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Thalidomide for the Treatment of Esophageal Aphthous Ulcers in Patients with Human Immunodeficiency Virus Infection

  1. Jeffrey M. Jacobson1,
  2. John Spritzler3,
  3. Lawrence Fox5,
  4. John L. Fahey8,
  5. J. Brooks Jackson6,
  6. Miriam Chernoff3,
  7. David A. Wohl10,
  8. Albert W. Wu7,
  9. Thomas M. Hooton11,
  10. Beverly E. Sha12,
  11. Cecilia M. Shikuma13,
  12. Laurie A. MacPhail9,
  13. David M. Simpson2,
  14. Carol B. Trapnell5,
  15. Nesli Basgoz4 and
  16. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Groupa
  1. 1Departments of Medicine, Mount Sinai School of Medicine, New York, New York
  2. 2Departments of Neurology, Mount Sinai School of Medicine, New York, New York
  3. 3Statistical and Data Analysis Center, Harvard School of Public Health
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
  5. 5Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda
  6. 6Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  7. 7Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  8. 8Department of Medicine, University of California, Los Angeles
  9. 9Department of Stomatology, University of California, San Francisco
  10. 10Department of Medicine, University of North Carolina, Chapel Hill
  11. 11Department of Medicine, University of Washington School of Medicine, Seattle
  12. 12Department of Medicine, Rush Medical College, Chicago, Illinois
  13. 13Department of Medicine, University of Hawaii School of Medicine, Honolulu
  1. Reprints or correspondence: Dr. Jeffrey M. Jacobson, Mount Sinai Medical Center, 1 Gustave L. Levy Place (Box 1009), New York, NY 10029 (jeffrey_jacobson{at}smtplink.mssm.edu).

  1. Presented in part: Twenty-fifth AIDS Clinical Trials Group Meeting, Washington, DC, 1–4 August 1998.

 
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Abstract

A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16–823.75; P = .033). Odynophagia andimpaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV.

Severe unremitting aphthous ulceration of the esophagus occurs in persons with human immunodeficiency virus (HIV) infection [1–3]. Patients usually have severe odynophagia and consequently impaired ability to eat. Although HIV RNA and protein can be detected in macrophages at the base of ulcers in some patients [2], the etiology is presumed to be immunologic and not a direct effect of HIV infection. Esophageal aphthous ulcers have been successfully treated with corticosteroids [1, 2, 4], but the relapse rate has been significant [5]. There have been uncontrolled observations of the effectiveness of treatment with thalidomide [5–7].

Similar lesions occur in the mouth and oropharynx in persons with AIDS [8, 9]. We previously reported the results of one stratum of the National Institute of Allergy and Infectious Diseases (NIAID)—sponsored AIDS Clinical Trials Group (ACTG) Protocol 251, which demonstrated the efficacy of thalidomide in healing oral aphthous ulcers [9]. We now report the results of the stratum of ACTG 251 that studied the safety and efficacy of thalidomide for the treatment of esophageal aphthous ulcers in patients infected with HIV.

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Methods

Study population

Patients enrolled in the study met entry criteria similar to those for the oral ulcer stratum of the trial as reported previously [9]. In brief, subjects were included in the study if they had documented HIV infection and a biopsy finding of an esophageal ulcer that caused symptoms of odynophagia or dysphagia for ⩾2 weeks that revealed no infectious, neoplastic, or other specific diagnosis. The surface diameter of the largest ulcer had to be ⩾5 mm. A negative culture of the ulcer for herpes simplex virus was required. Among the exclusion criteria were bilateral peripheral neuropathy more severe than grade 1 and corticosteroid use within 1 week before the first set of blood tests. Antiretroviral therapy was held constant beginning 4 weeks before study entry. Patients with both oral and esophageal aphthous ulcerations were enrolled into the oral ulcer rather than the esophageal ulcer stratum of the study.

Subjects were recruited at 11 sites in the United States. Stringent precautions taken to prevent and detect pregnancy in women of childbearing potential included the following: pregnancy testing (prior to study entry, weekly while on study, and 4 weeks after discontinuance of study medication), required pregnancy prevention (either heterosexual abstinence or effective barrier and hormonal contraception), and patient education and warning labels on medication packaging. Procedures also existed for counseling and monitoring should a pregnancy occur.

Treatment regimens

Study participants were randomly assigned in a double-blind fashion to receive a 4-week course of either two 100-mg capsules of thalidomide or two placebo capsules orally once a day at bedtime (study medications were provided by Andrulis Pharmaceuticals, Beltsville, MD). Patients whose esophageal aphthous ulcers had not completely healed by the end of the 4 weeks were offered the option of taking two 100-mg capsules of open-label thalidomide daily for the next 4 weeks. If the healing was still not complete after that period, patients were given the option of receiving 200 mg of thalidomide twice a day for an additional 4 weeks as tolerated.

Study protocol specified that should adverse effects (including excessive sedation) occur, study medication dosing could be modified. Depending on the nature and grade of the adverse effects, study medication was given at a reduced dose, permanently discontinued, or withheld until resolution of the adverse effect and then resumed at a reduced dose.

Criteria for response

The primary end point of the study was the complete absence of esophageal aphthous ulcers upon repeat esophagoscopy after 4 weeks of study treatment (a complete response). For various reasons, a few patients in each treatment arm had the repeat esophagoscopy as late as 7 weeks after the initiation of study treatment. This evaluation was accepted as long as the subject had remained on blinded study treatment during that time. A partial response at week 4 was defined as a decrease of ⩾50% in the combined surface area of the 3 largest ulcers compared with the 3 largest ulcers at baseline, with no formation of new ulcers. (The surface area was defined as the product of the ulcer's largest surface diameter and its largest perpendicular surface diameter.) A lack of response was defined as a decrease of <50% in the combined surface area or the occurrence of a new ulcer.

Evaluation of patients and follow-up

After the screening and baseline evaluations, the patients were seen weekly by site investigators unaware of the patients' treatment status to assess potential toxic effects of the study medication. At baseline and at each weekly visit, a quality-of-life questionnaire was administered to assess pain and eating ability. Repeat esophagoscopy was performed after 4 weeks of study treatment to assess the healing of esophageal ulcers. The follow-up laboratory evaluations included measurements of plasma levels of tumor necrosis factor (TNF)-α, soluble TNF-α receptor II, and HIV RNA as performed in the oral ulcer stratum of ACTG251 [9].

Quality-of-life measurements

The quality-of-life questionnaire contained 15 items that measured general health, pain, and eating ability during the study. Two of the items, from the Medical Outcomes Study: HIV [10], assessed general perceptions of health and pain; they were supplemented by an item assessing the patient's pain while eating. Two scales with 6 items each assessed discomfort while eating and the actual consumption of food (the latter scale was modified from the Sickness Impact Profile [11]). The responses to these questions were scored on scales of 1–5 or 1–6, with higher numbers indicating poorer health or more severe symptoms.

Statistical analysis

The study was designed to have a type I error rate of 0.05 and 80% power to detect the primary treatment effect of a 40% probability in one arm versus a 10% probability in the other arm of complete ulcer healing at week 4. The planned study population was 82 subjects. Due to slow accrual, particularly after the results of the oral aphthous ulcer stratum of the trial became public knowledge, the study was stopped after 24 analyzable patients had entered. The results in these 24 patients are presented. All analyses were performed on an intention-to-treat basis.

Two-by-two classifications of ulcer-related dichotomous end points were tested by use of stratified exact tests [12]. (Randomization was stratified according to whether a patient volunteered to be in a pharmacokinetic substudy.) First, the homogeneity of odds ratios (ORs) was tested across strata by use of a 2-sided test. If these ORs were found to be homogeneous, then a 2-sided exact test of the null hypothesis that the homogeneous OR was equal to 1 was performed. Two-by-two classifications of dichotomous safety end points were tested by use of a 2-sided Fisher's exact test [13]. For continuous and ordinal variables, appropriate 2-tailed Wilcoxon nonparametric rank sum or signed rank tests were used [14]. P values for end points other than the primary end point of complete ulcer healing are exploratory, not confirmatory; they have no well-defined type I error.

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Results

Study population

Twenty-six patients were enrolled in the esophageal ulcer stratum of ACTG 251 between March 1994 and October 1996. Two patients were excluded from the analysis because they were randomized inadvertently and never received study treatment. Of the 24 patients included in the analysis, 13 were randomized to receive placebo and 11 to receive thalidomide. Baseline characteristics of the two groups were similar (table 1). All patients had baseline CD4 lymphocyte counts of <200 cells/mm3. Almost all had significant odynophagia that interfered with eating.

Figure 1
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Figure 1

Aphthous ulceration in esophagus of 27-year-old man with AIDS. Ulceration healed completely after 4 weeks of treatment with thalidomide. A, Photo at study entry. Arrows indicate multiple large linear ulcers that extended length of esophagus. B, After 4 weeks of treatment with thalidomide, esophageal mucosa is entirely normal.

Table 1
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Table 1

Baseline characteristics of 24 HIV-infected subjects with esophageal aphthous ulcers treated with thalidomide or placebo.

Of the 57 patients enrolled in the oral ulcer stratum of ACTG 251, the results of which were reported elsewhere [9], one had both oral and esophageal aphthous ulcers. This patient is not included in this analysis.

Clinical data

Of the 11 patients in the thalidomide-randomized group, 8 (73%) had responded to therapy completely at the week 4 evaluation compared with 3 (23%) of the 13 in the placebo-randomized group (OR, 13.82; 95% confidence interval [CI], 1.16–823.75; P = .033). Figure 1 illustrates the complete healing of esophageal aphthous ulceration in a patient randomized to receive thalidomide.

Three patients enrolled in the esophageal ulcer stratum had cytomegalovirus infection diagnosed on a subsequent biopsy of the esophageal lesion on the basis of immunohistochemical staining but not on the biopsy at study entry. One patient was randomized to thalidomide treatment and had no ulcer response; the 2 patients randomized to placebo had no ulcer response. If these 3 patients were excluded from the analyses, the results would not change markedly; the complete healing rates would be 80% for the thalidomide group and 27% for the placebo group (OR, 15.05; 95% CI, 1.13–983.26; P = .036).

When complete and partial responses are combined, the results are similar. Nine (82%) of 11 patients randomized to thalidomide had a complete or partial response at week 4 compared with 4 (31%) of 13 patients randomized to placebo (OR, 11.06; 95% CI, 1.16–195.09; P = .033).

Three analytic approaches to the quality-of-life data indicated greater improvements after 4 weeks in the thalidomide arm than in the placebo arm. First, patients receiving thalidomide improved by almost 2 points more on the overall quality-of-life score than patients receiving placebo (median change [interquartile range], 1.7 [0.7 to 2.5] vs. −0.1 [−0.3 to 0.8]; P = .022). Second, the thalidomide group improved much more than the placebo group in attaining a relatively problem-free status (responses ⩽2) in all quality-of-life parameters measured (table 2). In particular, 80% more patients receiving thalidomide had experienced either very mild pain or no pain during the previous 48 h at the week 4 evaluation than at the baseline evaluation, whereas 5% fewer patients receiving placebo had experienced very mild or no pain during the previous 48 h at the week 4 evaluation compared with baseline. Finally, analysis using the dichotomized response variable—little or no trouble (response ⩽2) versus some or a lot of trouble (response ⩾3)—also showed that the quality of life of patients receiving thalidomide tended to improve in contrast to that of the patients receiving placebo (table 2). This trend was especially evident for the questions regarding pain (P = .0001) and pain while eating (P = .044).

Table 2
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Table 2

Quality of life (QOL) from baseline to week 4—numbers and percentages of patients with little or no problem at each week and with improvement.

Of the 9 patients randomized to thalidomide with no odynophagia at the week 4 repeat endoscopy, 2 patients still had ulcers present. Patients randomized to thalidomide gained a median of 1.0 kg during the first 4 weeks of the study, whereas those randomized to placebo had a median weight loss of 1.8 kg (P = .049).

Immunologic and virologic data

Changes in plasma levels of TNF-α, soluble TNF-α receptor II, and HIV load in this group of patients were similar to the changes in the oral ulcer stratum of the protocol previously reported [9]. The median plasma levels of TNF-α and soluble TNF-α receptor type II were elevated in both thalidomide-randomized and placeborandomized groups of patients before the study treatment began (table 3). Plasma levels of both TNF-α and soluble TNF-α receptor type II tended to increase in the thalidomide group compared with the placebo group (table 3), similar to findings in the oral ulcer stratum [9]. However, these trends did not reach statistical significance, possibly because of the smaller sample size in the esophageal ulcer stratum of the study.

Table 3
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Table 3

Changes in plasma levels of tumor necrosis factor (TNF)-α and soluble TNF-α receptor II (sTNFrII) in each treatment arm.

Plasma HIV RNA levels tended to increase with thalidomide treatment, as we observed in the oral ulcer stratum. There was a difference of 0.50 log10 between the median changes in plasma HIV RNA from baseline to week 4 of the thalidomide group (median change, an increase of 0.24 log10) and the placebo group (median change, decrease of 0.26 log10). This difference, while not statistically significant, was of a magnitude similar to that in the oral ulcer stratum.

There were no changes in CD4 or CD8 lymphocyte counts or percentages from baseline to week 4.

Safety data

One of the 11 patients in the thalidomide group discontinued the study medication because of a treatment-associated rash. Three days after study entry, 1 of the 13 patients randomized to receive placebo requested that all medical treatment, including study medication, be stopped, and the patient was transferred to a hospice. Five (45%) of 11 patients randomized to thalidomide either discontinued study medication or had a dose reduction during the 4-week randomized phase of the study, compared with 1 patient randomized to placebo (8%, P = .061).

During the first 4 weeks of randomized treatment, 5 patients (45%) assigned to thalidomide and 2 (15%) assigned to placebo (P = .182) had new grade 3 or treatment-limiting grade 2 adverse events (as classified by NIAID criteria). There were no grade 4 adverse events. Three patients (27%) assigned to the thalidomide group developed new or worsened peripheral sensory neuropathies by study week 4, whereas no patients assigned to placebo did (P = .082). None of the 3 patients who developed neuropathies were receiving other medications associated with this adverse effect. Four patients (36%) in the thalidomide group experienced somnolence, compared with 1 patient (8%) in the placebo group (P = .142). Rash occurred in 2 patients randomized to thalidomide (18%), including the 1 who ended study treatment just short of the 4-week treatment period because of a recurrence of the rash with rechallenge; no patients randomized to placebo had a rash during this period (P = .199). No patients in either group had a grade 3 or 4 neutropenia during the first 4 study weeks. Other adverse events in the thalidomide group, each observed in 2 patients or fewer, included seizures and serum pancreatic amylase elevations. In the placebo group, other adverse events included fever, nausea, seizures, and dehydration (table 4).

Table 4
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Table 4

Comparative incidence of adverse events among patients treated with thalidomide and placebo during the 4 weeks of randomized study treatment.

There were no new episodes of opportunistic infections during the first 4 weeks of study treatment. One patient assigned to placebo died before week 4 because of HIV disease progression (the patient who requested that all treatment be stopped 3 days after study entry). No pregnancies occurred.

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Discussion

This double-blind, randomized, placebo-controlled study shows that thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV. The esophageal ulcers healed completely by week 4 in 8 (73%) of 11 patients randomized to receive thalidomide, compared with 3 (23%) of 13 patients randomized to receive placebo. These results are consistent with those we reported previously regarding the effectiveness of thalidomide in treating patients infected with HIV who have aphthous ulceration of the mouth and oropharynx (oral ulcer stratum of ACTG 251) [9]. Quality-of-life measures indicated that the pain and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide.

It is important to note that 3 patients had negative immunohistochemical staining for cytomegalovirus on specimens taken from the screening ulcer biopsy but positive staining upon repeat biopsy. Thus, the possibility of undiagnosed cytomegalovirus infection should be considered when a patient fails to respond to thalidomide therapy for presumed aphthous ulceration of the esophagus.

More patients receiving thalidomide had serious adverse events than those receiving placebo, although this difference did not achieve statistical significance. Five (45%) of 11 patients randomized to thalidomide either discontinued the study medication permanently or had the dose reduced before the 4-week course of treatment ended. Nevertheless, the ulcers of 4 of these 5 patients healed completely.

As in the oral ulcer stratum, sedation and rash were associated with thalidomide use. In addition, new or worsened peripheral sensory neuropathy was noted in 3 of the 11 patients randomized to thalidomide but in none of the patients randomized to placebo. Although this difference is not statistically significant and the patient sample size is small, the occurrence of neuropathy preferentially in the thalidomide group during such a brief course of treatment is surprising. It suggests that caution should be taken in the use of this drug in this population of patients with advanced AIDS. (The median CD4 cell count was 27.5 cells/mm3 [0.2 × 109/L].) This population is exposed to other causes of neuropathy, including HIV itself, and various medications used to treat the HIV infection and its complications. No patients developed grade 3 or 4 neutropenia, a concern raised by the results of the oral ulcer stratum of the study [15].

Confirming our previous findings [9], thalidomide did not prove to be a systemic TNF-α inhibitor. As in the oral ulcer stratum, thalidomide did not lower plasma TNF-α levels. The trend, again, was toward an increase in the plasma levels of TNF-α and TNF-α receptor II, the latter being a measure of TNF activity. Thalidomide's in vitro TNF effects appear to vary with the cell type and the conditions of the laboratory experiment [16, 17]. If TNF expression is an important factor in aphthous ulcer pathogenesis, what may be more important than thalidomide's systemic effect is its effect on TNF expression in local tissues. However, factors other than TNF may be operative.

Also consistent with the oral stratum results was a trend toward a modest increase in plasma HIV RNA levels. However, none of the patients were receiving the potent protease inhibitor-containing antiretroviral regimens that became available subsequently. Thus, it is not known whether this trend would still be seen in patients who receive thalidomide at the same time as highly active combination antiretroviral therapy.

In conclusion, thalidomide proved to be effective in healing aphthous ulceration of the esophagus in HIV-infected subjects. Repeat biopsies should be performed on ulcers not responding to thalidomide treatment to exclude cytomegalovirus infection that may not have been diagnosed by the initial biopsy. Adverse effects were common and included sedation, rash, and peripheral sensory neuropathy.

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Additional ACTG 251 Protocol Team Members and Investigators

Protocol team

J. S. Greenspan, D. Greenspan, and F. Aweeka, University of California, San Francisco; N. Ketter and L. Purdue, Division of AIDS, NIAID; J. McFarland and W. Levy, ACTG Operations Center, Social and Scientific Systems, Rockville, MD; G. Jones, Data Management Center, Frontier Science Technology and Research Foundation, Amherst, NY; A. Bardequez, New Jersey Medical School, Newark; R. Clark, Tulane University, New Orleans; N. Quesada, University of California, Los Angeles; P. J. Andrulis, Jr., and M. W. Drulak, Andrulis Pharmaceuticals, Beltsville, MD.

Other investigators

K. Luykx, Mount Sinai Medical Center, New York; C. van der Horst, University of North Carolina, Chapel Hill; S. Forstat, University of California, San Francisco; B. A. Royer, University of Washington, Seattle; H. Kessler and J. Pulvirenti, Rush Presbyterian Medical Center, Chicago; D. Ogata-Arakaki; University of Hawaii, Honolulu; J. Doweiko and L. Johnson-Pope, Harvard Medical School, Boston; S. P. Raffanti, Meharry Medical College, Nashville, TN; R. Hewitt and D. Blair, State University of New York, Buffalo; L. J. Wheat and B. W. Zwickl, Indiana University, Indianapolis; and R. Delapenha and Y. Butler, Howard University, Washington, DC.

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Acknowledgments

We gratefully acknowledge the technical support of Susan Stehn and Jana Parson, the secretarial assistance of Charlene Kahn and Joyce Banks, the clinicians who referred patients to the study, and the patients who participated.

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Footnotes

  • ↵1 Additional investigators who participated in this trial are listed after the text.

  • Written informed consent was obtained from patients prior to enrollment into the study, and human experimentation guidelines of the US Department of Health and Human Services and those of the authors' institutions were followed in the conduct of the study.

  • Financial support: AIDS Clinical Trials Group, National Institute of Allergy and Infectious Diseases, NIH (grant AI-38855); General Clinical Research Center Units, National Center for Research Resources.

  • Received October 7, 1998.
  • Revision received February 24, 1999.
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  1. J Infect Dis. (1999) 180 (1): 61-67. doi: 10.1086/314834
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