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

1628 Failure of an antiretroviral regimen is defined as a
persistent increase in plasma HIV RNA concentrations
in a patient with previously undetectable virus, despite
continued treatment with that regimen (Department of
Health and Human Services, 2010). This indicates
resistance to one or more drugs in the regimen and
necessitates a change in treatment. Once resistance
occurs, resistant strains remain in cells (mainly T-lymphocytes)
indefinitely, even though the resistant virus
may not be detectable in the plasma. For example,
women who received a single dose of nevirapine to
prevent mother-to-child transmission of HIV (and thus
were more likely to harbor nevirapine-resistant virus)
had a higher treatment failure rate if initiating therapy
with nevirapine within 6 months, compared to treated
women who had never received nevirapine (Lockman
et al., 2007). The selection of new agents is therefore
informed by the patient’s treatment history, as well as
viral resistance testing, preferably obtained while the
patient is still taking a failing regimen to facilitate
proper recovery and characterization of the patient’s
virus (Kuritzkes, 2004). Treatment failure generally
requires implementation of a completely new combination
of drugs. Adding a single active agent to a failing
regimen is functional monotherapy if the patient is
resistant to all drugs in the regimen and is likely to
produce resistance to the new agent.
Treatment failure is usually the consequence of
non-adherence. The risk of failing a regimen depends
on the percentage of prescribed doses taken during any
given period of treatment, but it also depends on the
drugs in the regimen. Efavirenz-based regimens may
be more forgiving of occasional skipped doses, and thus
more useful because of the long t 1/2
of that drug; ritonavir-boosted
PI regimens may be relatively more forgiving
because of their higher genetic barrier to
resistance (Gardner et al., 2009).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
As antiretroviral therapy becomes more effective and easier
to take, long-term toxicity of these drugs is of greater concern. An
important consequence of long-term therapy is the development of
a metabolic syndrome characterized by insulin resistance, fat redistribution,
and hyperlipidemia and known as the HIV lipodystrophy
syndrome. Lipodystrophy occurs in 10-40% of treated patients and
has been seen with most drug combinations used in clinical trials.
Symptomatic manifestations have been most strongly linked to the
older generation of NRTIs, especially stavudine, which had more
substantial mitochondrial toxicities; these drugs are now less commonly
used in the developed world. The pathogenesis is still somewhat
mysterious but involves phenotypic and metabolic changes
similar to those seen with other human lipodystrophy syndromes
(Garg, 2004). Clinical features include peripheral fat wasting (lipoatrophy),
central fat accumulation including enlarged breasts and
buffalo hump, insulin resistance and hyperglycemia, and elevations
in serum cholesterol and triglycerides. Switching from one drug regimen
to another may not reverse the symptoms, emphasizing its
ubiquitous nature and possible role of HIV infection per se.
Treatment is symptom directed and should include management of
hyperlipidemias as recommended by the American Heart Association
(Chapter 31). Lipodystrophy has been associated with an increased
risk of myocardial infarction in virologically controlled patients,
emphasizing the importance of cardiovascular risk factor reduction.
There is evidence that chronic HIV infection per se increases
long-term cardiovascular risks, but the quantitative contribution of
drug therapy to this risk is not well defined. Metabolic abnormalities
associated with chronic HIV infection and possibly exacerbated by
some drugs include insulin resistance, hyperglycemia, and increased
risk of diabetes mellitus, as well as osteopenia and its attendant complications
(Calmy et al., 2009).
A potential concern that applies to all protease inhibitors and
NNRTIs is clinically significant pharmacokinetic drug interactions
(Piscitelli and Gallicano, 2001). All agents in these two drug classes
can act as inhibitors and/or inducers of hepatic CYPs and other drug
metabolizing enzymes, as well as drug transport proteins.
Prescribing practices should be guided by up-to-date knowledge of
these potential effects. Internet-based educational resources are
updated frequently (see, e.g., Flexner and Pham, 2009) and are an
excellent way to track evolving knowledge about the undesired
effects of drugs used in combination with antiretrovirals.
An increasingly recognized complication of initiating antiretroviral
therapy is accelerated inflammatory reaction to overt or
subclinical opportunistic infections or malignancies. This is
thought to reflect reversal of immunodeficiency, resulting in new
antimicrobial host defenses. This immune reconstitution inflammatory
syndrome (IRIS) is most commonly seen when initiating
therapy in individuals with low CD4 counts and/or advanced HIV
disease, and it is associated with a better virologic response to therapy
(Manabe et al., 2007). Not surprisingly, this is now most prevalent
in resource-poor countries, where it may occur in >10% of
newly treated patients. Infections most commonly associated with
IRIS include tuberculosis and other mycobacterial diseases, cryptococcosis,
hepatitis virus infections, and Pneumocystis pneumonia.
Duration of symptoms ranges from a few days to more than a year.
Symptomatic relief can be obtained with anti-inflammatory drugs,
but systemic corticosteroids do not appear to shorten the course of
symptoms (Manabe et al., 2007).
II.
Drugs Used to Treat HIV
Infection
NUCLEOSIDE AND NUCLEOTIDE
REVERSE TRANSCRIPTASE INHIBITORS
The HIV-encoded, RNA-dependent DNA polymerase,
also called reverse transcriptase, converts viral RNA
into proviral DNA that is then incorporated into a host
cell chromosome. Available inhibitors of this enzyme
are either nucleoside/nucleotide analogs or non-nucleoside
inhibitors (Figure 59–2 and Table 59–2).