Newer
Anti-HIV Drugs and How to Use Them: Part I
| There
are currently several new anti-HIV drugs that have been approved by the U.S. Food
and Drug Administration or that are in clinical testing. These new drugs belong
to various drug classes, including nucleoside/tide reverse transcriptase inhibitors
(NRTIs), protease inhibitors (PIs), CCR5 antagonists, and, maturation inhibitors
(the newest class of anti-HIV drugs). Most of these new agents were developed
for patients who have developed resistance to HIV, but a few show promise for
use in patients who have never taken antiretroviral drugs before. The article
reviewed here has drawn information on these drugs from research meetings, medical
journals, and treatment guidelines, and offers insights on best to use them in
HIV patients. |
Drugs
belonging to three drug classes have been those most frequently used in the treatment
of HIV infection so far: nucleoside analog reverse transcriptase inhibitors
(NRTIs), non nucleoside reverse
transcriptase inhibitors (NNRTIs),
and protease inhibitors (PIs).
However,
over the past five years, several new therapies have been developed that have
significantly improved clinicians' ability to manage HIV infection. These include
3 drug classes with new mechanisms of action against the replication of HIV: (1)
entry inhibitors
(one that blocks fusion and one that is a CCR5 antagonist) (2) others that attack
already-existing targets in the virus, and (3) one that blocks HIV maturation. These
drugs have created opportunities for improvements in how to optimize therapy in
treatment-experienced patients, and some have allowed for simplification of therapy
and for improving drug tolerability in patients starting treatment for the first
time. An article appearing in the May 2009 issue of Current
HIV/AIDS Reports, reviews highlights of several of these newer agents
that have been FDA-approved or are still in development, and offers strategies
on how they can best be utilized by HIV patients. Nucleoside
Reverse Transcriptase Inhibitors (NRTIs) Apricitabine
Apricitabine
is a cytidine analogue that remains active against HIV in the presence of the
M184V mutation that occurs with high level resistance to lamivudine (Epivir) and
emtricitabine (Emtriva). It has been shown that after 24 weeks of therapy, apricitabine
is as tolerable as lamivudine in treatment-experienced patients with the M184V
mutation. A
study among 50 treatment-experienced patients demonstrated that at 24 weeks, there
was greater anti-HIV activity in those taking apricitabine, 600 or 800 mg twice
daily, with 71% and 73% having HIV-1 RNA less than 50 copies/mL, respectively,
compared with 58% of those treated with a lamivudine-containing regimen. Elvucitabine
Like
apricitabine, elvucitabine is a cytidine analogue with activity against HIV-1
with the M184V/I mutation. It has been studied in treatment-naïve patients.
It is being compared in studies with lamivudine administered in combination with
tenofovir (Viread) and efavirenz (Sustiva). At 48 weeks, elvucitabine showed similar
efficacy to lamivudine in these Phase 2 trials. About 95% of patients in both
groups suppressed HIV-1 RNA to less than 50 copies/mL. Nonnucleoside
Analogue Reverse Transcriptase Inhibitors (NNRTIs) Etravirine
(Intelence)
Etravirine is a second-generation NNRTI, approved by
the FDA in 2008 for use in treatment-experienced patients who have developed resistance
to the first-generation NNRTIs, efavirenz and nevirapine (Viramune). FDA approved
etravirine on the basis of the results of 2
multi-international trials-DUET 1 and DUET 2. At
48 weeks, 61% of those receiving etravirine achieved plasma HIV-1 RNA levels below
50 copies/mL, compared with 40% in the placebo group. The safety and tolerability
of etravirine is similar to placebo, except for an increased frequency of a mild
rash. Like the NNRTIs efavirenz and nevirapine, etravirine also is an inducer
of the cytochrome P450 system. Therefore, it should be used with caution when
combined with certain other drugs. For example, it cannot be coadministered with
the PI tipranavir (Aptivus) and should be used with caution with PIs such as atazanavir
(Reyataz) and fosamprenavir (Lexiva).
Rilpivirine
Like
etravirine, rilpivirine is a second-generation NNRTI that shows activity against
the K103N mutation. It is in development for once daily use in treatment-naïve
patients. In a randomized trial in which rilpivirine and efavirenz at 96 weeks
exhibited similar potency against HIV-1, rilpivirine showed fewer adverse effects,
such as less, rash, dyslipidemia and neurologic and psychiatric symptoms. I addition,
an ongoing trial is evaluating a different formulation of rilpivirine that might
be effective when the drug is administered intramuscularly once monthly.
RDEA806
RDEA806
is an NNRTI that is active against HIV-1 with the K103N mutation, but unlike the
second-generation NNRTIs etravirine and rilpivirine (as well as the first-generation
NNRTIs efavirenz and nevirapine), RDEA806 does not inhibit or induce the cytochrome
P450 system. It has been studied in Phase 2 trials. After 7 days of monotherapy,
RDEA806 showed median plasma HIV-1 RNA reductions of approximately 2 log10 copies/mL.
[End
of Part 1 of this summary review. Part 2 will be posted on HIV
and Hepatitis.com on June 30, 2009-Ed].
Reference
HH
Kim and ES Daar. Newer Antiretroviral Agents and How to Use Them. Current HIV/AIDS
Reports 6(2): 55-62. May 2009.
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