Switching
from PIs to Nevirapine Usually Safe and Maintains Virological Suppression
Despite
the benefits of protease inhibitor (PI)-based HIV therapy, issues of tolerability,
dose frequency, pill burden, and long-term metabolic complications necessitate
evaluation of alternative treatment strategies. In an article in the November
2006 issue of HIV Medicine, C. L. Cooper of the University of Ottawa presented
an overview of research on switching from a PI-based regimen to one containing
the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine
(Viramune). Both
PI-based antiretroviral therapy and regimens containing nevirapine are established
choice for first-line treatment, based on their proven virological potency and
durability, as well as demonstrated reduction in opportunistic infection, hospitalization,
and death rates. Yet metabolic complications remain a concern when using PIs;
in particular, elevated blood lipid and glucose levels associated with drugs in
this class may increase the risk for cardiovascular disease. One
approach to address these concerns, Cooper noted, is to switch to NNRTI-based
regimens once virological suppression has been achieved using PI-based therapy.
To deteremine the safety and efficacy of this strategy, he conducted a Medline
search for medical journal articles describing switches to nevirapine, and also
reviewed abstracts from major international HIV/AIDS meetings. Results Cooper
identified 13 published manuscripts and 3 key review articles pertaining to nevirapine
switch studies; he also found several conference abstracts providing additional
information. These studies were all conducted in developed countries, mainly in
Europe (the U.K., Spain, Italy and France), with one each in the U.S. and Australia.
He reviewed 7 publications reporting results from randomized switch protocols
and 2 major retrospective cohort studies in more detail. Variables
determining switch efficacy "A
primary concern related to any switch from virologically potent and durable HIV
drug therapy is that virological suppression will be lost," Cooper wrote.
Many switch studies required a minimum period of virological suppression on PI-based
therapy (typically 3-9 months) before switching to nevirapine. Using this approach,
the incidence of post-switch virological failure generally ranged from 5% to 10%,
which does not differ from the failure rate in patients who remain on their PI
regimens. "A high rate of virological suppression maintenance was achieved
in those switched to nevirapine after a minimum of 9 months of PI-based HAART,"
Cooper noted, "despite the fact that 75% of this cohort had received non-suppressive
therapy (i.e. dual nucleoside reverse transcriptase inhibitor [NRTI] therapy)
before HAART." Studies
have shown that nevirapine is more successful in maintaining virological suppression
at 1 year in patients who remain on the same "backbone," compared with
those who both switch from a PI to nevirapine and change to a new combination
of nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs). Virological
and immunological outcomes "Switch
studies consistently demonstrate that nevirapine substitution can be performed
without excess virological failure," Cooper wrote. "In fact, some studies
suggest that the risk of virological breakthrough is diminished as a result of
improved adherence" -- perhaps related to improved convenience or lower pill
burden. Most published switch studies included subjects without prior NNRTI exposure.
In such patients, virological suppression was usually maintained (96% in one study).
In general, patients who switch to nevirapine also experience continued increases
in CD4 cell count. However,
he noted, "In subjects with a history of NNRTI exposure prior to initiation
of a PI-based regimen, the potential for resistance is obvious." Virological
breakthrough is also associated with low plasma trough plasma concentrations of
nevirapine. But overall, most studies suggest that the occurrence of virological
breakthrough is no higher among patients switched to nevirapine compared with
those switched to efavirenz (Sustiva)
or abacavir (Ziagen). Metabolic
considerations "A
switch from alternate regimens has been justified on the basis of the premise
that nevirapine regimens are 'lipid friendly' compared with PI-based treatment,"
Cooper explained. Indeed, several short-term and longer-term studies have reported
improved metabolic profiles after such a change. In one study, 12 months after
switching to nevirapine, patients experienced a mean reduction in low-density
lipoprotein (LDL or "bad") cholesterol, total cholesterol, and triglycerides,
which was not observed among those who switched to efavirenz or stayed on their
existing PI-based regimen. In this study, no changes in high-density lipoprotein
(HDL or "good") cholesterol, glucose metabolism, or body shape were
reported. Another study likewise observed greater reductions in triglycerides
and total cholesterol after a randomized switch to nevirapine compared with efavirenz.
However, use of lipid-lowering medications such as pravastatin (Pravachol) or
bezafibrate led to normalized lipid profiles more often than changing antiretroviral
therapy (about 50% vs 20% in one study). "Although
there are several short-duration studies suggesting that body habitus changes
may be halted or reversed following a switch to nevirapine from PI therapy, studies
of larger sample size, better design and longer duration suggest that any benefits
of this strategy are minimal," Cooper wrote. However, interpretation of data
from older studies is complicated by the fact that many subjects used NRTI backbones
that are no longer common -- such as ddI (didanosine;
Videx) plus d4T (stavudine; Zerit)
-- and which are known to contribute to lipodystrophy. "The accompanying
NRTIs used with nevirapine influence tolerance, adverse event frequency, maintenance
of virological suppression, and adherence," he noted, adding that, "Stavudine
will probably negate any beneficial metabolic effect of nevirapine inclusion." Liver
toxicity is another concern for patients taking nevirapine, especially those with
higher CD4 counts (above 250 cells/mm3 in women or 400 cells/mm3 in men). Other
signs of a nevirapine hypersensitivity reaction may include skin rash and fever.
Most studies show that such side effects are uncommon, however. In the ATHENA
cohort, no episodes of clinically overt liver toxicity were observed among 125
patients with HIV viral loads below 500 copies/mL who switched from a PI to nevirapine.
In another study, 2.9% of patients discontinued therapy after switching to nevirapine
due to liver-related adverse events, of whom 25% were coinfected with hepatitis
C virus (HCV). Based on the reviewed studies, Cooper wrote, "there is no
apparent increased risk for switch patients with high CD4 cell counts over patients
at other CD4 counts treated with nevirapine as an initial regimen," but he
noted that caution is still warranted in this population. Quality
of life "Quality
of life may be improved in those switching to nevirapine-based therapy from PI
treatment," Cooper stated based on the reviewed data. In one study, patients
who reported improved quality of life cited reduced pill burden and a better side
effects profile. "Reduced pill burden achieved with combination NRTIs [e.g.,
Combivir or Truvada]
or once-daily dosed NRTIs [tenofovir
(Viread) plus 3TC (lamivudine;
Epivir) or emtricitabine (Emtriva)]
may complement the benefits of the nevirapine switch," he added. Conclusion In
closing, Cooper concluded, "the weight of evidence demonstrates that a switch
from a PI-based regimen to one containing nevirapine can be accomplished safely
while maintaining virological suppression. There is no immunological cost and
there is probably an overall benefit in terms of the metabolic milieu and quality
of life. This treatment option should be considered for those achieving suboptimal
results with PI-based therapy." 12/01/06 Reference
C
L Cooper. Evaluation of nevirapine-switch strategies for HIV treatment. HIV
Medicine 7(8): 5537-543. November 2006.
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