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ORIGINAL ARTICLE
Year : 2010  |  Volume : 56  |  Issue : 2  |  Page : 71-75

Liposomal amphotericin B (Fungisome TM ) for the treatment of cryptococcal meningitis in HIV/AIDS patients in India: A multicentric, randomized controlled trial


1 Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Mumbai-400 012, India
2 Department of Medicine, Seth G.S. Medical College and KEM, Hospital, Mumbai-400 012, India
3 Department of Medicine and Infectious Disease, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Medicine, Post Graduate Institute of Medical Sciences, Chandigarh, India
6 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, India

Date of Submission12-Aug-2009
Date of Decision16-Jan-2010
Date of Acceptance18-Feb-2010
Date of Web Publication8-Jul-2010

Correspondence Address:
M P Jadhav
Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Mumbai-400 012
India
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Source of Support: Department of Biotechnology, New Delhi, India for providing the funds to conduct the study, Conflict of Interest: None


DOI: 10.4103/0022-3859.65276

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 :: Abstract 

Background : There is need to investigate the use of liposomal amphotericin B in cryptococcal meningitis in India. Aims : To compare the efficacy, safety, duration of treatment and cost of two doses of liposomal amphotericin B (Amp B) (Fungisome TM ) in cryptococcal meningitis in HIV/AIDS patients. Settings and Design : Prospective, randomized, multicenter study in tertiary care hospitals across India. Materials and Methods : Adult patients with culture-proven cryptococcal meningitis with HIV/AIDS were randomized to receive either 1 (Group A) or 3 mg/kg/day of Fungisome (Group B). Clinical efficacy and tolerability, laboratory evaluations and mycological response were assessed daily, twice weekly and weekly respectively. The patients were assessed at four and eight-week follow-up. Statistics : We calculated average and standard deviation for the various parameters. Results : The time to show clinical response was 13.66 days (1 mg) and 9.55 days (3 mg). In Group B (n=6 complete response), 50% patients responded within one week by microbial conversion, 83% in two weeks and 100% in three weeks. Patients with 1 mg dose (n=4 complete response), none showed microbial conversion within one week, 75% responded in two weeks, whereas one patient took four weeks. The average duration of treatment was 36.5±14.4 and 26.5±5.89 (S.D.) days in 1 and 3 mg/kg/day respectively. Drug was tolerated with little renal, hepatic or hematological toxicity. The cost was found to be 3.81 lacs and 1.74 lacs with 3mg/kg/day and 1mg/kg/day respectively. Conclusion : Higher dose showed better efficacy and quicker microbial conversion of Cerebrospinal fluid (CSF) (cerebrospinal fluid) than 1 mg/kg/day. It shortened the duration of treatment in days by 27% while drug cost almost doubled (Clinical trial registration number: ISRTCN 52812742)


Keywords: Amphotericin B, cryptococcal meningitis, HIV/Acquired immune deficiency syndrome, liposomes


How to cite this article:
Jadhav M P, Bamba A, Shinde V M, Gogtay N, Kshirsagar N A, Bichile L S, Mathai D, Sharma A, Varma S, Digumarathi R. Liposomal amphotericin B (Fungisome TM ) for the treatment of cryptococcal meningitis in HIV/AIDS patients in India: A multicentric, randomized controlled trial. J Postgrad Med 2010;56:71-5

How to cite this URL:
Jadhav M P, Bamba A, Shinde V M, Gogtay N, Kshirsagar N A, Bichile L S, Mathai D, Sharma A, Varma S, Digumarathi R. Liposomal amphotericin B (Fungisome TM ) for the treatment of cryptococcal meningitis in HIV/AIDS patients in India: A multicentric, randomized controlled trial. J Postgrad Med [serial online] 2010 [cited 2016 Sep 30];56:71-5. Available from: http://www.jpgmonline.com/text.asp?2010/56/2/71/65276


Cryptococcal meningitis is the second most common cause of opportunistic fungal infection in patients with AIDS, and remains associated with significant morbidity and mortality. Up to 37% of patients with cryptococcal meningitis die during induction therapy and only 18-30% patients survive for longer than 12 months. [1],[2],[3] Amphotericin B deoxycholate is the current reference standard of care for the initial treatment of cryptococcus meningitis in patients with HIV infection. Treatment with amphotericin B monothrapy (0.4 mg/kg/day) given intravenously for six weeks, clears the fungus in over half the patients treated. But the standard treatment has disadvantages like dose-related nephrotoxicity. Initial treatment with triazole, fluconazole and itraconazole is probably less effective. [4],[5],[6]

Fungisome TM is a liposomal preparation of amphotericin B (1 mg/kg/day dose) that has been shown to be safe and effective in the treatment of systemic fungal infections. In a Phase II study, six out of seven patients with cryptococcal meningitis showed complete response with 1 mg/kg/day dose of Fungisome TM . [7] It was launched in 2003, in the Indian market for the treatment of systemic fungal infections and leishmaniasis. [7],[8],[9],[10],[11]

In an attempt to optimize the dose, efficacy and safety, shorten the duration of treatment, and to reduce the cost of therapy for cryptococcal meningitis in HIV/AIDS patients, we conducted this multicentric, open, randomized study comparing two treatment regimens viz. 3 mg/kg/day vs. 1 mg/kg/day of liposomal amphotericin B (Fungisome TM ).


 :: Materials and Methods Top


The trial was conducted (May 2006 to December 2007) at five different sites across the country, viz. Departments of Medicine and Infectious Disease, Christian Medical College, Vellore, Tamil Nadu. Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, Department of Medicine, Post Graduate Institute of Medical Sciences, Chandigarh, Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, and Department of Clinical Pharmacology, Seth G S Medical College and King Edward Memorial (KEM) Hospital Mumbai, India. Male and female HIV-positive patients of any age with suspected cryptococcal meningitis were screened. Patients with CSF positive for cryptococcus on smear were enrolled and continued in the study only if the CSF culture was positive. Female patients of childbearing potential were included in the study if they had a negative pregnancy test within 14 days. Subjects with pregnancy, evidence of liver disease, (SGOT (serum glutamic oxaloacetic transaminase) or SGPT (serum glutemic pyruvic transaminase) > 10 times the upper limit of normal or total bilirubin >5 times the upper normal level), known allergy to any product containing amphotericin B, patients with concomitant medical condition (other than HIV), whose participation in opinion of the investigator may create unacceptable additional risk, patients with life expectancy judged to be less than one week, and if previous inclusion in this trial were excluded from the study.

The study was approved by the local ethics committees of all the five centers, and also registered (ISRTCN 52812742) with a clinical trial registry. Written informed consent was obtained from each participant before enrollment into the study.

A computer-generated central randomization master plan with block size of 04 was generated. As per the randomization plan the study medication labels either 1 mg or 3 mg/kg/day were put in envelopes and sealed. Each envelope had a unique center and identification number. The whole randomization plan and the envelopes were prepared by a third-party non-biased person who was not part of the clinical trial. The patients who met the inclusion criteria, were assigned patient ID number and randomized as per randomization plan by opening the sealed envelope to receive 1 mg/kg/day or 3 mg/kg/day of liposomal amphotericin B Fungisome TM . The minimum duration of treatment was three weeks and the maximum duration could exceed 12 weeks followed by eight-week post-treatment follow-up . Daily administration of study drug continued till patient successfully completed therapy, depending on response (both mycological and clinical) and stopped one week after obtaining two consecutive negative cultures in successive weeks. Follow-up treatment was provided with fluconazole 400 mg daily for four weeks followed by 200 mg daily for the subsequent four weeks.

The safety and efficacy of Fungisome TM (liposomal amphotericin B) were determined both clinically and mycologically. Signs and symptoms (fever, vomiting, blurred vision, headache, diplopia, confusion, neck stiffness, ocular pain etc.) indicating complete, partial or no response were documented each day by the attending physician during therapy. Complete response was defined when two consecutive CSF fungal cultures done at seven days' interval were negative and there was no recurrence of infection for more than eight weeks after stopping treatment. Partial response was defined as partial resolution of disease symptoms and signs or recurrence of disease observed within eight weeks of stopping treatment. No response was defined as no response to drug therapy within two weeks of starting treatment.

Culture results before treatment (baseline) were compared with all subsequent (every week) culture results and response rated according to following definitions. Eradication: previously positive culture, negative for cryptococcus neoformans for two consecutive weeks. Persistent: cultures either remained positive throughout therapy or became positive after earlier being negative despite therapy.

Safety was assessed from adverse events (AEs), vital signs and by clinically significant changes in laboratory evaluations (including hematological and biochemistry). The hematological (hemoglobin, hematocrit, platelets, red blood cells, white blood cells, neutrophills, eosinophills, monocytes, etc) and biochemical (sodium, potassium, serum glutamic oxaloacetic transaminase, serum glutemic pyruvic transaminase, alkaline phosphate, blood urea nitrogen, serum creatinine, total bilirubin etc.) parameters were monitored twice weekly by comparison of baseline laboratory values with those obtained during and after the study. Serious AEs, if any, were documented in source note, informed to the ethics committee and to the sponsor as per the standard reporting protocol. The AEs were graded as per the WHO scale for severity i.e. mild, moderate and severe.

The study drug before administration (stored at 2-8°C) was sonicated using a bath sonicator with thermostat, at ambient temperature (Enertech Electronics Pvt. Ltd. New Delhi) for 45 min in order to convert multilamelar vesicles (MLV) into unilamelar vesicles (ULV). The sonicated drug as per manufacturer's instructions was used within 24 h after sonication. The drug was diluted in 50 ml normal saline before intravenous administration. On Day 1 of the therapy a test dose of 1 ml was infused over 5 min. If no AE viz. anaphylaxis, fall in blood pressure, increase in heart rate, bronchospasm, hypersensitivity etc. occurred, the remaining dose was administered 30 min later over 2 h on Day 1 and over 1 h from Day 2 onwards.

The study was designed to show the superiority of Fungisome TM 3 g/kg/day in shortening the clinical and microbiological response time when compared to Fungisome TM 1 mg/kg/day. The primary endpoint for the study was the duration of treatment, total dose and response time for resolution of signs and symptoms of fungal infection and microbiological conversion with Fungisome TM 3 mg/kg/day versus Fungisome TM 1 mg/kg/day. The proportion of patients for clinical and microbiological response time at Day 7 (± SD 3 days) for Fungisome TM 1 mg/kg/day was expected to be 40% as compared to 80% expected for 3 mg/kg/day. To detect the difference of 40% with an alpha of 0.05 (two-sided) 29 patients per treatment group were needed in the protocol set to conclude superiority with power of 90%. With an expected rate of 20% dropout, it was planned to randomize 64 patients receiving eight doses or more who meet eligibility criteria.

The total cost of Fungisome TM was calculated for each patient on the basis of the total Fungisome TM dose administered and number of days of treatment. Depending on the total dose for each day, vials of 50, 25 or 10 mg of Fungisome TM were used. The non-drug cost was also calculated for concomitant medication, consumables, laboratory investigation charges, hospital costs (including procedures diagnostic/therapeutic, ward stay, medical intensive care/ ICU stay) and event cost (treatment of failure, relapse/recurrence/ premature termination due to adverse drug reaction (ADR).

While calculating the results for clinical, mycological response, duration of treatment, drug and non-drug cost, all assessable patients were considered. For calculating ADR all randomized patients were included.


 :: Results Top


During the study period, 32 patients were screened. Twenty-eight patients were enrolled in the study, of whom four were screen failure, three of whom refused consent and one did not meet the inclusion criteria due to hyperbilirubinemia. Of the 28 (randomized) patients, two patients were not culture-positive for cryptococcus meningitis. They were randomized on the basis of direct microscopy (India ink preparation), but since cultures were negative they were removed from the study. On ethical grounds as per protocol these patients were given treatment for three weeks till they showed clinical improvement.

Patient characteristics are summarized in [Table 1]. Out of 26 confirmed eligible, randomized patients, 11 received 1 mg/kg/day dose and 15 received 3 mg/kg dose of Fungisome TM .

Of the 11 patients randomized to 1 mg/kg/day treatment, six patients were assessable (those who have received minimum eight doses of drug), four patients showed complete response both clinically and mycologically and completed eight-week follow-up. The average time required for complete resolution of reversible signs and symptoms was 13.6 (±9.6 S.D.) days. Complete mycological response in this 1 mg/kg/day cohort were 0 of 11 patients at Day 7, three of 11 patients at Days 15 and 21, and four of 11 patients at Day 28 [Figure 1].

Two (33%) out of six patients showed partial response. These two patients did not show microbial conversions, took 6.5 days for the resolution of signs and symptoms, completed four-week follow-up but did not turn up for eight weeks' follow-up. Mean duration of treatment with 1 mg/kg/day dose was 36.5 (±14.4 S.D.) days. The average cost (drug) for the treatment with complete and partial response was estimated to be 1.65 lacs and 1.74 lacs millions per patient, respectively. The non-drug cost for all assessable patients was calculated to be Rs.28,000 per patient.

Of the 11 patients randomized to the 1 mg/kg/day arm, five were not assessable (did not receive eight doses of drug). Three patients died due to cardio-respiratory failure, two on Day 1 and on Day 8 of treatment and two succumbed to death due to raised intracranial pressure on the fifth day. As per the WHO causality analysis these serious adverse events (SAE) were unlikely due to drug. SAE were reported to the local ethics committee and sponsor as per standard protocol.

Eleven of the 15 patients randomized to 3 mg/kg/day dose, were assessable. Six (54%) of them showed complete, three (27%) partial response, and two (18%) did not respond to the treatment. The average time (days) required for complete resolution of reversible signs and symptoms was 9.5±5.9 days. Six of 15 had a complete response, three of 15 at Day 7, four of 15 at Day 14, and six of 15 at Day 21. In three patients who showed partial response, average time to resolution of signs and symptoms was five days, however, none of them showed any improvement in microbial conversion and they did not turn up for the eight-week follow-up visit. Two patients did not respond to the treatment.

Mean duration of treatment in the 3 mg/kg/day dose arm was 26.5±5.8 days. The average cost (drug) for the treatment with complete and partial response was estimated to be Rs.3.12 lacs and 3.81 lacs per patient, respectively. The non-drug cost for all was calculated to be Rs. 22,000 per patient.

Four of the 15 randomized to the 3 mg/kg/day arm were non-assessable. Two died due to raised intracranial pressure on Days 4 and 8 of the treatment, respectively. SAE were reported to the local ethics committee and sponsor as per standard protocol. Two withdrew consent on Days 3 and 5 and left the treatment in-between.

The AEs and the SAE in both the treatment groups were comparable indicating that the higher dose of the drug was well tolerated and did not cause any dose-dependent side-effects. The hematological parameters, renal, liver function tests were found to be within the normal range compared to baseline values in both the treatment arms. Two patients showed (one on 1 mg/kg and the other on 3 mg/kg dose) hypokalemia, which was corrected with potassium supplements. One female patient (Group A, 1 mg/kg/day) showed raised creatinine (raised by 1 mg/dl from the baseline), which normalized after reduction of the dose to half in subsequent assessment. The severity of AEs was mild overall, except two patients in the 1 mg/kg/dose showed moderate chills and rigors after drug infusion, which was corrected by giving premedication in the subsequent infusions. In the 3 mg/kg/dose one patient experienced moderate fever and two experienced vomiting. During causality analysis these were confirmed to be infusion-related AEs.


 :: Discussion Top


The objectives of treatment of AIDS-associated cryptococcal meningitis are to improve quality of life and suppress relapse after initial treatment. The treatment of cryptococcal meningitis has been investigated extensively. Although several large multicentric studies to determine the optimum drug regimen have been conducted, the most efficacious regimen has not yet been determined. [4],[12] Treatment with amphotericin B monotherapy (0.4 mg/kg/day) given intravenously for six weeks clears the fungus in over half the patients treated. [13] Combining conventional amphotericin B (0.5-1 mg/kg/day) and oral fluconazole (150 mg /day) for two weeks as induction therapy followed by oral fluconazole (400 mg/day) for 10 weeks is considered standard treatment regimen for cryptococcal meningitis. This dual therapy has shown sustained clearance of cryptococci from the CSF (60%), compared to amphotericin B alone (51%). Addition of fluconazole causes side-effects like diarrhea, hepatitis and bone marrow suppression, usually in the first two weeks in a third of patients. [14] Lipid-associated formulations have been studied for the treatment of cryptococal meningitis. Successful treatment outcomes have been reported in patients with cryptocococcal meningitis. [15],[16],[17],[18] The safety and efficacy of Fungisome TM has also been studied in patients suffering from various systemic fungal infections through Phase I to Phase IV studies. [19]

In the present study, in comparison to 1 mg/kg/day, 3 mg/kg dose resulted in quicker resolution of reversible signs and symptoms, and faster mycological response. However, the overall complete response at eight weeks was not different between 1 and 3 mg/kg/day dose. The overall cost of drug and non-drug treatment was nearly double with 3 mg/kg/day dose. Leenders et al., [15] compared conventional amphotericin B (0.7 mg/kg/day) with Ambisome (4 mg/kg/day) and observed CSF conversion on Days 7, 14 and 21 to be 40, 66 and 73% with Ambisome 4 mg/kg/day dose respectively compared to 8, 11 and 37% after plain amphotericin B. In comparison, CSF conversion rate with Fungisome TM was 0, 50, and 66% with 1 mg/kg/day and 27, 45, 54% with 3 mg/kg/day at Week 1, 2 and 3 respectively. Success rate at 10 weeks with Ambisome was 37% with 3 mg/kg/day dose and 49% with 6 mg/kg/day dose in comparison to complete response at eight weeks of 66% and 54% with 1 and 3 mg/kg/day of Fungisome TM . The cost of a 50 mg vial of Ambisome in the Indian market is $255 compared to Fungisome TM which is $120. The complete response at eight weeks with Fungisome TM 1 mg/kg/day was 66% and cost (drug and nondrug) $0.16 and 0.028 millions in comparison to 37% with Ambisome 3 mg/kg/day dose ($0.87 million). [7] The complete response at eight weeks with Fungisome TM 3 mg/kg/day was 54% ($0.31 millions). This difference in cost is without any difference in efficacy. The 3 mg/kg/day dose of Fungisome TM has the advantage of early onset of effect.

Though this study was a good attempt to generate the clinical data for the treatment of cryptococcal meningitis in HIV/AIDS patients, we could not find a significant superiority with the higher dosage and the cost was a major rate-limiting factor. Thus, it was felt that the advantage of quicker response with 3 mg/kg dose was offset by substantially high cost. Cost constraints made us terminate this study at the interim analysis. During the conduct of the study, we observed some of the rate-limiting factors: inability to reach the planned sample size which was very crucial, cost of the formulation was very high (but much less compared to the other available international brands), the sample size was small. We also faced problems in getting confirmed cases of cryptoccal meningitis at some of our centers. We were not able to do the species sub-typing during the study.

The present study findings suggest that 1 mg/kg/day dose is optimum to be given to such patients with cryptococcal meningitis. However, a study comparing 1 mg/kg/day alone with 3 mg/kg/day for first week followed by 1mg/kg/day dose subsequently, would be worthwhile to optimize the treatment with lowest possible cost.


 :: Acknowledgments Top


Department of Biotechnology, New Delhi, India for providing the funds to conduct the study.

 
 :: References Top

1.Dismukes WE. Cryptococcal meningitis in patients with AIDS. J Infect Dis 1988;157:624-8.  Back to cited text no. 1  [PUBMED]    
2.Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989;321:794-9.  Back to cited text no. 2  [PUBMED]    
3.Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with acquired immunodeficiency syndrome: Diagnostic features and outcome of treatment. Ann Intern Med 1986;104:234-40.  Back to cited text no. 3  [PUBMED]    
4.Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, et al. Comparison of Amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992;326:83-90.  Back to cited text no. 4  [PUBMED]    
5.Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. Ann Intern Med 1990;113:183-7.  Back to cited text no. 5  [PUBMED]    
6.Gans DJ, Portegies P, Tiessens G, Eeftinck Schattenkerk JK, van Boxtel CJ, van Ketel RJ, et al. Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 1992;6:185-90.   Back to cited text no. 6      
7.Kshirsagar NA, Panday SK, Kirodian BG, Sanath S. Liposomal drug delivery system from laboratory to clinic. J Postgrad Med 2005;51:S5-16.  Back to cited text no. 7      
8.Gokhale PC, Kotwani RN, Dange SY, Kshirsagar NA, Panday SK. Preclinical and pharmaceutical testing of liposomal amphotericin B. Indian J Med Res Br 1993;98:75-80.  Back to cited text no. 8      
9.Gokhale PC, Kshirsagar NA Panday SK. Development and therapeutic of liposomal amphotericin B. Curr Sci 1993;65:448-54.  Back to cited text no. 9      
10.Gokhale PC, Barapatre RJ, Advani SH, Kshirsagar NA Panday SK. Pharmacokinetics and tolerance of amphotericin B in patients. J Antimicrob Chemother 1993;32:133-9.  Back to cited text no. 10      
11.Kshirsagar NA, Kirodian BG. Liposomal drug delivery system form laboratory to patients: Our experience. Proc Indian Natl Sci Acad 2002;68:333-48.  Back to cited text no. 11      
12.Galgiani JN. Fluconaozle a new antifungal agent. Ann Intern Med 1990;113:177-9.  Back to cited text no. 12  [PUBMED]    
13.Subramanian S, Mathai D. Clinical manifestation and management of cryptococcal infections. J Postgrad Med 2005; 51: S21-6.  Back to cited text no. 13      
14.Drutz DJ, Spikard A, Rogers DE, Koeing MG. Treatment of disseminated mycotic infection: A new approach to amphotericin B therapy. Am J Med 1968;45:405-18.  Back to cited text no. 14      
15.Leenders AC, Reiss P, Portegies P, Clezy K, HopWim CJ, Hoy J, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997;11:1463-71.  Back to cited text no. 15      
16.Kotwani RN, Gokhale PC, Bodhe PV, Kirodian BG, Kshirsagar NA. Safety and efficacy of liposomal amphotericin B in patients with cryptococcal meningitis. J Assoc Physics India 2001;49:1086-90.  Back to cited text no. 16      
17.Esposito V, Viglietti R, Gargiulo M, Parrella R, Onofrio M, Sangiovanni V, et al. Successful treatment of cryptococcal meningitis with a combination of liposomal amphotericin B, flucytosine and posaconazole: two case reports. In Vivo 2009;23:465-8.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
18.Sloan D, Dlamini S, Paul N, Dedicoat M. Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. Cochrane Database Syst Rev 2008;8:CD005647.  Back to cited text no. 18      
19.Bodhe PV, Kotwani RN, Kirodian BG, Kshirsagar NA, Pandya SK. Open lable, randomized, comparative phase III safety and efficacy study with conventional amphotericin B and liposomal amphotericin B in patients with systemic fungal infections. J Assoc Physics India 2002;50:662-70.  Back to cited text no. 19      


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]

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