Immunotherapy for Infectious Diseases

Tuberculosis and Other Mycobacterial Infections 291
the combination of thalidomide and anti-TB drugs are protected from death compared
with animals treated only with anti-TB drugs (131). Based on these promising preclinical
data, a randomized, placebo-controlled trial of adjunctive thalidomide in HIVnoninfected
children with tuberculous meningitis is currently under way in South
Africa comparing treatment with thalidomide or placebo in addition to standard
anti-TB drugs and corticosteroids during the first month of TB treatment.
The side effect profile of thalidomide varies considerably among different patient
groups. Aside from its teratogenic effects, the major toxicity of thalidomide is a peripheral
polyneuropathy that occurs in 20–50% of patients. It is predominantly sensory and
can be irreversible. Other side effects include sedation, orthostatic hypotension, xerostomia,
and rash. Thalidomide was approved in 1998 for use in the United States for
the treatment of severe erythema nodosum leprosum and is under active investigation
in other immunologically mediated conditions such as HIV wasting syndrome. Because
of its teratogenicity and neurologic toxicity, its use has been reserved for conditions
refractory to other medical therapy and is strictly regulated in women of child-bearing
age. Patients on chronic therapy must be followed closely for neurologic toxicities.
Other Inhibitors of TNF-�
Pentoxifylline is a phosphodiesterase inhibitor used for treatment of intermittent
claudication, in which it acts to increase the deformability of the red blood cell membrane.
Pentoxifylline also inhibits the production of TNF-� at the transcriptional level,
as well as the effects of the cytokine on target tissues (132–134). It reduces the pulmonary
toxicity of TNF-� in animal models of sepsis (135). Pentoxifylline inhibits
HIV-1 expression by monocytes and lymphocytes in acute and chronic in vitro expression
models (136,137). Oral administration of 1200–2400 mg daily to AIDS patients
without TB or other active opportunistic infections results in reduced TNF-� mRNA
in circulating mononuclear cells, reduced capacity to produce TNF-� following stimulation
in cell culture, and reduced serum triglyceride, but it has no effect on plasma
HIV RNA (138,139).
A double-blind, placebo-controlled study of adjunctive therapy with pentoxifylline
(1800 mg/day) as a timed-release formulation was performed in Ugandan HIV-infected
patients with pulmonary TB. Subjects had early HIV disease (mean CD4 cell count,
380/�L) and did not receive other antiretroviral drugs. They were treated for the first 4
months with standard TB therapy. Pentoxifylline resulted in decreased plasma HIV RNA
and serum �2-microglobulin and, in a subset of moderately anemic patients, improved
blood hemoglobin levels. Trends were noted toward reduced TNF-� production in vitro
and improved performance scores, but these did not reach statistical significance. No
effect was noted on body mass, CD4 cell count, TB relapse, or survival (140,141).
Several studies of prednisolone or other corticosteroids as adjunctive therapy for
HIV plus TB are currently under way. Like pentoxifylline and thalidomide, prednisolone
inhibits TNF-� expression but also affects many other cellular processes. An
uncontrolled trial of prednisolone 0.5 mg/kg for 6 months and then 0.3 mg/kg daily in
AIDS patients without TB found increased numbers of circulating CD4 cells (�119/�L
from baseline) but no effect on plasma HIV RNA (142). A pilot study of prednisolone
in HIV plus TB, administered during the second month of TB therapy, found that
a daily dose of 2 mg/kg was required to decrease expresson of TNF-� and HIV RNA