Biology Reference
In-Depth Information
T A B L E
3.5. Some Questions and Problems Stemming from HAART Therapy
Virologic problems
.
How low should viremia be to prevent disease progression? Is it necessary to
maintain viremia under the detection limit (>20 copies/mL)? Is it necessary to
eradicate?
.
How long will the suppression of HIV replication last?
.
How can we reach HIV that is in latently infected cells and sheltered in particular
anatomical sites (e.g., the central nervous system)
Immunologic problems
.
Augmentation of CD4 T cells is partial and (probably) limited in time
.
Augmentation of CD4 T cells is mostly supported by memory CD4 T cells
.
Increase of CD4 T-cell functions is partial and HIV-speci®c functions are not
recovered
.
CTL are defective in HAART-treated patients
Clinical problems
.
Access to therapy is not available to the vast majority of patients worldwide
.
Lack of response to HAART in a sizable quantity of patients (HIV viral load is
not suppressed and/or CD4 counts do not increase)
.
Side e¨ects
.
Lack of availability of immune modulators
®rst several days of therapy is the result of memory cells re-entering the blood
from lymphoid tissue (redistribution), together with a decrease in activation-
induced apoptosis. Peripheral expansion (cell division), which is believed to
occur slowly and continually, is only observed in the following weeks by a
slower increase of CD4 cells once redistribution has occurred. However, many
believe that the increase is caused by expansion alone. At present, the overall
theory of the kinetics of T-cell reconstitution is under debate.
Other positive e¨ects induced by HAART can be summarized as follows: 1)
consistent and signi®cant clinical improvements; 2) reduction in plasma HIV
viral load; 3) limited increases in CD4 T-helper functions (antigen-stimulated
proliferation, cytokine production); and 4) reduction in the percentage of acti-
vation markers bearing cells (i.e., diminished expression of CD38 on CD8
T
cells).
Nevertheless, HAART is ine¨ective in a sizable percentage of patients (up to
50% of individuals fail ®rst-line therapy and up to 80% fail second-line rescue
therapy) (Kaufman et al., 1998). HAART unresponsiveness can be manifested
as a lack of virologic e¨ect (i.e., HIV plasma viral load does not diminish sig-
ni®cantly), a lack of immunologic e¨ect (CD4 counts do not improve), or as a
lack of both virologic and immunologic e¨ects) ( Kaufman et al., 1998). Recent
data show that virological failure (i.e., signi®cant increases of HIV viral load
after an initial reduction of viremia) is a relatively common phenomenon in
HAART-treated individuals, and that salvage therapy in these individuals is
rarely
e½cacious.
Prompt
identi®cation
of
HAART-unresponsive
patients
