Being Alive; September 1996
presented by Mark Katz MD and reported by Jim Stoecker

As we have mentioned in past updates, a consensus is building that the goal of antiviral therapy is to get the viral load down as low as possible for as long as possible. But how low is low? In the past, with the first generation of viral load tests, a count of less than 5000 viral copies per unit of blood might have been considered undetectable. At that time, many thought that a count of less than 10,000 meant that there was little cause for concern.

Now, with second and even third generation tests, we are able to measure viral copies as low as 50. Thus, what we used to call undetectable was a much higher level of virus in the blood than what we might now call undetectable. And this difference can be crucial. A recent study took a single viral load reading and then determined the survival statistics for the study group. Those with a reading of less than 5000 copies per unit of blood had a significantly higher rate of survival for the six years looked at than did those with a reading over 5000. So when we talk about undetectable levels of virus, we need to be sure we know the sensitivity of the particular test that we are using.

Questions, of course, remain. Does pushing the viral load lower (say from 5000 to 50) ultimately make a difference in survival? We do not as yet have the data to answer this. Most people in the field, however, would say that the answer is yes. Another important and closely related question: if the viral load is significantly reduced, does that reset your survival outcome? For example, if through antiviral therapy your viral load is reduced from 100,000 copies to 5000, does that mean your survival profile is that of someone whose maximum reading has never been greater than 5000? Again, we do not know, though many are guessing that the answer is yes. Obviously, we need more data to get at definitive answers to these essential questions for people with HIV.

* Flu Shots Again

With the coming of fall, we once again have the issue of whether hiv+ people should get a flu shot. This year, the Centers for Disease Control (CDC) are still recommending that people with hiv get this shot. We know, however, from studies released last year, that a flu shot temporarily raises the level of hiv in the blood. What we do not know is whether such transiently elevated levels of virus have any significance for long term health and survival. We can say that people with hiv do not seem to get the flu more frequently or more severely than hiv-negative individuals. So should you get the flu shot or not? This is an issue to talk over with your medical provider. There is not, at present, a definitive answer.

* Combination Therapy Studies

We continue to see more studies of combination antiviral therapies. In a recent Annals of Internal Medicine (August 1, 1996), researchers reported on a study of 254 people who were previously on AZT monotherapy. The group was randomized to one of three combination regimens: AZT plus ddC, AZT plus low dose 3TC (150 mg twice a day, the current CDC recommendation), AZT plus high dose 3TC (300 mg twice a day). After one year, researchers report a mean gain of 43 T-cells in the AZT/high dose 3TC combination, while there was a loss of T-cells in the other two groups. After a year, there was no statistically significant difference in viral load reduction among the three combination studies; all reduced load an average of about half a log.

We also have results of the so-called CAESAR trial (all at sites outside of the US and including sites in Canada, Europe and Australia). Almost two thousand individuals were involved; 80% were already on some antiviral regimen at the start of the study. Baseline CD4 counts averaged 130 for the study group and viral load average was about 100,000 per unit of blood. This study kept everyone on their present regimen. One third of the group added 3TC and another third added 3TC and loviride, an experimental non-nucleoside reverse transcriptase inhibitor. After 28 weeks, the groups that added 3TC to their antiviral regimen had a mean CD4 rise of 20 and a viral load drop of half a log. The group that simply remained on their current regimen, without the addition of 3TC, had no significant change in these measures.

What to make of all this? Is it really the addition of 3TC that makes a combination stronger or would the addition of any antiviral show similar results? What is the best combination of antivirals? The answer to this important question is highly individual and only found through experience. Take what works for you. If you are on a combination regimen that is tolerable and that suppresses your viral load, that is the antiviral combination for you. Until we have more data, that is the best answer we have.

* A Drug with No Name: 1592U89

There is growing excitement about a new nucleoside analog antiviral that is under development at Glaxo-Wellcome (makers of AZT and 3TC). This reverse transcriptase inhibitor does not yet have a name, so it is referred to as 1592U89. In early phase I/II studies, this drug appears to be synergistic with (i.e., enhances the efficacy of) other reverse transcriptase and protease inhibitors. In addition, it appears to be superior to all current antivirals in penetrating the central nervous system. Early studies were reported at the recent International aids Conference in Vancouver. About 60 people, all with less than twelve weeks of prior AZT therapy, were given the drug. On this monotherapy regimen, at the end of four weeks, viral load for the study participants had dropped from 1.5 to 2.2 logs. Further studies are underway, and word is that Glaxo-Wellcome hopes to have FDA approval by late 1997. By that time, one hopes, 1592U89 will have a name.

* The Current Consensus on Antiviral Therapy

There is a consensus emerging among those involved in treating people with hiv on how one should approach decisions about antiviral therapy. This is not necessarily the official standard of care, nor is it fully backed up by many studies in the medical literature. Nonetheless, it seems to be where we are today and is worth considering.

When to start antiviral therapy? Most would recommend the viral load as the first marker to consider. If the viral load is detectable or if the load is above a certain "threshold" (and this threshold is variously defined), then one should begin antiviral therapy. One should also consider CD4 count and other clinical criteria when making this decision.

What antiviral regimen to use? Usually, people are beginning with two reverse transcriptase inhibitors (AZT, ddI, ddC, 3TC, d4T). The most common combination is AZT/3TC and this combination may give the greatest viral load reduction. Other combination, however, are being used. How to monitor the efficacy of the antiviral regimen? Viral load tests should be done every several weeks after initiating a regimen and then every three months or so. When do you change your current antiviral regimen? Again, the viral load, the actual amount of hiv in the blood, is the first marker to consider. If viral load is consistently detectable or goes up or returns to baseline (i.e., the level before treatment began) or shows less than a half log decrease, then a change should be made.

And what should you change to? Here you have a number of options with no clear consensus yet as to which is the best. Some would recommend that you scrap all the drugs that you are on and start with a whole new combination. Others would say that you can add nevirapine or a protease inhibitor to your existing combination.

* Cidofovir Approved for Treatment of CMV Retinitis

Cidofovir (brand name Vistide) has now been approved by the FDA as an alternative to ganciclovir and foscarnet for the treatment of CMV retinitis. The major advantage of this new treatment is the dosing schedule of the drug. Initial therapy with cidofovir is one injection a week for two successive weeks; maintenance therapy is one injection every other week. Treatment with ganciclovir, in contrast, initially requires up to 30 injections in the first two weeks of therapy. The main side effect of cidofovir is kidney toxicity. The drug must be infused in a controlled situation. There is also the issue of cost: some $16,000 per year. This cost, however, may be comparable to ganciclovir when one considers the cost of implanting a central line for the infusion of ganciclovir. Gilead, the maker of cidofovir, has set up a financial assistance program and can be reached at 800.445.3235.

* New Option for MAC Prophylaxis

To date, we have had two options for MAC prophylaxis: rifabutin and clarithromycin. The drawback of rifabutin is that it cannot be used with some of the new protease inhibitors. The concern with clarithromycin is that one can develop resistance to the drug and thus not be able to take it as therapy should MAC develop.

Now the FDA has approved another option for MAC prophylaxis, azithromycin (brand name Zithromax). The main advantage is that you need to take only one 1200 mg dose once a week; this is about as patient friendly a dosing schedule as we could hope for. To date, there have been no reports of interactions with protease inhibitors. Research also indicates that if MAC develops, there is less likely to be resistance to azithromycin than there is to clarithromycin. For all these reasons, azithromycin may soon become the standard prophylaxis for MAC.

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