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Being Alive
An Update on Antiviral Therapy
presented by Mark Katz MD and reported by Jim Stoecker
April 5, 1997
Being Alive 1997 Apr 5: 8

Over the last year, more and more evidence has emerged to support the proposition that viral load is the single most important factor in the progression of hiv disease. All things being equal, we can say that the higher the viral load, the faster the progression of the disease.

A recent report at the National Conference on Retroviruses presented additional data on the correlation between viral load and the suppression of the immune system. Researchers reviewed data on 1604 hiv+ men in the ongoing MACS study (or Multicenter aids Cohort Study). They measured the initial viral load of the study participants and then plotted their annual decline in T-cells over an average 7.7 years. Those with an initial viral load of less than 500 had an average CD4 decline of 36 a year, while those with a starting viral load of greater than 30,000 showed an average yearly decline of 76 T-cells.

With our new understanding of the importance of suppressing viral load in effectively treating hiv disease comes some new answers on when to start and when to change antiviral therapy. Our purpose here is to review what we know today, as well as outline some questions still to be answered.

The Goal of Antiviral Therapy At the recent Conference on Retroviruses, Dutch physician Joep Lange put it best: "The minimal goal of antiviral therapy should be to suppress hiv replication as much as possible for as long as possible." Simply put, the purpose of any antiviral therapy is to get the viral load down as low as possible and keep it down. The ultimate goal is to achieve aviremia, i.e. undetectable levels of hiv in the blood.

Some experts would argue that there is an exception to the goal of undetectable virus. If an individual has "low" viral load, "decent" CD4 count, and has been infected a "long time," then some would argue that the person's own immune system is keeping hiv in check. In such a case, they would recommend frequent monitoring of viral load and CD4 count, but no antiviral treatment. The problem, of course, is that there is little consensus on what is a "low" viral load (less than 5000?), what is a "decent" CD4 count (greater than 500?), and what is a "long time" for hiv infection (10 years? 15 years?).

Starting Antiviral Therapy With the greater use of viral load testing, medical providers have new data with which to determine when to start an individual on antiviral therapy. Only a year ago, most physicians would have agreed that a viral load of less than 10,000 was probably acceptable. In the absence of falling T-cells and/or opportunistic infections, antiviral treatment was probably not necessary. Today, that thinking has changed. If the goal is to reduce the viral load as low as possible for as long as possible, then anyone with a detectable viral load should be considered a candidate for antiviral therapy. Most experts are advocating treatment for anyone with detectable viral load; they believe that if the viral load is brought down, this is better for the individual in the long run. This is a big change in treatment approach over just the last year.

If we have greater consensus today on when to start therapy, we still don't know which drug regimen is "best" to start with. Certainly, we now know that monotherapy (treatment with only one antiviral) is not the way to go. Most physicians recommend two reverse transcriptase inhibitors. Some would add a protease inhibitor as well, especially if the individual has a long standing infection with viral load above a certain threshold or CD4 below a certain threshold. Defining that threshold, however, varies from physician to physician.

For the last couple of years, AZT plus 3TC has been the most common initial combination antiviral regimen. Today, we are seeing more use of the d4T/3TC combination. This latter combination has the advantage of twice a day dosing (AZT is still usually taken on a three times a day schedule). Also, recent studies have shown that both d4T and AZT penetrate the cerebral spinal fluid (CSF) equally well. Previous thinking was that AZT had the advantage here.

Some experts are questioning whether 3TC is the best drug to start with. They assert that using 3TC up front may induce a resistance pattern that will limit an individual's future antiviral choices. These experts recommend ddI as an alternative, although no trial data on effectiveness is currently available.

Changing Antiviral Therapy With the widespread use of viral load testing has come the ability to closely monitor the effectiveness of an antiviral regimen. Medical providers had been judging a regimen as a failure if it did not suppress an individual's viral load greater than .5 log (or about one third of the initial viral load). Now, they are more likely to call a particular drug combination a failure if it is not able to suppress the virus to undetectable levels.

In the recent past, if the individual was using a combination of two reverse transcriptase inhibitors and began to "fail," a third drug, most likely a protease inhibitor, was added to the antiviral regimen. Evidence is suggesting, however, that such an approach is akin to monotherapy with the protease inhibitor. The two RT inhibitors were not sufficient to suppress the virus and thus the virus may no longer be sensitive to these two drugs. Today, the tendency is to change one or both of the RT inhibitors, as well as to add a protease inhibitor.

Combining Protease Inhibitors We are also noting today an increasing use of protease inhibitor combinations. The drug company Abbott recently reported on a trial that combined ritonavir and saquinavir. The trial included 141 hiv+ individuals with T-cell counts between 100 and 500 and with no prior therapy with a protease inhibitor. After 22 weeks of the protease inhibitor combination, viral load was suppressed an average 2.5 logs. Aviremia (a viral load of less than 200) was achieved in three-fourths of the study participants. Four hundred mg twice a day of each drug proved to be effective and the least toxic dosing regimen.

Other trials of two protease inhibitor regimens are being planned. These trials will include the use of nelfinavir (Viracept), a fourth protease inhibitor that received FDA approval in March. We should soon have more data on this new approach to antiviral therapy.

Four-Drug Regimens As one of the participants at the Conference on Retroviruses noted, "There is nothing magic about the number three." We are seeing study data emerging on the use of four-drug regimens, i.e. quadruple combination therapy. Early studies suggest that this may be an approach that is particularly effective for those with advanced aids.

One study involved 18 PWAs who had been diagnosed with aids an average of 4.1 years at the start of the study. The mean viral load for the group was over 100,000. Some of the group added one protease inhibitor to their regimen of two reverse transcriptase inhibitors; this group saw about a one-log drop in viral load. Those who added two protease inhibitors to their regimen experienced closer to a two-log reduction in virus in the blood. Another study of 32 individuals with T-cells less than 250 showed similar results when a combination of ritonavir and saquinavir was added to their antiviral regimen. These are small studies and additional data are needed. However, it may be that in the future protease inhibitors will be combined, just as RT inhibitors are today. Indeed, the magic may be in four (or more) antiviral drugs.

Open Questions With all we do know today about effective antiviral therapy, there is still much that we do not know. When should we add a third drug? At the very start of therapy or when failure on two drugs is determined? And how do we gauge failure? How low is low when it comes to viral load? Is an undetectable level possible for every individual with hiv? Which protease inhibitor is the best? Should we start with two, rather than one? And what about sanctuaries for hiv? Is it enough to lower the viral load in the blood stream? These and many other questions remain to be definitively answered.

We have come a long way in the last couple of years in treating hiv disease; let no one doubt, however, that we still have a way to go.

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