Until the widespread adoption of specific prophylaxis in the late 1980s, Pneumocystis carinii pneumonia was among the most common life-threatening opportunistic infections associated with infection with the human immunodeficiency virus (HIV) in industrialized countries. Primary prophylaxis against P. carinii pneumonia is currently recommended for all HIV-infected patients with CD4 cell counts of less than 200 per cubic millimeter and for those receiving cytotoxic chemotherapy. Secondary prophylaxis is recommended for all patients with a history of P. carinii pneumonia.
The advent of highly active antiretroviral therapy, which can drastically inhibit HIV replication and lead to substantial increases in CD4 cell counts, raised the possibility that prophylaxis against P. carinii pneumonia might be safely discontinued in some patients. Observational studies supported this possibility in patients with low plasma HIV RNA levels and more than 200 CD4 cells per cubic millimeter, although exactly how long the CD4 cell count had to remain above this threshold before prophylaxis could be withdrawn was unclear. In 1999, the Public Health Service and the Infectious Diseases Society of America, as well as several European expert groups, revised their recommendations to permit the discontinuation of primary prophylaxis in this subgroup of patients. Given the paucity of data on the discontinuation of secondary prophylaxis, recommendations on this topic were more conservative.
In this issue of the Journal, a randomized trial by Lopez et al. and an observational study by Ledergerber et al. clarify the conditions under which primary and secondary prophylaxis can safely be discontinued. Ledergerber et al. analyzed data from eight European cohorts of HIV-infected patients receiving highly active antiretroviral therapy. Secondary prophylaxis was discontinued in 325 patients when their CD4 cell counts rose to 200 or more per cubic millimeter (from a median nadir of 50 per cubic millimeter). The patients were monitored prospectively for a median of 13 months (374 person-years), during which time no further episodes of P. carinii pneumonia occurred (99 percent confidence interval, 0 to 1.2 per 100 person-years).
In the randomized trial conducted in Spain by Lopez et al., prophylaxis against P. carinii pneumonia was either maintained or discontinued in 474 patients receiving primary prophylaxis and in 113 patients receiving secondary prophylaxis. All patients had to have had CD4 cell counts of 200 or more per cubic millimeter for at least three months. No cases of P. carinii pneumonia occurred during a median follow-up of 19 months (758 person-years) among the 240 patients who discontinued primary prophylaxis (95 percent confidence interval, 0 to 0.85 episode per 100 person-years). There were also no cases of P. carinii pneumonia during a median follow-up of 12 months among the 60 patients who discontinued secondary prophylaxis (95 percent confidence interval, 0 to 4.5 episodes per 100 person-years).
The results obtained by Lopez et al. after the discontinuation of primary prophylaxis confirm the results of the observational studies on which guideline modifications have been based and the results of a similar but shorter trial recently conducted in Italy. In the study by Lopez et al., the patients receiving primary prophylaxis were required to have had CD4 cell counts of 200 or more per cubic millimeter (and plasma HIV RNA levels below 5000 copies per milliliter) for at least three months. The median CD4 cell count in the group discontinuing prophylaxis was 342 per cubic millimeter, and the lowest value was 277 per cubic millimeter.
The most innovative data are those concerning the discontinuation of secondary prophylaxis. Both studies conclude that prophylaxis may be discontinued even in patients with a history of P. carinii pneumonia if CD4 cell counts increase to more than 200 per cubic millimeter and plasma HIV RNA levels remain low.
The consistency of the results of the observational study by Ledergerber et al. and the randomized trial by Lopez et al. is reassuring. Both teams used a broad definition of new episodes of P. carinii pneumonia that included presumptive cases. What, then, are the practical implications of these findings? With respect to the threshold CD4 cell count at which prophylaxis can safely be discontinued, the median value in both studies was about 350 per cubic millimeter, which is appreciably higher than the 200 per cubic millimeter required for inclusion. Therefore, neither study explicitly justifies the immediate discontinuation of prophylaxis when the CD4 cell count reaches 200 per cubic millimeter. Indeed, there is no hurry, since most patients are used to taking this prophylactic treatment and tolerate it well. Also, the absolute CD4 cell count on which treatment decisions are based can fluctuate; this is not the case for the percentage of CD4 cells among total lymphocytes, which might provide useful information in this setting.
In making decisions about prophylaxis, other independent risk factors for P. carinii pneumonia must also be taken into account. Prophylaxis should not be discontinued if the patient has oral candidiasis, has ongoing weight loss, or is receiving cytotoxic chemotherapy or long-term corticosteroid therapy. The plasma HIV RNA level is the best predictor of changes in the CD4 cell count. In the study by Ledergerber et al., 93 percent of patients had plasma HIV RNA levels of less than 10,000 copies per milliliter, and a level of less than 5000 copies per milliliter was an inclusion criterion in the trial by Lopez et al. Close monitoring of the CD4 cell count is necessary, so that prophylaxis can be reintroduced if the count falls below 200 per cubic millimeter. Patients and practitioners should be aware that P. carinii pneumonia occasionally occurs when the CD4 cell count exceeds 200 per cubic millimeter.
An important related question concerns the effect of discontinuing prophylaxis against P. carinii pneumonia on the risk of other HIV-related infectious complications. Trimethoprim-sulfamethoxazole is the drug combination most widely used, and it also prevents opportunistic toxoplasmosis and bacterial infections of the respiratory tract. Although no cases of cerebral toxoplasmosis occurred in the two studies, we do not know the number of patients who were at risk, and toxoplasmosis generally occurs at a more severe stage of immunodeficiency (<100 CD4 cells per cubic millimeter) than does P. carinii pneumonia. The incidence of respiratory tract infections was low in both studies. The economic effect of discontinuing prophylaxis is marginal for most patients, since they are receiving low-cost regimens such as trimethoprim-sulfamethoxazole, dapsone, or dapsone plus pyrimethamine, but the impact on cost is substantial for patients who are receiving pentamidine aerosols or atovaquone. Discontinuing prophylaxis against P. carinii pneumonia may also help reduce fears about the emergence of strains of P. carinii that are resistant to trimethoprim-sulfamethoxazole and atovaquone and about the risk of pneumococci with reduced sensitivity to penicillin emerging during long-term prophylaxis with trimethoprim-sulfamethoxazole.
The studies by Lopez et al. and Ledergerber et al. confirm the reliability of the widely used CD4 cell count for HIV-related treatment decisions, although ideally we should have functional tests of immunity against specific opportunistic pathogens. These reports also support the value of long-term cohort studies that confirm, under real-life conditions, the results of controlled trials. It can be difficult to find funding for de-escalation studies such as these, since the pharmaceutical industry is unlikely to sponsor them.
The current reports complement others that show the feasibility of discontinuing prophylaxis against major opportunistic pathogens such as mycobacteria and cytomegalovirus. All these studies are good news for people living with HIV, but they also make the gulf in treatment between rich and poor countries even more glaring and unacceptable.
Pierre-Marie Girard, M.D.
Faculte de Medecine Saint-Antoine
F-75252 Paris, France
Copyright © 2001 by the Massachusetts Medical Society. All rights reserved.