Page 47 - AIDSBK23C

Page 47

Drug intolerance and drug toxicity are significant problems for all drugs used to treat
HIV infection. Many of these adverse effects appear to be mediated via mitochondrial toxicity,
such as liver toxicity with steatosis and lactic acidosis seen with NRTI therapy, manifested by
abdominal pain, nausea, or vomiting, and with a mortality rate near 50%.[259] Patients must be
monitored carefully for signs and symptoms of these complications. Zidovudine can cause
gastrointestinal symptoms of nausea and vomiting, like other NRTI’s, as well as headache, but
more importantly, it can occasionally lead to severe bone marrow suppression with anemia,
usually in the first few months of administration. Myopathy may also occur with long term
zidovudine therapy.[255] Hepatic mitochondrial damage can occur with the NRTIs zidovudine
or didanosine.[260]
Major toxicities associated with didanosine therapy that limit its use include
hepatotoxicity, pancreatitis, peripheral neuropathy, and gastrointestinal problems such as
diarrhea. Zalcitabine therapy was most often complicated by peripheral neuropathy (which led to
its removal from use), pancreatitis, maculovesicular cutaneous eruptions, and aphthous oral
ulcers (stomatitis). Stavudine’s major side effect is peripheral neuropathy, though anemia and
pancreatitis may also occur. There are infrequent major adverse reactions with lamivudine
therapy, the most common being gastrointestinal upset.[254,261] Abacavir therapy can be
complicated by a hypersensitivity reaction with flu-like symptoms, abdominal cramping,
diarrhea, and skin rash in up to 5% of cases.[256] Stevens-Johnson syndrome and/or toxic
epidermal necrolysis has been reported to complicate NRTI, NNRTI, and PI therapy.[262]
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been developed to treat
HIV infection. These drugs act via direct and non-competitive binding to a hydrophobic pocket
close to the active site of the reverse transcriptase enzyme of HIV. This binding causes a
conformational change and disrupts the catalytic site of reverse transcriptase.[254] Mutations
render HIV-1 group O and HIV-2 strains either resistant or less effective at non-toxic dosages to
all drugs within the entire NNRTI class, due to a single amino acid, Leu-188.[102] The first
generation drugs include nevirapine, delavirdine, and efavirenz. Second generation drugs with
less cross-resistance include the diarylpyrimidines: etravirine and rilpivirine. They are most
useful when either is used in combination with other antiretroviral agents. The major
complication after starting NNRTIs is skin rash, usually within six weeks.[261,263]
The NNRTIs nevirapine and efavirenz are inducers of hepatic cytochrome CYP3A4,
while delaviridine inhibits it. Hepatotoxicity with hepatic enzyme elevation has been reported
with NNRTIs. The use of PIs in combination with either efavirenz or nevirapine was associated
with an increased risk of hepatotoxicity compared to efavirenz or nevirapine alone In addition,
nevirapine and efavirenz are associated with hypersensitivity reactions, including skin rash. The
HLA-DRB1*01 allele is significantly associated with isolated rash alone in patients exposed to
nevirapine or efavirenz. Nevirapine is associated with a high rate of treatment discontinuations
from gastrointestinal intolerance. Nevirapine is associated with pancreas-related toxicities, but
not efavirenz.[260]
Protease inhibitors have been developed as anti-HIV drugs. The processing of large HIV
precursor proteins, such as p55 and p40 encoded by the gag and gag-pol genes of HIV into
smaller structural proteins p17, p24, and p7 of the viral core is performed via proteolytic
cleavage by an HIV-encoded aspartic protease. This late step in virus production is necessary for
maturation of immature viral particles into infectious virions. These drugs are synthetic
analogues of the HIV protein and block the action of HIV-protease to interfere with viral
replication. Protease inhibitors may also function by decreasing CD4 lymphocyte apoptosis