Joel Palefsky

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EDITORIAL COMMENTHIV protease inhibitors to prevent progression of
cervical intraepithelial neoplasia to cervical cancer:
therapeutic opportunities and challenges
Joel PalefskyAIDS 2012, 26:1035–1036Human papillomavirus (HPV)-related cancers remain
one the most common causes of cancer-related mortality
worldwide [1]. HIV-infected women are at even higher
risk of cervical cancers compared with HIV-uninfected
women, and HIV-infected men and women are at
increased risk of anal cancer compared with their HIV-
uninfected counterparts [2–4]. HPV-associated cancers
are largely preventable. Primary prevention is available
through HPV vaccination to prevent cancers associated
with vaccine HPV types (HPV 16 and HPV 18) [5,6].
Secondary prevention is accomplished through detection
of high-grade cancer precursors such as cervical
intraepithelial neoplasia (CIN) or anal intraepithelial
neoplasia (AIN) and physical removal/destruction of
these lesions to prevent progression to cancer. These
measures are effective for preventing cervical cancer and
their efficacy is inferred, although not yet definitively
established for anal cancer. Treatment of high-grade
precancerous lesions is invasive and associated with side-
effects such as pain, bleeding, scarring and, in the case of
CIN treatment, premature delivery [7]. Better strategies
for eradication of precancerous lesions are clearly needed.
The article by Barilleri et al. [8] points to a new approach
to treat HPV-associated precancerous lesions, employing
protease inhibitors commonly used to treat HIV infection
to inhibit matrix metalloproteinases (MMPs).
There is a substantial body of evidence suggesting that
expression of MMPs by cervical epithelial cells plays an
important role in progression from CIN 3 to invasive
cancer and, possibly, in spread of cancer once it hasCopyright © Lippincott Williams & Wilkins. Unaut
University of California San Francisco, San Francisco, California,
Correspondence to Joel Palefsky, Department of Medicine, 513 Pa
San Francisco, San Francisco CA 94143, USA.
E-mail: joel.palefsky@ucsf.edu
Received: 12 February 2012; accepted: 16 February 2012.
DOI:10.1097/QAD.0b013e328352ae2f
ISSN 0269-9370 Q 2012 Wolters Kluwer Headeveloped [9,10]. Barilleri et al. demonstrate elegantly in
vitro that cells derived from low-grade CIN express
MMPs and that inhibition of MMP expression in these
cells by HIV protease inhibitors saquinovir and ritonavir
reduces their ability to invade in an in-vitro model.
What are the clinical implications of their findings? On
the basis of their results, the authors propose that protease
inhibitors may be useful to prevent progression of CIN
3 to cervical cancer. However, evidence of the efficacy of
protease inhibitors to prevent cancer in clinical studies
is limited at best. Although the authors cite studies
demonstrating that HAART reduces the risk of cervical
cancer in HIV-infected women, the data are not
conclusive. Cancer registry and other studies have not
shown a reduction in cervical cancer since the introduction
of HAART [4,9]. Data on the effect of HAART on anal
cancer and its precursors have shown that the incidence of
anal cancer has actually increased, not decreased. Most
studies have shown that HAART use is associated with
limited or no reduction in the incidence of high-grade
CIN or AIN [10–12]. Similarly, most studies have not
shown any protective effect of HAARTon cervical or anal
HPV infection [10,13]. It must also be noted that none of
the clinical studies cited by the authors showed that
protease inhibitors prevent progression to cancer, an issue
that can only be addressed in a randomized clinical trial,
which cannot be done for ethical reasons.
Does this mean that saquinovir or ritonavir does not work
as proposed by the authors? No. Studies of HIV-infectedhorized reproduction of this article is prohibited.
USA.
rnassus Ave, Room S420, Box 0654, University of California,
lth | Lippincott Williams & Wilkins 1035
Co
1036 AIDS 2012, Vol 26 No 8individuals on HAART have multiple limitations to
address this question rigorously. Individuals in these studies
were on a wide variety of HAART regimens, some of
whom were not on protease inhibitors at all, and some of
whom were taking different protease inhibitor regimens.
As shown by the authors, different protease inhibitors have
different effects on MMPs and, thus, different HAART
regimens will vary with respect to their ability to inhibit
MMPs, however, at this point, there is no evidence to
recommend that treatment decisions for HIV infection,
including choice of protease inhibitors, should be based on
their purported effect on HPV-related lesions.
The authors rightly propose the use of protease inhibitors
in HIV-uninfected individuals. As their results suggest
that MMP inhibition may not inhibit cancers once they
develop, they instead propose that protease inhibitors be
used to treat CIN to prevent progression to cancer.
However, as their results also show that at the
concentrations used there was no induction of cell death
or apoptosis of cells derived from a CIN lesion, CIN
lesions may persist when patients are treated at doses
leading to relatively low local tissue concentrations. Even
if they reduce the risk of progression to cancer at these
concentrations, a woman may need to take the protease
inhibitor for as long as the lesion persists. As systemic use
of protease inhibitors has side-effects, an interesting
alternative approach would be to apply protease inhibitors
topically. Higher local concentrations could induce
apoptosis and, if so, this approach might lead to regression
of high-grade CIN. Studies to address the local effects of
topical protease inhibitors could be done for a limited
period, with lesion regression as an endpoint and with
close follow-up to ensure that patients have not
progressed to cancer during the study.
Overall, Barilleri et al. are to be commended for pointing
to a potentially interesting new approach for preventing
HPV-associated cancers, particularly since the proposed
drugs are already in use and associated with a well known
toxicity profile. Their data highlight as many challenges as
opportunities, but careful selection of the appropriate
therapeutic target, such as high-grade cancer precursors
and the appropriate approach to dosing, such as topical
therapy, might lead to promising results that will benefit
both men and women at risk of HPV-associated cancers.pyright © Lippincott Williams & Wilkins. UnauthoAcknowledgements
Conflicts of interest
J.P. is a member of the Scientific Advisory Board of Aura
Biosciences, for which he has received stock options.References
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HIV protease inhibitors to prevent progression of cervical intraepithelial neoplasia to cervical cancer: therapeutic opportunities and challenges

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HIV protease inhibitors to prevent progression of cervical intraepithelial neoplasia to cervical cancer: therapeutic opportunities and challenges

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