Background: In the ‚USPHS/IDSA Guidelines for Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus‚, the indications for chemoprophylaxis are based on nadir CD4 cell count. Many patients have, however, experienced an increase in CD4 cell count after the introduction of highly active antiretroviral therapy (HAART).
Objectives: To assess incidences of opportunistic infections after discontinuation of chemoprophylaxis in HIV-infected patients, who have experienced a HAART-induced increase in CD4 cell count.
Methods: The Danish guidelines for chemoprophylaxis against opportunistic infections in HIV-infected patients were revised in late 1997, allowing discontinuation of chemoprophylaxis after initiation of HAART if the CD4 cell count remained above a specified limit for more than 6 months. Consecutive patients were followed, and incidences of opportunistic infections after discontinuation of chemoprophylaxis were assessed.
Results: A total of 219 patients discontinued Pneumocystis carinii pneumonia (PCP)-chemoprophylaxis (12% maintenance therapy). One case of PCP was diagnosed within 174 person-years (PY) of follow-up, resulting in an incidence of 0.6 cases/100 PY follow-up (95% confidence interval, 0.0-3.2). No cases of cerebral toxoplasmosis, cytomegalovirus chorioretinitis, or disseminated Mycobacterium avium infection were observed. Follow-up time for these was, however, limited.
Conclusion: PCP-chemoprophylaxis can be safely discontinued after HAART-induced increase in CD4 cell count to more than 200×106 cells/l. Among consecutive patients who discontinue chemoprophylaxis according to well-defined guidelines, the observed incidence of PCP is below those reported earlier in patients with similar CD4 cell count.
The introduction of highly active antiretroviral therapy (HAART) has dramatically changed the prognosis for HIV-infected patients, in terms of decreasing mortality rate and decreasing incidences of opportunistic infections, as well as a reduced need for hospitalization among these patients[1-3]. The effect of HAART is also well established for surrogate-markers such as the viral load and the CD4 cell count[4,5].
Many patients experience a marked increase in CD4 cell count, and possibly recovery of CD4 cell function[6-8]. Therefore, it has been natural to question whether chemoprophylaxis against opportunistic infections can be safely discontinued when the CD4 cell count increases to above the level considered to be the lower limit for initiating chemoprophylaxis against the same infections. Only very limited data is available on this matter[9,10]. So far, the indications for chemoprophylaxis in the USPHS/IDSA guidelines, remain based on the nadir CD4 cell count rather than the latest value of the CD4 cell count.
In Denmark, the guidelines for discontinuation of chemoprophylaxis against opportunistic infections after initiation of HAART were changed in late 1997. We report the results for patients who discontinued their chemoprophylaxis thereafter.
Guidelines for discontinuing chemoprophylaxis were changed in December 1997 at four major HIV-clinics in Denmark; consecutive patients who discontinued chemoprophylaxis according to these guidelines were included in an observational cohort. Patients who discontinued chemoprophylaxis for other reasons were not included.
Chemoprophylaxis was discontinued if the CD4 cell count stayed above the following limits for >6 months: Pneumocystis carinii pnemonia (PCP), CD4 count >200×106 cells/l (both primary chemoprophylaxis, and maintenance therapy); Toxoplasmosis gondii encephalitis, >100×106 cells/l (primary chemoprophylaxis), and >200×106 cells/l (maintenance therapy); cytomegalovirus (CMV) chorioretinitis, >100×106 cells/l (maintenance therapy); and disseminated Mycobacterium avium infection, >100×106 cells/l (maintenance therapy). No recommendation was made for primary chemoprophylaxis for M. avium infection, as use of this type of chemoprophylaxis has so far not been generally recommended in Denmark.
At the time of discontinuing chemoprophylaxis, data on the following parameters was collected: demographic characteristics, antiretroviral and prophylactic treatment, latest viral load, and CD4 cell count (latest value and nadir value). HAART was broadly defined as any triple drug regimen.
Patients were evaluated every 3 months, or more frequently if necessary. Under prospective follow-up, cases of the infections listed above were registered, as was re-initiation of chemoprophylaxis, and the reason for doing so (CD4 cell count decreasing to below the CD4 threshold for discontinuation of chemoprophylaxis, patient‚s/investigator‚s request, or other reason). In the present analysis, follow-up until April 15th, 1999 was included.
Incidences were assessed for all four diseases; 95% confidence intervals (CI) were calculated by using a Poisson distribution. For a subset of patients with positive T. gondii antibody test available, the incidence of cerebral toxoplasmosis after discontinuation of primary chemoprophylaxis was assessed also.
A total of 219 patients discontinued chemoprophylaxis against PCP (of whom 26 discontinued maintenance treatment), 45 against cerebral toxoplasmosis (eight discontinued maintenance treatment), whereas five and six patients, respectively, discontinued maintenance therapy for CMV and disseminated M. avium infection. Characteristics for the patients, who discontinued one or more type of chemoprophylaxis against PCP, cerebral toxoplasmosis, CMV, and disseminated M. avium infection, are given in Table 1.
In all groups, median time since initiating HAART was about 18 months, and in general the median CD4 cell count was >300×106/l, and median viral load generally low, whereas the proportion of patients with complete viral suppression ranged from 17% to 62%. The median nadir CD4 cell count documented that most patients had previously been severely immunosuppressed, although less so in the groups discontinuing primary chemoprophylaxis against PCP and cerebral toxoplasmosis. The median nadir CD4 cell count in these groups were 117 and 135×106 cells/l, respectively, whereas the CD4 cell count among patients who discontinued maintenance therapy was considerably lower-in all groups less than 50×106 cells/ml.
After discontinuation of chemoprophylaxis, one patient was diagnosed with PCP within a total of 174 person years (PY) of follow-up. This patient had a CD4 cell count of 216×106 cells/l and a viral load of 40000 copies/ml at discontinuation of primary chemoprophylaxis, whereas his nadir CD4 cell count was 43×106 cells/l, and HAART was initiated 1.7 years before discontinuation. After 5 months without trimethoprim- sulphamethoxazole, PCP was diagnosed and verified microbiologically. During the acute infection his CD4 cell count was 143×106 cells/l, which was the first CD4 cell count <200×106 cells/l to be measured after discontinuation of chemoprophylaxis. In the last 2 months before the diagnosis of PCP, the patient received treatment with granulocyte colony stimulating factor (G-CSF) as part of a randomized clinical trial.
Two patients, both receiving primary chemoprophylaxis against PCP, re-initiated their chemoprophylaxis, as their CD4 cell count fell below 200×106 cells/l. One patient, an injecting drug user, died as a consequence of verified staphylococcal septicaemia. Based on this, the incidences of the four opportunistic infections were assessed (Table 2).
Our findings document that chemoprophylaxis against PCP can be discontinued after HAART-induced increase in CD4 cell count. The incidence of PCP (0.6 cases/100 PY follow-up (95% CI, 0.0-3.2) is lower than or equal to those previously reported among HIV-infected patients with a CD4 cell count of 200-300×106 cells/l, or more than 200×106 cells/l, being 3.0 (2.5-4.4), and 1.4 cases/100 PY follow-up, respectively[12,13].
One case of PCP was reported after discontinuation of chemoprophylaxis. This patient received treatment with G-CSF up to the diagnosis of PCP. He had CD4 cell count increases before the initiation of this treatment, so it is unlikely that the PCP was caused by an overestimation of the immune reconstitution due to a G-CSF-inflated CD4 cell count. It is more likely that the anti-inflammatory capacity of G-CSF may have triggered the PCP, as G-CSF is a known inhibitor of tumour necrosis factor-agr; and interferon-γ?production. Furthermore, at the time of discontinuation, the patient had not achieved viral suppression, and one might question whether chemoprophylaxis can be safely discontinued in patients with viraemia in spite of a HAART-induced increase in CD4 cell count. However, although nearly half of the patients did not have fully suppressed viral load, only one case of PCP developed. For these patients, regular follow-up is needed to allow re-initiation of chemoprophylaxis in case of decreasing CD4 cell counts to below the limit for re-initiation of chemoprophylaxis.
The present study provides a considerable total follow-up. Schneider et al. recently reported on discontinuation of chemoprophylaxis against PCP in 78 patients and found no cases of PCP during 83 PY of follow-up. In a Swiss study of discontinuation of primary PCP chemoprophylaxis, no cases of PCP were observed among 262 patients with a total follow-up time of 238 PY (published after resubmission of this paper). In contrast to this study, we also included patients with a prior episode of PCP, being a group of patients at higher risk of PCP.
In an analysis within the EuroSIDA study, 378 patients discontinued chemoprophylaxis against PCP after initiation of HAART, providing 186 PY of follow-up with CD4 cell counts >200×106 cells/l without any cases of PCP. A selection bias may have been introduced in this analysis, as patients were included regardless of the reason for discontinuing chemoprophylaxis, and not according to defined guidelines as in the present study.
For cerebral toxoplasmosis, this study is the first to report on the safety of discontinuation of primary chemoprophylaxis as well as maintenance therapy. Previous studies on discontinuation of maintenance treatment for disseminated M. avium infection and CMV chorioretinitis, have reported no relapses[17-21]. However, most studies have been based on selected patients, and only a limited overall follow-up time for these diseases is available. Therefore, further results are needed for these infections to allow conclusions on the safety of discontinuation of primary chemoprophylaxis and maintenance therapy.
Because it included exclusively consecutive patients in accordance with well-defined guidelines, our study has an advantage over most other series in that no selection was introduced, leaving inclusion solely dependent on the CD4 cell level. This has important implications for how to translate the results into general recommendations. In addition, the Danish guidelines require a prolonged time of elevated CD4 cell count before discontinuing chemoprophylaxis, so that events developing as part of an immune reactivation syndrome are not a matter of concern[22,23].
Observational studies are important sources for evaluating the safety of discontinuation of chemoprophylaxis. That is, due to the very low incidence of opportunistic infections reported after discontinuation, a randomized trial should be of a considerable size and provide a considerable follow-up time. However, results are urgently needed, as patients in clinical practice now tend to discontinue chemoprophylaxis after HAART-induced increases in CD4 cell count.
In conclusion, PCP-chemoprophylaxis can be safely discontinued after HAART-induced increase in CD4 count to more than 200×106 cells/l. Among consecutive patients, who discontinue chemoprophylaxis according to well-defined guidelines, the observed incidence of PCP is below those reported earlier in patients with similar CD4 cell counts. No cases of cerebral toxoplasmosis, CMV chorioretinitis, or disseminated M. avium infection were observed. Follow-up time for these was, however, limited.
After resubmission of this paper, a Swiss study has reported on discontinuation of primary chemoprophylaxis against PCP (as referenced) and cerebral toxoplasmosis. Their findings are generally in agreement with our findings.
1. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998, 352:1725-1730.
2. Palella FJJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998, 338:853-860.
3. Mouton Y, Alfandari S, Valette M, et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. Federation National des Centres de Lutte contre le SIDA. AIDS 1997, 11:F101-F105
4. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997, 337:725-733.
5. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337:734-739.
6. Li TS, Tubiana R, Katlama C, Calvez V, Ait MH, Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998, 351:1682-1686.
7. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997, 277:112-116.
8. Pakker NG, Notermans DW, de Boer RJ, et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nature Med 1998, 4:208-214.
9. Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999, 353:201-203.
10. Lopez J, Peña J, Miro J, Podzamczer D, and the GESIDA 04/98 study group. Discontinuation of PCP prophylaxis (PRO) is safe in HIV-infected patients (PTS) with immunological recovery with HAART. Preliminary results of an open, randomised and multicentric clinical trial (GESIDA 04/98). Sixth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1999 [abstract LB7].
11. USPHS/IDSA. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Ann Intern Med 1997, 127:922-946.
12. Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis 1998, 178:1126-1132.
13. Mocroft A, Youle M, Phillips AN, et al. The incidence of AIDS-defining illnesses in 4883 patients with human immunodeficiency virus infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group. Arch Intern Med 1998, 158:491-497.
14. Hartung T. Anti-inflammatory effects of granulocyte colony-stimulating factor. Curr Opin Hematol 1998, 5:221-225.
15. Furrer H, Egger M, Opravil M. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1 infected adults treated with combination antiretroviral therapy. Swiss HIVCohort Study. N Engl J Med 1999, 340:1301-1306.
16. Weverling GJ, Mocroft A, Ledergerber B, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. Lancet 1999, 353:1293-1298.
17. Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis 1998, 178:1446-1449.
18. Gill J, Moyle G, Nelson M. Discontinuation of Mycobacterium avium complex prophylaxis in patients with a rise in CD4 cell count following highly active antiretroviral therapy [letter]. AIDS 1998, 12:680.
19. Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998, 177:1080-1083.
20. Macdonald JC, Torriani FJ, Morse LS, Karavellas MP, Reed JB, Freeman WR. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis 1998, 177:1182-1187.
21. Vrabec TR, Baldassano VF, Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 1998, 105:1259-1264.
22. Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997, 349:1443-1445.
23. Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 1998, 351:252-255.
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