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Types of Antiretroviral Drugs
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NRTIs
Nucleotide Inh
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zidovudine
didanosine
stavudine
lamivudine
abacavir
emtracitabine
tenofovir
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Retrovir, AZT
ddI, Videx
D4T, Zerit
3TC, Epivir
Ziagen
Emtriva
Viread
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NNRTIs
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delavirdine
nevirapine
efavirenz
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Rescriptor
Viramune
Sustiva
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PIs
Viral Fusion
Inbitors
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saquinavir
ritonavir
indinavir
nelfinavir
amprenavir
lopinavir/ritonavir
atazanavir
enfuvirtide
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Fortovase, Invirase
Norvir
Crixivan
Viracept
Agenerase
Kaletra
Reyataz
T-20, Fuzeon
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At the present time, specific antiretroviral agents can be classified
into two groups: reverse transcriptase inhibitors and protease inhibitors.
Reverse transcriptase inhibitors (RTI's) work by preventing reverse transcription
of viral RNA into host DNA, and include zidovudine (AZT), didanosine (ddI),
zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir, ziagen (ABC), and emtriva.
Combination pills including AZT, 3TC and abacavir exist to enhance
compliance. These are all considered nucleoside RTI's. Nevirapine,
delavirdine and efavirenz are nonnucleoside RTI's available that work much
the same way. Side effects recently described with some agents in this
class include mitochondrial toxicity and lactic acidosis.
Protease inhibitors work by preventing the cleavage of protein
precursors into viral particles, and include saquinavir, ritonavir,
indinavir, nelfinavir and amprenavir. In combination with nucleosides,
protease inhibitors can reduce viral load to undetectable levels in certain
patients, but must be continually maintained at optimum doses to avoid the
development of resistance. Unlike RTI's, where occasional skipped doses
have minimal impact on viral resistance, protease inhibitors must be taken
on a strict, and complicated, schedule to avoid resistance.
Cross-resistance is likely to occur to most other protease inhibitors
available. Other drawbacks to the protease inhibitors include poor
solubility, drug interactions, inadequate CNS penetration and large number
of pills to be taken. Fat redistribution, insulin resistance and
hyperlipidemia have been associated with protease inhibitor use with
variable frequency. Combining low-dose ritonavir with other protease
inhibitors allows for administering a lower dose of the other agent,
because ritonavir increases the other drug's concentration level. This not
only reduces number of pills taken and the degree of side effects seen but
will increase the concentration and efficacy of the other protease
inhibitor as well.
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When starting therapy in a patient who has not been on
any antiretroviral agents (treatment naive), begin with a regimen that is
expected to reduce viral replication to undetectable levels. Strongly
recommended regimens include either efavirenz, or a boosted (combined with
low-dose priming ritonavir) protease inhibitor combination with two NRTI
agents such as zidovudine/lamivudine, abacavir/lamivudine,
stavudine/lamivudine or zidovudine/lamivudine/abacavir. Tenofovir has also
been considered as part of an initial regimen.
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Changing regimens is predicated on toxicity,
intolerance, nonadherence, or treatment failure, which can initially be
signalled by an increase in viral load of 0.5 to 1.0 log and confirmed
through resistance testing. When drug failure or resistance is an issue,
new regimens should include all new drugs to which the virus is
susceptible, much like that of tuberculosis treatment practices.
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Logarithmic Changes in Clinical Practice/b>
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Log Drop
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Change
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Change
(copies) for Pt w/100,000 copies HIV RNA
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0.3
0.5
0.6
1.0
1.5
2.0
2.3
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2-fold
3-fold
4-fold
10-fold
30-fold
100-fold
200-fold
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50,000
33,000
25,000
10,000
3300
1000
500
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Indications
for changing therapy:
- Treatment failure, as suggested by a confirmed
rising plasma HIV RNA level or failure to achieve the desired
reduction in plasma viral load; declining CD4+ cell count; or
clinical disease progression
- Unacceptable toxicity of, intolerance of, or
nonadherence to the regimen
- Current use of suboptimal treatment regimens,
as reflected by resistance assay findings, or using fewer than three
agents21
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Decisions regarding changes in antiretroviral therapy because of
treatment failure not due to noncom-pliance should ideally be guided by
results of resistance testing. Specific criteria that should prompt
consideration for changing therapy include: less than a 1 log reduction by
8 weeks; failure to suppress plasma HIV RNA to undetectable levels within
20 - 24 weeks of initiating therapy; repeated detection of virus in plasma
after initial suppression to undetectable levels, (suggesting the
development of resistance); any reproducible significant increase (3-fold
or greater) from the nadir of plasma HIV RNA not attributable to
intercurrent infection, vaccination or test methodology; persistently
declining CD4 T-cell count, clinical deterioration, toxicity, intolerance,
non-adherence or suboptimal current regimen. (20)(21)
Virologic failure, defined as an increase in viral load from previously
undetectable levels, can be assessed through antiretroviral resistance
assays. Testing for HIV resistance to antiretroviral drugs is a prudent way
to guide antiretroviral therapy. The two types of resistance testing are
genotypic, in which the patient's HIV genome strain is defined, and
phenotypic, where the patient's HIV virus is subjected to various
medications and its growth characteristics are studied. HIV resistance
testing is currently recommended for patients with virologic failure during
HAART as well as suboptimal suppression of viral load after initiation of
antiretroviral therapy. Testing should be considered for acute HIV
infection, but is not generally recommended for chronic HIV infection prior
to initiation of therapy or for patients with a viral load less than 1000
HIV RNA copies/ml. Testing should be performed on the patient's
"failing" regimen, since virus usually reverts to its native
"wild" form when antiviral medications are discontinued.
Insurance reimbursement can still be problematic with some resistance assay
products. Genotypic assays are, in general, more difficult to interpret,
but provide more insight into the clinical relevancy of different mutation
patterns and tend to have a more rapid turnaround time than phenotypic
assays.
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When
viral load should be measured:
Baseline,
3-4 weeks, 3-6 months, 3-4 weeks after changing therapy
Guidelines for
interpreting viral load:
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Long-term goals: sustain the decrease in viral load
- A decrease of 0.5 log - 1.0 log = therapy is working
- An increase of 0.5 - 1.0 log = treatment failure = need to change
therapy regimen
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T cells and viral load should be done at baseline, and repeated at 4,
8-12 and 16-24 weeks after initiating or changing therapy. Unlike CD4 cell
counts, which may take several months to respond, response rate with viral
load testing occurs within 4 weeks. The CD4 T-cell count and HIV-RNA viral
load tests each provide specific information, and one should not be used in
lieu of the other.
Viral load can be influenced by vaccinations and viral illness. If a
particular test result increases out of proportion to clinical symptoms or
even CD4 counts, it is advisable to repeat the test before switching
regimens. Two assays, the branched chain DNA and RT-PCR methods, are
commercially available for viral load testing, although only the RT-PCR
method has been approved by the FDA. The test is also complicated to run:
blood needs to be spun down, frozen and received by a processing laboratory
within four hours. As such, it should only be drawn in centers equipped to
handle this procedure.
As is readily apparent with the above recommendations, the medical
management of HIV infection is a very complex matter. Improper, inadequate
and inconsistent therapy can irreversibly jeopardize an HIV-infected
person's chances of prolonged survival by allowing the virus to develop
resistance and subsequent cross-resistance to the agents available in
providing viral suppression. It is within reason to suggest that no
treatment--at least initially--would be better than inappropriate
treatment. As such, referral to a physician with expertise in the
management of HIV-infected persons, or at least with access to the latest
developments in this disease, should be seriously considered in all cases.
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