Page 97 - HIV/AIDS Guidelines

The clinical implications of HIV RNA in the range of >48 to <200 copies/mL in a patient on ART are
controversial. Unlike the case with higher levels of HIV RNA, most, if not all, circulating virus from
individuals with this level of HIV RNA results from the release of HIV from long-lived latently infected cells
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and does not signify ongoing viral replication with the emergence of drug-resistant virus. Although some
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studies have suggested that viremia at this low level predicts subsequent failure and can be associated with
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the evolution of drug resistance, a large retrospective analysis showed that using an HIV RNA threshold for
virologic failure of <200 copies/mL had the same predictive value as using a threshold of <50 copies/mL. 11
Newer technologies (e.g., Taqman assay) have made it possible to detect HIV RNA in more patients with low
level viremia (<200 copies/mL) than was possible with previous assays. Use of these newer assays has
resulted in more confirmatory viral load testing than may be necessary. 12-14

Persistent HIV RNA levels >200 copies/mL often are associated with evidence of viral evolution and drug-
resistance mutation accumulation; this is particularly common when HIV RNA levels are >500
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copies/mL. Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should therefore be
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considered as virologic failure.
Viremia “blips” (e.g., viral suppression followed by a detectable HIV RNA level and then subsequent return
to undetectable levels) usually are not associated with subsequent virologic failure. 17

Management of Virologic Failure

Once virologic failure is confirmed, generally the regimen should be changed as soon as possible to avoid
progressive accumulation of resistance mutations. 18

Ideally, a new ARV regimen should contain at least two, and preferably three, fully active drugs on the basis
of drug treatment history, resistance testing, or new mechanistic class (AI). 19-27 Some ARV drugs (e.g.,
NRTIs) may contribute partial ARV activity to a regimen, despite drug resistance, while others (e.g., T-20,
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NNRTIs, RAL) likely do not provide partial activity. 28-30 Because of the potential for drug-class cross
resistance that reduces drug activity, using a "new" drug that a patient has not yet taken may not mean that
the drug is fully active. In addition, archived drug-resistance mutations may not be detected by standard
drug-resistance tests, emphasizing the importance of considering treatment history and prior drug-resistance
tests. Drug potency and viral susceptibility are more important than the number of drugs prescribed.

Early studies of ART-experienced patients identified factors associated with better virologic responses to
subsequent regimens. 31-32 These factors included lower HIV RNA level and/or higher CD4 cell count at the
time of therapy change, using a new (i.e., not yet taken) class of ARV drugs, and using ritonavir (RTV)-
boosted PIs in PI-experienced patients.

More recent clinical trials support the strategy of conducting reverse transcriptase (RT) and protease (PT)
resistance testing (both genotype and phenotype) while an ART-experienced patient is taking a failing ARV
regimen, designing a new regimen based on the treatment history and resistance testing results, and selecting
at least two and preferably three active drugs for the new treatment regimen. 20-21, 23-24, 33 Higher genotypic
and/or phenotypic susceptibility scores (quantitative measures of drug activity) are associated with better
virologic responses. 23-24 Patients who receive more active drugs have a better and more prolonged virologic
response than those with fewer active drugs in the regimen. Active ARV drugs include those with activity
against drug-resistant viral strains, including newer members of existing classes (the NNRTI—ETR, the
PIs—darunavir [DRV] and tipranavir [TPV]) and drugs with new mechanisms of action (the fusion
inhibitor—T-20, the CCR5 antagonist—maraviroc [MVC] in patients with R5 but not X4 virus, and the
INSTI—RAL). Drug-resistance tests for patients experiencing failure on fusion inhibitors (FIs) and/or
INSTIs and viral tropism tests for patients experiencing failure on a CCR5 antagonist also are available. (See
Drug-Resistance Testing.)

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-4

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