In this first day of the conference, the first session had a talk about the development of DNA based vaccines. DNA based vaccines are in preclinical development. If the hoped for immunoogical response is observed in laboratory and animal testing, clinical trials in uninfected and hopefully infected individuals will follow. One DNA based vaccine, which may not be as promising as in the one in earlier stage of study, is in a clinical trial of infected individuals but results are not yet available. The speaker here said it is difficult but possible to achieve significant protection against disease infection; and, it’s impossible to achieve broadly sterilizing immune responses. That’s his opinion.

Lynn Moffenson of the NIH reviewed the data from AZT treatment reducing vertical transmission. Briefly, in ACTG 076 a prescribed course of AZT treatment reduced HIV transmission in that study by 68%. Using that prescribed course vertical transmission has been dramatically reduced in the USA to 3 to 5% in AZT previously untreated women. She also reported that membrane rupture greater than 4 hours during labor significantly increases risk of transmission (9.8 times). More recently a study conducted in Thailand used a short course of AZT treatment to reduce transmission. Transmission was reduced by 50%. These results are key because in developing countries where resources are much less than in developed countries a less expensive resource required regimen can also be successful in reducing transmission.

As mentioned in yesterday’s report reducing viral load to <50 copies/ml is emphasized here. At this lecture Doug Richman also said reducing viral load to <50 copies should increase durability. At a prior ACTG meeting he said the goal of therapy should be <1 copy/ml. Although virus may be <50 copies/ml this does not necessarily mean virus is not replicating or detectable in lymph tissue. At the Resistance Meeting in Lake Maggiori, data was reported comparing individuals with <20 copies/ml in plasma. One group was taking 2 or 3 NRTIs and the other group was taking a protease regimen. The individuals taking the protease regimen had less virus in lymph tissue than those taking NRTIs. It could be due to higher potency; or, lymph tissue contains activated cells and Pis are more effective in activated cells. But, this was new data and this difference is not well understood. The researchers said they will conduct a study comparing a NNRTI regimen to a PI regimen.

Richman reviewed phenotypic and genotypic resistance testing. At Lake Maggiori new data was reported correlating baseline genotypic and phenotypic resistance with predicting clinical outcome. Several studies were presented showing this correlation. At the NATAP forum at NYU Medical Center on July 18, representatives from the manufacturers of two phenotypic tests will discuss this information. As well, Dr Doug Mayers, a resistance expert, will discuss these issues. Call NATAP at 212 219-0106 for seat reservations.

With regards to phenotypic and geno- testing Richman said--

• phenotypic tests detect reduced susceptibility to inhibition of HIV replication
• testing provides info on predominant virus mutations but may not pick up mutations present at low level
• mutations that emerged from prior therapy may disappear but could emerge upon recontinuation of therapy with drug in same class. Resistance testing could miss that mutation. Therefore, testing could underestimate presence of resistance
• geno testing results may not correlate with pheno testing results
• geno testing is an indirect measure of resistance while pheno is more direct measure
• expert interpretation of results may be required to understand and apply results
• there are several methods for detecting genotypic resistance; the LIPA method of geno testing better detects mutations apparent at lower levels
• costs for testing are high
• testing may show which drugs will not work better than which drugs might be effective
• in the past it was thought that clinically significant cutoff values of resistance were not well defined by test results. But new data shows that we may be beginning to define these values for some drugs. For example, data reported at Chicago Retrovirus Conf showed baseline phenotypic resistance might be definable for 1592U89. Persons with <4 fold resistance were sensitive to 1592; those with 4 to 7 fold resistance had some sensitivity and those with >7 fold had no sensitivity. This data is reviewed in NATAP Reports newsletter (current edition) and on web site.
• one potential limitation involves drug blood levels. What if pheno test shows 5 fold resistance but blood levels of drug are very high and high enough to overcome that resistance. Forexample, the new Abbott protease, ABT-378, provides trough levels of drug up to 100 fold above the IC50 for wild type virus. Four fold resistance may not accurately describe real sensitivity

Patrick Yeni reported data from ACTG 290. Individuals with extensive AZT resistance did not respond to d4T but with ddI reduced viral load by 0.44 log. Yeni stressed the data from ACTG 343 and another study where 23% of individuals who reached <50 copies/ml with IDV/AZT/3TC were unable to maintain that reduction if they reduced their regimen to only AZT/3TC or IDV. However, he said maintenance therapy following induction therapy needs further study. We may be able to identify a strategy for successful induction/maintenance but we have not done that yet.

Yeni discussed a Mega HAART study reported at New Orleans Salvage Therapy Meeting which was described briefly in NATAP Reports’s current issue. 24 patients received 6, 7 (n=11), or 8 (n=2) drugs regimens including recycled drugs. There was an average 2.97 log reduction; 70% were <500 copies/ml; 30-40% were <50 copies/ml. However, the researcher reported tolerability was not good and maintenance therapy following MEGA HAART was not as effective. Further maintenance regimens are being explored.

That’s it for now. I’m off to eat lunch and view posters.