Immunotherapy for Infectious Diseases

164 Connick
counts ranged from 73 to 86 cells/mm 3 in the combination therapy groups after 6
months of therapy, almost double that of the subjects receiving only two nucleoside
analog drugs. Over the past 4 years, a variety of combinations of antiviral drugs have
been shown to be equally if not more potent in suppressing HIV-1 replication and
inducing increases in CD4� T-cell counts (8–12). These various combinations of
potent antiviral medications, frequently referred to as highly active antiretroviral therapy
(HAART), have become the standard of care for HIV-1 infection (13).
Commensurate with the introduction of HAART, there has been a dramatic decline
in mortality and morbidity from HIV-1 infection in the United States and other industrialized
countries. In the United States, AIDS-related deaths in adults declined from a
peak of 50,610 in 1995 to 16,273 in 1999 (14). The Adult/Adolescent Spectrum of HIV
Disease (ASD) sentinel surveillance project, which prospectively reviews medical
records of HIV-1-infected individuals in 11 U.S. cities, reported a significant decline
in the incidence of 15 of the 26 AIDS-defining illnesses between 1992 and 1997 (15).
A study of 1255 subjects in eight different U.S. cities with a history of at least one
CD4� T-cell count under 100 cells/mm 3 found significant declines in the incidence of
Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC), and
cytomegalovirus (CMV) retinitis between 1994 and 1997 (Fig. 1) (16).
These declines in opportunistic infections (OIs) cannot be explained by increases in
prophylactic measures to prevent them (15,16). Similar declines in the incidence of OIs
have been reported by other studies in the United States as well as Europe and Australia
(17–24). Randomized trials of potent combination antiretroviral therapy compared
with less potent regimens have demonstrated that it is the superior control of
HIV-1 replication and the increase in CD4� T-lymphocyte counts induced by potent
regimens that are associated with the reduced incidence of OIs (6,25,26).
Further evidence to suggest that HAART results in immune reconstitution comes
from numerous case reports of the resolution of OIs after initiation of therapy. Progressive
multifocal leukoencephalopathy (PML) (27–33) diarrhea owing to cryptosporidia
and microsporidia (34,35), treatment-refractory oral candidiasis (36,37),
molluscum contagiosum (38,39), and Kaposi’s sarcoma (40–42) have been reported to
regress after the initiation of potent combination antiretroviral therapy. Individuals with
a history of CMV retinitis, which in the absence of CMV-specific therapy usually progresses
within a few weeks, have had primary anti-CMV therapy withdrawn without
disease recurrence after receiving HAART (43–45). Similarly, disseminated MAC
infection, which previously required lifelong therapy for containment, has failed to
recur in several individuals despite cessation of primary therapy after a good response
to HAART (46). Primary prophylaxis for both PCP (47–51) and MAC (52–54) have
been safely withdrawn in subjects previously at risk after they had achieved sustained
increases in CD4� T-cell counts on HAART. These data suggest that the decrease in
OIs seen with potent antiretroviral therapy is owing not only to a halt in the progression
of HIV-1-induced immune deficiency but also to reconstituted immunity, which
allows individuals to contain infections immunologically that they were unable to control
previously. As a result of these data, guidelines regarding prophylaxis of OIs have
been modified to allow for the discontinuation of primary PCP and MAC prophylaxis
in individuals with sustained elevations in CD4� T-cell counts above threshold levels
in the setting of HAART (55).