AIDS TREATMENT NEWS Issue #211, November 18,1994
John S. James

This talk also makes the point that lowering viral load, as measured by HIV RNA count in blood plasma, is likely to result in immune-system recovery, even without special therapies for immune reconstitution.

This information changes the outlook for AIDS research, creating opportunities for much faster progress.

Note: We were unable to run this transcript by Dr. Richman, as he was out of the country as we went to press. To avoid changing his meaning inadvertently, we did not edit the oral presentation for readers who do not have access to the slides he was using. As a result, the following text is sometimes difficult to follow.

Dr. Richman: "Shifting gears a bit, this is a point almost related to pathogenesis, something that Mike Saag brought up yesterday. These are two patients given nevirapine, and almost like a PK [pharmacokinetic] study looked at daily plasma HIV RNA levels. Here's a person with 8,000, and here's a person with 35,000, at baseline; at 24 hours after the administration of drug, no change here, slight change here. 48, 72 hours, an incredible drop; basically by day four or five, everything that the drug is going to do has been done. The same sorts of data have been shown by Clive Loveday in London with AZT, and Charles Boucher in Amsterdam with 3TC, and David Ho with protease inhibitors, also; the same phenomenon is occurring with all of the antiretroviral drugs.

"There are two major take-home lessons that I think are very important about this. One is, as Mike mentioned yesterday, the turnover rates, the half-lives here, even if you assume that the drug is inhibiting replication 100 percent, which is a worst-case phenomenon, probably unlikely, the half-life here is 24 hours, or even less. So that these ten to the five levels of plasma RNA that we're seeing, those hundred thousand copies, weren't there yesterday; those are today's virus. The implication is that, with this high turnover, if you can stop the production, you significantly down-shift what's going on.

"And in terms of pathogenesis, a similar phenomenon has been shown; the very nice data with the Abbott compound that David Ho showed in Atlanta, that unfortunately we didn't get to see yesterday, showed that with more potent drugs, as with the Merck protease inhibitor and the Abbott compound, this same phenomenon occurs, but you get two and three log drops, instead of a one or one and a half log drop. And in association with drops of that magnitude, instead of getting 75 or 100 [T-helper] cell rises, they were seeing two, three, four, five hundred CD4 cell rises, in a couple of weeks. The implications of that are (and I think somewhat different from the Ashley Haas model that Mike was talking about) -- my perception is that there's a stem-cell population, CD34 cell population, that is producing CD4 cells; and if you can arrest the replication, the high turnover rate of new cells will reconstitute the immune system. The implications of that are that immune reconstitution is not necessary if you can block virus production. That also means that the stem cell population isn't being infected -- and there are other studies showing that the CD34 cell population is not CD4 positive, is not susceptible to the virus. And that's good news, we have a stem-cell population that is not infected. If it were, I would argue that this wouldn't be a chronic disease.

"There's one other implication of all of this. And that is, with all of these drugs we're seeing the same kinetics. That means that in a two-week study, you can show whether a drug works or doesn't work, and you can do a dose-response curve. Now it doesn't tell you what's going to be a useful drug, because it's a chronic disease, so it doesn't tell you what's going to happen long term. And this virus -- and we're doing studies with Scott Eastman, to do the allele-specific characteristics of this virus -- we've shown in seven days a drug resistant virus emerging. So that this is going to be resistant virus, this is sensitive virus. So in terms of being a useful drug, we need longer studies. But in phase I studies to ascertain whether you've got a drug that works or not, you only need a two-week study; and there is a protease inhibitor that we've just finished evaluating in which the decision to stop the development of the drug was based on two-week studies, and 48 patients who had plasma RNA levels, sequentially, not one of them had more than a three-fold variation. So that with a half-log change, you only need [few] patients and if you have half-log changes, that's different than you're going to see in the natural course over a short period of time in the patients."

Note: The audio tape of Dr. Richman's talk, "Antiviral Drug Resistance: Genetic and Phenotypic Mechanism -- Clinical Significance," is available from J. Schimmel Associates, 10251 Granada Lane, Shawnee Mission, Kansas 66207, 913/649- 5743; ask for tape #94-14 from the New Directions in Antiviral Chemotherapy conference. The price is $10, which includes shipping. You can also get a list of the 16 audio tapes available from the conference; while few of the talks have new information, they do have useful reviews on a number of topics, including combination therapy, early intervention, delavirdine, nevirapine, the Abbott and Merck protease inhibitors, cytokine therapy for HIV, gene therapy for HIV, treatment for CMV, and treatment for hepatitis.]

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