Highlights Part 1 from Mike Norton, PA, for NATAP

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 After the 83 days, PMPA was withdrawn and the virus rebounded for several weeks prior to being brought under control by virus specific immunity that these macaques had developed.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.