Discontinuation of Secondary Prophylaxis against Disseminated Mycobacterium avium Complex Infection and Toxoplasmic Encephalitis

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1 HIV/AIDS MAJOR ARTICLE Discontinuation of Secondary Prophylaxis against Disseminated Mycobacterium avium Complex Infection and Toxoplasmic Encephalitis Valérie Zeller, 1 Chantal Truffot, 2 Rachid Agher, 1 Philippe Bossi, 1 Roland Tubiana, 1 Eric Caumes, 1 Marc Jouan, 1 François Bricaire, 1 and Christine Katlama 1 Departments of 1 Infectious Diseases and 2 Bacteriology, Pitié-Salpêtrière Hospital, Paris, France We retrospectively studied outcomes for patients infected with human immunodeficiency virus who received highly active antiretroviral therapy (HAART) and had stopped receiving secondary prophylaxis against toxoplasmic encephalitis (TE) or disseminated Mycobacterium avium complex (MAC) infection. Nineteen patients had a history of TE, and 26 had a history of disseminated MAC infection. The median duration of secondary prophylaxis was 27 months, and the median duration of HAART before discontinuation of secondary prophylaxis was 22 months. Median CD4 + cell counts at the time of cessation of secondary prophylaxis against TE or disseminated MAC infection were 404 and 105 cells/mm 3, respectively. Plasma virus load was undetectable in 68% of the patients who had a history of TE and in 31% of patients who had a history of disseminated MAC infection. Patients were followed up for a median of 29 months after discontinuation of secondary prophylaxis; no relapses occurred in patients with a history of TE, and 3 relapses occurred in patients with a history of disseminated MAC infection (incidence, 4 relapses per 100 person-years). The use of highly active antiretroviral therapy (HAART) in recent years has markedly reduced the risk of opportunistic infections and death in HIV-infected patients [1, 2]. The clinical benefit is related to immune reconstitution, which is associated with a quantitative and qualitative improvement in CD4 cells [3, 4]. This raises the possibility that prophylaxis against opportunistic infections can be discontinued for patients with a good immunologic and virologic response to HAART. Indeed, simplification of therapy is a major factor in Received 15 June 2001; revised 1 October 2001; electronically published 24 January Reprints or correspondence: Dr. Valérie Zeller, Service des Maladies Infectieuses et Tropicales, CHU Pitié-Salpêtrière, Bd. de l Hôpital, Paris Cedex 013, France (valerie.zeller@psl.ap-hop-paris.fr). Clinical Infectious Diseases 2002; 34: by the Infectious Diseases Society of America. All rights reserved /2002/ $03.00 adherence to treatment and in the efficacy of antiretroviral drugs. Several prospective trials have shown that primary prophylaxis against opportunistic infections such as Pneumocystis carinii pneumonia, toxoplasmic encephalitis (TE), cytomegalovirus (CMV) retinitis, and disseminated Mycobacterium avium complex (MAC) infection can be safely discontinued for patients receiving HAART who have good immunologic and virologic response [5 12]. Discontinuation of secondary prophylaxis for opportunistic infections in patients successfully treated with HAART has been less widely investigated. Because of its high toxicity, CMV maintenance therapy was one of the first courses of prophylaxis to be evaluated in this respect. Several studies [13 16] have shown that CMV maintenance therapy can be discontinued in patients receiving HAART whose CD4 cell count remains 662 CID 2002:34 (1 March) HIV/AIDS

2 cells/mm 3 for 3 6 months [12]. More recently, 2 large studies (a cohort study and a randomized study) concluded that secondary prophylaxis against P. carinii pneumonia could be discontinued safely for patients receiving HAART in whom CD4 cell counts increase to 1200 cells/mm 3 [17, 18]. In contrast, few data are available on the safety of discontinuing secondary prophylaxis for other opportunistic infections, such as cerebral toxoplasmosis, disseminated MAC infection, and cryptococcal meningitis [19 22]. We undertook a retrospective study designed to evaluate outcomes for HIV-infected patients treated with HAART who discontinued secondary prophylaxis against TE and disseminated MAC infection. PATIENTS AND METHODS We reviewed the charts of all HIV-infected patients treated in the Department of Infectious Diseases at Pitié-Salpêtrière Hospital, Paris, who had a history of documented TE or disseminated MAC infection. Cerebral toxoplasmosis was diagnosed on the basis of a clinical and radiological response to specific treatment in patients who had clinical and neuroradiological evidence of a space-occupying cerebral lesion and who had IgG antibodies against Toxoplasma gondii (as determined by ELISA and an immunofluorescence assay). Disseminated MAC infection was diagnosed on the basis of 1 blood culture positive for MAC. Patients were included in the study if they were already receiving HAART when they stopped receiving secondary prophylaxis, and if they had at least 6 months of followup after discontinuing secondary prophylaxis. The following data were recorded for each patient: sex, age, risk factor for HIV infection, date of diagnosis and treatment of the opportunistic infection, date of initiation of HAART, date of cessation of secondary prophylaxis, and CD4 lymphocyte count and plasma virus load at diagnosis of the opportunistic infection, at initiation of HAART, and at discontinuation of secondary prophylaxis. All patients had their last follow-up visit during the period July December All clinical events that occurred after cessation of secondary prophylaxis were recorded. The following data were recorded for patients who died after June 1996: date of HAART initiation, date of cessation of secondary prophylaxis, and cause of death. Patients who died before June 1996 (i.e., before initiation of HAART) were excluded from the study. RESULTS One hundred thirteen patients with a history of TE and 49 patients with a history of disseminated MAC infection were seen in the Infectious Diseases Department of Pitié-Salpêtrière Hospital from June 1996 through December 2000 (figure 1). Twenty-six of these patients died. The causes of death are shown in figure 1. One patient died after a seizure at home, 1 month after starting treatment with sulfadiazine and pyrimethamine for cerebral toxoplasmosis. Another patient died of disseminated MAC infection; this patient had stopped taking both anti MAC and antiretroviral treatment. The other patients died of causes apparently unrelated to the opportunistic infection for which they were receiving prophylaxis. The cause of death was unknown for 7 patients, 6 of whom had not stopped taking secondary prophylaxis against the opportunistic infection. All 22 patients who were lost to follow-up for 11 year were still receiving secondary prophylaxis at the time of the last visit. Sixty-nine patients were still receiving secondary prophylaxis. Forty-five patients had stopped receiving secondary prophylaxis, for TE in 19 patients and for disseminated MAC infection in 26 patients (figure 1). The clinical characteristics of these 45 patients are shown in table 1. Forty-four patients (98%) were men, and the median age was 39 years (range, years). Risk factors for HIV infection were homosexual sexual activity for 27 patients (60%), heterosexual sexual activity for 10 patients (22%), injection drug use for 5 patients (11%), blood transfusion for 1 patient (2.2%), and undetermined factors for 2 patients (4.4%). Three of the 26 patients with a history of disseminated MAC infection experienced a relapse (incidence, 4 relapses per 100 person-years). The first patient developed disseminated MAC infection 2 months after starting primary prophylaxis with clarithromycin and 1 month after starting HAART. He was initially treated with a combination of ethambutol, clofazimin, ciprofloxacin, and azithromycin, but azithromycin was discontinued after 6 months because the infecting strain was resistant to clarithromycin (MIC, 128 mg/l) and the patient had poor compliance. The other drugs were maintained for an additional 6 months. The second patient was treated for disseminated MAC infection that developed 1 month after initiation of HAART with clarithromycin, ethambutol, and rifabutin for 12 months. Compliance with clarithromycin therapy was poor. Three months after they stopped receiving anti-mac treatment, both patients had clinical and radiological signs of joint and bone infection. Relapse of infection was diagnosed on the basis of a culture of a bone biopsy specimen (with use of Loewenstein-Jensen medium) that was positive for MAC. The infecting strains from both patients were susceptible to clarithromycin (MIC, 4 mg/l). At the time of relapse, the patients were afebrile, blood cultures for MAC remained negative, and the patients had a good immunologic and virologic response to HAART (CD4 cell count, 126 and 160 cells/mm 3, respectively; virus load,!200 copies/ml for both patients). Prolonged treatment (1 and 2 years, respectively) of the MAC infection relapse with HIV/AIDS CID 2002:34 (1 March) 663

3 Figure 1. Summary of outcomes for study patients with HIV infection who discontinued secondary prophylaxis (SP) against disseminated Mycobacterium avium complex (MAC) infection or toxoplasmic encephalitis. CMV, cytomegalovirus. specific multidrug regimens (which included clarithromycin, ethambutol, sparfloxacin, and amikacin) was successful in both patients. No additional relapses had occurred 16 and 19 months, respectively, after the end of treatment of the MAC infection relapse. Genotyping of the resistant and susceptible strains isolated from the first patient (by use of M. avium direct repetitive element PCR) revealed identical profiles. The third patient had disseminated MAC infection that was successfully treated with clarithromycin, ethambutol, and rifabutin for 12 months. His CD4 cell count was 107 cells/mm 3 when he stopped receiving anti-mac treatment. He experienced a late relapse 40 months after discontinuing maintenance treatment. At that time, he was severely immunodeficient (CD4 cell count,!50 cells/mm 3 ) and had had a high plasma virus load (1100,000 copies/ml) for 2.5 years. MAC was isolated from a subcutaneous abscess (2 colonies) and a blood culture (1 colony). Salvage antiretroviral therapy was started in October 2000, simultaneously with anti-mac treatment consisting of clarithromycin, rifabutin, and ethambutol. Six months later, at the time of this analysis, his condition was stable and a culture of a blood sample on Loewenstein-Jensen medium was sterile; however, antiretroviral therapy was virologically and immunologically ineffective (CD4 cell count, 1 cell/mm 3 ; plasma virus load, 400,000 copies/ml). Genotyping of the initial and relapse strains showed different profiles, which suggested reinfection, rather than relapse. An additional 25 clinical events occurred in 14 of the 45 patients after discontinuation of secondary prophylaxis: there were 11 viral infections (CMV in 5 patients, varicella-zoster virus in 4 patients, and herpes simplex virus in 2 patients), CID 2002:34 (1 March) HIV/AIDS

4 Table 1. Clinical characteristics of 45 patients with HIV infection who discontinued secondary prophylaxis against disseminated Mycobacterium avium complex (MAC) infection or toxoplasmic encephalitis. Characteristic Toxoplasmic encephalitis (n p 19) Disseminated MAC infection (n p 26) Duration of therapy, median months (range) Secondary prophylaxis 28 (9 69) 23 (6 48) HAART before discontinuation of secondary prophylaxis 29 (12 45) 13 (1 39) CD4 cell count by time point, median cells/mm 3 (range) At diagnosis of opportunistic infection 88 (1 220) 10 (1 171) At discontinuation of secondary prophylaxis 404 ( ) 105 (1 254) At last follow-up visit 497 (1 813) 309 (1 735) Patients per CD4 cell count category, no. (%) At discontinuation of secondary prophylaxis!50 cells/mm (27) cells/mm (19) cells/mm (31) 1200 cells/mm 3 19 (100) 6 (23) At last follow-up visit!50 cells/mm (11.5) cells/mm (4) cells/mm 3 1 (5) 3 (11.5) 1200 cells/mm 3 18 (95) 19 (73) Duration of elevated CD4 count a before discontinuation of secondary prophylaxis, no. (%) of patients 3 months 18 (95) 8 (31) 6 months 18 (95) 6 (23) Virus load, median copies/ml (% of patients with!200 copies/ml) At diagnosis of opportunistic infection 135,862 (0) 380,000 (4) At discontinuation of secondary prophylaxis 4478 (68) 83,864 (31) At last follow-up visit 1307 (52) 1851 (46) Duration of follow-up after discontinuation of secondary prophylaxis, median months (range) 20 (8 50) 35 (15 57) Relapse rate, % (95% CI) (0 24) NOTE. HAART, highly active antiretroviral therapy. a Greater than recommended threshold: for patients with toxoplasmic encephalitis, 1200 cells/mm 3 ; for patients with disseminated MAC infection, 1100 cells/mm 3 [23]. bacterial infections (pneumonia in 5 patients, sinusitis in 1 patient, colitis in 1 patient, cutaneous abscess in 1 patient, and catheter-related infection in 1 patient), 1 case of P. carinii pneumonia (in a patient with a history of MAC infection), 3 malignancies (progression of Kaposi s sarcoma in 1 patient, Castleman s disease in 1 patient, and rectal cancer in 1 patient), and 1 hip fracture. DISCUSSION The efficacy of HAART has raised the possibility that potentially toxic maintenance therapies against common opportunistic infections can be discontinued for patients whose CD4 cell count increases substantially during antiretroviral therapy. Good adherence to antiretroviral therapy is crucial to maintaining its efficacy and can be encouraged by use of simple, well-tolerated regimens. Therefore, clinicians managing HIV-infected patients should aim to minimize pill intake, drug toxicity, and potential drug interactions. To assess the feasibility of this objective in the post-haart era, we evaluated the safety of discontinuing secondary prophylaxis against 2 major opportunist infections: cerebral toxoplasmosis and disseminated MAC infection. In this retrospective series, there were no relapses in the 19 patients with a history of cerebral toxoplasmosis after a median HIV/AIDS CID 2002:34 (1 March) 665

5 follow-up of 20 months. All the patients had CD4 cell counts of 1200 cells/mm 3 when they discontinued secondary prophylaxis, and 95% of them maintained this level for 16 months. These results support the recommendations of recent draft of the US Public Health Service (USPHS) guidelines [23] and suggest that secondary prophylaxis for TE can be discontinued for patients receiving HAART whose CD4 cell counts remain 1200 cells/mm 3 for 3 6 months. Soriano et al. [20] described 9 patients treated with HAART who discontinued secondary prophylaxis for cerebral toxoplasmosis when their CD4 cell counts were 1100 cells/mm 3 and their plasma HIV RNA loads were!500 copies/ml. No relapses were noted during 18 months of follow-up. Data on discontinuation of secondary prophylaxis for disseminated MAC infection are more limited. Aberg et al. [19] described 4 patients with a history of disseminated MAC infection who were receiving HAART and discontinued their maintenance treatment when their CD4 cell counts were 1100 cells/mm 3 and their virus loads were!10,000 copies/ml. All had received a macrolide-based anti-mac regimen for at least 1 year. No relapses occurred during 8 13 months of followup. Soriano et al. [20] described 7 patients treated with HAART who discontinued maintenance treatment for MAC infection. No relapses occurred during 18 months of follow-up. More recently, Shafran et al. [22] conducted a retrospective study of 33 patients with a history of disseminated MAC infection who discontinued maintenance treatment while receiving HAART. At a median of 17 months of follow-up, only 1 patient experienced relapse (37 months after discontinuing MAC prophylaxis); it is noteworthy that this patient had uncontrolled HIV disease after having discontinued HAART. We retrospectively studied 26 patients who discontinued secondary prophylaxis for disseminated MAC infection while receiving HAART. When secondary prophylaxis was discontinued, the median CD4 lymphocyte count in these patients remained low (99 cells/mm 3 ); 7 patients (27%) had a CD4 count!50 cells/mm 3, and only 6 patients (23%) had CD4 count 1100 cells/mm 3 for at least 6 months. There were 3 relapses of MAC infection among these 26 patients during a median of 35 months of follow-up (range, months), corresponding to a relapse rate of 11.5% (95% CI, 0% 24%) and an incidence of 4 relapses per 100 person-years. This relapse rate is lower than was observed in the pre-haart era among patients receiving secondary prophylaxis. Two of these patients received suboptimal anti-mac therapy, possibly explaining the persistence and slow growth of mycobacteria in bone, despite immune restoration (CD4 cell counts, 1100 cells/mm 3 ). The third relapse occurred in a severely immunodeficient patient who had stopped receiving antiretroviral treatment. Genotyping of the 2 strains suggested reinfection rather than relapse. Our results suggest that specific immune responses to MAC are rapidly restored after initiation of HAART, even in patients with severe immunodeficiency and only partial viral suppression. Hadad et al. [24] described a patient who had 1 blood culture that grew a single colony of MAC and who was treated with HAART alone. Symptoms resolved completely, and subsequent blood cultures were negative for MAC. Havlir et al. [25] measured immune responses to M. avium before and during HAART in HIV-infected patients with a history of disseminated MAC infection. Proliferative responses to M. avium were present in 47% of patients before the initiation of HAART, in 61% of patients 3 months after the initiation of HAART, and in 77% of patients 6 months after the initiation of HAART. According to the 2001 USPHS guidelines [23], patients are thought to be at low risk for relapse of MAC infection once they have completed at least 12 months of anti-mac treatment and have had a sustained increase (at least 6 months) in their CD4 cell counts (to 1100 cells/mm 3 ) while receiving HAART. Our results, and those of Shafran et al. [22], support these guidelines and suggest that maintenance treatment for disseminated MAC infection can be stopped for patients receiving HAART whose CD4 cell counts remain 1100 cells/mm 3 for 3 6 months. Primary MAC infection should be treated with a combination of 3 drugs that includes clarithromycin. Optimal adherence to such regimens is crucial, but the minimum duration of anti-mac therapy in patients treated with HAART is unclear. Relapse and reinfection can occur in patients whose CD4 cell counts decrease to!100 cells/mm 3 while they are receiving HAART. Such patients should be monitored closely, and blood cultures (on Loewenstein-Jensen medium) should be performed regularly. Such patients may also qualify for a resumption of secondary prophylaxis. Furthermore, clinically atypical relapses can occur despite immune reconstitution in patients who have received suboptimal anti-mac treatment. We conclude that it is feasible and desirable to discontinue secondary prophylaxis for some common opportunistic infections in patients who have a satisfactory virologic and immunologic response to HAART. Acknowledgments We thank Jérome Briquet, Sophia Girard, Mélina LeBarbier, Jennifer LeGrand, and Fanny Pellegrin, for their help. References 1. Palella F, Delaney K, Moorman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: Miller V, Staszewski S, Nisius G, et al. Risk of new AIDS diseases in people on triple therapy. 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