OI Update: Pneumocystis carinii Pneumonia
The Incidence Is Down, the Treatments Are Better, But the Threat Remains
Maximally suppressive antiretroviral therapy has revolutionized the treatment of HIV disease. Patients who respond well to the potent multidrug regimens that are now standard therapy for individuals with advanced HIV infection not only achieve clinical stability, they seem to experience some degree of immune reconstitution. We now know that the initiation of highly suppressive therapy leads to a dramatic rise in CD4 count -- an increase that results from peripheral expansion of pre-
What we do not yet know is how much of the immune system's old memory repertoire is regained in this process, but the evidence at hand suggests that some immune function is regained. This would explain the drastic reduction we have seen in the incidence of AIDS-related opportunistic infections in patients with late-stage HIV disease. Although OI rates began to drop before the advent of the protease inhibitors -- thanks to a combination of earlier intervention, more effective prophylaxis, combination nucleoside therapy, and improved clinical care -- truly dramatic reductions occurred only after the widespread adoption of the protease-
Overall, the incidence of OIs has dropped a stunning 70% since the protease inhibitors became widely available two and a half years ago. Evidence continues to accumulate that maximally suppressive antiretroviral therapy has a significant impact on AIDS-
That's the good news. The bad news is that OIs continue to pose a threat to individuals with advanced HIV disease. There have, for example, been reports of fulminant CMV retinitis in patients whose CD4 counts had risen, as a result of highly active antiretroviral therapy, well above the supposed threshold level for breakthrough infections. To keep clinicians abreast of new developments in the treatment of these old threats to their patients, the editors of HIV Newsline are inaugurating "OI Update," a series of succinct and timely reports on the current standard of care for a wide range of opportunistic infections, beginning with the best-known OI of all -- PCP.
-- The Editors
Pneumocystis carinii pneumonia -- once the most common presenting symptom in HIV-
Previously categorized as a protozoan and now classified as a fungus, P. carinii can be isolated from the environment by means of a spore trap and identified by polymerase chain-
Pneumocystis is known to be host-
PCP is typically diagnosed by visualization of the organisms in clinical samples of induced sputum and/or bronchoalveolar lavage using immunofluorescence or Giemsa, toluidine blue, or Gomori methenamine silver stains (Figure). PCR assays to detect both single-copy genes and multiple-copy genes are currently under development. To date, the results of these assays have been disappointing, with sensitivities varying from zero to 100% in different studies of the same assay.
The fungus that causes P. carinii pneumonia in patients with advanced HIV disease can be diagnosed by visualization of the organisms in clinical samples of induced sputum and/or bronchoalveolar lavage using immunofluorescence or one of these stains: Giemsa, toluidine blue, or Gomori methenamine silver. When the latter method is used, the P. carinii particles show up as dark, ovoid shapes against a blue-
Current treatment recommendations
Corticosteroids should be given to patients with PCP who are hypoxic (i.e. have a pO2 less than 70 mm Hg or an alveolar-arterial pO2 difference exceeding 35 mm Hg). The recommended treatment is 40 mg of prednisone b.i.d. for five days, then 40 mg daily for five days, then 20 mg daily for 11 days. The use of adjunctive corticosteroids for the treatment of PCP does not increase mortality or the risk of common HIV-associated complications.
Prophylaxis for PCP should be initiated for all HIV-
TMP/SMX is the preferred prophylactic agent, at a dose of one double-strength tablet daily. In addition to its proven efficacy and low cost, TMP/SMX reduces the incidence of toxoplasmosis and bacterial infections. Single-strength tablets may also be effective, and they may be better tolerated.
As all clinicians who treat HIV-
As ACTG 268 clearly demonstrated, the gradual initiation of TMP/SMX prophylaxis improves its tolerability. In that trial, patients started on the full dose of TMP-SMX were 2.3 times more likely to discontinue therapy than those who received the ramped dose outlined in Table 2. (For further information on this dosing schedule, see "ACTG 268: Gradual vs. Routine Initiation of PCP Prophylaxis," Vol. 3, No. 2) Clinicians may want to consider this therapeutic option when initiating TMP-SMX therapy, especially in patients with CD4 counts below 50 cells/mm3, since low CD4 counts are predictive of therapeutic failure.
More recently, Community Programs for Clinical Research on AIDS Trial 006 found that initiating PCP prophylaxis with thrice-
Individuals who are initially intolerant of TMP/SMX should be rechallenged according to the dosing schedule in Table 2. Patients who are at risk for toxoplasmosis as well as PCP and who are persistently intolerant of TMP/SMX should be offered one of two alternative prophylaxis regimens: dapsone (50-100 mg qd) plus pyrimethamine (50 mg weekly) and leucovorin (25 mg weekly); or dapsone (200 mg/day) plus pyrimethamine (75 mg weekly) and leucovorin (25 mg weekly) (Table 3). The relatively small number of patients who are intolerant of both TMP/SMX and dapsone should be prophylaxed with either aerosolized pentamidine or atovaquone suspension.
The patients most likely to experience a breakthrough infection while on PCP prophylaxis are those with CD4 counts below 50 cells/mm3, but nonadherence and previous treatment with regimens other than TMP/SMX are also predictive of prophylaxis failure. Locke and colleagues have reported that patients receiving TMP/SMX or dapsone are more likely to develop dihydropteroate synthase gene mutations than those not receiving prophylaxis. Despite the presence of this mutation, these patients respond to therapy with TMP/SMX, and the role of resistance in breakthrough PCP is unknown.
PCP prophylaxis should be offered to all pregnant HIV-
Although pneumocystis is less of a threat to people with HIV than it once was, PCP still causes significant morbidity and mortality in this population. Clinicians should therefore prescribe prophylaxis for all at-risk patients, and they should encourage consistent compliance with whatever regimen patients are assigned. This advice applies to all patients, even those who have experienced a significant degree of immune reconstitution as a result of highly active antiretroviral therapy.
Judith A. Aberg, M.D., is with the UCSF AIDS Program, San Francisco General Hospital.