Original Article
The Efficacy of Inosine Pranobex in Preventing the Acquired Immunodeficiency Syndrome in Patients with Human Immunodeficiency Virus Infection
N Engl J Med 1990; 322:1757-1763June 21, 1990
- Abstract
- Abstract
We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of inosine pranobex (isoprinosine) in the treatment of patients with human immunodeficiency virus (HIV) infection but without manifest acquired immunodeficiency syndrome (AIDS). A total of 866 patients were enrolled in 21 centers in Denmark and Sweden. The patients were stratified in three groups according to their CD4+ cell count and randomly assigned to receive either inosine pranobex (1 g three times a day) (n = 429) or matching placebo (n = 437) for 24 weeks.
Of the 831 patients who could be evaluated, AIDS developed in 17 in the placebo group as compared with 2 in the inosine pranobex group (P<0.001; odds ratio, 8.6 [95 percent confidence limits, 2.2 and 52.6]). There were no significant differences between the groups with respect to changes in CD4+ cell count or the development of other HIV-related conditions, with the exception of thrush, which developed in fewer patients in the inosine pranobex group (P = 0.05). No serious side effects were observed.
We conclude that treatment with inosine pranobex delays progression to AIDS in patients with HIV infection. The duration of this beneficial effect, the optimal dose, and the mode of action of inosine pranobex remain to be clarified. (N Engl J Med 1990; 322:1757–63.)
Media in This Article
Figure 1
Cumulative Rates of Progression to AIDS during Double-Blind Treatment.Table 1
Base-Line Comparability of the Treatment Groups.Article Activity
- Article
THE acquired immunodeficiency syndrome (AIDS) is characterized by severe opportunistic infections, certain types of cancers, and degeneration of the central nervous system. The causative agent of the underlying immunodeficiency is a human retrovirus designated the human immunodeficiency virus (HIV).1 , 2 It is estimated that more than 5 million people worldwide are infected with HIV.3 Since AIDS may ultimately develop in the great majority of these infected people, effective therapeutic regimens are needed urgently. Treatment may include drugs with antiviral activity, drugs with properties that enhance immune function, and drugs that prevent the development of serious complications.
Inosine pranobex (isoprinosine), the para-acetamidobenzoic acid salt of N,N-dimethylamino-2-propanol:inosine in a 3-to–l molar ratio, has been shown to enhance the function of various cells of the immune system in numerous studies in vitro and in vivo.4 5 6 The effect may be due to improved production of interleukin-1, interleukin-2, or both.7 8 9 In patients with the AIDS-related complex and in immunocompromised men with persistent generalized lymphadenopathy, inosine pranobex has been reported to enhance the proliferative responses of T cells10 , 11 and the activity of natural killer cells.12 , 13 One study has suggested a possible clinical effect of treatment with the drug in patients with HIV infection.12
On the basis of these investigations and the absence of serious side effects attributed to inosine pranobex, we decided to conduct a trial to assess the clinical efficacy of the drug in the treatment of patients with HIV infection. This report presents the results of a 24-week randomized, double-blind, placebo-controlled study in patients with HIV infection in whom manifest AIDS had not developed.
Methods
Patients
Patients from 18 to 75 years of age, attending 21 medical centers in Denmark and Sweden, who were seropositive for HIV antibody on both enzyme immunoassay and immunoblot assay and who gave informed consent were eligible for entry into the study. The exclusion criteria included the following: systemic treatment with glucocorticoids, cytotoxic agents, or antiviral drugs within the month before study entry; the presence of any kind of acute infection, malignant disease, severe chronic or terminal disease, or AIDS according to the 1985 definition of the Centers for Disease Control (CDC)14; a history of gout or uric acid urolithiasis; current gastric ulcer; pregnancy or nursing; and serum uric acid levels above the normal limit and creatinine levels more than 1.5 times the normal limit.
Study Design
The study was designed as a randomized, double-blind, placebo-controlled trial. Patients were stratified into three subgroups according to their CD4+ cell count (<200×l06, 200 to 500×106, or >500×106 per liter). Within each subgroup the patients were randomly assigned to receive either inosine pranobex (1 g; Imunovir, Leo Pharmaceutical Products, Ballerup, Denmark) or placebo three times daily for 24 weeks. Randomization was performed according to a computer-generated table of random numbers. Each participating center received the trial medication in blocks of 10, each block containing 5 inosine pranobex treatments and 5 placebo. Patients were included in the study in the numerical order established by the code numbers on the labels. Inosine pranobex has a distinctive bitter taste. In order to improve blinding, a small amount of quinine hydrochloride (2.4 mg) was added to each placebo tablet. The placebo tablets were thus indistinguishable in appearance from the inosine pranobex tablets and similar in taste and smell. The study medication was withdrawn if serious side effects or medical deterioration that the physician considered harmful to the patient's well-being developed. Patients given systemic treatment with glucocorticoids, cytotoxic agents, or antiviral drugs for more than 14 days were withdrawn from the study. Patients who failed to attend two or more follow-up visits were considered to have defaulted and were withdrawn from the study. All patients withdrawn from the study were followed for the development of serious HIV-related complications.
Clinical evaluation, including a medical history and a physical examination, was performed at entry and after 2, 8, 16, and 24 weeks. General well-being was measured by the patients with use of a visual-analogue scale, with no reference to previous recordings. Laboratory determinations, including the hemoglobin level; leukocyte, differential, and platelet counts; total serum bilirubin level; aspartate aminotransferase concentration; and alkaline phosphatase, creatinine, and uric acid levels were performed at entry and after 2, 8, 16, and 24 weeks. T-cell counts were performed at entry and after 8 and 24 weeks. On withdrawal, patients were evaluated as after 24 weeks.
Compliance was assessed by analyzing urine samples (collected consecutively from a subgroup of patients after 16 and 24 weeks) for para-acetamidobenzoic acid, a metabolite of inosine pranobex.15 Tablet counts were not performed.
A steering committee consisting of eight representatives from the participating centers and one from the manufacturer of the drug monitored the progress of the study. Only blinded data on side effects and reasons for withdrawal from the trial medication were available to the committee's members. The occurrence of side effects was monitored by a safety-monitoring committee consisting of one independent senior scientist who did not otherwise take part in the study. This scientist had access to the study code but never used it.
The study was approved by the respective ethics committees and health authorities and was conducted according to the principles of the Helsinki Declaration.
Response Criteria
The primary response criterion as stated in the protocol was an improvement or a deterioration in the patient's clinical condition, as measured according to a modified Walter Reed Staging Classification.16 It differed from the original classification in not including skin anergy. Deterioration was defined as movement to a higher stage in the modified Walter Reed classification, the development of specified signs and symptoms, or both. Improvement was defined as movement to a lower stage in the modified classification, the disappearance of specified signs and symptoms, or both.
In September 1988, at the end of the study but before the code was broken or any analysis of the data had begun, the steering committee decided that disease progression should be evaluated according to a purely clinical staging system in addition to the modified Walter Reed classification. This decision was taken in the light of the following observations. First, the CDC classification system for HIV infection had been introduced and widely adopted,17 and in 1987 the criteria used to define AIDS had been revised.18 Second, the suitability of the graduated system of the modified Walter Reed classification had been questioned, in view of the finding that persistent generalized lymphadenopathy does not by itself signify a more severe stage of HIV infection.19 , 20 In our revised system of classification, patients were categorized as follows: stage 1 — CDC Group II or Group III (either no symptoms or persistent generalized lymphadenopathy); stage 2 — CDC Group IV without AIDS-defining conditions (symptoms but not AIDS); stage 3 —AIDS (according to the 1987 CDC definition). Classification was hierarchical, in that patients classified in a particular group were not reclassified if the clinical findings resolved.
Information about adverse effects was elicited by asking the patients general and nonleading questions.
All patients in whom AIDS developed and all whose classification was doubtful were reevaluated independently by an end-point—assessment committee consisting of two physicians representing the participating centers. This evaluation was completed before the code was broken and before data analysis had begun.
Calculation of Sample Size
A calculated sample size of 870 patients was based on the following assumptions: that the rate of Type I errors would be 0.05, and the rate of Type II errors 0.20; that the clinical condition of at least 10 percent of the patients in the placebo group would progress, according to the modified Walter Reed classification; and that the sample size should allow us to detect a difference of 5 percent between the progression rates in the inosine pranobex and placebo groups.
Statistical Analysis
Most data were analyzed with use of SAS version 5. We compared the two treatment groups at base line using Student's t-test, the chi-square test, or Fisher's exact test.21 Progression from stage to stage was analyzed with Fisher's exact test.
Changes in the CD4+ cell count, CD8+ cell count, the ratio of CD4+ to CD8+ cells, body weight, general well-being (as measured on the visual-analogue scale), and laboratory indexes were analyzed with Student's t-test. Progression to AIDS and the occurrence of thrush, hairy leukoplakia, and herpes zoster were analyzed with techniques of survival analysis (Kaplan–Meier estimates and the log-rank test22) with the use of SAS LIFETEST. Exact 95 percent confidence limits of the true odds ratios of the frequencies of progression to AIDS in the placebo and inosine pranobex groups were estimated with use of Batista and Pike's algorithm.23
We corrected for the influence of possible prognostic factors with a logistic regression analysis using SAS CATMOD. The regression analysis included the following base-line variables: treatment group; CD4+ cell count; weight loss; and the presence of at least one of the following symptoms: hairy leukoplakia, candida infection, or diarrhea, or the presence of at least two constitutional symptoms. All P values were two-sided. All analyses were performed before the code was broken.
Results
A total of 866 patients from 18 to 75 years of age (mean, 35) entered the study between November 1986 and February 1988. Four hundred sixty-one patients (53.2 percent) were enrolled in Denmark, and 405 (46.8 percent) in Sweden. There were 808 men (93.3 percent) and 58 women (6.7 percent). Seven hundred seventeen patients (82.8 percent) were homosexual or bisexual men, 80 (9.2 percent) were intravenous drug abusers, and 9 (1.0 percent) had hemophilia. The remaining 60 were heterosexual and had no identifiable risk factors for HIV infection. The patients in the study made up about one fourth of the total number of patients (approximately 3400) in Denmark and Sweden known to be seropositive for HIV at the time. Four hundred twenty-nine patients (49.5 percent) were assigned to receive inosine pranobex, and 437 (50.5 percent) were assigned to placebo. The patients in the two groups were comparable in terms of sex, risk behavior, age, body weight, medical history within three months of study entry, clinical staging, general well-being according to the visual-analogue scale, substrata according to CD4+ cell count, and mean number of CD4+ and CD8+ lymphocytes at base line (Table 1Table 1
Base-Line Comparability of the Treatment Groups.). Nonsignificant differences included a lower CD4+ cell count and a higher frequency of thrush, hairy leukoplakia, diarrhea, and unexplained weight loss in the placebo group.Thirty-three patients (17 in the inosine pranobex group and 16 in the placebo group) were not part of our analysis of efficacy. Reasons for exclusion were AIDS at base line (according to the 1985 definition) in 2 patients (1 in each group); lack of positive enzyme-linked immunosorbent assay and Western blot assay results at randomization in 5 patients (3 in the inosine pranobex group and 2 in the placebo group); inadequate compliance between base line and week 2 in 5 patients (2 inosine pranobex and 3 placebo); and nonattendance at the visit during week 2 in 21 patients (11 inosine pranobex and 10 placebo). The remaining 833 patients, 412 in the inosine pranobex group and 421 in the placebo group, made up the "efficacy population."
A total of 129 subjects were withdrawn from the study for the reasons stated in Table 2Table 2
Withdrawals from the Study.*. However, follow-up data with respect to progression to AIDS were available for 127 of them. Only two patients, both assigned to receive inosine pranobex, who moved to other countries were completely lost to follow-up.The proportion of patients whose condition progressed according to the modified Walter Reed classification was 25 percent in the inosine pranobex group and 26 percent in the placebo group (data not shown). Serious clinical events, namely, opportunistic infections (modified Walter Reed stage 5) or Kaposi's sarcoma, developed in 13 patients (3.1 percent) in the placebo group and in 1 patient (0.2 percent) in the inosine pranobex group (P = 0.002; odds ratio, 13.1 [95 percent confidence limits, 2.1 and 275.1]).
The proportions of patients whose condition progressed according to the current CDC criteria are shown in Table 3Table 3
Disease Progression According to CDC Group at Base Line.. AIDS developed in 17 patients (4.0 percent) in the placebo group as compared with 2 (0.5 percent) in the inosine pranobex group (P<0.001; odds ratio, 8.6 [95 percent confidence limits, 1.9 and 54.5]). There was no significant difference between groups in the number of patients whose condition progressed from CDC Group II or III to CDC Group IV (without AIDS) or in the number who acquired any of the diseases that define Group IV (but that are not considered indicative of AIDS), with the exception of thrush, which developed in 11.2 percent of those in the inosine pranobex group and in 15.6 percent of those in the placebo group (P = 0.05). Progression to AIDS was always more marked in the placebo group, irrespective of the CD4+ cell count at entry into the study (Table 4Table 4
Disease Progression According to Base-Line CD4+ Cell Count.).The temporal relation between study entry and progression to AIDS is shown in Figure 1Figure 1
Cumulative Rates of Progression to AIDS during Double-Blind Treatment.. Progression occurred evenly throughout the study period.The base-line characteristics and AIDS-defining diseases of the patients whose condition progressed to AIDS are shown in Table 5Table 5
AIDS-Defining Conditions and Base-Line Characteristics of Patients Whose Condition Progressed to AIDS.. Pneumocystis carinii pneumonia was the most common disease defining AIDS, accounting for more than 50 percent of all cases. In none of the patients who were withdrawn for reasons other than the development of AIDS did AIDS develop within 24 weeks after entry.The information the study provided on the number of patients in whom AIDS developed during double-blind treatment was confirmed by cross-checking with national AIDS registers in Denmark and Sweden.
The logistic regression analysis showed that progression to AIDS was significantly associated with treatment group (P = 0.001; odds ratio, 7.11) and a lower CD4+ cell count at base line (P = 0.01), but not with weight loss or the presence of hairy leukoplakia, candida infection, diarrhea, or constitutional symptoms at base line.
The CD4+ cell count decreased significantly during the study period. In the inosine pranobex group it dropped from 597 to 561×106 per liter (P = 0.02), and in the placebo group from 562 to 528×106 per liter (P = 0.01). There was no difference between the groups. There was also a decrease in the ratio of CD4+ to CD8+ cells. Similar changes were seen in both the placebo and the inosine pranobex groups. There were no significant differences between the groups with respect to changes in CD8+ cell count, body weight, general well-being as measured on the visual-analogue scale, or routine laboratory indexes. Serum uric acid levels had increased in the inosine pranobex group after two weeks (mean [±SD], 0.33±0.07 vs. 0.42±0.10 mmol per liter; P<0.001) and remained elevated throughout the study, although no further increase was observed. None of the patients given inosine pranobex had any clinical signs attributable to an elevated serum uric acid level.
Adverse events were recorded with equal frequency in both groups (Table 6Table 6
Adverse Effects Recorded during Treatment.). No serious adverse events were recorded. Trial medication was withdrawn in 19 patients in the inosine pranobex group and in 8 in the placebo group because of possible side effects (P = 0.03).None of the patients received zidovudine or primary prophylaxis against P. carinii pneumonia.
Urinalyses for para-acetamidobenzoic acid were performed in 73 patients. Para-acetamidobenzoic acid was detectable in 32 of the 35 samples (91.4 percent) from patients in the inosine pranobex group. No information was available on the interval between the ingestion of the tablet and the collection of the urine sample in the three patients in whom para-acetamidobenzoic acid was not detected. Para-acetamidobenzoic acid was present in 1 of the 38 patients taking placebo who were tested, but the amount (16 μg per milliliter) was just above the detectable limit. This amount compared with a median concentration of 686 μg per milliliter (range, 99 to 3685) in the samples from the 32 patients in the inosine pranobex group in whom the metabolite was detected.
Discussion
In this double-blind, placebo-controlled trial, the proportion of HIV-positive patients in whom AIDS developed during the 24-week study period was significantly lower in the inosine pranobex group than in the placebo group. The study population was stratified in three subgroups according to base-line CD4+ cell count. The beneficial effect of treatment with inosine pranobex was noted in all three subgroups, irrespective of the CD4+ cell count at base line. This indicates that the drug may also affect clinical progression in patients with impaired immune function, as indicated by a reduced CD4+ cell count.
Although our findings suggest that the reduction in the progression to AIDS was caused by treatment with inosine pranobex, other explanations, such as base-line imbalance between the two groups, must be considered. Although the two groups were generally well matched, there were minor, nonsignificant pretreatment differences between them that may have influenced the subsequent risk of disease progression. These included a lower CD4+ cell count and a higher frequency of some clinical variables (thrush, hairy leukoplakia, diarrhea, and unexplained weight loss) in the placebo group. However, in a logistic regression analysis correcting for the influence of these possible prognostic factors, the beneficial effect of treatment with inosine pranobex was still significant. It is therefore reasonable to conclude that the results of the study were not caused by clinical or immunologic differences between the groups before treatment. The progression rate in the placebo group (3.1 percent per six months, according to the 1985 CDC definition) is comparable to rates observed in other cohorts, in which the patients had been infected with HIV for some years.24 25 26 In three of four patients in the subgroup with CD4+ cell counts above 500×106 per liter at entry, the first AIDS-defining disease was Kaposi's sarcoma, which may occur in patients with normal CD4+ cell counts.27 The distribution of AIDS cases according to initial AIDS-defining diseases corresponds closely to that observed among the first 231 Danish patients with AIDS (Pedersen C, et al.: unpublished data). The study also included a large number of patients and had a high rate of compliance and a low rate of withdrawal, all factors that strengthen the validity of the data. When planning the study, we decided to measure serum uric acid levels. This decision may in theory have influenced the blinding of the investigators, but we were not aware that it did. That it did not is supported by the finding of similar rates of withdrawal in the two groups and the fact that the effect of inosine pranobex was noted on well-defined end points. Unblinding of the patients was unlikely; they were not informed about their test results, and the placebo tablets were matched for taste as well as appearance.
The study was not intended to determine the mode of action of inosine pranobex. However, the results obtained indicate that the drug does not increase the number of CD4+ cells in patients infected with HIV. This finding does not rule out the possibility that inosine pranobex may act by enhancing the function of the remaining T cells or the activity of natural killer cells, as has been proposed by others.4 5 6 7 8 9 10 11 12 13 Previous studies indicate that inosine pranobex possesses minimal or even no antiviral activity against HIV.28 , 29
P. carinii pneumonia was the most common AIDS-defining disease in our group of patients and had the greatest influence on the observed difference in progression to AIDS between the inosine pranobex and placebo groups. The possibility that the drug exerts an antimicrobial effect against P. carinii cannot be excluded, but the issue has to our knowledge never been investigated. Infection with HIV is lifelong. Eliminating the virus from infected patients seems a remote possibility with the existing forms of therapy. However, therapy to reduce the frequency of serious complications will be beneficial to patients. Such treatment, preferably by the oral route, must have minimal toxicity, since it may be needed for many years. In the present study, 24 weeks of treatment with inosine pranobex had negligible toxic effects. Previous experience confirms that the drug can be administered for several years without marked adverse effects.30 Inosine pranobex may be well suited for the treatment of patients infected with HIV. However, although we found that it produced a substantial clinical benefit, there was no apparent restoration of immune function, as assessed by CD4+ cell count, suggesting that therapy with inosine pranobex and an antiviral drug may be more effective than treatment with either alone. Several antiviral drugs have been or are being evaluated in patients with different stages of HIV infection,31 32 33 34 but controlled trials to evaluate the efficacy of antiviral agents in preventing clinical progression are rare. Zidovudine,34 an inhibitor of viral reverse transcriptase, has been approved for the treatment of patients with AIDS and AIDS-related complex.
In conclusion, our study suggests that treatment with inosine pranobex can delay progression to AIDS. The duration of this beneficial effect, the optimal dose, and the mode of action remain to be clarified. Further studies are justified to determine the possible effect of inosine pranobex against P. carinii and other microorganisms and to compare the benefit of inosine pranobex treatment with other treatments that might delay the progression of disease in patients with HIV infection.35
Note added in proof: Since the submission of this article a subgroup of investigators has evaluated the effect of isoprinosine on levels of HIV antigen during the trial.36 Base-line and follow-up serum samples from 397 patients (199 in the inosine pranobex group and 198 in the placebo group) were examined. There were no significant changes in antigen levels.
*The members of the study group are listed in the Appendix.
Source Information
From the Department of Infectious Diseases, Hvidovre Hospital, Copenhagen (C.P., J.O.N.), the Department of Dermatovenereology, Södersjukhuset, Stockholm (E.S., A.K.), the Department of Dermatovenereology, Bispebjerg Hospital, Copenhagen (C.S.P.), the Department of Infectious Diseases, Östra Hospital, Göteborg, Sweden (G.N.), the Department of Infectious Diseases, Rigshospitalet, Copenhagen (J.G., K.C.C.), the Department of Dermatovenereology, Sahlgrenske Hospital, Göteborg, Sweden (C.H.), the Department of Infectious Diseases, Roslagstulls Hospital, Stockholm (P.O.P.), and Leo Pharmaceutical Products, Ballerup, Denmark (H.J.J.). Address reprint requests to Dr. Pedersen at the Department of Infectious Diseases, 144, University of Copenhagen, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
Appendix
The Scandinavian Isoprinosine Study Group included the following institutions and investigators.
Denmark — Department of Dermatovenereology, Bispebjerg Hospital, Copenhagen: Carsten Sand Petersen, M.D., Susanne Kroon, M.D., Anne-Marie Worm, M.D., Jens Sindrup, M.D., Maja Stangerup, M.D., Birgitte Løkke Jensen, M.D., and Jørgen Søndergaard, M.D.; Department of Infectious Diseases, Rigshospitalet, Copenhagen: Ib Bygbjerg, M.D., Bjørn Søeberg, M.D., Tom Hartvig, M.D., Jens Ersbøll, M.D., Knud Chr. Christensen, M.D., and Jan Gerstoft, M.D.; Department of Dermatovenereology, Rigshospitalet, Copenhagen: Susanne Ullman, M.D., Kamma Lange, M.D., Marianne Kieffer, M.D., and Tonny Karlsmark, M.D.; Department of Infectious Diseases, Hvidovre Hospital, Copenhagen: Court Pedersen, M.D., Lars Mathiesen, M.D., Jens Ole Nielsen, M.D., Jesper Hertz, M.D., and Anders Thornval, nurse; Department of Dermatovenereology, Gentofte Hospital, Copenhagen: Jette Christophersen, M.D.; Department of Internal Medicine F, Hillerød Hospital, Hillerød: Jens Heiberg, M.D., and Annie Engelholm, M.D.; Department of Internal Medicine C, Odense Hospital, Odense: Mads Buhl, M.D., and Henrik Isager, M.D.; Department of Dermatovenereology, Odense Hospital, Odense: Finn Schultz Larsen, M.D., and Grete Laurberg, M.D.; Department of Infectious Diseases, Marselisborg Hospital, Århus: Palle Tauris, M.D., Jette Bøttzauw, M.D., and Finn Black, M.D.; and Department of Dermatovenereology, Marselisborg Hospital, Århus: Ellis From, M.D.
Sweden — Department of Dermatovenereology, Södersjukhuset, Stockholm: Eric Sandström, M.D., Anders Karlsson, M.D., Gunnar Ramstedt, MD., Jan Torssander, M.D., Anders Furuncrona, M.D., Göran Bratt, M.D., and Irene Axman, nurse; Department of Infectious Diseases, Roslagstulls Hospital, Stockholm: PehrOlov Pehrson, M.D., Elisabeth Eklund, nurse, Barbro Hultberg, nurse, and Stefan Lindback, M.D.; Department of Infectious Diseases, Danderyds Hospital, Stockholm: Peter Rönnerfalk, M.D., Mats Karlsson, M.D., Knut Lidman, M.D., and Susanne Hammers-Berggren, M.D.; Department of Dermatovenereology, Sahlgrenska Hospital, Göteborg: Charles Håkansson, M.D., and Gun-Britt Löwhagen, M.D.; Department of Infectious Diseases, Östra Hospital, Göteborg: Gunnar Norkrans, M.D., and Rune Wejstål, M.D.; Department of Infectious Diseases, University Hospital of Lund: Bengt Ljungberg, M.D., Bo Ursing, M.D., and Bertil Christensson, M.D.; Department of Infectious Diseases, Malmö Hospital, Malmö: Torkil Moestrup, M.D., and Peter Sjöwall, M.D.; Department of Infectious Diseases, Vasterås Hospital, Vasterås: Sven Blomqvist, M.D.; Department of Infectious Diseases, Örebro Hospital, Örebro: Erik Back, M.D.; Department of Infectious Diseases, Kalmar Hospital, Kalmar: Åke Ringner, M.D.; and Department of Dermatovenereology, Akademiske Hospital, Uppsala: Anders Strand, M.D.
Steering Committee — Court Pedersen, Eric Sandström, Carsten Sand Petersen, Gunnar Norkrans, Jan Gerstoft, Knud Chr. Christensen, Charles Håkansson, PehrOlov Pehrson, and Hans Jessen Jürgensen.
End-Point Assessment Committee — Court Pedersen and Anders Karlsson.
Safety-Monitoring Committee — Erik Juhl, M.D. (Department of Hepatology, Hvidovre Hospital, Copenhagen).
Coordination and Data-Handling and Analysis Center — Leo Pharmaceutical Products, Ballerup, Denmark: Elin Reines, M.D., Erik Kirkegaard, M.D., Susan Hedman Johnson, Pharm. Dr., and Claus Bay, M.Sc.Stat. (Statistician).
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