DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A reservoir of long-lived quiescent T cells harboring
infectious HIV DNA integrated into the host chromosome
was identified independently by several groups
of investigators (Chun et al., 1998; Finzi et al., 1997).
Infectious HIV can be produced by these quiescent
cells after chemical activation ex vivo (and presumably
if the cells are activated by immune stimuli in vivo), but
the nonreplicating form of the viral genome is not susceptible
to antiretroviral drugs. Most estimates suggest
that at least some of these cells will survive for decades
and probably for the life of the patient (Siliciano et al.,
2003) regardless of the type of anti-HIV treatment.
Fortunately, in the presence of suppressive combination
antiretroviral therapy it appears that residual viremia is
the consequence of release of virus from pre-formed
latent reservoirs, and the risk of developing drug resistance
in such treated patients is negligible (Nettles et al.,
2005). Episodic detection of low level plasma HIV
RNA in otherwise suppressed individuals (also known
as blips) almost certainly represents release of previously
formed virus from resting cells; intermittent
detection of HIV RNA at a concentrations <500
copies/mL is not associated with increased risk of treatment
failure or drug resistance, unless this is accompanied
by nonadherence (Kieffer et al., 2004).
Drug resistance is a key problem that must be prevented
and circumvented through a combination of regimen
selection and patient education. There is a high
likelihood that all untreated infected individuals harbor
viruses with single-amino-acid mutations conferring
some degree of resistance to every known antiretroviral
drug because of the high mutation rate of HIV and the
tremendous number of infectious virions (Coffin,
1995). Starting treatment with only a single antiretroviral
drug inevitably provokes the emergence of drugresistant
virus, in some cases within a few weeks (Wei
et al., 1995). Drug therapy does not cause mutation but
rather provides the necessary selective pressure to promote
growth of drug-resistant viruses that arise naturally
(Coffin, 1995). A combination of active agents
therefore is required to prevent drug resistance, analogous
to strategies employed in the treatment of tuberculosis
(Chapter 56). Intentional drug holidays, also
known as structured treatment interruptions, allow the
virus to replicate anew and increase the risk of drug
resistance and disease progression (Lawrence et al.,
2003). Recrudescent replication of HIV after stopping
therapy is associated with an acute increase in the risk
of death, mainly from cardiovascular events (El-Sadr et
al., 2006). This may be the consequence of increased
immune activation that accompanies replication of the
virus; HIV infection is associated with endothelial cell
dysfunction, although the absolute increase in cardiovascular
risk after controlling for other risk factors is
small (Aberg, 2009).
The current standard of care is to use at least three
drugs simultaneously for the entire duration of treatment.
The expected outcome of initial therapy in a previously
untreated patient is an undetectable viral load
(plasma HIV RNA <50 copies/mL) within 24 weeks of
starting treatment (Department of Health and Human
Services, 2010). In prospective comparative trials, twodrug
regimens were more effective than single-drug
regimens (Fischl et al., 1995; Hammer et al., 1996;
Saag et al., 1998), and three-drug regimens are more
effective still (Collier et al., 1996; Gulick et al., 1997;
Hammer et al., 1997). Mathematical models of HIV
replication suggested that three is the minimum number
of agents required to guarantee effective long-term suppression
of HIV replication without resistance (Muller
and Bonhoeffer, 2003). However, earlier models may
not adequately predict the effects of newer and more
potent antiretrovirals.
Randomized controlled trials found that a combination of
two potent drugs (e.g., an NNRTI plus a PI) had equivalent virologic
efficacy to either agent plus two NRTIs (Riddler et al., 2008).
In treatment-naive patients, a regimen containing a non-nucleoside
plus two nucleoside reverse transcriptase inhibitors was as effective
as a regimen containing an additional nucleoside (Shafer et al.,
2003), indicating the equivalence of these three-drug and four-drug
regimens. Four or more drugs may be used simultaneously in pretreated
patients harboring drug-resistant virus, but the number of
agents a patient can take is limited by toxicity and inconvenience.
Even for heavily treatment-experienced patients, a three-drug regimen
containing at least two potent active agents is often as
effective as regimens containing additional active agents (Steigbigel
et al., 2008).
Several small studies have now shown that patients who are
fully suppressed (HIV plasma RNA <50 copies/mL) for months on
a triple drug combination may be switched to a single “boosted” protease
inhibitor (e.g., lopinavir/ritonavir or atazanavir/ritonavir) and
maintain full suppression of viral replication for years on antiretroviral
monotherapy. Such simplification strategies are investigational
and should only be used in patients who are known to be highly
adherent and are closely monitored, because randomized trials have
found higher failure rates in patients maintained on only a single
active agent (Wilkin et al., 2009).
Pharmacodynamic synergy is probably not an important consideration
in regimen selection, although most prescribers prefer to
use drugs that attack at least two different molecular sites. This could
include NRTIs that target the active site of the enzyme combined
with an NNRTI that binds to a different site on the same enzyme, or
an inhibitor of a different enzyme, such as HIV protease or integrase.
Regimens containing an NNRTI or PI plus two NRTIs have similar
long-term efficacy.
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CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION