2917_a02_p35-44

AIDS RESEARCH AND HUMAN RETROVIRUSES
Volume 17, Number 1, 2001, pp. 35–43
Mary Ann Liebert, Inc.
The Antiviral Drug Docosanol as a Treatment for Kaposi’s Sarcoma Lesions in HIV Type 1-Infected Patients: MICHAEL J. SCOLARO,1 LUCY B. GUNNILL,2 LAURA E. POPE,2 M.H. KHALIL,2 ABSTRACT
Docosanol inhibits a broad spectrum of lipid-enveloped viruses in vitro including HSV-1, HSV-2, VZV, CMV,
HHV-6, and HIV-1. These observations led us to conduct a pilot clinical study with docosanol 10% cream as
a topical treatment for Kaposi’s sarcoma (KS) in HIV-1-infected patients. In this open-label study 28 cuta-
neous KS lesions in 10 HIV-1-infected patients were treated topically five times daily for 4 weeks with eval-
uation of lesion characteristics of area, edema, and color. All patients elected to enroll in an extended treat-
ment protocol and continued to treat for up to 35 weeks. Within 28 days, 2 of 10 patients exhibited a partial
response based on standardized criteria exhibiting 74 to 83% reductions in total target lesion areas. With ex-
tended treatment, a partial response was exhibited in two additional patients where total target lesion area
was reduced by 52% in one patient and target lesions in another patient that had been large, swollen, and
painful at study initiation were no longer visible. No patient experienced disease progression or signs of vis-
ceral disease. The average percent decrease in lesion area for all target lesions was 20% (p Ͻ 0.01). A pa-
tient’s response to therapy appeared to be independent of anti-HIV regimen, HIV viral load, or previous KS
treatments. These results suggest that docosanol merits further investigation as a potential topical therapy in
the treatment of AIDS-associated Kaposi’s sarcoma lesions.
INTRODUCTION
virus, and human herpesvirus (HHV) 6. Non-lipid-envelopedviruses including poliovirus, adenovirus, and reovirus are re- DOCOSANOL (n-docosanol, 1-docosanol, behenyl alcohol) is sistant to inhibition by the compound. Lipid-enveloped viruses
a 22-carbon fatty alcohol that inhibits a broad spectrum of that enter cells by endocytic means also resist inhibition by do- lipid-enveloped viruses.1 Formulated as docosanol 10% cream, cosanol. Studies indicate that docosanol has a novel mechanism it has recently been approved by the U.S. Food and Drug Ad- of action, exerting its anti-HSV activity predominantly by in- ministration as a topical treatment for recurrent oral-facial her- terfering with the process of viral fusion with the host cell.1,5,8,9 pes simplex infections (trade name Abreva™). Its efficacy in Kaposi’s sarcoma (KS) is the most common tumor in HIV- reducing the healing time and symptoms of oral-facial herpes 1-infected individuals and contributes substantially to the mor- simplex infections has been demonstrated in Phase 3 placebo- bidity and mortality suffered in patients with AIDS.10 The cu- controlled clinical trials2 and, previously, in a Phase 2 clinical taneous lesions characterizing the disease can be numerous, trial.3 The drug has an excellent safety profile in the clinic, and disfiguring, and painful. The etiology of the disease appears to no toxic potential is indicated from the results of extensive and have an infectious component involving both HIV-1 and HHV- 8.11–15 HIV-1 infection may increase levels of several cy- In vitro antiviral activity of docosanol has been demonstrated tokines, including tumor necrosis factor interleukin-1, inter- against a number of lipid enveloped viruses.1,5–8 Susceptible leukin-6, and basic fibroblast growth factor that may promote viruses include HIV-1, herpes simplex viruses (HSV) 1 and 2, the growth of KS cells.16 DNA sequencing studies,17,18 have cytomegalovirus, varicella zoster virus, respiratory syncytial revealed a close association between KS and HHV-8, also re- 1The Scolaro Medical Coalition, Beverly Hills, California 90211.
2Avanir Pharmaceuticals, San Diego, California 92121.
SCOLARO ET AL.
ferred to as Kaposi’s sarcoma-associated herpesvirus (KSHV), dose was applied under the direction of the investigator and/or and it is becoming accepted that HHV-8 is necessary but not the research nurse. Patients kept a diary to record the date and sufficient for development of KS neoplasms.14,15 time of each application. The protocol specified that those pa- The optimal treatment for KS depends on the severity of the tients who completed the 28-day trial and who the investigator disease and the immunological status of the patient.19 Patients judged would benefit from continued treatment were eligible to with relatively discrete mucocutaneous KS can be effectively continue treatment under an extended use protocol.
treated with local therapies including intralesional chemother- The number, area, and appearance of all KS lesions were apy, surgical excision, and radiotherapy.19–21 Patients with ad- recorded at study enrollment. Lesions were numbered and two vanced KS, including patients with widespread mucocutaneous or three target lesions that were easily accessible and previously disease or visceral disease, are generally treated with systemic untreated with either local radiation or topical chemotherapy were chemo-therapy with cytotoxic agents such as liposomal an- selected by the investigator at study enrollment to be examined thracyclines, vinca alkaloids, or paclitaxel.19,22–25 Other treat- for clinical response to therapy. All patients were to be assessed ment options include interferons, human chorionic go- once weekly. The target lesion dimensions and appearance [i.e., nadotropin, all-trans-retinoic acid (tretinoin), 9-cis-retinoic lesion-associated edema, color, and lesion nodularity (raised ver- acid, granulocyte–macrophage colony-stimulating factor, and sus flat)] were to be recorded during these visits.
whole body hyperthermia.19,26–28 Panretin gel has receivedFDA approval for topical treatment of KS lesions.29 Consid- ering the inhibitory effects of docosanol on viral replication of The primary efficacy assessment was the proportion of pa- HHV-6 and HIV-1, docosanol might also be clinically effec- tients experiencing a partial or complete response using proto- tive in the treatment of AIDS-associated KS in patients with col-defined criteria. The protocol specified that clinical re- discrete lesions while lacking the toxicity or invasiveness of sponse of the target lesions to treatment was to be graded the above treatments. We, therefore, initiated the pilot clinical relative to baseline as complete response [CR] (complete reso- trial reported here to examine the safety and efficacy of topi- lution of target lesions with histological confirmation), partial cally applied docosanol 10% cream in the treatment of cuta- response [PR] (loss of lesion color and/or Ն25% reduction in neous KS in HIV-1-infected patients.
lesion area of target lesions), no response [no change in coloror area of target lesions (these patients are also referred to asstable)], or progression (increase in area or vascularization of MATERIALS AND METHODS
target lesions). Because this differs from the standardized uni-form evaluation and response assessment criteria (ACTG re- sponse criteria) for KS, the data are evaluated here accordingto standard accepted criteria. The major difference is that a par- Each gram of docosanol 10% cream contains 100 mg do- tial response is defined by ACTG as a Ն50% decrease in the cosanol formulated into a white, nonstaining, moisturizing number of lesions that lasted for at least 4 weeks, or complete cream that is easily applied and is readily absorbed into skin flattening of Ն50% of all previously raised lesions, or a Ն50% decrease in the sum of the products of the largest perpendicu-lar diameters of the marker lesions and no new lesions or new visceral sites of involvement and no new worsening of tumor- HIV-1-positive male patients over 18 years of age with clin- ically determined cutaneous KS lesions confirmed by a posi- Lesion area was calculated from the product of two perpen- tive biopsy were screened and enrolled at a single study site dicular diameters, which were measured using a single calibrated (Scolaro Medical Coalition, Beverly Hills, CA). Eligible pa- slide caliper. Total lesion area for each patient was calculated tients were otherwise clinically stable with no evidence of ac- by summation of the individual target lesion areas. Change in tive opportunistic infection as documented by medical history, mean lesion area from baseline was calculated for the individ- physical examination, and clinical laboratory examination per- ual target lesions and also for total lesion area by patient.
formed at baseline. Patients with known systemic KS disease Lesion color was recorded generally as purple, burgundy, were specifically excluded. Patients were also excluded if they deep red, pink, brown, or tan. Lesions that began as purple, bur- had a history of chronic alcoholism or drug abuse. Patients sta- gundy, or deep red and were later described as tan or brown bilized on an antiretroviral regimen with no change in regimen were interpreted to have undergone a loss of lesion color.
within 14 days prior to study initiation were eligible to partic-ipate but were to abstain from new antiretroviral or KS treat- Demographic information and patient medical history infor- mation were summarized for the study group. Lesion area and All eligible patients were dispensed docosanol 10% cream Efficacy analysis included all patients who had baseline and to be applied five times per day for 28 days. Patients were ad- Week 4 (final) visit (N ϭ 10). A paired, two-tailed t-test was vised that they could treat all of their current as well as any used to assess the change in lesion area from baseline to trial new cutaneous KS lesions that might occur. They were in- endpoint. Safety evaluations were based on all treated patients structed to apply enough cream to cover the entire lesion plus (N ϭ 13). Statistical efficacy analysis was not conducted on approximately one-half inch around the lesion border. The first data obtained from the extended protocol.
DOCOSANOL TREATMENT OF CUTANEOUS KAPOSI’S SARCOMA
of 34.2 mm2 (range ϭ Ϫ280.0 to 0.0 mm2) during the 28-daydocosanol 10% cream treatment period with an average percent Safety assessments were to be made based on the reporting decrease in lesion area of 20%. The decrease in mean lesion of adverse events and from clinical laboratory measurements area was statistically significant (p Ͻ 0.01).
including blood chemistry, urinalysis, and hematology atweekly clinic visits.
The mean of patients’ total target lesion area (the sum of the product of two perpendicular diameters for all target lesions)was 923.7 mm2 at baseline and decreased by 95.7 mm2. The largest decrease in total lesion area was 355 mm2 and the small-est was 0; the average percent decrease in total lesion area was 23% between baseline and the final visit. Borderline statisticalsignificance (p ϭ 0.057) was found in the analysis of change Thirteen HIV-1-infected men with a mean age of 39 years from baseline total lesion area by patient.
(range 27 to 52 years) were enrolled in the trial. Ten patientscompleted the 28-day treatment. Three discontinued prema- Lesion color. In all but one patient (JTG; three lesions) analy- turely because of conflicts with protocol requirements. The dis- sis of weekly color assessments of target lesions revealed a pro- ease characteristics of those patients completing the study are gressive lightening or fading in color with treatment. None of summarized in Table 1. KS was confirmed by histopathologi- the target lesions became darker in color during the treatment cal evaluation in all patients (e.g., see Fig. 1A). In 8 of the 10 period. Of the 28 target lesions evaluated, 16 (57%) faded from patients, KS was the AIDS-defining illness and had been pres- deep red, burgundy, or purple at baseline to pink, brown, or tan ent for 1 year or more. Seven of the 10 patients had a history by 28 days. Five lesions faded to a tan or brown color.
of prior opportunistic infections. All patients presented withmultiple cutaneous KS lesions (2 to 21) with no oral or nodal Histological evaluation. Lesions biopsies provided histo- lesions. One patient reported severe tumor-associated edema pathological confirmation of KS in all patients. Following treat- and pain and a second patient reported severe tumor-associated ment, biopsies of lesions in patients exhibiting partial responses pain. One to two nodular lesions were described for each of were taken for histological evaluation. For example, sections of three patients, however, only one of the nodular lesions was se- a KS lesion from patient WEB taken prior to treatment shows lected as a target lesion. Of the patients who completed the spindle cell proliferation that forms vascular slits with ex- study, eight were concurrently receiving multidrug antiretrovi- travasated erythrocytes (Fig. 1A). The lesion extended into the ral treatment therapy; in six of these patients the regimen in- superficial panniculus. Hemosiderin pigment was noted and cluded a protease inhibitor. The antiretroviral regimens in the chronic inflammatory cells were identified. The lesion appeared eight such treated patients had been stable for at least 2 months to be in the plaque stage of development. Following 4 weeks in all but one patient. Two patients were not receiving con- of treatment, skin sections (Fig. 1B) of a KS lesion from the same patient demonstrated improvement. The pathologist’s re-port described focal residual KS characterized by a few irreg- ular dilated blood vessels accompanied by a few vascular slits The area, color, and characteristics of the 28 lesions evalu- in the superficial papillary dermis with extravasated erythro- ated during the treatment period at baseline and at the 4-week cytes and hemosiderin pigment. The lesion appeared to be con- visit are summarized in Table 2. Assessments made at other weekly intervals throughout the study are not shown. Accord-ing to standardized criteria, two patients exhibited a PR based Edema. Lesion-associated edema was present at baseline in on Ͼ50% reduction in total target lesion area (patients WEB one patient (SHC). Target KS lesions were located on his right and D-D whose total target lesion areas were reduced 74% and foot and these lesions were associated with localized lymphatic 83%, respectively). Loss of lesion color was observed in one obstruction and lymphedema with massive edema up to mid- patient, SHC. By the 28-day visit the total target lesion area in calf. The three target lesions ranged in area from 200 to 1200 SHC had decreased by 16% and the severe edema and pain mm2, were purple in color, firm to the touch, and caused dis- around the lesions at baseline were largely resolved.
abling pain at study initiation. This patient experienced a par- None of the patients manifested progression of their target tial resolution of the lymphedema following 1 week of do- lesions, as indicated by changes in area or color, or developed cosanol treatment. By 28 days, the edema was largely resolved, any signs of visceral dissemination of KS during treatment in the lesions were no longer painful, and total target lesion area either the 28-day treatment period or during the extended treat- was reduced 16%. After 35 weeks of treatment the lesions were ment study (although one patient, LMK, developed a single new reported to be no longer visible (see below). A second patient KS lesion at an untreated cutaneous site during the 28-day treat- reported decreased lesion-associated pain by the 28-day visit ment period). No patients exhibited a complete response. The quantitative and qualitative treatment effects observed follow.
Other lesion characteristics. In this study, no baseline le- Lesion area and number. None of the patients exhibited a sions were described as raised and only one lesion was reported decrease in the total number of KS lesions. The average indi- as nodular at baseline so effects of treatment on decreasing the vidual lesion area for the 28 target lesions was 329.9 mm2 at vertical dimension of the lesion could not be assessed. The tar- baseline (range ϭ 12 to 1216 mm2), and decreased by a mean get lesion described as nodular at baseline was reduced 44% in DISEASE CHARACTERISTICS OF STUDY PATIENTS aTarget lesion characteristics are listed in Table 2.
bBy ACTG criteria.
cNA, Not available; ND, none described.

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