13th
World AIDS Conference
Durban,
South Africa
Day 1 - Tuesday,
July 11, 2000
Reported by Michael Norton
Amidst the political
volleys and somewhat odd celebrations that have characterized the first 24 hours
of the 13th International AIDS Conference, were a few items that have clinical
relevance, especially in the developed world.
Here are some of those:
UNDETECTABLE
VIRAL LOAD IN MONKEYS AFTER STOPPING PMPA THERAPY
Kumar,
A and colleagues made an oral presentation of 4 macaque monkeys.
All four were inoculated with SHIVKU (a virus similar to HIV that causes
AIDS in macaques). 2 of the
macaques were controls and did not receive antiviral therapy.
They subsequently lost cd4+ís, and after 6 months died of AIDS.
2 of the macaques received PMPA (Tenofovir = a nucleotide reverse
transcriptase inhibitor in development by Gilead and currently available to a
limited number of patients under an expanded access program).
These 2 macaques started PMPA therapy 1 week after inoculation
with SHIVKU and continued taking PMPA for 83 days.
During the 1-week prior to initiation of PMPA these 2 macaques
experienced a decline in cd4ís that recovered to baseline during the therapy
period. During therapy the SHIV viral load became undetectable and remained
there throughout the duration of therapy. After the 83 days, PMPA was
withdrawn and the virus rebounded for several weeks prior to being
brought under control by virus specific immunity that these macaques had
developed. In contrast to their
counterparts who developed AIDS quickly and died from SHIV, these 2 macaques
after 83 days of therapy have been able to mount a SHIV specific immunity and
control SHIV viremia with that immunity for greater than 1 year. Commentary by this
author: These sorts of studies
are invaluable in building a body of knowledge that shows that immunity to a
virus similar to HIV can be manipulated or allowed to develop after a period of
antiviral therapy. Investigations
are currently underway in humans to see if this can be duplicated.
Further information on this subject (STIís) will be forthcoming later
this week here in Durban. Most human studies appear to need multiple
interruptions to prime the immune system.
INTERMITTENT
VIRAL LOAD BLIPS BETWEEN 50 to 400 COPIES/ML
Doug
Ward and colleagues had a poster titled ìThe significance of low-level Viremia
in patients with previously undetectable HIV-1 RNA levels.î
They presented 32 patients who had had 2 previous viral loads of <50
copies/ml, who then presented with a viral load between 50 and 400 copies/ml.
Upon discovery of these viral load blips, patients were asked to repeat
the viral load on follow-up visit. On
subsequent viral loads, without change of therapy, 75% returned to <50
copies/ml, all but 2 patients of those on the very next viral load.
25% of the 32 patients who blipped did not return to undetectable or
<50 copies/ml. The authors
concluded that adherence can play an important role in why patients blip.
That if a patient were on his/her first regimen, they are more likely to
return to <50 copies/ml with simply adherence advice and the continuance of
the same antiretrovirals. This is
important given the limited options available once a patient switches regimens.
On the other hand, those that were already on their 2nd or 3rd
regimen and blipped, were most likely not to return to <50 copies/ml.
Once again showing that that initial regimen is the regimen most likely
to deliver durability of viral suppression.
CONTINUE
DOING PAP SMEARS EVEN IF ON HAART
Duerr,
A and colleagues compared PAP results among 3 groups of women who had < 500
cd4ís. Group 1 were on HAART. Group
2 were on antiretrovirals not considered a HAART regimen (n=176).
And group 3 were receiving no HIV antiviral therapy (n=267). Twelve
months after the index visit, CD4 count had increased
significantly for the HAART group (median increase 72 cells/ml)
but not for the ART or no ART groups. In the HAART group (n=159)
at baseline, 26% of the women had SIL (squamous intra-epithelial lesions) and
26% had ASCUS (atypical squamous cells of undetermined significance).
1 year later, among the HAART group, it was found that 33% of the women
now had SIL and 17% still had ASCUS. 2
years later, once again among the HAART group, 33% of the women still had SIL
and 19% had ASCUS. Somewhat
surprising perhaps, there was no significant regression of PAP abnormalities
between the group on HAART, the group on less then HAART and the group without
any therapy. However there was a
less likelihood of newly acquired PAP abnormalities in the HAART group when
compared with the other two groups. Commentary: These results argue strongly in favor of the continued
mandate to follow HIV+ females with PAP smears every 6 months.
CAN
SERUM SELENIUM LEVELS PREDICT LIPID ELEVATIONS?
In
what was a new angle to this observer, Rodriguez, A and colleagues reported on
92 of their patients who attend their research clinic in the US.
They are all HIV+ with a history of IVDU.
They set out to compare their patients who were on HAART with those who
werenít and how many in each group developed hypertriglyceridemia,
hypercholesterolemia and hyperglycemia. The
most striking finding was, the significant predictive value of oncoming
hyperglycemia among the HAART group by serum levels of selenium.
DOES
VIRAL LOAD HAVE TO BE BELOW 50 COPIES/ML?
Jeff
Greene and colleagues in New York reached once again into their large
observational database to share an interesting item that runs contrary to
prevailing wisdom. They presented
95 patients who were divided into 2 groups starting in 1998 when the more
sensitive HIV RNA assays (ultrasensitive assay <50 copies/ml) were
implemented in their clinic. In
group I, 54 patients were below the level of quantification for by both the 1st
generation and 2nd generation assay, meaning their viral loads were
<50 copies/ml. In group II, 41
patients were detectable by the 2nd generation assay but not by the 1st
generation, meaning their viral loads were between 50 and 400 copies/ml.
The groups were similar when looking at age, race, risk factor, time from
HIV diagnosis, sex, time on HAART, and the total # of HAART regimens they had
been on. The results show that
there was no difference among the two groups over the examined period of
approximately 2 years when comparing mean change in cd4ís, incidence of OIís,
and death rates (there was no HIV related deaths in either arm).
Most strikingly, there was no difference in virologic failure, defined as
2 consecutive viral loads > 400 copies/ml, between the two groups.
The authors concluded that optimal clinical response may not require
viral suppression to < 50 copies/ml. Commentary: These observations, while real, are in conflict with the
body of work that exists showing that < 50 copies/ml lends to a more durable
virologic response when compared to those who nadir is between 50 and 400
copies/ml. Perhaps with more time
those not < 50 copies/ml will virologically fail at higher rate, but it is
equally conceivable that if sustainable between 50 and 400 copies/ml of HIV RNA
will translate into equally efficacious clinical outcomes.
DRUG
RESISTANCE TESTING: benefits & shortcomings
During
the afternoon of this first day, there was a symposium of considerable interest,
chaired by Joep Lange and Joe Eron, and entitled ìManagement of Drug
Resistanceî. The
speakers were Doug Mayers, John Mellors, and B. Clotet.
From
Mayers, a slide classifying agents as being able to rapidly develop resistance,
moderately develop resistance, and slowly develop resistance.
Below are the agents and where he placed each.
Rapid/Low
Resistance Barriers:
3TC ñ NVP ñ DLV ñ EFV
Moderate/High
Barriers to Resistance:
AZT ñ ABC ñ FTV/SQV ñ AMP ñ NFV ñ IDV - RTV
Slow/Difficult
Resistance both to develop and characterize:
DDI ñ D4T ñ DDC
During
the Q & A session Mayers stated that the Narval 088 study was a study of
ìfunctional monotherapyî which we know doesnít work and is why it showed
no significant difference between the resistance and non-resistance assay arms.
He also stated that 80 plus % of patients were given DDI or D4T in their
next regimens and that the understanding of their resistance is difficult.
And that with the currently available phenotypic assays, 2 fold
resistance in D4T may mean full resistance in the presence of mutations caused
by other nucleosides, and/or a long history of prior nucleoside usage.
At
Sitges, Calvez from Spain reported that he found a 1.8 fold change in phenotypic
resistance spells d4T resistance. See Resistance Workshop Reports
on NATAP web site for more details on this study.
John
Mellors discussed his recent work in the area of understanding the reversal of
resistance to nucleoside RT inhibitors. He
presented his groups recent work showing that, AZT monophosphate excision is
enhanced by an AZT mutant RT enzyme, when compared to wild type.
And that foscarnet by causing a mutation at site 88, when added to a
background of AZT mutatations, reduces the excision of AZT monophosphate by that
AZT and Foscarnet mutated RT enzyme. Commentary: While this is an important development in the
understanding of the reversal of some nucleoside resistance, it may be sometime
off before this understanding can be translated into clinical success.
In the opinion of this clinician who worked with Foscarnet prior to the
advent of HAART in the fight against CMV, its toxicities are a significant
hurdle.
Mellors
went on to state that resistance testing does not measure adherence or drug
levels! All it allows clinicians to
do is chose active drugs if they are available.
Mellors
also drove home the emerging theme with regards to phenotypic assays, that fold
cut offs for determining resistance will vary for different agents, and may also
vary with respect to patient drug history.
Examples cited were 2.5 fold cut off for Abacavir is to low.
One can get a clinically significant response to ABC at a higher cut off.
4.0 fold increase in susceptibility for ABT/378r is definitely not going
to be appropriate and may not hold for other PIís enhanced by Ritonavir.
And also, that a 4.0 fold cut off for NNRTIís may be too low in naÔve
patients, based on recent findings that patients starting EFV with low level
baseline resistance still had a full response to EFV if they were naÔve to the
NNRTIís.
Mellors
also reminded the audience that minor species are not detected by currently
available resistance assays. And
that major species become minor species within weeks when therapy is removed.
He also cautioned that the reproducibility of the genotypic assays must
be improved and standardized between labs.
During
the Q & A portion, Mellors responded to an insightful question from the
audience. ìWhy do all the studies
that look at genotyping and/or phenotyping seem to have short end points (the
longest Viradapt runs 24 weeks)? And
also, why do these studies show only small viral load differences that are
barely, if at all, statistically significant?î
Mellors response was, even a .4 log decrease in viral load translates
into a clincially significant difference and therefore it would be ethically
challenging to continue these studies for the purpose of the control arm.
In responding to the viral load differences, all of the currently
completed studies look at resistance at one point in time.
The optimal usage of these tests may be progressive/serial analysis of
the major species of a patients viral population.
Thus allowing the clinician to continually choose active agents as the
viral population shifts in response to drug pressure.
In one of the studies that did show statistical significance, VIRA 3001,
the patients were individuals who were failing their first regimens. When considering M Fischl's study of DOT among prisoners
showing 100% success in first regimens after one year, one could assume that a
number of patients enrolling in this study may in fact be patients who are not
adhering well to medication. If
that is the case, this study may underestimate the power of the phenotypic assay
to predict success because these patients may in fact be patients who do not
take their drugs religiously.
B.
Clotet in his presentation chimed the same chorus.
He stated that GART, VIRADAPT, VIRA 3001, and HAVANNA all give us data
that point to a justification for resistance testing, when a patient is failing
one regimen that he/she is taking as prescribed, while seeking to have the best
chance at virologic suppression with a subsequent regimen.