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Antimicrobial Agents and Chemotherapy, July 2007, p. 2639-2641, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01446-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Safety and Activity of the Immune Modulator HE2000 on the Incidence of Tuberculosis and Other Opportunistic Infections in AIDS Patients{triangledown}

Dwight R. Stickney,1* Zoja Noveljic,2 Armando Garsd,1 Daniel A. Destiche,1 and James M. Frincke1

Hollis-Eden Pharmaceuticals, Inc., San Diego, California,1 Karl Bremmer Hospital, Cape Town, Republic of South Africa2

Received 17 November 2006/ Returned for modification 26 January 2007/ Accepted 20 April 2007


   ABSTRACT
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Twenty-five AIDS patients were treated with HE2000, a synthetic adrenal hormone. The drug was well tolerated and safe and reduced both the incidence of tuberculosis coinfection by 42.2% (P < 0.05) and the cumulative incidence of opportunistic infections (P < 0.05). These results warrant further clinical investigation of HE2000.


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AIDS remains a major health problem worldwide, and opportunistic infections (OIs) continue to be the main cause of AIDS mortality (18). HE2000, 16{alpha}-bromo-3β-hydroxy-5{alpha}- androstan-17-one ({alpha}-Epi-Br), is a synthetically modified androstane adrenal hormone. In human immunodeficiency virus (HIV)-infected patients, HE2000 decreases inflammatory cytokines and increases circulating dendritic cells, T-NK cells and HIV-specific activated CD8 T cells (13). HE2000 is clinically active in clearing malarial parasites in patients with uncomplicated malaria (7). It is also active against feline immunodeficiency virus, rodent tuberculosis, and rodent malaria (1, 6, 8, 12).

We evaluated the safety and tolerability of HE2000 administered intramuscularly in a small group of AIDS patients. We also assessed (in a double-blind study) the incidence of tuberculosis and the cumulative incidence of OIs. A treatment course (6 weeks) consisted of intramuscular injections of either 100 mg of HE2000 or placebo (as a control) once daily for 5 days, followed by a 37-day observation period. The study permitted up to seven courses. Physical examinations were performed at the initiation of treatment and on days 15 and 36 of each treatment cycle. Safety analyses, laboratory testing, and checks for adverse events and OIs continued monthly and, if possible, for 3 months following the final treatment cycle.

Twenty-six AIDS patients at the Tiervlei Trial Centre of the Karl Bremmer Hospital in Cape Town, Republic of South Africa, participated in this study. The study followed the guidelines of the International Conference on Harmonization and the Declaration of Helsinki. It was reviewed and approved by the Hospital Ethics Committee and the Medicines Control Council of South Africa. This study was conducted at a time when antiretroviral drugs were not permitted in South Africa and, consequently, could not be offered to the patients who participated. Patients eligible for the study had CD4-cell counts ≤100 cells/mm3 and HIV RNA levels (at screening) ≤1 x 106 copies/ml, as measured by the Quantiplex branched DNA test (Chiron, Emeryville, CA) (10). Patients were excluded if they had evidence of an acute OI. All patients were provided a supplement of multivitamins with minerals (Centrum; Wyeth). Prophylactic trimethoprim-sulfamethoxazole was initiated at randomization.

HE2000 was provided in a vehicle formulation of polyethylene glycol 300, propylene glycol, benzyl benzoate, and benzyl alcohol. Each vial of placebo contained 1 ml of the vehicle formulation only. A central laboratory, Niehaus-Ungerer Pathologists, Inc., Pretoria, South Africa, performed the hematology and chemistry analyses of blood. Viral Dynamix Laboratory (Pty.) Ltd., Hatfield, South Africa, performed HIV viral load quantification and CD4/CD8 cell quantification by flow cytometry immunophenotyping. Thirty OIs were coded (2). The analysis included all coded OIs that emerged after the completion of the first course of therapy. Calculations were performed with SAS and StatXact software (3, 14). The time to the first event was analyzed by the Kaplan-Meier method and the exact log rank test. The significance of the incidence of an OI was modeled by use of exact multiple logistic regression by using as independent variables current treatment (placebo or HE2000) and an indicator of whether the patient had previously received treatment for a similar OI that occurred during the baseline period. Interactions were also tested. The cumulative incidence of OIs was approached by the nonparametric mean cumulative function models according to both Nelson's method (11) and the exact Poisson test for the significance of a trend difference in OIs by treatment group (9).

A total of 26 patients initiated treatment with HE2000 (14 patients) or placebo (12 patients). However, the data for one placebo patient were excluded from the analysis because he received only one treatment course. Table 1 shows the characteristics of the initial 26 patients at the baseline by assigned treatment. The treatment-specific median times, 288 days for placebo and 244.5 days for the treated group, were not significantly different. The futility in showing the formal efficacy of HE2000 for the treatment of the progressing conditions of the remaining patients led to a decision of early study closeout.


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  		TABLE 1. Baseline characteristics of treatment groupsa

 
Table 2 summarizes the incidences of the main adverse events in all 26 patients. The most common adverse events were diarrhea (<1 month), lymphadenopathy, and increased blood amylase levels. These were unrelated to the treatment. Injection site reactions were regarded as probably related to the treatment by the investigator. Pain, irritation, and swelling were reported in six patients receiving HE2000 and two patients receiving placebo. These events were transient and mild to moderate in severity and resolved before the next series of scheduled injections. There were no clinically significant changes in safety hematology or chemistry laboratory values.


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  		TABLE 2. Summary of safety for all 26 patients

 
Table 3 shows the distribution of OIs. Twenty-four patients developed an OI. One HE2000-treated patient did not develop an OI during her 406 days at risk. The most common OI involved Candida albicans, with Mycobacterium tuberculosis being the second most frequent. A total of 10 cases of tuberculosis developed during the study, in 7/11 patients (63.6%) in the placebo group and 3/14 patients (21.4%) in the HE2000-treated group, respectively, which was a statistically significant difference of 42.2 percentage points (exact 95% confidence interval, 1.7% to 71.3%; P = 0.0303). After accounting for the differential times at risk, the mean time to M. tuberculosis coinfection was delayed by approximately 49 days in the treated group, from 271 days for the placebo group to 320 days for the HE2000-treated group. After approximately 140 days on study, no further M. tuberculosis coinfections were observed in the HE2000-treated group, whereas continued M. tuberculosis infections occurred until the end of the study in the placebo group. After stratification by baseline age, the differences were nearly statistically significant (P = 0.055), with a stronger immune response in older (age, >32.2 years) patients treated with HE2000.


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  		TABLE 3. Distribution of opportunistic infections

 
The overall rate of accumulation of OIs at the end of the study was lower in the HE2000-treated group (P = 0.025). After adjustment for the number of days at risk, by the end of the study the patients in the placebo group had accumulated more OIs, 6.68 per patient, than patients in the active agent-treated group, 3.84 OIs per patient (P = 0.045), with the point of divergence occurring at about the end of cycle 5 of treatment. There was no statistical difference in viral load or CD4-cell counts between the two groups.

HE2000 was well tolerated and safe. In a previous clinical trial with HE2000 with an HIV-positive population (CD4 cell counts, >200/ml), dendritic cells, early activated (CD69+ CD25–) CD8 T cells, HIV GAG-specific CD8 T cells, and T-NK cells were stimulated (13). All patients who entered this study had prior experience with OIs. Consequently, the development and incidence of opportunistic infections rather than the time to the first OI were more sensible end points. HE2000 did not stop the progression of OIs. However, it did confer therapeutic activity. In the present study, we found that the incidence of life-threatening M. tuberculosis coinfections was significantly lower in the HE2000 group. Siegal and others suggest that OIs result from defects in both natural and adaptive components of cellular immunity and could be prevented if alpha interferon-producing cells (IPCs) were present in sufficient numbers, regardless of the total CD4+-cell counts.(4, 5, 15-17) We postulate that the decreased number of OIs observed in this study may involve an increase in IPCs as a result of the immune-regulating activity of HE2000.

In conclusion, the evidence suggests a potential and promising role for HE2000 in the fight against tuberculosis and AIDS, although formal proof of this concept will necessitate a larger confirmatory clinical study.


   ACKNOWLEDGMENTS
 
We are indebted to the nursing and medical staff of the Karl Bremmer Hospital in Cape Town, South Africa. We gratefully acknowledge Judy Addison for her many contributions to this project and Karen Schlangen and Richard Weng for their assistance with the preparation of the tables. Finally, we express our gratitude to the patients and their families for participating in the study.

The study was supported by Hollis-Eden Pharmaceuticals, Inc., San Diego, CA.

Potential conflicts of interest are as follows: D.R.S., A.G., D.A.D., and J.M.F. are employees of Hollis-Eden Pharmaceuticals, Inc.; and Z.N. received research support from Hollis-Eden Pharmaceuticals, Inc.


   FOOTNOTES
 
* Corresponding author. Mailing address: Hollis-Eden Pharmaceuticals, Inc., 4435 Eastgate Mall, Suite 400, San Diego, CA 92121. Phone: (858) 587-9333. Fax: (858) 558-6470. E-mail: dstickney{at}holliseden.com Back

{triangledown} Published ahead of print on 30 April 2007. Back


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Antimicrobial Agents and Chemotherapy, July 2007, p. 2639-2641, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01446-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




This Article
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