The Body PRO Covers: The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy

Antiretroviral Resistance (Poster Session 176)

December 18, 2001

  • Impact on Fitness Conferred by Amprenavir (APV) Resistance Mutations
    Abstract 1766
    Authored by W. Harris, S. Randall, V. Manohitharajah, F. Xu, R. Elston, M. Tisdale, W. Snowden, (GlaxoSmithKline, Stevenage, United Kingdom)
    View the original abstract

Why should a person with HIV or a clinician care about fitness? We are not, by the way, talking about aerobic exercise here, but viral fitness. HIV viral "fitness" is a complex topic that is often meant to include the abilities of the virus to reproduce efficiently (replicative capacity), to compete with other HIV strains (true fitness to a virologist) and to kill CD4 cells and cause disease progression (probably best called pathogenicity).

The reason many believe this is important is that some drug-resistant viruses are markedly less fit (as a non-virologist, I will use the term "fit" loosely to include different measures of fitness). There is a fair bit of evidence that this contributes to a so-called "disconnect," in which people who remain on their drugs despite having a resistant virus and detectable viral load may do very well, particularly if the viral load is reduced from the untreated level. Several studies, most notably those of Dr. Steve Deeks and his group, show that when these patients stop taking medications, the detectable virus reverts to wild type, the CD4 count starts to plummet again, and the patient may develop opportunistic infections.

It has been observed that there are several major pathways to amprenavir resistance. In patients with relatively low drug levels of amprenavir, the I54L or I54M mutation is often seen, but when the trough levels are higher -- as seen in ritonavir-boosted regimens -- this mutation is rarely seen. Rather, the I50V mutation predominates, although other pathways are seen. Since the I50V mutation creates a much higher level of resistance than the mutations at 54, a key question is why the I50V mutation is not seen in patients with lower drug exposure.

The answer appears to be fitness. A virus with I50V is severely "fitness-challenged" whether measured by competition studies or replicative capacity. Adding the compensatory mutations M46I or L33F provided some improvement, but the investigators from GlaxoSmithKline's research site at Stevenage, UK conclude that it remains a very compromised virus. As shown in abstract 1765, other mutations in the gag cleavage sites also help restore fitness, but it remains a weakened virus.

Is this clinically relevant? Perhaps. The clinical proof of concept might come from examining patients on ritonavir-boosted amprenavir compared to non-boosted amprenavir and looking at the rate of CD4 decline. Another way of determining if it is "good" to have I50V is to look at patients in deep salvage who have partial suppression in the setting of I50V and let them take a treatment interruption. If the viral load rises and the CD4 falls, it would suggest that I50V is a corner into which we can back the virus.

The conclusion? People with HIV (and their doctors) should try to stay fit and keep their viruses flabby!

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This article was provided by TheBodyPRO. It is a part of the publication 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2001).

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