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Effectiveness
of Antiretroviral Therapy after Protease Inhibitor Failure
Approximately
60% 90% of patients receiving antiretroviral therapy (ART)
for the first time achieve and maintain undetectable
HIV RNA levels for ≥1 year. However, regimen failure rates of 10%--40% create the need for subsequent antiretroviral regimens, which are generally associated
with diminished rates of virologic suppression.
A
decision to switch ART raises several questions:
Which regimen should be next? How many drugs
should it include? What are the most effective
options available? The July 1993 guidelines state that "assessing and managing a patient with
extensive prior antiretroviral experience and treatment
regimen failure is complex" [7,
p. 28]. Comparing published reports examining antiretroviral
efficacy in subsequent regimens is challenging because studies have different designs and are limited
by small sample sizes. In addition, patient
diversity in terms of drug exposure and previous
treatment duration further complicate measurement of subsequent ART efficacy.
To examine effectiveness of subsequent
antiretroviral therapy (ART), studies published during
the period of 1 January 1997 through 31 May 2003 involving patients who had failed a protease inhibitor (PI)containing
regimen and were switched to another regimen
were reviewed.
Twelve studies describing 1197
patients were analyzed.
A total of 38% of patients had human immunodeficiency virus (HIV) RNA levels
of <500 copies/mL at 24 weeks.
After adjustment for baseline
HIV RNA level, the rate of virologic suppression
ranged from 16% for patients switching drugs within
previously failed classes to 54% for non nucleoside reverse-transcriptase inhibitor (NNRTI)naive
patients switched to boosted PI- and NNRTI-containing
regimens.
ART regimens in patients who failed a PI-containing regimen provided virologic
suppression only in a few patients.
The best response was seen in
NNRTI-naive patients receiving NNRTI- and boosted PI-containing regimens.
New approaches are needed to achieve better suppression in pretreated HIV-infected patients.
Discussion
In
summary, we have demonstrated by meta-analytic techniques that addition of a new drug class and addition
of a drug from the same class capable of overcoming
in-class resistance (e.g., lopinavir-ritonavir) are most effective for subsequent therapy in patients
who fail a PI-containing regimen. Baseline
HIV RNA was independently associated with virologic suppression after adjusting for regimen type, whereas
baseline CD4 cell count at the time of switching had only a small influence on outcomes from subsequent regimens.
These
results suggest that switching regimens while
HIV RNA levels are low may lead to better
suppression with subsequent regimens. One possible explanation for this is that ongoing viral replication at higher levels may select for further drug resistance mutations, diminishing the efficacy
of new drugs within the same class.
The
use of a drug class to which the patient has
not been exposed, such as an NNRTI and a novel PI designed to overcome PI resistance, appears to be the most effective treatment strategy, although how this will apply to patients who fail a
boosted PI regimen is unclear.
The
availability of another new drug class, the
fusion inhibitors (such as enfuvirtide), may also
provide improved virologic suppression in patients who fail PIs and other regimens. The judicious use of new drugs and new drug classes provides
an opportunity for more effective and longer-lasting virologic suppression of HIV replication.
Boston University School of Public Health, Massachusetts General Hospital and Harvard Medical School and Brigham and Women's Hospital, Boston, MA.
05/21/04
Reference
E Losina
and others. Effectiveness of Antiretroviral Therapy after Protease
Inhibitor Failure: An Analytic Overview. Clinical Infectious Diseases 38(11): 1613-1622. June 1, 2004.
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