statistics, the number of AIDS deaths plummeted in 1997, the last year for which figures are available -- to half the number recorded in 1996 and one-third the number recorded in 1995, when a record 43,000 Americans died of AIDS-related illnesses. This heartening trend is attributable to many factors, among them better detection and treatment of opportunistic infections in people with advanced HIV disease, but the paramount reason for the dramatic drop in AIDS deaths is the widespread adoption of multidrug antiretroviral regimens that include at least one protease inhibitor. Welcome as this news is, it is tempered by another N.C.H.S. statistic: the number of new infections reported in 1997, approximately 40,000, is essentially unchanged from the previous year and the year before that -- indicating that we are doing a much better job of controlling HIV infection in individuals than in the population at large.

Since the antiretroviral drugs currently available to us have no intrinsic antimicrobial effects against these organisms, the fact that we have seen such dramatic reductions in OI rates since the introduction of the protease inhibitors suggests that these powerful drugs, when used in combination with other antiretroviral agents, exert their effect on opportunistic infections indirectly, probably by improvements in immune function.⁽³⁾

Those of us who treat patients with advanced HIV infection see another kind of evidence that suppressive therapy leads to partial immunologic recovery. This evidence comes from the observation that when our patients on multidrug therapy do develop an OI, they often have the sort of inflammatory response to infection that we would expect from an individual with an immune system that is at least partly functional: fever and lymphadenitis in patients with MAC, and vitritis in patients with CMV.⁽⁴⁾

Laboratory evidence of immune rebound

What is the laboratory evidence that immunological recovery is occurring in patients who respond to maximally suppressive antiretroviral therapy? It is well recognized that HIV infection leads to progressive loss of the CD4 lymphocyte population, and we know that so-called naïve cells -- those not yet committed to recognition of specific antigens -- are lost more rapidly than memory cells. In addition, progressive HIV infection is associated with progressive, and apparently random, loss of the T-cell repertoire -- that is, with loss of diversity of response.

"The initial rise in CD4 count that is seen in patients who respond well to suppressive therapy is predominantly an increase in memory T-cells. However, after several months of continued therapy naïve cells also reappear in the circulation. This has led many investigators to conclude that successful suppressive therapy does indeed lead to partial immunological recovery."

Early data from studies of patients on maximally suppressive antiretroviral therapy suggested that although suppressive therapy did produce a rise in CD4 cells, the number of naïve cells increased only if those cells were present prior to the initiation of suppressive therapy. The same early studies also suggested that losses in the T-cell repertoire were not repaired by even the most potent multidrug regimens.⁽²⁾ However, these conclusions appear to have been premature.

More recent data, drawn from many sources, suggest that the CD4 cell response to maximally suppressive therapy is, in fact, biphasic. The initial rise in CD4 count that is seen in patients who respond well to suppressive therapy is predominantly an increase in memory T-cells. However, after several months of continued therapy naïve cells also reappear in the circulation. This, coupled with evidence that the T-cell repertoire begins to recover during this second phase -- at least in some patients -- has led many investigators to conclude that successful suppressive therapy does indeed lead to partial immunological recovery.^(5,6) In fact, this may be a continuous process -- and prolonged therapy may be associated with ongoing immunological benefits. Preliminary evidence indicates that specific immune responses to important pathogens may also reappear with sustained combination therapy.⁽⁷⁾

Prophylaxis following immune reconstitution

Encouraging as this emerging picture is, it tells us very little about when we can stop prophylaxis. At the 12th World AIDS Conference in Geneva, several groups reported on cohorts of patients in whom primary prophylaxis for P. carinii pneumonia was discontinued. Prophylaxis was stopped in patients whose CD4 counts had risen above 200 cells/mm³ on potent combination therapy. In these patients -- about 300 individuals in all -- no cases of PCP occurred during a median follow-up of slightly more than six months. This does not prove that stopping prophylaxis is completely safe -- the follow-up is not nearly long enough to tell us that -- but it is reassuring.

Some of the most intriguing evidence that maximally suppressive therapy does restore immune function -- and that in some patients who respond well to such therapy prophylaxis can indeed be stopped -- comes from case studies in which maintenance prophylaxis was discontinued in patients with established opportunistic infections who demonstrated both immunologic and virologic evidence of response to anti- retroviral therapy. Several groups have reported that it is possible to discontinue maintenance therapy for CMV retinitis in selected patients whose CD4 counts rise in response to potent antiretroviral therapy.^(8,9)

The decision to withdraw suppressive therapy from such patients is not without risk, however. Torriani and colleagues from U.C.S.D. reported at Geneva that vitritis -- possibly immune-mediated -- can occur in up to 60% of patients whose therapy for CMV retinitis is stopped.⁽¹⁰⁾

Last February, Aberg and colleagues from San Francisco described four patients with disseminated MAC in whom specific antimicrobial therapy was stopped when those patients' CD4 counts rose above 100 cells/mm³ with sustained suppression of viral replication.⁽¹¹⁾ Those patients remained free from relapse for at least nine months (see "HAART therapy leads to resolution of MAC infection," AIDS Care, Vol. 2., No. 1, page 16).

These results are particularly impressive given that prior to the advent of protease-inhibitor-containing therapies, discontinuation of such therapies would have led to rapid relapse in virtually every instance. We formerly regarded these infections, once acquired, as infections for life. It now appears that some of them can be cured, at least in certain fortunate patients.

At this juncture the U.S.P.H.S./I.D.S.A. guidelines for prophylaxis, relying as they do on a single CD4 count, are probably too conservative. I believe it is reasonable to consider discontinuing prophylaxis in informed and reliable patients who have exhibited sustained viral control and whose CD4 count has risen above the threshold where prophylaxis would be indicated -- that is, above 50 cells/mm³ for MAC and 200 cells/mm³ for PCP -- and stayed above that threshold. Although there are clinical data indicating that some patients on combination therapy experience sustained increases in CD4 cell counts even with incomplete or transient reductions in viral load, I would be inclined to continue prophylaxis in such instances, because I believe that immunological deterioration is likely to recur in such patients.

I think it is also reasonable to consider stopping maintenance therapy for OIs in patients with established infection -- but only in informed patients who understand the risks involved. Ideally, this withdrawal of maintenance therapy can occur in the context of a clinical trial. In any case, withdrawal is only possible for patients who have received adequate initial antimicrobial therapy and who have shown sustained virologic and immunologic responses to antiretroviral therapy as well. At the very least, we need to include effective management of HIV infection itself among our therapeutic strategies for all AIDS-associated opportunistic infections.

References

1. U.S. Public Health Service/Infectious Disease Society of America. Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 1997; 46 (RR-12).

2. Connors M, Kovacs JA, Krevat S, 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. Nature Med 1997; 3: 533-40.

3. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338: 853-60.

4. Sepkowitz K. Effect of prophylaxis on the clinical manifestations of AIDS-related opportunistic infections. Clin Infect Dis 1998; 26: 806-10.

5. Roederer M. Getting to the HAART of T cell dynamics. Nature Med 1998; 4: 145-6.

6. Powderly WG, Landay A, Lederman M. Recovery of the immune system with antiretroviral therapy: the end of opportunism? JAMA 1998; 280: 72-77.

7. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112-6.

8. Macdonald JC, Torriani FJ, Morse LS, Karavellas MP, Reed JB, Freeman WR. Lack of reactivation of cytomegalovirus retinitis after stopping maintenance therapy in AIDS patients with sustained elevation of T cells in response to highly active antiretroviral therapy. J Infect Dis 1998; 77: 1182-7.

9. Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998; 177: 1080-1083.

10. Torriani F, Freeman WR, Durand D, et al. Evidence that HAART-induced immune recovery vitritis in CMV retinitis patients is immune-mediated. 12th World AIDS Conference, Geneva, Switzerland, 1998. Abstract 22240.

11. Aberg JA, Yajko DM, Jacobson MA. Eradication of disseminated Mycobacterium avium complex in four patients after twelve months anti-mycobacterial therapy and response to highly active antiretroviral therapy. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 729.

William G. Powderly, M.D., is with the AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, MO.