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Pneumocystis jiroveci pneumonia (PCP) prophylaxis is not required with a CD4+ T-cell count < 200 cells/μl when viral replication is suppressed
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AIDS:Volume 21(13)20 August 2007p 1711-1715
D'Egidio, Gianni Ea; Kravcik, Stephena,b,c; Cooper, Curtis La,c; Cameron, D
Williama,b,c; Fergusson, Dean Aa,b; Angel, Jonathan Ba,b,c
From the aDepartment of Medicine, University of Ottawa, Canada
bOttawa Health Research Institute, Canada
cDivision of Infectious Diseases, Ottawa Hospital, Ottawa, Canada.
Abstract
Objective: To determine the safety of discontinuing Pneumocystis jiroveci pneumonia (PCP) prophylaxis, in patients on effective antiretroviral therapy with CD4+ T-cell counts that have plateaued at < 200 cells/μl.
Methods: We prospectively evaluated a cohort of HIV infected patients at a multidisciplinary HIV clinic with sustained HIV RNA levels < 50 copies/ml and CD4+ T-cell counts that have plateaued at < 200 cells/μl and who have discontinued PCP prophylaxis.
Results: Nineteen patients fulfilled the above criteria. Eleven had been taking daily trimethoprim-sulfamethoxazole, seven were receiving monthly aerosolized pentamidine, and one patient never received any prophylaxis. The median CD4+ T-cell count at the time of discontinuation and at the most recent determination were 120 (range, 34-184) and 138 (range, 6-201) cells/μl, respectively. To date, patients have been off PCP prophylaxis for a mean of 13.7 ± 10.6 months and a median of 9.0 (range 3-39) months for a total of 261 patient-months. To date, no patient has developed PCP. This is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/μl in untreated HIV infection (rate difference 9.2%; 95% confidence interval, 5.7 to 12.8%; P < 0.05).
Conclusion: With sustained suppression of viral replication, PCP prophylaxis may not be necessary, regardless of CD4+ T-cell count. This illustrates a degree of immune recovery that occurs with virologic suppression that is not reflected in absolute CD4+ T-cell count or percentage and suggests that guidelines for P. jiroveci pneumonia prophylaxis may need to be re-evaluated.
Introduction
It is well established that human immunodeficiency virus (HIV)-infected individuals with CD4 cell counts of less than 200 cells/μl are at substantial risk for developing Pneumocystis jiroveci pneumonia (PCP) [1]. The benefits of PCP prophylaxis are well documented [2] and recommendations are clearly outlined in the 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections [3]. For individuals on antiretroviral therapy (ART) and CD4 cell counts that have increased and remained above 200 cells/μl, prophylaxis can be discontinued safely [4-15]. Cessation of prophylactic regimens has the potential to reduce pill burden, drug toxicity, drug interactions, selection of drug-resistant organisms, cost, and for those on aerosolized pentamidine, eliminates the inconvenience of monthly hospital/clinic visits. Although prophylaxis can be safely discontinued if the CD4 cell count remains greater than 200 cells/μl in response to antiretroviral therapy, it is unclear if prophylaxis is still required in the setting of maximal suppression of plasma viremia with ART and a plateau in CD4 cell count below 200 cells/μl.
Discussion
Before the development of effective antiretroviral therapy, prophylactic regimens were required for the duration of a patient's life because HIV-related immunodeficiency was considered to be irreversible. Following the widespread use of highly effective antiretroviral therapy (HAART) and the subsequent prospective observational and randomized controlled trials [4-15], it became apparent that discontinuation of PCP prophylaxis was safe when a sustained CD4 cell count of greater than 200 cells/μl was achieved. In studies looking at the discontinuation of primary PCP prophylaxis the risk of developing PCP was very low [4,5,8-13,15]. In the majority of studies no cases of PCP were reported [8-13,15] and, in fact, no cases of PCP have been reported in such patients that have remained off prophylaxis and on maximally effective ART with a CD4 count of > 200 cells/μl.
The risk of developing PCP is also very low when discontinuing secondary prophylaxis [4,6-8,10,11,15], although there have been rare cases of PCP in this setting despite sustained CD4 cell counts and continued ART [18].
There have been no studies attempting to determine whether PCP prophylaxis (or any prophylactic therapy) can be discontinued in patients whose CD4 cell count is in the range in which prophylaxis is recommended but who have effectively suppressed viral replication. We have followed a group of 19 patients with undetectable viral loads over a total of 261 patient months that currently have a median CD4 cell count of 138 cells/μl (range, 6-201 cells/μl) who are not receiving any means of PCP prophylaxis. To date there have been no cases of documented or presumed PCP. In a historic group followed by the Multicenter AIDS Cohort Study, whose CD4 cell count was below 200 cells/μl and who were not receiving HAART, approximately 20 cases per 100 patient-months would have been expected over this duration of follow-up [1]. Our observation of no cases of PCP over a period of 261 patient-months of follow-up is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/μl in untreated HIV infection (rate difference, 9.2%; 95% CI, 5.7-12.8%; P < 0.05) as reported in the MACS cohort.
Since HAART use became widespread in 1996, it has become increasingly clear that chemoprophylaxis for opportunistic infection need not necessarily be life-long. Antiretroviral therapy can restore immune function, typically thought to be reflected in an increased CD4+ T-lymphocyte count. It is, however, becoming increasingly clear that a lower viral load is associated with improved immune function and a decreased risk of developing opportunistic infections independent of CD4+ T-cell count [19-21].
In addition to protection from opportunistic infections, improved immune function associated with a lower viral load is also evident when assessing responses to vaccination. Lower viral loads have been associated with improved responses to hepatitis A, hepatitis B, and varicella vaccine independent of CD4+ T-cell count [22-24].
It has been suggested that CD4 percentage is an independent risk factor for the development of PCP [25]. Patients with a CD4 cell percentage of less than 14 are at an increased risk of developing PCP, independent of absolute CD4+ T-cell count and should be considered for primary PCP prophylaxis. In our patient cohort, the median CD4 percentage at the time of discontinuation of prophylaxis was 10.7% (range, 2.8-25.6%) and this value remained stable while off prophylaxis as indicated by the current median value of 10.6% (range, 3.9-23.6%) (Fig. 1b). This further suggests that immune function is gained independent of CD4+ T-cell percentage.
Discontinuing prophylactic regimens can reduce pill burden, reduce toxicity and drug interactions, decrease cost of care, and possibly improve compliance with antiretroviral regimens. It has been reported that the rate of adverse reactions with trimethoprim-sulfamethoxazole is as high as 50% and because of this almost one-third of patients need to change their prophylactic regimen [26,27]. Other prophylactic regimens are not without their risks and inconvenience. Monthly visits to a healthcare facility are required to receive inhaled pentamidine.
Our results support the concept that there is independent immunologic benefit gained from suppressing viral replication. Although the mechanism of this immune recovery is unknown it does open the window to further research into this field. There is also no reason to believe that this immune recovery is not relevant to opportunistic infections other than PCP. The risk of specific opportunistic infections and therefore the use of prophylactic therapies have not been related to plasma HIV RNA levels and therefore current guidelines do not include criteria based on plasma viral load. These data would suggest that guidelines for discontinuing PCP prophylaxis not only take into account absolute CD4 numbers but virologic response to antiretroviral therapy as well.
Methods
Study population
We describe a cohort of HIV-infected patients followed at a multidisciplinary HIV clinic who discontinued PCP prophylaxis in the setting of sustained suppression of plasma viremia and a CD4 cell count remaining below 200 cells/μl. Patients were included if their CD4 cell counts were stable and they were on effective antiretroviral therapy as indicated by plasma HIV RNA levels less than 50 copies/ml for at least 3 months. Patients either discontinued an accepted regimen for PCP prophylaxis or were never receiving any PCP prophylaxis. Patients who were receiving aerosolized pentamidine were considered to be off prophylaxis at a time commencing 1 month after their last dose of pentamidine. Patients never receiving prophylaxis were included when their viral load was suppressed to less than 50 copies/ml for a minimum of 3 months.
Follow-up and end points
Patients were typically seen every 3 months. Each visit included a directed medical history and a general physical examination and laboratory work included a CD4 cell count, viral load, complete blood count with differential, renal function tests, liver function tests, and lipid profiles.
The primary end point was the occurrence of PCP, either diagnosed definitively through microscopic analysis of induced sputum, bronchoalveolar fluid, or lung tissue specimen, or diagnosed presumptively based on clinical signs and symptoms, radiographic changes and a response to therapy for PCP.
Statistical analysis
Patient characteristics
Baseline characteristics of the patient cohort were assessed using frequency distributions and univariate descriptive statistics including measures of central tendency and dispersion. Mean values were presented with standard deviations and median values were presented with ranges.
We compared the incidence of PCP in our patient group to the incidence in a group of 1665 patients in the Multicenter AIDS Cohort Study who were not receiving any prophylaxis against PCP and who were followed for 48 months [1]. From the cohort, a cumulative percentage of 33.3% at 36 months was reported for 77 patients with CD4+ T-cell count < 200 cells/μl. Assuming all 77 patients were followed for the entire period of observation, a total of 2772 (77 X 36) and 25.6 cases (0.333 X 77 patients) were observed. With these conservative assumptions, PCP incidence in the historical cohort was estimated as 0.0092 cases per month.
The incidence rate of the historical control was compared to our incidence rate by calculating an incidence rate difference and 95% confidence intervals (CI) based on Byar's approximation of the exact Poisson test [16].
Results
Patient characteristics
Nineteen individuals met the inclusion criteria for evaluation in this report. Details of these patients are shown in Table 1. The population was predominantly male (15 of 19) and the median age was 47 years (range, 29-62 years). Four individuals had previous AIDS-defining opportunistic infections or malignancies. Eight patients had a previous risk factor (fever, thrush, weight loss) for developing PCP as defined by others [1,17]. Median pretherapy CD4+ T-cell count and HIV RNA levels were 28 cells/μl (range, 6-164 cells/μl) and 192 396 copies/ml (range, 3050- > 500 000 copies/ml), respectively. Eleven patients were receiving trimethoprim-sulfamethoxazole, seven were receiving aerosolized pentamidine and one patient never received prophylaxis. In one patient this was secondary PCP prophylaxis whereas in the remaining eighteen it was primary prophylaxis. Patients were taking PCP prophylaxis for a median duration of 12 months (range, 0 to 108 months). Patients had plasma HIV RNA level < 50 copies/ml before the cessation of prophylaxis for a median of 6 months (range, 0-58 months). The median CD4+ T-cell count at time of discontinuation of prophylaxis was 120 cells/μl (range, 34-184 cells/μl). To date, patients have been off PCP prophylaxis for a mean of 13.7 ± 10.6 months and a median of 9 (range, 3 to 39 months) for a total of 261 patient-months. The median CD4+ T-cell count at most recent follow-up was 138 cells/μl (range, 6-201 cells/μl).
Absolute CD4 cell count over time
Pretherapy CD4 cell counts and CD4 cell counts at 6 and 3 months prior to cessation of prophylaxis were recorded. CD4 cell counts increased from a median pretherapy level of 28 cells/μl (range, 6-164 cells/μl) to a median of 140 cells/μl (range, 77-207 cells/μl) at 6 months prior to discontinuing prophylaxis, 120 cells/μl (range, 34-184 cells/μl) at the time of discontinuing therapy and thereafter remained stable over the period of follow-up (Fig. 1a).
Percentage of CD4 positive cells over time
Pretherapy CD4 percentage and CD4 percentage at 6 and 3 months prior to cessation of prophylaxis were recorded. CD4 percentage increased from a median pretherapy value of 4.1% (range, 0.6-24.1%) to 8.9% (range, 2.1-23.5%) at 6 months prior to discontinuing prophylaxis, and to 10.6% (range, 3.9-23.6%) at the time of discontinuing therapy and thereafter remained stable over the period of follow-up (Fig. 1b).
Clinical follow-up
Five patients had CD4 cell counts above 200 cells/μl at a single point in time while off PCP prophylaxis. One patient had two CD4 cell counts above 200 cells/μl but the values were not consecutive and therefore did not meet guideline recommendations for the discontinuation of PCP prophylaxis. Five patients had 'blips' in plasma HIV RNA levels defined as transient increases in viral load to above 50 copies/ml. Two of these patients had more than one blip. One patient received a 1-week course of trimethoprim-sulfamethoxazole for a urinary tract infection. To date, no patient has developed either definitive or presumed PCP or any other opportunistic infection.
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