BEING ALIVE; March 1995
Walt Senterfitt

The essential method of both studies was to give study participants an antiviral drug and observe the results each day. Ho used Abbott's protease inhibitor and Shaw used nevirapine. Every two days, the level of HIV in the bloodstream was reduced by half (unfortunately, the effect was short lived). Since neither of these drugs can eliminate virus already in infected cells, the sharp reduction meant that new virus was being "cleared" by the drug's action in the body. And the rebound meant that new virus is being created at an incredible rate - billions of virus particles a day.

Ho's team went on to show that the sharp decline in HIV is accompanied by a sharp rise in T-cell counts, as much as 600 in a single month. The starting count of the 20 people in Ho's study ranged from 36 to 490. The team calculated that the total CD4 population in the bloodstream in infected people is doubling every 15 days. This means, according to Colorado's Dr. Robert Schooley, that "there's a hell of a lot more immunological reserve than people would have thought."

What It Means

These findings will change the way everyone thinks about HIV's resistance to antiviral drugs. So far, many antivirals are effective for a comparatively brief period. The rapid development of resistance was thought to result from HIV's high mutation rate. This turns out now to be a misconception. HIV does not mutate any faster than other RNA viruses, such as the ones that cause measles, mumps, yellow fever or encephalitis. Rather, what causes drug resistance is the high rate of replication. In other words, the mutations that do occur are rapidly amplified because billions of new virus are produced every day. Sooner or later, the drugs eliminate the types of virus sensitive to the drugs, leaving behind a population of resistant virus that multiplies very fast These studies also confirm the hopes of many that the immune system can be largely reconstituted once viral replication is stopped. An infected person can produce a lot more new T-cells faster and at later stages than we previously knew. We still don't know exactly how far along the slope of T-cell decline this regenerative capacity will be sufficient. And, of course, Step 1 remains to be completed: developing sufficiently effective antiviral drugs that either alone or in combination will stop virus production for at least a very long time.

Practical Implications for Research

I can only be speculative. The findings are too new and too dramatic for one to be sure of all the changes that will happen in basic and clinical research. A few things seem likely, however. For one, evaluations of potential new drugs will have to be scheduled at much closer intervals than before (daily, for instance, rather than the typical every two weeks). As UC San Diego's Doug Richman said, "If a drug doesn't have an effect by day 14, it isn't worth developing."

It should also permit much faster drug testing. It reinforces using "viral load" (the amount of virus in the body or in the bloodstream) as the best available "surrogate marker" for drug effectiveness. Long term studies are urgently needed to correlate precisely these viral load measurements and variations with symptoms and survival.

It helps explain why thus far every antiviral drug eventually loses effectiveness due to viral resistance. This fact may not ever change. The hoopla over "triple combination therapy" two years ago highlighted the hope that some form of "convergent combination therapy" could break the drug resistance cycle by deliberately stimulating mutations that in combination would render the virus sterile. Some researchers continue to believe in this possibility even though the original excitement was later reported to be based on erroneous data. Others would now question whether this cycle can ever be broken once and for all.

But these data contain hope for much more effective containment strategies, by individualizing care based on repeated measurements of viral load. That way individual drugs and combinations can be changed or rotated based on each individual's own pattern of response. Together with the development of more new classes of drugs that act at different parts of the viral life cycle, this may offer the realistic hope of converting HIV infection into the long-promised "manageable chronic infection."

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