Pneumocystis Carinii Pneumonia: What's New in the Era of Combination Antiretroviral Therapies and Protease Inhibitors?
Despite the fact that the incidence and prevalence of Pneumocystis carinii pneumonia (PCP) among AIDS patients has declined over the years, due to the widespread use of prophylaxis, it remains an important cause of morbidity and mortality in advanced patients with HIV infection. At a symposium held at the 4th National Retrovirus Conference in Washington, D.C. Dr. Henry Masur from the National Institutes of Health reviewed the state of the art in the management and prevention of the infection in the era of combination antiretroviral therapies and protease inhibitors. One of the unanswered questions is what to do with patients whose CD4 counts rises over 200 cells/mm3, the threshold below which prophylaxis is usually initiated. He presented data showing that the repopulation of CD4 cells after indinavir therapy includes both memory and naive cells, yet some clonal deletions of some CD4 subsets (including some in the TCRV beta repertoire) may result in inadequate protection against PCP as well as other opportunistic infections.
The latest revision of Guidelines for the Prevention of Opportunistic Infections in Persons with HIV Infection to be issued by the United States Public Health Service and the Infectious Disease Society of America recommend initiating prophylaxis for PCP based on the lowest CD4 count and not discontinuing it even if the CD4 count rises over 200 cells/mm3 with antiretroviral therapy. Determinants of PCP breakthrough episodes discussed by Dr. Masur included a prior AIDS defining opportunistic infection, a CD4 count < 50 cells/mm3 and use of a regimen other than trimethoprim/sulfamethoxazole (Bactrim or Septra). The latter remains the prophylactic agent of choice, yet the exact dosing schedule is still being debated. Studies indicate that one single strength tablet per day, one double strength tablet per day or one double strength tablet thrice weekly are effective, yet as the weekly dose increases so does the incidence of intolerability. Investigational agents which can be considered for prophylaxis include clindamycin/primaquine, atovaquone, malarone, azithromycin, benzimidines and pneumocadins.
The question of whether the Pneumocystis carinii organism becomes resistant is still being investigated. As the fungus cannot be isolated in culture determination of phenotypic resistance is impossible. A study showing genotypic resistance among PCP breakthroughs was presented at the conference, which showed that mutations at two nucleotide positions of the dihydropteroate synthase (DHPS) gene were present in 4 of 6 patients who had broken through sulfa prophylaxis. Due to the lack of effective prophylactic therapies for patients with sulfa breakthroughs, Masur recommended using higher doses of trimethoprim/sulfamethoxazole (TMP/SMX) in these patients to prevent subsequent breakthroughs. Another strategy which was reported was that of gradual initiation of trimethoprim/sulfamethoxazole as primary prophylaxis using a suspension (8 mg TMP/40 mg SMX per ml) given gradually over two weeks. In a randomized, double-blind , placebo-controlled study of 377 patients, significantly fewer subjects discontinued TMP/SMX when it was initiated gradually than when its was initiated as a double-strength tablet.
Another researcher from the University of Oxford, Dr.Ann Wakefield presented animal data supporting the concept that PCP is host-species specific, and unlikely to be a zoonosis in humans. Genotyping of isolates of human-derived Pneumocystis carinii have demonstrated various different subtypes or polymorphisms. In 4 of 7 patients with recurrent PCP the genetic sequences observed differed among the subtypes recovered at each episode. She postulated that PCP in patients with AIDS may result from either reactivation or from reinfection with a different subtype. Using spore traps she was able to capture ambient air at rural sites and successfully recover the PC spores using PCR techniques. Whether the recovery of PC spores in ambient air from hospitals imply that the infection is airborne and patients with AIDS and PCP should be isolated remains unanswered, since the infectiousness of these spores and their reservoir is unknown.