Download Non-nucleoside reverse transcriptase inhibitors

FIGHTING BACK AGAINST HIV
Non-nucleoside reverse transcriptase inhibitors
Laura Waters, Laurence John, and Mark Nelson*
Since the introduction of highly active antiretroviral
therapy (HAART) the life expectancy and quality of life
enjoyed by HIV-infected individuals have improved
dramatically. Guidelines for HAART-naïve subjects recommend two nucleoside analogues (NRTI) with either a
non-nucleoside reverse transcriptase inhibitor (NNRTI)
or a ritonavir-boosted protease inhibitor (PI).
PI vs NNRTI; EFV vs NVP
There are little data comparing NNRTIs and PIs but more
evidence exists for NNRTI-based HAART first-line. In
terms of which NNRTI, efavirenz (EFV) or nevirapine
(NVP), most guidelines favour EFV due to more evidence,
less liver toxicity, and the CD4 count restrictions limiting
the use of NVP.
Arguments for using a PI first include transmitted
resistance. Studies show increasing primary resistance
but recent European data show it may be levelling off
or even decreasing. The World Health Organization
advises baseline resistance testing when primary resistance exceeds 5% and baseline testing is standard of care
in Western countries.
Mathematical modelling has predicted that routine
resistance testing will be unnecessary in Africa for at least
the next decade. NNRTIs therefore remain a suitable choice
for most patients. NNRTIs are genetically ‘fragile’ so must
be combined with fully active NRTIs to reduce the risk of
resistance; this is most likely first-line. A boosted PI may
be best when adherence is likely to be poor.
EFV is superior to unboosted PIs and at least as effective
as boosted-PIs. Much of the data is retrospective, unrandomised, or rests on cross-study comparisons. The 2NN
Study compared EFV with NVP for first-line therapy. Viral
suppression rates were similar but EFV tended to perform
better at low CD4 counts. Cohort analyses favour EFV over
NVP but should be interpreted with care. Several African
*From left to right: Laurence John, Research Registrar, Infectious
Diseases; Laura Waters, Specialist Registrar GU/HIV Medicine;
and Mark Nelson, Consultant Physician, HIV Medicine. All at
the Chelsea and Westminster Hospital, London, UK
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cohorts support the safety and efficacy of both EFV- and
NVP-based HAART in real clinical settings.
Adverse events
Hepatic adverse events are important, especially in those
co-infected with hepatitis B or C. HAART carries a risk of
liver toxicity and this is commoner on NVP, particularly
once daily, than EFV. Early NVP hepatotoxicity is commoner in females and correlates with CD4 count at time of
starting therapy. A CD4 cut-off of 250 in females and 400
in males significantly reduces the rate of hepatic events
to levels similar to EFV and PIs. NVP is also associated
with more liver fibrosis in co-infected individuals. Rash
occurs in up to one quarter of patients on NVP; it is severe
in 1.7% compared with 0.2% in control groups. In 2NN
moderate to severe rash was significantly less frequent
on EFV than NVP once daily but not twice daily. PIs can
also cause a rash.
PIs have class-related toxicities of gastrointestinal
disturbance and possibly fat redistribution. Advanced
HIV is a risk for abnormal lipids as is the use of PIs.
Even atazanavir (ATV), promoted as ‘lipid friendly’, was
associated with significant increases in cholesterol and
triglycerides in BMS 089. Lipids were more favourable on
NVP than EFV in 2NN, but for patients with abnormal
lipids on a PI, starting a lipid-lowering drug appears to
be more effective than switching to an NNRTI. HAART
is associated with heart disease, mostly due to PIs. As
blood pressure and lipid control have improved the rate
of heart disease appears to have levelled off.
EFV commonly causes dizziness, poor concentration,
and sleep disturbance but symptoms are usually mild and
transient. A questionnaire study showed no significant
differences between subjects on a PI or EFV in terms of
depression or emotional status.
Patients prefer once-daily therapy and small reductions in pill burden increase patient satisfaction; whether
adherence improves is conflicting. Despite improved PI
formulations, NNRTIs still offer the lowest pill counts.
Generic fixed-dose NRTI and NNRTI combinations reduce
pill burden further. Ritonavir requires refrigeration.
NVP and EFV have long half lives so NNRTI regimens
must be stopped carefully when interrupting therapy.
Options include stopping the NNRTI before the NRTI
components or switching to a PI first. However, some
subjects metabolise NNRTIs differently and have detectable drug levels for much longer.
Pregnancy and mother-to-child
transmission (MTCT)
There has been enough reported use of NVP and EFV
in pregnancy to detect a 2-fold increase in birth defects;
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FIGHTING BACK AGAINST HIV
none has been found to date. Recommendations are to
avoid EFV in pregnancy due to birth defects in animals
and case reports of fetal abnormalities in women with first
trimester EFV exposure. Women must be counselled about
the risks of EFV and if planning pregnancy EFV should be
avoided. NVP CD4 count restrictions do not apply to the
use of single-dose NVP (sdNVP) to reduce MTCT. PIs can
be used in pregnancy; nelfinavir and boosted-saquinavir
are recommended in the US guidelines but unboosted PIs
are no longer standard of care.
The huge reductions in MTCT with AZT, HAART, and
carefully planned delivery have made MTCT rare. Investigation of cheap, simple strategies to reduce MTCT in the
developing world includes large-scale studies sdNVP.
HIVNET 012 compared sdNVP with short-course AZT;
significantly fewer neonatal infections occurred on NVP.
sdNVP conferred a 41% reduction in rate of neonatal HIV
compared with AZT out to 18 months. There were no
serious NVP-related events. sdNVP has also been shown
to be as effective as short-course AZT+3TC.
However, sdNVP is associated with NNRTI resistance;
up to three-quarters of women have resistance mutations at 2 weeks depending on the test used. This may
impair response to NNRTI-based HAART in the future
although some studies demonstrate good response rates
despite sdNVP exposure. Small studies show high rates
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of NNRTI-resistance in infants who are infected despite
sdNVP. Adding short-course single or dual NRTI therapy
to sdNVP significantly reduces NNRTI resistance.
Drug interactions
Interactions are an important and complex issue. TB
medication interacts with antiretrovirals and treating
TB is a major reason for stopping or changing HAART in
Africa. If HAART cannot be delayed NNRTIs are better
than PIs; EFV is preferred as it can be safely administered
with all TB drugs but NVP necessitates the use of agents
that are expensive and not widely available. Antimalarials also have the potential to interact with antiretroviral
agents and should be monitored carefully.
Conclusion
NNRTI-based HAART remains the best studied and
most convenient treatment option for most patients but
choice is influenced by a number of factors. NNRTI-based
regimens can perform very well in resource poor setting
but the risk of interrupted therapy secondary to cost and
access, transmitted resistance and use of sdNVP may
necessitate increasing consideration of PI-based first-line
therapy in the future.
Please apply to the Editor for references to this article
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