AIDS TREATMENT UPDATE Issue 26 - Feburary 1995
Edward King

Researchers in New York and Alabama treated different HIV-positive people with the anti-HIV drugs nevirapine (a non-nucleoside reverse transcriptase inhibitor), ABT-538 or L-735,524 (two new protease inhibitors). The drugs were highly effective in the short-term and rapidly reduced the amount of HIV in the blood. However, within days or weeks strains of HIV that were resistant to nevirapine had developed, and very few drug-susceptible viruses could be found in the blood. The researchers realised that for such a rapid replacement of drug-sensitive strains by drug-resistant ones to occur, very large amounts of HIV must be being produced every day.

By teaming up with mathematicians and studying the rate at which HIV was killed and the speed at which nevirapine-resistant virus strains developed, they estimated that nevirapine was killing about 1 billion HIV viruses per day, or about 30% of the total amount of virus in the body. However, similar numbers of new viruses were also being produced to replace those being killed.

Likewise, the estimated that billions of CD4 cells are destroyed each day, and replaced by billions of new ones. An accompanying editorial suggests that the most likely way in which CD4 cells are lost is that cytotoxic T-cells (also known as CD8 cells) very efficiently detect and destroy HIV-infected CD4 cells.

The end result is a process in which every day vast numbers of new HIV particles are produced, and the immune system fights back by killing vast numbers of HIV-infected CD4 cells and producing new ones to replace them. However, it is theorised that the immune system is unable to maintain such an extraordinarily high level of activity over the long term and is eventually overwhelmed by HIV's sheer force of numbers.

Treatment implications

These new insights may have important implications for the treatment of HIV infection. Virologists have long argued that HIV infection should be tackled like any other viral infection, in which earlier treatment is usually more effective than later treatment. The evidence that very high levels of HIV replication are taking place at all stages of infection reinforces this view. Researchers have recently found that the longer HIV replicates, the more likely it is that mutant strains that are resistant to treatment will develop, even in people who have never taken treatments. Theoretically, this means that drugs are likely to be less effective the later they are taken.

However, although the theory of early intervention makes sense, available drugs seem to be insufficiently effective to turn it into a reality. Studies such as Concorde have shown that AZT monotherapy is no more effective when used early than when used after symptoms develop. In the studies reported in Nature, the dramatic antiviral effect of nevirapine and the protease inhibitors was quickly lost as resistance developed. There is now an overwhelming consensus among researchers that drug combinations offer the only real hope of effective anti-HIV treatment, but studies to assess the clinical effectiveness of currently available drug combinations have yet to produce results.

Professor Tony Pinching of St Bartholomew's Hospital in London also questions the logic of early treatment on the basis of the new research. "The fact that you can demonstrate high rates of viral replication doesn't necessarily mean that it's clever to try to suppress replication early. It doesn't seem to me that early intervention is a very sensible thing to do if it results in the rapid development of resistance when a person is still quite well, and when you have a limited number of antiviral drugs. If the immune system is successfully dampening down viral replication, why exhibit your antiviral armamentarium early?"

The second implication is that the immune system may be able to rebuild itself if HIV can be sufficiently inhibited. Professor Jonathan Weber of St Mary's Hospital points out that the fact that the body is able to produce so many CD4 cells to replace those killed during HIV infection suggests that effective antiviral treatments might enable the CD4 count to recover even in people with relatively low CD4 counts. In other words, the priority for treatment may be to stop HIV replication - even in advanced disease - and not to boost the immune system, since the immune system seems perfectly able to recover on its own once HIV is inhibited.

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