Published in Volume
123, Issue 9
(September 3, 2013)J Clin Invest.
Copyright © 2013, American Society for Clinical
The Attending Physician
Lack of protease inhibitor resistance following treatment failure
— too good to be true?
Department of Medicine and the Duke Global Health Institute, Duke
University Medical Center, Durham, North Carolina, USA.
Address correspondence to: John A. Bartlett, Department of Medicine and the
Duke Global Health Institute, Box 3238, Duke University Medical Center, Durham, North
Carolina 27710, USA. Phone: 919.681.8043; Fax: 919.681.7748; E-mail:
First published August 27, 2013
A 29-year-old man with recently diagnosed HIV infection and a CD4 cell count of
225/mm3 began treatment with atazanavir (300 mg), ritonavir (100 mg),
emtricitabine (200 mg), and tenofovir (300 mg) daily. For 18 months, he was treatment
adherent and his plasma HIV RNA level was below the limit of detection. He then began
a relationship with a new partner, who introduced him to methamphetamines. His
medication adherence became erratic, and he missed appointments in clinic.
Eventually. he was hospitalized for rehabilitation, and he resumed taking his
medications on schedule. Following his discharge, he was found to have a plasma HIV
RNA level of 11,400 copies/ml. Genotypic resistance testing revealed only an M184V
mutation associated with emtricitabine resistance. A decision regarding his next
treatment regimen needs to be made.
The clinical dilemma posed by this patient is commonly encountered by clinicians
treating HIV-infected patients. This patient has clearly failed his treatment regimen,
but genotypic resistance tests have failed to provide much guidance in choosing the next
Protease inhibitors (PI) represent valuable tools in the armamentarium of clinicians
treating HIV-infected persons. Clinical trials in both treatment-naive and
treatment-experienced subjects have demonstrated outstanding PI activity, and regimens
containing PI may be recommended for use across these different patient populations
(1). Indeed, two of the four recommended
regimens for the initial treatment of HIV infections include PI (atazanavir and
Challenges for the PI class have included the need for pharmacologic boosting with some
members of the class, especially if patients are more heavily treatment experienced and
most notably if they are PI experienced (1).
Numerous studies of patients who fail PI have not identified mutations in the protease
gene associated with resistance (2–5). In a systematic review of failure of first-line
antiretroviral therapy, persons failing PI-containing regimens had the least
accumulation of drug resistance mutations, both within the protease gene and, to a
lesser extent, in the reverse transcriptase gene (6). This conundrum has baffled investigators for many years and defies the
evolutionary logic that virologic failure should be accompanied by mutations in the drug
target. From a clinical perspective, the apparent lack of resistance complicates the
choice of a PI in future combination regimens.
The observations of Rabi et al. shed new light on the inhibition of the HIV life cycle
and alternative mechanisms of resistance to PIs (7). First, the authors have utilized a series of clever experiments to identify
the inhibitory effect of PIs on several steps in the life cycle, including virus entry,
reverse transcription, and posttranscription events. Previous descriptions of PI
activity have identified inhibition of the proteolytic cleavage of precursor proteins, a
relatively late step in the HIV life cycle, as the mechanism for their antiretroviral
effect. Second, in nine subjects who failed PI-containing regimens with no detectable
mutations in their protease genes in genotypic assays, they have identified
env mutations with additional sequencing. Given that commercially
available genotypic resistance assays do not sequence and report env
genes, clinicians may be falsely assured that PI resistance has not occurred.
Certainly these observations are intriguing and may prove to be very important in
clinical management. However, it remains uncertain how commonly the env
mutations occur in patients failing PIs. Additional studies are needed to address this
question and may eventually lead to a need for expanded resistance assays, including
env sequencing, to optimize selection of subsequent PIs.
Rabi et al. speculate on three resistance mechanisms to explain PI failure in the
absence of protease mutations. The first involves nonadherence by the patient, and due
to the absence of the drug, no resistance mutations in the protease gene are selected.
The second explanation involves the unique pharmacologic and pharmacodynamic properties
of PI with high potency and relatively short half-lives, resulting in brief periods
within the mutant selection window. Finally, the newly described env
mutations may compromise PI activity. A fourth mechanism involving mutations at
proteolytic cleavage sites has also been associated with PI resistance in a limited
number of patients (8).
What are the implications for HIV clinical care? Until larger studies are completed
assessing the frequency of env mutations, clinicians are likely to
follow a simple paradigm. On the detection of virologic failure, reinforcing adherence
to medications will result in resuppression of some patients. If resuppression does not
occur, conventional genotypic resistance testing may identify mutations in the protease
gene and guide the choice of subsequent PIs. However, in patients with a wild-type
protease gene, clinicians will remain uncertain about the optimal choice of a PI for the
next regimen. They will make an educated guess on the PI choice and will need to closely
follow their patients on the new treatment regimen.
The author receives salary support from NIH awards P30AI64518, U01AI067854, D43CA153722,
Conflict of interest: The author has declared that no conflict of
Citation for this article:J Clin Invest. 2013;123(9):3704–3705. doi:10.1172/JCI71784.
See the related article beginning on page 3848.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines
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adolescents. Department of Health and Human Services Web site.
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