Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: Prospective multicentre study
"...Our study supports the hypothesis that a sustained increase in the CD4 cell count to > 200 and 14% of the total peripheral lymphocyte count over at least 12 weeks, leads to a significant immune restoration with protection against opportunistic infections over a median follow-up of 3.3 years... There was no case of toxoplasmic encephalitis in our study population as was to be expected given the shown safety of discontinuation of primary prophylaxis against toxoplasmosis..."
AIDS: Volume 18(15), 21 October 2004
Zellweger, Claudine; Opravil, Milosa; Bernasconi, Enosb; Cavassini, Matthiasc; Bucher, Heiner Cd; Schiffer, Veroniquee; Wagels, Thomasf; Flepp, Markusa; Rickenbach, Marting; Furrer, Hansjakob; and the Swiss HIV Cohort Study
From the Division of Infectious Diseases, University Hospital of Berne, Berne, the aDivision of Infectious Diseases, University Hospital of Zurich, Zurich, the bDivision of Infectious Diseases, Cantonal Hospital of Lugano, Lugano, the cDivisions of Hospital Preventive Medicine and Infectious Diseases, University Hospital of Lausanne, Lausanne, the dDivision of Infectious Diseases and Basel Institute for Clinical Epidemiology, University Hospital of Basel, Basel, the eDivision of Infectious Diseases, University Hospital of Geneva, Geneva, the fDivision of Internal Medicine, Cantonal Hospital of St Gall, St Gall, and the gData Center Swiss HIV Cohort Study, Lausanne, Switzerland.
Objectives: To assess the long-term safety of discontinuation of secondary anti-Pneumocystis prophylaxis in HIV-infected adults treated with antiretroviral combination therapy and who have a sustained increase in CD4 cell counts.
Design: Prospective observational multicentre study.
Patients: and methods: The incidence of P. jirovecii pneumonia after discontinuation of secondary prophylaxis was studied in 78 HIV-infected patients on antiretroviral combination therapy after they experienced a sustained increase in CD4 cell counts to at least 200 × 106 cells/l and 14% of total lymphocytes measured twice at least 12 weeks apart.
Results: Secondary prophylaxis was discontinued at a median CD4 cell count of 380 × 106 cells/l. The median follow-up period after discontinuation of secondary prophylaxis was 40.2 months, yielding a total of 235 person-years of follow-up. No cases of recurrent P. jirovecii pneumonia occurred during this period. The incidence was thus 0 per 100 person-years with a 95% upper of confidence limit of 1.3 cases per 100 patient-years.
Conclusions: Discontinuation of secondary prophylaxis against P. jirovecii pneumonia is safe even in the long term in patients who have a sustained immunologic response on antiretroviral combination therapy.
Potent antiretroviral treatment has lead to a dramatic decrease in HIV-associated morbidity and mortality. This decline is the result of a successful suppression of plasma virus concentration which leads to an increase in CD4-positive T cell lymphocytes associated with a clinically important restoration of the immune response and protection against opportunistic infections.
The question as to whether or not treatment-associated restoration of the immune response allows primary and secondary prophylaxis against Pneumocystis jirovecii pneumonia (PCP) to be discontinued has been examined in combined cohort studies and prospective trials. While there are convincing and long-term results with regard to the safety of discontinuation of primary prophylaxis in patients who responded to potent antiretroviral therapy with a sustained increase in CD4 cell counts, results from two randomized controlled trials and results from several cohort studies indicate that the discontinuation of maintenance therapy is also safe. However, except for the recently published randomized controlled trial by Mussini et al. median follow-up time in these studies was less than 18 months and some concern about the long-term safety of stopping secondary prophylaxis therefore remains. Thus, the decision to discontinue a convenient, highly effective, and inexpensive prophylaxis such as thrice weekly trimethoprim-sulfamethoxazole asks for a higher level of evidence and certainty.
We therefore conducted this prospective multicentre study to evaluate the long-term safety of discontinuing chemoprophylaxis against recurrent PCP in patients whose CD4 cell count had risen to > 200 and 14% of peripheral lymphocyte count for at least 12 weeks during an median observational period of more than 3 years.
The discontinuation of secondary prophylaxis against PCP in HIV infected patients with a sustained increase in the CD4 cell count to > 200 and 14% of total peripheral lymphocytes could significantly improve the patients' quality of life. However, from the era before potent antiretroviral therapy became available it is known that the incidence of a PCP relapse after an initial episode is up to 50% within 6 months without prophylaxis compared to 3.5-18% with secondary prophylaxis. In addition, there is uncertainty about continued risk of PCP recurrence despite quantitative increases of the CD4 cell counts in the long term. Thus, the potential benefits of a discontinuation of the secondary prophylaxis have to be balanced against the remaining risk for a PCP relapse and against the potential problems associated with the prophylactic drug such as hypersensitivity to sulfonamides, development of drug-resistant P. jirovecii and bacteria  and costs.
Our study supports the hypothesis that a sustained increase in the CD4 cell count to > 200 and 14% of the total peripheral lymphocyte count over at least 12 weeks, leads to a significant immune restoration with protection against opportunistic infections over a median follow-up of 3.3 years. When the study was designed the required increase of the CD4 cell count over at least 12 weeks took into account the then published presumed minimal time required for naive CD4 cells to recover. None of the 78 prospectively enrolled patients developed a PCP after secondary prophylaxis was discontinued. It is noteworthy that the follow-up time in this study was 235 person-years, the longest follow-up time described so far. The upper 95% confidence limit of the incidence of PCP relapse was only 1.3 cases per 100 person-years of follow-up. Although the possibility of a PCP relapse cannot be excluded absolutely, the remaining risk seems to be very low. In addition, no case of toxoplasmic encephalitis has occurred. Thus, these results indicate that discontinuation of secondary prophylaxis is safe over an extended observation period in patients who respond to antiretroviral therapy with a sustained increase in the CD4 cell count to > 200 and 14% of the total lymphocyte count, irrespective of the CD4 cell nadir.
Several studies have previously addressed this issue with similar results, but their main limitations were short periods of observation, small sample sizes and therefore wide confidence intervals of the point estimates of low incidence rates observed. In contrast to the previously published studies showing relapse rates of zero after discontinuation of secondary PCP prophylaxis a recent randomized controlled trial by Mussini et al. described one definitive and one presumptive case of PCP in patients who discontinued maintenance therapy. These relapses occurred in patients with undetectable plasma HIV RNA and CD4 cell counts > 200 but one of these patients had received corticosteroids for asthma. Cases of PCP despite high CD4 cell counts were also, albeit rarely, observed in patients who discontinued primary prophylaxis. The CD4 cell count during antiretroviral therapy remains a very good, but not an absolutely perfect, marker of immunocompetence against opportunistic infections and awareness of clinicians caring for HIV-infected patients who discontinue prophylaxis is vital. We agree with Mussini et al. who point out that the dynamics of the CD4 cell count have to be monitored closely and that a re-initiation of secondary prophylaxis should be considered in the case of additional risk factors, such as glucocorticoid treatment or antineoplastic chemotherapy.
A particular issue of discontinuation trimethoprim-sulfamethoxazole is the loss of a potential secondary benefit, namely the protection against cerebral toxoplasmosis and common bacterial infections. There was no case of toxoplasmic encephalitis in our study population as was to be expected given the shown safety of discontinuation of primary prophylaxis against toxoplasmosis.
Prior to the introduction of highly active antiretroviral therapy (HAART) Hirschtick et al. were the first to report a significant reduction in the incidence of bacterial pneumonia (67%) among HIV-infected patients receiving prophylaxis with trimethoprim-sulfamethoxazole. However, since the introduction of HAART the incidence of bacterial pneumonia has significantly decreased. Recently published data of discontinuation primary and secondary PCP prophylaxis did not provide evidence of a significantly increased risk of bacterial pneumonia among patients who have discontinued the prophylaxis.
This observation was confirmed by a prospective cohort study in which the incidence of community-acquired pneumonia was compared between 336 patients with a sustained CD4 cell count increase to >= 200 and 14% of the total lymphocyte count who discontinued trimethoprim-sulfamethoxazole prophylaxis, and 78 patients who continued receiving prophylaxis. The difference in the incidence rate was not statistically significant and event rates were very low. Thus, this analysis showed that discontinuation of trimethoprim-sulfamethoxazole prophylaxis is not associated with a clinically significant increase in the incidence of bacterial pneumonia.
In our study we did not routinely check for the incidence of bacterial infections, but there was one patient who was withdrawn from the study because he restarted trimethoprim-sulfamethoxazole because of recurrent sinusitis.
In conclusion, the present study adds to the evidence that discontinuation of secondary prophylaxis against PCP in patients who have a sustained immunological response to antiretroviral combination therapy indicated by a CD4 cell count > 200 and 14% of the total lymphocyte count is safe with a minimal risk of recurrent PCP even in the long term.
A total of 274 patients followed up within the SHCS fulfilled the entry criteria. As of September 2002, 78 (28.5%) of them had consented to be enrolled. The enrolled patients did not differ significantly from the unenrolled patients with regard to CD4 cell count, CD4 cell percentage, plasma HIV RNA, age or presumed mode of HIV transmission. Their baseline characteristics at the time of the discontinuation of secondary prophylaxis against PCP are shown in Table 1.
Risk Factor for HIV
CD4 count during p. jirovecii pneumonia median: 41
% of total peripheral lymphocytes median: 6
Cd4 count at disct of secondary prophylaxis: 380
% of total peripheral lymphocytes: 22
CD4 count at end of study: 463
% of total peripheral lymphocytes: 26
Plasma HIV RNA at disct of secondary proph: < 50
Patients w/plasma HIV RNA <50 c/ml at disct: 68%
Plasma HIV RNA at end of study: <50
Pts w/plasma HIV RNA <50 c/ml at end of study: 76%
Duration of prophylaxis since p. jirovecii pneumonia at study entry (months): 40 mos
Proph against p. jirovecii pneumonia at study entry %
-trimethoprim pentamidine: 78%
-aerosolized pentamidine: 14%
Duration of HAATT at disct of secondary: 35 months
-3 drugs: 69%
-more than 3 drugs: 28%
-regimen including 1 or more PIs: 86%
-regimen including 1 NNRTI: 13%
Most of the patients were men (74%), the median age was 39 years. Fifty-three (68%) of the enrolled patients had plasma HIV RNA levels < 50 copies/ml, and the median CD4 cell count was 380 × 106/l at the time secondary prophylaxis was discontinued. The median nadir CD4 cell count had been 24 × 106/l (5% of total peripheral lymphocytes). In 61 patients (78%) the discontinued prophylactic regimen consisted of trimethoprim-sulfamethoxazole, 11 patients (14%) stopped aerosolised pentamidine and in the remaining six patients (8%) the secondary prophylaxis consisted of dapsone, dapsone/pyrimethamine, atovaquone or other drugs. Two of the enrolled patients had a history of one relapse and one of two relapses of PCP.
The median duration of the secondary prophylaxis after PCP was 40 months. All enrolled patients had to be on antiretroviral treatment. The median time since initiating antiretroviral therapy was 35 months (interquartile range, 26-40 months). In 97% the antiretroviral therapy consisted of at least three drugs, while 28% were treated with at least one protease inhibitor; only two patients were on a two-drug regimen.
Seven patients were withdrawn from the study because their chemoprophylaxis against PCP had to be re-initiated. In three of them the reason for restarting the secondary prophylaxis was a decrease of the CD4 cell count to < 200 × 106/l or < 14% of total peripheral lymphocytes documented by two consecutive measurements; in two patients the treating physician decided to restart prophylaxis because of a decrease of the CD4 cell count but without confirmation in a second measurement; in one patient the prophylaxis was re-initiated according to the patient's wish; and in one patient the reason for re-starting the trimethoprim-sulfamethoxazole were recurrent episodes of sinusitis. Two patients were lost to follow-up, one because he moved outside of Switzerland and the other because he withdrew from the study.
Incidence of PCP
During a total follow-up time of 235 person-years there were no cases of PCP, corresponding to a 95% upper confidence limit of 1.3 per 100 person-years. There was no diagnosis of toxoplasmic encephalitis and no deaths during the study.
Patients and methods
The Swiss HIV Cohort Study
Participants of the Swiss HIV Cohort Study could be included into the study. The Swiss HIV Cohort Study (SHCS; www.shcs.ch ) is a prospective cohort study with ongoing enrolment of adult HIV-infected patients. Patients are followed in one of seven study centres (Basle, Berne, Geneva, Lausanne, Lugano, St Gall, and Zurich). Enrolment is independent of stage of disease or degree of immunosuppression, and information is collected according to standardized criteria on structured forms at enrolment and at follow-up visits at 6-month intervals. Written informed consent is mandatory for inclusion into the study and the study is approved by all local ethical committees. Clinical stage is defined according to the 1993 classification system for HIV infection of the Centers for Disease Control and Prevention (CDC). CD4 cell counts are measured using flow-cytometric assays and plasma HIV-RNA levels are measured using the Roche Amplicor assay (Roche Diagnostics, Basle, Switzerland) with a lower detection limit of about 200 copies/ml. An ultrasensitive modification of the assay with a limit of detection of 2-40 copies/ml was introduced during 1998.
Inclusion and exclusion criteria
SHCS participants receiving secondary prophylaxis after a definitive or presumed diagnosis of PCP were eligible if they had a response to combination antiretroviral therapy consisting of at least two drugs with a sustained increase of the CD4 cell counts to at least 200 × 106/l and 14% of the peripheral lymphocyte count for at least 12 weeks.
Patients who took chronically immunosuppressive drugs (except hydroxyurea) in a maximal dosage of 500 mg twice daily, or had a history of toxoplasmic encephalitis were excluded.
According to the protocol secondary PCP prophylaxis would be resumed if: (i) the CD4 cell count fell below one of the threshold values on two consecutive measurements; or (ii) in the case of newly prescribed immunosuppressive drugs; or (iii) according to the patient's or the physician's wish. Recruitment started in January 1999, and ended in September 2002, follow-up was censored in September 2003.
A definitive or presumed diagnosis of PCP was the primary endpoint of this study: A definitive diagnosis of PCP was defined as microscopic detection of P. jirovecii in spontaneous or induced sputum or bronchoalveolar fluid, or on histologic examination of a lung specimen. A presumed diagnosis of PCP was defined as the presence of dyspnea on exertion, or a non-productive cough without evidence of bacterial pneumonia in a patient who responded to standard PCP treatment.
The secondary end points of the study were a definitive or presumed diagnosis of toxoplasmic encephalitis or death.