Thalidomide Treatment for Refractory HIV-Associated Colitis: A Case Series
Thalidomide Treatment for Refractory HIV-Associated Colitis: A Case Series
Leann Johnson 2
Joseph N. Jarvis 1
Edmund G. L. Wilkins 2
Phillip E. Hay 0
0 Department of Genitourinary and HIV Medicine, St. George's Hospital , London , United Kingdom
1 Centre for Infection, Department of Cellular and Molecular Medicine, St. George's University of London
2 Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital , Manchester
Thalidomide has been used as a treatment for various human immunodeficiency virus (HIV)-associated and non-HIV-associated illnesses, generally in cases in which inflammatory disease is refractory to standard therapy. Here, we discuss the successful use of thalidomide in 3 patients with severe, idiopathic HIV-associated colitis.
Thalidomide has been used as a treatment for various
HIVassociated illnesses, mainly for the occasional complication of
a severe, refractory inflammatory reaction, as occurs in patients
with major oral and esophageal aphthous ulceration [
hypertrophic mucocutaneous herpes simplex , and prurigo
]. It has also been used to treat HIV-related
malignancies (e.g., Kaposi sarcoma [
] and Castleman disease)
and other chronic HIV-related illness (e.g., wasting [
chronic enteropathy). We discuss the successful use of
thalidomide in 3 patients with severe, idiopathic HIV-associated
Case reports. A 51-year-old, HIV-infected white man
presented in 2003 with a 6-week history of diarrhea. HIV infection
had been diagnosed 7 years earlier. The patient was treatment
naive. His CD4 cell count was 670 cells/mL, and his viral load
was 82,000 copies/mL. There was no other significant medical
history—specifically, no history of gastrointestinal disease.
Colonoscopy revealed colitis with scattered deep ulceration that
ran the length of the colon (figure 1). Histologic examination
revealed moderate inflammation with occasional crypt
abscesses but no evidence of an infective etiology.
Over 4 months, symptoms persisted, with marked diarrhea
and weight loss. Extensive investigations failed to elicit a cause,
and no bacterial (including Bartonella species, Chlamydia
trachomatis, and spirochetes), protozoal, or viral (including
cytomegalovirus and adenovirus) infective pathology was found.
The colitis failed to respond to treatment with high-dose
steroids, azathioprine, or empirical courses of ciprofloxacin,
metronidazole, valganciclovir, and clarithromycin, which were
given to cover potential causes. Antiretroviral therapy with
didanosine, tenofovir, and ritonavir-boosted lopinavir was
initially started and later switched to efavirenz, stavudine, and
lamivudine. Because of the unrelenting course of the colitis,
the patient was referred for panproctocolectomy, but a
therapeutic trial of thalidomide was undertaken first. Five days later,
the patient was passing semisolid stools, and surgery was
cancelled. After 2 weeks of therapy, the patient had gained 8 kg
in weight and was passing normal solid movements once per
day. He was discharged from the hospital 3 weeks after
commencement of thalidomide treatment to complete a 12-week
course of thalidomide (100 mg twice per day), followed by
lower-dose thalidomide treatment for 1 year. The patient has
subsequently been symptom free for 13 years.
Patient 2 was a 43-year-old HIV-infected man who presented
with a 1-month history of watery diarrhea and weight loss in
2005. HIV had been diagnosed 15 years previously, and the
patient had extensive experience with treatment. At
presentation, his CD4 cell count was 77 cells/mL, and his viral load was
3413 copies/mL; at the time, his combination treatment
regimen was tenofovir, emtricitabine, and ritonavir-boosted
tiHIV/AIDS • CID 2008:47 (1 July) • 133
pranavir. Medical history included Pneumocystis jiroveci
pneumonia, and since HIV diagnosis, he had experienced several
self-limiting episodes of endoscopy-proven nonspecific colitis.
Sigmoidoscopy revealed inflammation and linear ulceration
in the sigmoid and rectum (figure 2). Histologic examination
showed active chronic inflammation. Mesalazine treatment
provided no benefit, and the patient lost an additional 6 kg in
weight over 2 weeks. Additional endoscopy revealed severe
inflammation and exudative ulcers from the rectum to
midtransverse colon. No infective process was identified, and
prednisolone enemas were commenced. Extensive rectal bleeding
required multiple blood transfusions, and high-dose oral
steroids were added to the treatment regimen, with no
improvement. A panproctocolectomy was planned, and a trial regimen
of thalidomide (100 mg per day) was administered. Within a
few days of treatment, the patient’s symptoms had completely
resolved, and additional flexible sigmoidoscopy at day 7
demonstrated healing ulcers (figure 3). Five days later, the patient
was discharged from the hospital free of symptoms. The
antiretroviral regimen was changed to darunavir, ritonavir,
emtricitabine–tenofovir disoproxil fumarate, and enfuvirtide.
Three months later, he remained healthy, and his viral load was
undetectable; his CD4 cell count was 230 cells/mL. The
thalidomide regimen was stopped with gradual dose reduction over
a 3-month period. In 2006, the patient had 1 additional episode
of colitis, which was attributed to Campylobacter infection, but
he has otherwise remained healthy.
Patient 3 was a 31-year-old white man who presented to the
hospital in 2004 with a 2-month history of bloody diarrhea.
Initial sigmoidoscopy demonstrated proctitis suggestive of
inflammatory bowel disease, but treatment with mesalazine and
steroid enemas was not effective. Fecal cultures yielded negative
results, and no ova, cysts, or parasites were noted. One month
later, a second endoscopic examination revealed multiple deep,
punched ulcers, and histologic examination demonstrated
ulceration with florid inflammation and intranuclear inclusion
bodies (figure 4). Findings were initially thought to be
consistent with cytomegalovirus (CMV) colitis, so the patient was
advised to undergo an HIV test, the results of which were
positive. The patient commenced valganciclovir treatment.
However, on subsequent review, CMV inclusion bodies were
not confirmed, and there was no biopsy evidence of any
infective pathology. Immunohistochemistry tests for CMV and
herpes simplex virus yielded negative results.
At the time of presentation with colitis, the patient’s CD4
cell count was 279 cells/mL, his HIV load was 4370 copies/mL,
and the results of a CMV PCR were negative. He commenced
treatment with lamivudine-zidovudine and efavirenz, followed
shortly by thalidomide (50 mg per day for 1 week then 50 mg
twice per day thereafter). Diarrhea had improved markedly
within 1 month and had completely resolved by 2 months. An
additional sigmoidoscopy was performed 4 months later and
revealed healing ulcers (figure 5), and the patient’s CD4 cell
count had increased to 672 cells/mL. Two months later, he was
symptom free. Thalidomide therapy was stopped after a total
of 6 months treatment.
Discussion. HIV-associated infective colitis is well
described, with the major opportunistic pathogen being CMV. It
may manifest as a complication of seroconversion. The
diagnosis of noninfective, HIV-related colitis is also well recognized;
this diagnosis may be made once infective pathologies have
been excluded and the disease remains refractory to standard
therapies for inflammatory bowel disease. It may be difficult
to distinguish this condition from inflammatory bowel disease,
because they can be very similar histologically. Recent years
have seen a resurgence in the use of thalidomide for a variety
of inflammatory conditions—notably Behcet disease [
inflammatory bowel disease [
], graft-versus-host disease, and
other dermatological and rheumatological conditions [
During 1996–2000, several randomized, double-blind,
placebo-controlled trials of thalidomide use in HIV infection were
performed. Two studies by Jacobson et al. [
a benefit of thalidomide use in HIV-infected patients with
refractory oral and esophageal aphthous ulceration. Patients were
treated with 200 mg of thalidomide per day for 4 weeks; the
oral ulceration study demonstrated complete or partial
resolution in 90% of patients (complete resolution in 55%), and
73% of patients with esophageal ulceration experienced
complete resolution. In 2000, Kaplan et al.  studied the efficacy
and safety of thalidomide use in patients with AIDS who had
associated wasting. One hundred three patients were recruited
and randomized to 3 groups to receive either placebo or
thalidomide at 100 mg per day or 200 mg per day for 8 weeks;
significant weight gain was demonstrated in both thalidomide
groups. Reyes et al. [
] reported similar results in a smaller
study of thalidomide (100 mg 4 times per day for 12 weeks),
finding an increase in weight and higher Karnofsky score in
the thalidomide group, compared with the placebo group. All
4 studies reported mild-to-moderate adverse effects (mainly
rash, somnolence, and sensory peripheral neuropathy). Other
case reports have described the beneficial use of thalidomide
in HIV-infected patients with alopecia areata, hypertrophic
genital herpes infection [
], prurigo nodularis [
], Kaposi sarcoma
], and Castleman disease.
In the non-HIV arena, the benefit of thalidomide use is being
increasingly recognized for the treatment of inflammatory
bowel disease that is resistant to standard therapies. It has been
used in several small studies to treat refractory disease at a
variety of dosages; however, randomized, controlled trials have
yet to be performed. Bariol et al. [
] described a significant
improvement in symptoms and histologic findings in 11
patients with a range of inflammatory bowel pathologies who
were treated for 12 weeks. Similar findings were reported by
Plamondon et al. [
] in a study of 25 patients with luminal
and fistulating Crohn disease.
The mechanisms underlying the immunomodulatory and
anti-inflammatory actions of thalidomide remain unclear,
alHIV/AIDS • CID 2008:47 (1 July) • 135
though modulation of inflammatory cytokines, particularly
TNF-a, appears to be important [
]. The drug has been shown
to inhibit lipopolysaccharide-induced TNF-a production in
human monocytes [
], although the exact mode of action has
yet to be determined. Thalidomide has also been shown to have
antiangiogenic effects [
], which are thought to be mediated
by suppression of vascular endothelial growth factor. This is
thought to contribute to antitumor activity and has also been
shown to be beneficial for cases of refractory intestinal bleeding
due to Crohn disease and angiodysplasias.
Adverse reactions to thalidomide are well described, and
apart from its well known potential for teratogenicity, it has
also been associated with rash, somnolence, peripheral
neuropathy, constipation, dizziness, neutropenia, and headache.
Rare complications include hepatotoxicity and toxic epidermal
The optimum dosage and duration of therapy of thalidomide
are unknown because of a lack of pharmacotherapeutic studies.
Generally, the dose is adjusted on the basis of clinical response
and tolerability, and it is gradually reduced once disease has
been suppressed and a decision is made to stop therapy.
In these cases that we have described, the pathology
underlying HIV-associated refractory colitis is unclear. Thalidomide
has proven to be effective for treating such patients. However,
it remains to be seen whether this efficacy is because the patient
had undiagnosed inflammatory bowel disease or another
HIVrelated pathology. Large, randomized, controlled trials of
treatment of both HIV-associated and non–HIV-associated colitis
need to be performed to learn more about the underlying
pathologies of this condition and about the safety and efficacy of
treatment with thalidomide.
Potential conflicts of interest. All authors: no conflicts.
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