The NIH panel convened late last November to develop new state-of-the-art
guidelines for the treatment of HIV infection included a series of
provocative (some would say alarming) presentations regarding resistance
considerations in the choice of antiretroviral combination regimens. TAG's
indefatigable scribe and provocateur in his own right, Mark Harrington,
provided this transcript of the cross-fire which featured, among others:
Merck's Emilio Emini, Tufts University's John Coffin, University of
Montréal's Mark Wainberg, Roche's Noel Roberts, the CDC's Harold Jaffe,
Chiron's David Chernoff, the ACTG's Robert ("Chip") Schooley and John Mellors, as well as fellow treatment activist Dawn Averitt-Doherty of
Atlanta-based Woman's Information Service and Exchange (WISE).
Mark Wainberg presented interesting resistance data from BI 1046 (the INCAS
study of AZT+ddI+nevirapine (NVP) vs. AZT+ddI vs. AZT+NVP in treatment
naïve individuals with CD4 cell counts 200-600), analyzing compliance as
defined by any patient who did not miss more than 28 days of any therapy.
On triple drug therapy, viral load was reduced by 1.5 logs at 23 weeks.
Patients non-compliant to ddI rapidly became resistant to nevirapine. At
twelve months, even some of those who were compliant developed NVP
resistance, although in most patients on triple therapy (87%) it was
difficult to culture virus. At twelve months, virus could not be cultured
from any patient whose viral load was beneath the limit of detection (LOD).
When treatment reduces viral load below LOD, virus culturable from
peripheral blood mononuclear cells (PBMCs) at six months is wild-type. When
treatment fails, virus culturable from PBMCs as six months is NVP
resistant, but not as frequently (or as highly so) as in patients receiving
only AZT and NVP.
Coffin: Both studies (BI 1046 and the Merck 035 study, presented earlier
that day) raise the question of whether there's a rationale to include AZT
anymore. It makes no difference between experienced and naïve patients. NVP
and AZT didn't push the virus very hard.
Wainberg: Combinations without AZT should be looked at-they're tantalizing.
Emini: The combination of d4T and 3TC should be looked at.
Coffin: We need to study the fitness of various mutants in the absence of
therapy. Some mutants will have a high cost to fitness, and will be
infrequent; while others may have a low cost and may be more common. There
may be an evolutionary bottleneck early in disease before which such
pre-existent mutants are rare, but six months into infection-or after a
year-you've lost that advantage.
Harrington: It seems to me there are two ways to avoid the development of
resistance here: one is to suppress maximally with potent antiretroviral
regimens. The other is to wait to begin therapy until it's necessary to
prevent irreversible immunologic damage. If the only point at which to
throttle the virus from an evolutionary standpoint [to limit the pool of
pre-existing drug-resistant viral mutants] is in the first 6-12 months of
infection, this has little relevance to most chronically-infected patients
who, given the limitations of our arsenal, might be better of waiting for a
clear need to emerge.
Roche's Noel Roberts presented cross-resistance data on clinical isolates
which had been presented at the Birmingham conference, suggesting that HIV
that has developed resistance to any of the three licensed protease
inhibitors is likely to be resistant to the other ones (licensed and
unlicensed) as well, and that resistance to IDV (currently the most widely
prescribed protease inhibitor) appeared to confer 60% cross-resistance to
SQV, 80% cross-resistance to the Vertex compound (141WU94) and 100%
cross-resistance to RTV and NFV! University of North Caro-lina's Robert
Swanstrom took it a step further and looked at HIV that had become doubly
protease resistant (to SQV+RTV, RTV+IDV and SQV+IDV). In his in vitro
experiments, HIV that was doubly resistant to IDV+RTV was 400-fold less
susceptible to SQV. And HIV with dual resistance to SQV+RTV was 60-fold
less sensitive to IDV. So the implication for people failing SQV, IDV or
RTV appear grim-at least from this data.
Schooley: We need to be pretty careful and do in vivo studies of switching
people from saquinavir to other protease inhibitors and vice versa.
Roberts: That study is underway.
Chernoff: In these trials, drug is continued post-failure, unlike in
clinical practice. [This is not true; many doctors continue patients on
therapy post-failure. What else can they do? There are no clinical practice
guidelines out there, and many people have failed all available drugs.]
Roberts: Perhaps patients should change therapy as soon as viral load
starts to rise.
Mellors: It troubles me to hear a comparison of the frequency of resistance
without controlling for the potency of the various regimens. The two
variables are related-viral turnover and the selection process imposed by
more or less potent regimens.
Jaffe: If resistant mutations are associated with a selective disadvantage
will they disappear after treatment is removed?
Emini: Two patients who stopped taking indinavir (one after taking
low-dose, then full-dose) had a reversion to wild-type within 4-5 months
post-cessation. One restarted treatment at full-dose idv, and within three
weeks we isolated idv-resistant virus. This is why we say the virus is
During the coffee break, I joined three activists outside to share nicotine
and despair. What was the point of quitting smoking if we were still all
passengers on the speeding train heading for the cliff? The Birmingham
resistance data were wrenching. Our fears of multiple cross-resistance,
from November 1995's 3TC and saquinavir FDA approval hearings, reared their
ugly heads. Several months of post-Vancouver euphoria crumbled in a moment
as it became clear that many of those who developed resistance to ritonavir
and idv-as thousands clearly would-might have no protease inhibiting
options ahead of them. Today's resistance news made for a toxic cocktail.
As I left the auditorium I bumped into Emilio Emini.
Harrington: So what do you do if you fail Crixivan?
Emini: [sighs] We don't know what to do.
Harrington: Take two new nucleosides and nevirapine?
Emini: Yeah. And pray.
No one had yet assessed the healing effects of prayer on viral load. This
was what we'd come to. I rushed into the lobby of the Interior Department
and ran into a colleague, who was wild with fear and disappointment.
AC: I'm going to die.
Harrington: This is everything we were hoping wouldn't happen.
AC: I don't have anything to switch to. I'm going to stop everything.
Dawn Averitt tried to calm our colleague down: Why don't you wait for you
next viral load?
AC: I'm already back at baseline!
Averitt: But your CD4 count is 250, and it was down to 60 in January.
AC: True, but my viral load is back to half a million.
Averitt: Why don't you wait until you get your latest numbers and see what
your resistance profile is?
AC: I'm going to go outside and have a nervous breakdown.
We went outside. It was frigid, and fragile snowflakes swirled around in
the wind. Sometimes the gap between how the researchers felt and how we
felt became an abyss. They were excited about the endless possibilities
opened up by the research advances of 1996; we were terrified about the
limited treatment options facing people who had exhausted most of the
current arsenal of antiretroviral therapy. What to do with those whose
viral load refused to go undetectable? What to do with those who added a
protease inhibitor to a failing two-drug regimen and appeared doomed to
develop resistance, most of it-especially with ritonavir and
idv-cross-resistant to all other protease inhibitors? What to do with those
who jumped aboard last year's bandwagon, AZT+3TC, and now appeared likely
to have developed 3TC resistance and, with it, cross-resistance to ddI, ddC
and possibly 1592? The Chinese menu approach to antiretroviral treatment sud
denly looked much less appetizing, and much less nourishing.
Dawn and I went upstairs where the committee was having a working lunch,
discussing process. Many members questioned the existence of two
committees. Why have one committee setting up principles (NIH) and one
setting up practice guidelines (PHS)? Wasn't this a recipe for bureaucratic
confusion-and delay? How could we disseminate principles of HIV therapy
without making practice guidelines? What if the principles contradicted the
data? Considering what we had just seen, doing something fast seemed
On the other hand, many of the researchers present did not share the
activist sense that we were facing a crisis that, if handled improperly,
might make things worse than before. This was not the prevailing view
propounded by gun-happy virologists, drug-happy pharmaceutical companies,
media captivated by a surprising good-news story and many people with HIV
still struggling to absorb the complex developments of 1996. Just that
week, back-to-back articles in The Wall Street Journal and The New York
Times Magazine, both written by HIV-infected journalists, declared that the
epidemic was virtually over. We were staring into the precipice while
others were still climbing the hill.