|
Reports
from the |
5th Resistance Workshop |
June
4-8, 2001
Scottsdale, Arizona |
Report 1
Written by Jules LevinThe temperature here ranges from 98 to 110. 98 is considered cool and when its 110 & sunny, forget about it. You could fry a rock. More detailed reports will follow.
Is Eradication Still Possible?
In abstract 34, David Margolis (University of Texas southwestern Medical Center) reports on very early research with a chemical pyrrole-imidazole polyamides. His premise is that this chemical binds to HV DNA in cells and may be capable of forcing latent HIV out of reservoirs while on HAART. And after this is done therapy could be stopped. He estimates human trials to be two years away. Don’t quit until the cure comes. It’s still possible. You never know what research will find.
Lisa Frenkel and her group from the University of Washington Seattle reported on a child on HAART with 8 viral blips of between 50-101. Over the course of 5 years the child had 11 viral load tests of <50 copies/ml and 8 tests reported blips between 50-100. This patient developed new mutations in PBMCs (cells). This was compared to one child who had one blip of 104 copies/ml during 4 years of effective HAART. The "blipper" was intensified with a more potent regimen of 4 drugs. The premise of Frenkel, although this is a very small study, is that more potent HAART may be required for many patients to keep viral load <50, and the goal of therapy should be to keep viral load <50. She suggests that resistance and subsequent viral failure will occur as a result of blips and resistance.
Abbott reports about 40 patients had virologic rebound to Kaletra in their study comparing to nelfinavir in treatment naives. To this day, Abbott has not detected any genotypic mutations in these patients. This has created much controversy as to why. Nelfinavir resistance developed for many patients virologically failing nelfinavir in this study. Suggestions from several sources including Abbott and non-Abbott sources think it’s possible that it is particularly difficult to develop resistance to Kaletra. It certainly is premature to conclude this until further research is done. Kaletra does however lead to increased cholesterol and triglycerides. Today, in an oral session Richard Harrigan (Virco, UK; British Columbia Center for Excellence in HIV, Vancouver) talked about Kaletra resistance. In looking at 1000 Kaletra phenotypic tests of treatment naïve persons from the Virco database, he reported 98% had <2.5 fold resistance. They also looked at 2500 total patients blood samples (isolates) phenotyped. The Kaletra resistance profile correlates most closely with ritonavir, and indinavir is a close second. Although slightly lower levels of Kaletra resistance than ritonavir resistance is evident from phenotypic testing of the isolates. Harrigan reported that over 30 protease inhibitor mutations were associated with decreasing Kaletra susceptibility. The 10 mutations most commonly found in patient’s samples in decreasing prevalence associated with 2.5 fold or less Kaletra reduced susceptibility were: 90M, 10I, 71V, 82A, 54V, 46I, 73S, 84V, 46L, 32I. Perhaps more important, these were the mutations in decreasing order most associated with 10-fold decreased susceptibility to Kaletra: 10I, 71V, 82A, 90M, 54V, 46I, 84V, 73S, 20R. Some of f the mutations in the second group associated with 10 fold Kaletra resistance which are not in the first group (82A, 46L, 20R).
Two abstracts reported an I50V mutation associated with Kaletra resistance. This mutation is associated with amprenavir resistance and suggests that if a 50 emerges from using APV some measure of cross resistance to Kaletra could occur. In poster 64, Abbott reports mutations at 10, 46, 54 and 82 appear most commonly in patients rebounding from Kaletra in the srudy of PI experienced patients.
In abstract 61, Abbott reports from a small number of patients receiving Kaletra in the multiple PI experienced study that 54 and 82 were statistically associated with virologic failure. They also suggested that the 10 and L90M mutations may possibly be key mutations associated with Kaletra resistance. Although this should be obvious, in abstract 90, which reports also on patients in the multiple PI experienced study, Abbott reports that the response rate to Kaletra was higher in patients who started therapy with lower baseline viral loads, higher baseline cd4s, lower baseline Kaletra resistance, and less PI experience.
Two New Protease Inhibitors: DPC 681 and DPC 684
Lee Bacheler from DuPont reported preliminary data on these two new protease inhibitors for PI resistant virus. In preliminary research these protease inhibitors appear to be effective against viruses with extensive PI resistance and may be effective for people with PI resistance. The activity of this potent PI was tested against mutant viruses constructed to contain single and multiple PI mutations which are known to confer resistance to first generation protease inhibitors. The following viruses were tested in vitro to determine levels of resistance to DPC 681 and 684: D30N (nelfinavir mutation), I84V (common PI mutation), M46I, 47V, I50V (APV mutations), V82F/I84V, M46I, L63P/A71V/V82F/I84V (RTV resistant), L10R/M46I/L63P/V82T/I84V (IDV resistant).
Bacheler reported reported no loss in potency against the D30N nelfinavir resistant virus or a saquinavir M48V/L90M mutant. 681 had 6.5 fold or less resistance and 684 had 3.5 fold or less resistance against viruses resistant to multiple protease inhibitors and with extensive PI resistance. Since 681 and 684 are potent drugs, DuPont researchers are hopeful that less amount of drug will be required to suppress PI resistant viruses. However, what remains for them to explore is precisely how much drug will be required to adequately and safely suppress extensively resistant viruses. Single and multiple dose phase I human studies are ongoing.
TMC 120 and 125: two NNRTIS for resistant virus in early research
Viruses resistant to NNRTIs (efavirenz, delavirdine and nevirapine) were tested in vitro against these two new NNRTIs. TMC 120 and 125 retained potency against many or most clinical isolates (from patient samples) resistant to current NNRTIs. In addition, experiments showed resistance to 120 and 125 developed more slowly and increasingly more slowly with increasing drug dose.
Mike Miller from Gilead Sciences reported on resistant data that is not that much new. 97.5% of 1000 treatment-naives had 3 fold or less reduced susceptibility to PMPA. Miller reported that 3-fold represents the level above which reduced PMPA susceptibility occurs using the Virco phenotypic test. This point was controversial as researchers here raised concerns. It appears that 3 fold may be a reasonable preliminary cut-off for judging PMPA resistance. However, more research is needed to better define and explore a cut-off.
Miller reported data from 5000 patient isolates submitted to Virco from treatment experienced patients with 69% >10 fold resistance to a drug from one class, 43% resistant to drugs from 2 classes, and 16% were resistant to all 3 classes of drugs (NRTI, NNRTI, PI). Among NRTIs, 40% and 17%, respectively, had >10 fold resistance to 3TC and AZT. 49% had 10 fold reduced susceptibility to NNRTIs.
88% of the recombinant clinical isolates had <3 fold reduced susceptibility to PMPA: 47% had <1 fold, 30% had 1-2 fold, and 11% had 2-3 fold. And 12% had 3 fold pr greater reduced PMPA reduced susceptibility: 8% had 3-5 fold reduced susceptibility, 3% had 5-10 fold reduced susceptibility and 1% had >10 fold reduced susceptibility.
Clinical isolates with >10 fold PMPA resistance (n=51; 1%) had high level AZT resistance (54-fold) reduced susceptibility to AZT. One patient clinical isolate remained within normal AZT susceptibility despite having PMPA 10-fold resistance. 37% of isolates with >10 fold PMPA resistance were within the normal range of sensitivity to d4T (if they are able to have an accurate cut-off for d4T resistance). And 51% with >10 fold PMPA resistance remained with ddI normal sensitivity range (the same can be said about ddI cutoffs). It appears difficult to identify accurate cutoffs for d4T and ddI resistance.
Greater than 10-fold PMPA resistance reported associated with T69S insertion mutation (18/51, 35%), multiple AZT mutations including T215Y/F (43/51, 84%), and infrequent association with K65R or Q151M mulinucleoside (4/51, 8% each). Only 17/5000 samples (0.3%) had both K65R and >3 fold reduced susceptibility to PMPA.
Safety of STIs: 3TC resistance and HIV reservoirs
Cecile Tremblay (Mass General) discussed whether STI can contribute to the replenishment of HIV reservoirs and is there resistance when viral load rebounds following an STI. Can STIs foster the emergence of resistance. She reported on 14 individuals treated during acute infection. Levels of infectious virus (infectious units per million cells, IUPM) were computed at time points before and after STIs. Tremblay reported there was no increase in the level of infectious virus recovered from CD8 PBMCs following an STI in the 7 studied patients.
One of 14 subjects had a 3TC 184 mutation detected for the first time after start of first STI. HIV was re-suppressed when 3TC was restarted along with other drugs, but 184 re-emerged at next STI. In two subjects in total, rebounding virus showed some evidence of viral evolution (resistance) from the 1st to 2nd STI. This study does not in my opinion ease concerns about the safety of STIs regarding resistance. The emergence of 3TC resistance could be because of the longer intracellular half-life of 3TC, which raises concerns about efavirenz and nevirapine which also have long half-lives. This is a preliminary study which does not address safety issues of STIs very well, but in fact raises concerns about resistance.
Rates of HIV Resistant Virus Increase and Response to Therapy Reduced
Susan Little from UC San Diego updated us on her study of transmitted resistance in treatment-naïve men (n=389; enrolled 7/95-5/00) with recent infection in 9 North American cities (Montreal, LA, NY, Seattle, Dallas, Denver, Vancouver, Birmingham). This is an update from most recent talk at Retrovirus 2001. She also reports on their response to therapy. 65% were men who have sex with men, 11% heterosexual, and 14% IVDU. This is important because CDC poster at this meeting reports finding lower transmission rates in African American heterosexual men (14% vs 4%) than in MSM.
She reported these increases in drug resistance (from <2.5 fold to >10 fold) transmitted to newly infected persons. All were either statistically significant increases or very close.
| 1995-98 | 1999-2000 | |
| Any 1 or more drug | 3.8% | 14.1% |
| --NRTI | 3.0% | 7.6% |
| --NNRTI | 1.7% | 7.6% |
| --PI | 0.0% | 8.7% |
| 2 or more drugs | 1.3% | 6.2% |
One or more major mutations: increased from 5.5% to 18.5% from 95-98 to 99-00 (0.001); major mutations + 215 D/N/S 7.2% to 21.7% (0.0004); 2 or more drug classes by genotype 1.3% to 5.4% (0.04).
The patients started therapy on average 120 days after HIV infection. They had the Phenosense resistance tests on average 94 days after infection. Perhaps most important, the time to viral suppression after starting therapy was reduced for patients with >10 fold reduced susceptibility to 1 or more drugs compared to patients with 2.5 fold or less reduced susceptibility. The probability of treatment failure was more likely to occur and occurred sooner for patients with >10 fold resistance compared to those with <2.5 fold reduced susceptibility. The CDC reported lower rate of transmission in AA men could be due to less access to therapy than MSM, or possibly to less HIV exposure by IVDU or heterosexual sex than thru MSM. Another poster here reports that in chronically infected treatment-naïve persons 18% had detectable resistance and response to therapy (undetectable) was delayed compared to those without resistance. This poster will be presented tomorrow and will get further discussion.
| to top > |