The Prophylaxis Dilemma
With the advent of highly active antiretroviral therapy (HAART) that can induce partial immune reconstitution with replenishment of the CD4 cell repertoire, advanced stage opportunistic infections have become less frequent and some have practically disappeared. The toxicities of some of the antimicrobial agents used for primary and secondary prophylaxis and the risk of resistance developing, not to mention the cost of the drugs, led a panel of experts sponsored by the US Public Health Service and the Infectious Disease Society of America (IDSA) to review the existing recommendations surrounding prophylaxis of opportunistic infections (OIs) as these were drawn up at a time before HAART and, therefore, relied on the CD4 cell count as the surrogate marker which best predicted the risk of developing an OI. The revised recommendations were published in May of 1999 on the Internet (http://www.hivatis.org) and reflected the panel's interpretation of the existing data -- much of which was incomplete or lacking as the clinical trials to determine the relative benefit of OI prophylaxis in the era of HAART were still not complete, for the most part. The bulk of the changes in the recommendations pertain to discontinuation of prophylaxis when patients' CD4 counts have risen above a certain threshold. The following is a summary of the most salient changes in the recommendations that are cited in the new guidelines.
Pneumocystis Carinii Pneumonia (PCP)
Several studies have now shown that PCP prophylaxis can be safely discontinued in patients who are responding to HAART with a sustained increase in CD4 cell counts over 200 cells/uL and who have never had an episode of PCP (primary prophylaxis).(1, 2, 3, 4) The panel therefore advised that discontinuation of primary prophylaxis could be done if patients had sustained increases in CD4 cells over 200 cells/uL for at least 3-6 months. If a patient has already had an episode of PCP, the panel did not feel that the data supported changing the recommendation of use of prophylaxis to prevent a recurrence. The recommendations also have not changed for children and for pregnant women.
Insufficient numbers of patients have been studied to recommend routine discontinuation of prophylaxis in patients whose CD4 counts increase to >100 cells/uL in response to HAART; thus the panel did not feel that the recommendation to initiate prophylaxis at that CD4 level should be changed.
Presently other than avoiding primary exposure through avoidance of contaminated water, oral-anal sexual contact, pet feces and fomites (dried droplets of respiratory secretions) from other persons with active disease, chemoprophylaxis is not routinely recommended.
The panel recommends that all HIV-infected persons with a positive PPD skin test but no evidence of active tuberculosis be treated with either a nine month course of isoniazid administered daily or twice weekly, or two months of rifampin and pyrazinamide.(5) This latter regimen is likely to be contraindicated in many patients already on HAART since rifampin decreases plasma concentrations of many of the protease inhibitors and NNRTIs.
Mycobacterium Avium Complex (MAC)
One observational study suggests that a low rate of disseminated infection with MAC among people who responded to HAART with an increase in CD4 count from <50 to >100 cells/uL.(6) The panel asserts that discontinuation of primary MAC prophylaxis is reasonable if the CD4 cell count is >100 cells/uL for 3-6 months and if there is sustained suppression of HIV plasma RNA. Patients who have had an episode of disseminated MAC should continue chronic maintenance therapy since data are insufficient to recommend discontinuation of MAC therapy in such patients.
Invasive Fungal Infections (Cryptococcosis, Candidiasis, Coccidioidomycosis and Histoplasmosis)
The panel recommends no change in the present recommendation to continue maintenance therapy with the appropriate antifungal drug after treatment of an acute infection with any of these fungal organisms.
Several studies have found good outcomes in discontinuing maintenance therapy with CMV retinitis for people whose CD4 cells counts have increased to over 100-150 cells/uL and whose plasma RNA has been suppressed in response to HAART.(7) These patients largely continue to remain disease free for >30-90 weeks, whereas in the pre-HAART era retinitis recurred in 6-8 weeks. The panel felt it was appropriate to recommend discontinuation of prophylaxis in patients with a sustained CD4 count of 100-150 cells/uL on HAART. The decision should be made in consultation with an ophthalmologist and should consider the location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient and the response to HAART. Restarting CMV prophylaxis should be done if the CD4 count decreases to <50-100 cells/uL. A recent multicenter prospective study conducted in Spain evaluated the incidence of CMV retinitis in a cohort of 172 HIV-positive patients with a CD4 count below 100 cells/uL at the time of starting protease inhibitor therapy.(8) The incidence of CMV retinitis was 5% at one year and 6% at two years. Only a positive CMV PCR test at the time HAART was started was significantly associated with development of disease, as the rate of retinitis was 38% in those PCR positive versus 2% in those PCR negative.
Overall, the changes in the OI recommendations are quite conservative, as the panel usually reviews data from only controlled trials, and the data for most of the studies evaluating OI incidence in the era of HAART were from observational studies or noncontrolled trials. There are many remaining questions to be answered regarding OI prophylaxis such as the relative value of the viral load in predicting OI recurrences; whether the interpretation of CD4 thresholds once partial immune reconstitution has occurred is valid; and whether resistant organisms are being engendered by keeping patients on long term chemoprophylaxis. These and other questions are being investigated by several large trials and through analyses of large prospective patient databases.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.