aJohns Hopkins University School of Medicine, USA
bHoward Hughes Medical Institute, Baltimore, Maryland, USA.
Received 17 April, 2009
Accepted 5 June, 2009
Correspondence to Dr Robert F. Siliciano, Department of Medicine, Johns Hopkins School of Medicine, Broadway Research Building Suite 871, 733 North Broadway, Baltimore, MD 21205, USA. Tel: +1 410 955 7757; fax: +1 410 502 1144; e-mail: email@example.com
We read with interest the novel strategy described by Papendorp and van den Berk  regarding instituting a standard highly active antiretroviral therapy (HAART) regimen (tenofovir, emtricitabine, and efavirenz) and raltegravir to reduce HIV-1 viral load rapidly in order to decrease perioperative infectious risk. Although raltegravir-containing HAART affords a more rapid viral load decline compared with other antiretroviral regimens , there remains a period of several weeks before virions are cleared from the plasma. This may represent an unacceptably long time to wait for urgent surgery. Building upon Papendorp and van den Berk's innovative concept  of using the pharmacodynamic properties unique to particular classes of antiretrovirals to reduce perioperative risk, we describe an alternative strategy that theoretically offers the same benefit within a much shorter time period.
Raltegravir, the first integrase inhibitor approved for clinical use, blocks incorporation of HIV-1 reverse transcripts into the host cell genome. Infected cells that have already undergone HIV-1 DNA integration at the time raltegravir is initiated will not be blocked from producing infectious virions. The rapid viral load decay seen in patients taking raltegravir may be the result of the blockade of a later stage of viral replication than other currently available antiretroviral drugs . For example, it is likely that a larger population of infected cells can continue to produce virus in patients starting an efavirenz-based regimen than in patients starting a raltegravir-based regimen. With efavirenz initiation, all infected cells that have undergone reverse transcription will continue to produce virus, whereas, with raltegravir, only cells that have undergone viral integration will produce virus. This is likely the basis of the more rapid decay in plasma HIV-1 RNA levels in patients starting raltegravir . However, with respect to occupational exposure, the critical issue is not the absolute level of plasma virus, but rather the level of infectious virus.
In theory, virions produced by previously infected cells in a patient starting an integrase inhibitor will be fully infectious if transferred to another host because integrase inhibitors act only on the integrase–viral DNA complex in newly-infected cells and not on the free enzyme in the virion . The situation is different in patients starting protease inhibitors. These drugs inhibit the enzyme responsible for the cleavage of immature viral proteins within the virion during and after budding from the host cell. Previously infected cells, at all stages of replication, will continue to produce virions when a protease inhibitor is initiated . For this reason, the viral load decay on protease inhibitor regimens is not as rapid as that observed with raltegravir. However, all virions produced in the presence of therapeutic concentrations of a protease inhibitor are immature and incapable of infecting a new target. Thus, within hours of initiating a protease inhibitor-based regimen, patients will have a falling viral load composed of immature, noninfectious virions that likely represent a minimal risk for blood-borne viral transmission.
In the case of protease inhibitors with a slow off rate, such as darunavir , enzyme inhibition may persist following occupational transmission of virus particles to a recipient for longer than the virion lifetime, affording complete protection. If the drug does dissociate, the virion would still need to complete the maturation process to become infectious. The nonnucleoside reverse transcriptase inhibitors potentially represent an intermediate case. In principle, they can bind to the reverse transcriptase molecules in virions, rendering them noninfectious. However, as soon as the inhibitor dissociates, reverse transcription could continue. Thus, in order to minimize the probability of occupational transmission, slowly dissociating protease inhibitors offer the most rapid way to reduce infectious virus in the plasma.
A potential concern of the drug regimen described by Papendorp and van den Berk  is the relatively low barrier to resistance of both efavirenz and raltegravir , which may present a risk to the patient long after surgery. This risk is compounded by initiating HAART on an urgent basis in a setting radically different from the outpatient HIV clinic, in which a support structure is ideally in place to maximize long-term positive patient outcomes. Protease inhibitor-based regimens have a significantly higher barrier to resistance than efavirenz or raltegravir and, for this reason, can often be given with confidence in settings when the presence of drug-resistance mutations cannot be fully assessed. In summary, both the mechanism of action and the superior resistance profile of protease inhibitor-based HAART argue for its use in this specific setting. In regard to blood-borne transmission risk, both the quality and quantity of virus should be considered.
Both authors contributed equally to the authorship of this correspondence.
1. Papendorp SG, van den Berk GE. Preoperative use of raltegravir-containing regimen as induction therapy: very rapid decline of HIV-1 viral load. AIDS 2009; 23:739.
2. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, et al
. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46:125–133.
3. Sedaghat AR, Dinoso JB, Shen L, Wilke CO, Siliciano RF. Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proc Natl Acad Sci USA 2008; 105:4832–4837.
4. Espeseth AS, Felock P, Wolfe A, Witmer M, Grobler J, Anthony N, et al
. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc Natl Acad Sci USA 2000; 97:11244–11249.
5. Dierynck I, De Wit M, Gustin E, Keuleers I, Vandersmissen J, Hallenberger S, et al
. Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J Virol 2007; 81:13845–13851.
6. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al
. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359:355–365.
© 2010 Lippincott Williams & Wilkins, Inc.