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

Antiretroviral Agents and
Treatment of HIV Infection
Charles Flexner
I. Overview of HIV Infection
and its Treatment
There are currently several million people taking
chronic combination antiretroviral therapy to suppress
human immunodeficiency virus (HIV) infection,
including >3 million in sub-Saharan Africa alone. This
is an amazing achievement for a disease that was uniformly
fatal and with few treatment options just two
decades ago. Combination antiretroviral therapy prolongs
life and prevents progression of disease caused
by HIV. The pharmacotherapy of HIV infection is a
rapidly moving field. In 2009, 24 antiretroviral drugs
were available in the U.S. Three-drug combinations are
the minimum standard of care for this infection, so current
agents constitute several thousand possible regimens.
The long-term management of a patient on
antiretroviral therapy can be daunting, even for experienced
healthcare providers. Knowing the essential features
of the pathophysiology of this disease and how
chemotherapeutic agents affect the virus and the host
is critical in developing a rational approach to therapy.
Unique features of this drug class include the need for
lifelong administration to control virus replication and
the possibility of rapid emergence of permanent drug
resistance if these agents are not used properly.
Increasingly, the public health impact of this epidemic
has shifted to those regions least able to afford
treatment. Because combination antiretroviral therapy
has the capacity to improve the quality of human health
and to produce near-normal life expectancies (Lee et al.,
2001), there is a strong impetus to provide these drugs
to as many infected individuals as possible. Through a
combination of increased foreign aid, access to generic
antiretrovirals, and willingness on the part of legacy
pharmaceutical companies to allow violation of intellectual
property law for this class of drugs, HIV treatment
is now a possibility for much of the world.
Because the number of effective treatment options is
large, emphasis is shifting from efficacy to long-term
convenience, tolerability, and safety. One outcome has
been the development of single tablet fixed-dose combinations
of drugs that can be taken orally once or twice
a day. Because treatment is taken for years if not
decades, the potential adverse effects of each drug take
on increasing importance.
PATHOGENESIS OF HIV-RELATED
DISEASE
Human immunodeficiency viruses (HIV) are lentiviruses,
a family of mammalian retroviruses evolved to establish
chronic persistent infection with gradual onset of clinical
symptoms. Unlike herpesviruses, replication is constant
following infection, and although some infected cells may
harbor nonreplicating virus for years, in the absence of
treatment there generally is no true period of viral latency
following infection (Greene and Peterlin, 2002). Humans
and nonhuman primates are the only natural hosts for
these viruses.
There are two major families of HIV. Most of the
epidemic involves HIV-1; HIV-2 is more closely related
to simian immunodeficiency virus (SIV) and is concentrated
in western Africa. HIV-1 is genetically diverse,
with at least five distinct subfamilies or clades. HIV-1
and HIV-2 have similar in vitro sensitivity to most antiretroviral
drugs, although the non-nucleoside reverse
transcriptase inhibitors (NNRTIs) are HIV-1-specific and
have no activity against HIV-2. Within HIV-1 isolates,