Gilead Sciences Inc this week announced that adefovir will be made available
through the French government compulsory expanded access arrangement (an `ATU').
But other European countries will have to wait until the programme has been
approved in each country, which means that it is unlikely that the drug will be
available in the UK before the end of June.
Adefovir is a nucleotide analogue, a drug which stops the activity of HIV's
reverse transcriptase enzyme in a slightly different way from the nucleoside
analogue drugs such as AZT and 3TC. Adefovir is also active against HIV which is
already resistant to AZT and 3TC, so it may be an attractive `salvage' option
for people who have taken most of the available anti-HIV drugs already.
Gilead has announced that the drug will be made available to adults who have
failed treatment with at least two nucleoside analogues and one protease
inhibitor regardless of their viral load or CD4 count. The company advises that
another new antiretroviral agent should be added at the same time.
Risk of treatment failure greater above 30,000 copies
Current debates about the efficacy of various regimens in people with high
viral load (see BHIVA guidelines para 6.6) are likely to be further complicated
by data from San Francisco General Hospital which shows that the chance of
achieving and maintaining viral load below 500 copies out to 48 weeks was
significantly lower in people who started a PI -containing regimen with a viral
load above 31,000 copies.
After 48 weeks, 50.4% of 337 patients had viral load below 500 copies.
Baseline predictors of detectable viremia at week 48 were:
- CD4 count below 200, and especially below 100
- Adding a PI to existing NRTIs
Nelfinavir-resistant virus less harmful to immune system?
Harvard Institute researchers have discovered that HIV which develops
resistance to the protease inhibitor nelfinavir is significantly slower to
replicate than HIV which has never been exposed to drugs before. It is also
slower to replicate than virus which has developed resistance to other protease
inhibitors such as saquinavir and indinavir.
Dr Richard D'Aquila and colleagues tested viruses with specific mutations
known to be associated with drug resistance to see how quickly they replicated
in the test tube. They found that virus with the D30N mutation, which is usually
the first sign of nelfinavir resistance, grew 30% more slowly than virus not
exposed to any drugs (Martinez-Picadia).
Similar findings were reported by two teams at the Chicago Retroviruses and
Opportunistic Infections Conference in February. A joint Franco-American team
reported that virus highly resistant to saquinavir did not cause T-cell
depletion in a SCID-HU Thy/Liv mouse model after 28 days, despite low level
viral replication, and another French team reported on the loss of viral fitness
in 14 people receiving protease inhibitors who experienced viral rebound. During
20 months median follow-up, viral fitness (the ability to replicate) declined by
27.5% despite an average viral load increase of 1.4 log copies. The degree of
decline in viral fitness showed a strong inverse association with CD4 increase;
in other words, the less fit the virus after 20 months, the bigger the CD4
increase. There was no association between viral load and the size of the CD4
increase (Stoddart; Faye).
These findings suggest that some protease mutations make HIV less harmful to
CD4 cells even when viral load is rising, and that rather than restricting
apoptosis of CD4 cells or lengthening their lifespan(as suggested by other
research groups), protease inhibitor therapy may preserve CD4 cell populations
by reducing the pathogenicity of HIV. However, Faye and colleagues warned that
eventually, if CD4 cell numbers kept rising and drug pressure was removed, wild
type virus would come back very quickly because of the large number of CD4
target cells available for infection.
Implications for current practice
These findings highlight the discordance between virological and
immunological responses to HAART that has been widely reported (e.g. Deeks).
They also raise questions about which events should trigger changes in therapy,
and how that change should be managed.
For example, if you are taking nelfinavir, is it necessary to switch from the
drug immediately upon virological failure? The D30N mutation is almost always
the first to appear, and does not commonly confer cross-resistance to other PIs.
If that is the case, might it be beneficial to stay with nelfinavir for some
time, in order to cripple the virus even further, in the hope that any CD4
increase might be maintained? This option may be attractive to some people who
find that a nelfinavir-containing combination suits them.
However, there are no long-term data to support this approach, and many would
consider a trial which tested this theory to be unethical because of the risk of
cross-resistance to other PIs.
It may be safer to assume that any virological rebound should be treated the
same, regardless of the drugs involved. However, what happens afterwards will be
governed by which drugs you took previously.
So, in circumstances where protease resistance produces less viral fitness
(with nelfinavir or saquinavir, but not with indinavir and ritonavir) it may be
unwise to take a drug holiday, because this will permit the return of wild-type
virus which is more fit. In other situations however, a drug holiday has been
shown to improve the response to salvage therapy, and it would be interesting to
know the resistance profiles of those who appeared to benefit from drug holidays
(Youle).
References
Faye A et al. Viral fitness in patients with discordant CD4 and plasma HIV
RNA evolution following protease inhibitor failure. Sixth Conference on
Retroviruses and Opportunistic Infections, Chicago, abstract 331, 1999.
J Martinez-Picado et al. Replicative fitness of protease inhibitor resistant
mutants of human immunodeficiency virus type 1. Journal of Virology 73(5):
3744-3752, 1999.
Stoddart C et al. Lack of fitness of protease-inhibitor resistant HIV-1 in
vivo. Sixth Conference on Retroviruses and Opportunistic Infections, Chicago,
abstract 4, 1999.
Youle M et al. Hydroxyurea in a late stage salvage study. Research Institute
for Genetic and Human Therapy, Second Meeting, Washington, 1999.