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Multiple Drug Class-wide Resistance Is Associated
with Poorer Survival after Treatment Failure
The objective of the current study was to evaluate the
effect of drug
class-wide resistance (CWR) on survival in HIV-infected
individuals who underwent genotypic resistance testing
(GRT) after antiretroviral treatment failure.
In this observational, longitudinal cohort study, HIV-infected
individuals experiencing treatment failure were enrolled at first
genotypic resistance test.
End-points were death
for any cause, AIDS-related death and AIDS-defining
event/death. CWR was defined according to the International
AIDS Society consensus. Survival
analysis was performed with Cox's model.
Results
·
Among 623 patients
enrolled and followed for a median of 19 months, Kaplan-Meier analyses
for end-points at 48 months in patients with no CWR, one CWR, two
CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for
death;
·
End points were 6.1,
9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0,
17.7, 19.3 and 35.9%, respectively, for new AIDS event/death.
·
In a multivariate
Cox's model, higher HIV RNA level, previous AIDS and detection of
three CWR were all significantly associated with increased risk
of death, while higher CD4 cell count and use of a new boosted protease
inhibitor drug after identifying genotypic resistance were associated
with reduced risk.
·
Detection of three
CWR was also significantly associated with higher risk of AIDS-related
death and new AIDS event/death.
Conclusions
The authors conclude, “Even in the late era of highly
effective antiretroviral treatments, detection of CWR, particularly
if extended to all three drug classes is related to poorer clinical
outcome and represents a risk-marker of disease
progression and death.
Discussion
Assuming that most drug failures within any class were
the result of developing resistance, the authors’ observations estimated
the risk of disease progression related to increased acquired resistance
at drug failure. This occurred independently of CD4 cell count
changes during therapy, although the latter is considered the most
powerful predictor of death in treated patients so far.
The authors observe, “As viral load remains a major risk factor for maintaining
CD4 cell count in patients with multiple failed regimens, and assuming
that, at present, achieving viral
suppression after acquiring several CWR is generally
unlikely, our data give a possible explanation of the clinical effects
of virological failure among patients at advanced stages of treatment.
In conclusion, the authors write, “The results described
here, if confirmed in other sets of patients and in evaluations
of different patterns of drug class resistance, may have implications
in the management of HIV-infected patients treated with antiretroviral
drugs. Therefore, GRT may also have a role in the evaluation of
a possible increased clinical progression risk, particularly in
heavily pretreated patients.”
“Though the interval between the occurrence of drug
resistance and death may be long, both clinicians and patients should
be aware that the onset of a wide pattern of resistance could represent
a strong negative prognostic factor for survival.”
“Finally, our results may have implications in transmission
of drug-resistant viruses. It should become a priority to prevent
the development of resistance by the correct use of resistance tests,
by drug sequencing in regimens and by patient education regarding
the risks of developing resistance if they have poor
adherence to therapy.”
Clinical
Department, Laboratory of Antiviral Drug Monitoring, National Institute
of Infectious Diseases 'Lazzaro Spallanzani', Rome, Italy.
06/22/05
Reference
M
Zaccarelli and others (for the Collaborative Group for Clinical
Use of HIV Genotype Resistance Test (GRT) at National Institute
for Infectious Diseases 'Lazzaro Spallanzani'). Multiple drug class-wide
resistance associated with poorer survival after treatment failure
in a cohort of HIV-infected patients. AIDS 19(10): 1081-1089.
July 1, 2005.
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