Page 48 - AIDSBK23C

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through decreased CD4 interleukin-1ß-converting enzyme (ICE, or caspase 1)
expression.[264,265] Tipranavir is a non-peptidic protease inhibitor.[266]
All protease inhibitors are substrates for cytochrome P450, mainly CYP3A4, and most
are inhibitors of this metabolic pathway. Ritonavir is the most potent inhibitor. both lopinavir
and tipranavir are inducers of CYP3A4. Thus, protease inhibitors have extensive interactions
with each other. Most antiretroviral regimens with protease inhibitors include ritonavir with
another agent in order to boost effective drug concentrations.[254]
Problems in the development of this class of drugs have included finding an effective,
specific inhibitor of HIV protease that does not also interfere with normal cellular proteases, as
well as HIV viral resistance. Effective drugs include saquinavir (saquinavir mesylate), ritonavir,
indinavir (indinavir sulfate), nelfinavir, and amprenavir, all of which are well tolerated and
efficacacious in reducing plasma HIV-1 RNA along with increasing CD4 lymphocyte counts. In
addition, protease inhibitors show efficacy in combination with reverse transcriptase
inhibitors.[264,267] Nevertheless, HIV resistance to protease inhibitors does occur and limits
effectiveness.[268]
Protease inhibitors are often most effective at high dosages, but adverse reactions to these
toxic agents may limit their use. All of them may cause gastrointestinal symptoms including
nausea, vomiting, and diarrhea. GI intolerance is a cause of lopinavir/ritonavir therapy
modification or interruption. Their use may be accompanied by the adipose tissue redistribution
known as protease inhibitor-associated lipodystrophy (PIAL), though this phenomenon may
occur in persons with AIDS not taking protease inhibitors. This syndrome is associated with loss
of facial fat, dorsocervical tissue accumulation, increased internal abdominal fat accumulation,
hyperlipidemia (often exceeding 1000 mg/dL), peripheral insulin resistance and impaired
glucose tolerance, but there is a wide variation in the severity and clinical presentation of these
metabolic side effects. The dyslipidemia is most pronounced with ritonavir.[269] The agent
atazanavir appears to affect glucose metabolism less than other protease inhibitors.[270]
All PIs, and ritonavir in particular, appear to be associated with hepatic transaminase
elevations. Unconjugated hyperbilirubinemia can also occur with PIs, particularly
indinavir.[260] Protease inhibitor therapy can be a risk factor for development of HIV-
associated sensory neuropathy.[271] Nephrolithiasis may complicate indinavir therapy when
patients do no receive adequate hydration. In addition, hyperbilirubinemia may occur with
indinavir therapy. Paresthesias may complicate ritonavir therapy. Amprenavir is associated with
skin rashes and with hypersensitivity reactions. Hypersensitivity to abacavir is determined by the
presence of HLA B*5701, which can be tested prior to starting therapy. Gastrointestinal
intolerance frequently leads to saquinavir therapy modification or interruption. Dosing regimens
for these and other medications can be complex and difficult to follow for patients, but must be
followed carefully in order to have maximum effectiveness and prevent development of HIV
resistance.[256,260,264,267] Since protease inhibitors are metabolized by the cytochrome
CYP450 enzymes in the liver and small intestine, there is a potential for drug interactions via this
metabolic pathway.[272]
The use of NRTIs, NNRTIs, and PIs formed the mainstay of antiretroviral therapy
st
through the early 21 century. New classes of antiretroviral drugs include fusion inhibitors,
integrase inhibitors, maturation inhibitors, and CCR5 antagonists. The rate at which new
antiretroviral drugs are being produced suggests that multiagent, synergistic treatment regimens
may keep viremia suppressed for decades in infected persons.