Page 105 - HIV/AIDS Guidelines

with viral drug resistance are outlined below. Simplifying regimens in patients who have extensive prior
treatment histories is complicated. In such a case, a patient’s treatment history, treatment responses and
tolerance, and resistance test results should be thoroughly reviewed before designing a new regimen. Expert
consultation should be considered whenever possible.

Types of Treatment Simplification
Within-Class Simplifications. Within-class substitutions offer the advantage of not exposing patients to
still-unused drug classes, which potentially preserves other classes for future regimens. In general, within-
class substitutions use a newer agent; coformulated drugs; or a formulation that has a lower pill burden, a
lower dosing frequency, or would be less likely to cause toxicity.

• NRTI Substitutions (e.g., changing from zidovudine [ZDV] or stavudine [d4T] to tenofovir [TDF]
or abacavir [ABC]): This may be considered for a patient who has no history of viral resistance on an
NRTI-containing regimen. Other NRTIs may be substituted to create a regimen with lower dosing
frequency (e.g., once daily) that takes advantage of coformulated agents and potentially avoids some
long-term toxicities (e.g., pancreatitis, peripheral neuropathy, lipoatrophy).

• Switching of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g., from nevirapine
[NVP] to efavirenz [EFV]): This may be considered to reduce dosing frequency or to take advantage of
coformulated agents.
• Switching of PIs: This switch can be from one PI to another PI, to the same PI at a lower dosing
frequency (such as from twice-daily to once-daily RTV-boosted lopinavir [LPV/r] or RTV-boosted
darunavir [DRV/r]) or, in the case of atazanavir (ATV), to administration without RTV boosting. 6
(Unboosted ATV is presently not a preferred PI component and not recommended if the patient is taking
TDF or if the patient has HIV with reduced susceptibility to ATV.) Such changes can reduce dosing
frequency, pill count, drug-drug or drug-food interactions, or dyslipidemia or can take advantage of
coformulation. These switches can be done with relative ease in patients without PI-resistant virus.
However, these switches are not recommended in patients who have a history of documented or
suspected PI resistance because convincing data in this setting are lacking.

Out-of-Class Substitutions. One common out-of-class substitution for regimen simplification involves a
change from a PI-based to an NNRTI-based regimen. An important study in this regard was the NEFA trial,
which evaluated substitution of a PI-based regimen in virologically suppressed patients with NVP, EFV, or
ABC. Although the baseline regimens in the study are no longer in widespread use, the NEFA findings are
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still relevant and provide information about the risks and benefits of switching treatment in patients with
virologic suppression. In this study, 460 patients on stable, PI-based regimens with virologic suppression
(<200 copies/mL for the previous 6 months) were switched to their randomized treatment arms. After 36
months of follow-up, virologic failure occurred more frequently in patients switched to ABC than in patients
switched to EFV or NVP. The increased risk of treatment failure was particularly high in patients who had
previous suboptimal treatment with mono- and dual-NRTI therapy. This emphasizes the need to consider the
potential for drug-resistant virus prior to attempting simplification. 8

Newer agents that target different sites in the HIV life cycle, such as the integrase strand transfer inhibitor
(INSTI) raltegravir (RAL) and the CCR5 antagonist maraviroc (MVC), also offer opportunities for out-of-
class substitutions, particularly in patients who have a history of virus resistant to older HIV drugs. Three
randomized studies have evaluated replacing a boosted PI with RAL in virologically suppressed patients. In
two of these studies, 9-10 the switch to RAL was associated with an increased risk of virologic failure in
patients with documented or suspected pre-existing NRTI resistance; a third study did not find this higher
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risk, possibly due to a longer period of virologic suppression before the change. Overall, these results
suggest that in ART-experienced patients, RAL should be used with caution as a substitute for a boosted PI.

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-12

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