Being Alive; November 1997
Jim Stoecker

On Monday, October 13, Being Alive, L.A. Shanti and APLA sponsored a panel discussion on the news from ICAAC. Mark Katz, MD, served as moderator and presenters included Judith Currier, MD, Medical Director of County-USC's 5P21, Charles Farthing, MD, Medical Director of AIDS Healthcare Foundation, and Dan Bowers, MD, of Pacific Oaks Medical Group. This report is based on their presentations and on information gathered from the Internet.

Not Everyone is Doing Well on Protease Inhibitors

By now, most people involved in AIDS care are aware that not everyone who is taking triple combination therapy with a protease inhibitor is doing well. Many of us have heard stories of people failing to achieve undetectable levels of virus in their blood, even on so-called HAART (or highly active antiretroviral therapy). At the conference, two reports put some statistics behind the anecdotes and offered some explanation why some people thrive and others do not when taking triple combination antivirals. At the University of California in San Francisco, researchers followed the course of 136 people who were taking either ritonavir or indinavir in combination with two nucleoside analogs. The researchers determined that this regimen failed the individual if his/her viral load measured greater than 500 after four months on therapy. Based on this criterion, the triple combination failed 54% of the study subjects.

The UCSF researchers wanted to know why the failure rate was so high, since some studies have shown upwards of a 90% success rate on this regimen. They found that baseline viral load was a factor in success. If initial viral load is greater than 100,000, the individual is less likely to achieve undetectable levels. Those with lower initial CD4 counts were four times as likely to fail on the regimen than those with higher initial counts. In some cases, there was also suspicion of non-adherence to the treatment requirements; such suspicions were based on clinical records that revealed missed appointments and/or failures to refill prescriptions. The most prominent reason for failing on the therapy, however, proved to be not starting with three new drugs. Those who simply added a protease inhibitor to their existing regimen of reverse transcriptase inhibitors were 14 times more likely not to achieve undetectable viral load than those who began with three drugs that they had not previously used.

A study by the California Collaborative Treatment Group (CCTG) followed a group of 97 individuals who were taking a combination regimen that included at least one protease inhibitor. The CCTG researchers found only 31% of this group had viral levels of less than 400 after six months of therapy. They concluded that if an individual was already on a protease inhibitor or was taking less than three drugs, then he/she was less likely to achieve an undetectable level of virus.

We already know that adherence to the treatment regimen is important. Added knowledge here is the importance of initial viral load and CD4 count in predicting the impact of therapy. And the most important fact seems to be that one should start a triple combination regimen with all new drugs; those that simply add a protease inhibitor to their existing regimens are less likely to achieve undetectable vital load.

Combinations with a Protease Inhibitor Appear to be Superior

Two European studies that were presented at ICAAC point out the superior efficacy of a combination regimen that includes a protease inhibitor, even for those individuals who had no prior antiviral therapy or had high initial CD4 count.

The so-called Avanti-2 study included about 100 individuals with CD4 counts between 150 and 500. None of the study subjects had been on antiviral therapy prior to the onset of the study. The participants began a regimen of either AZT+3TC or AZT+3TC+ indinavir. After one year, researchers found that 60% on the triple combination had less than 500 copies of virus per mL of blood, while only 18% of those on the two-drug-combination tested at less than 500.

Another study, dubbed EARTH for Early Antiviral Therapy, included only people with greater than 400 T-cells at the start of the study. None had prior antiviral therapy. Participants received either AZT+3TC or AZT+3TC+ritonavir. After six months, 94% on the three drugs had viral loads less than 500, while only 31% of those on two drugs tested at less than 500.

An interesting aspect of the EARTH trial is that participants whose viral load was greater than 1000 after three months were switched to a new regimen. This recognizes the importance of both close monitoring of the impact of an antiviral regimen and of switching to something else if undetectable viral levels are not achieved in a reasonably short time. When you look at the difference in the results of these two studies, you also see the importance of initial CD4 count. In the Avanti study, where initial CD4 counts were as low as 150, only 60% reached undetectable levels, while in the EARTH study where everyone began with a CD4 count greater than 400, some 94% tested at less than 500 viral copies/mL.

How About Triple Combinations Without a Protease Inhibitor?

Participants in the INCAS study began with CD4 counts between 200 and 600 and had no antiviral therapy prior to the start of the study. Three regimens were offered: AZT+ddI+nevirapine, AZT+ddI, AZT+nevirapine. After one year, 57% on the triple combination had a viral load of less than 500, while only 27% on the AZT/ddI combination tested at this level. None of the participants taking AZT+nevirapine showed a viral load of less than 500. When using a more sensitive PCR test, researchers found that about 51% on the triple combination tested at less than 20 viral copies/mL. These results still leave almost half the people on the triple combination with detectable viral load.

In reviewing the data, researchers found that those with a lower initial viral load were more likely to achieve undetectable viral loads. Thus, it may be that viral load at the start of antiviral therapy may be a determining factor in which combination of drugs to use. If initial viral load is low, a protease inhibitor may not be needed.

Effective Triple Combination Means Three New Drugs

More evidence on the importance of concurrent therapy was presented at ICAAC. Researchers reported on the results of a follow-up of the Merck 035 study. Study subjects began on one of three regimens: AZT+3TC, indinavir alone, AZT+3TC+indinavir. After six months, those on indinavir alone added AZT+3TC, while those on AZT+3TC added indinavir. Thus, six months into the study, all participants were on the same antiviral regimen.

When looking at how many were still testing at less than 500 viral copies/mL after two years, however, researchers found marked differences. Of those that began the study on the three-drug combination 80-85% were testing at less than 500. In contrast, only 30-40% of those that added drug(s) six months into the study were showing viral loads of less than 500. This is rather dramatic evidence of the superiority of concurrent therapy (three new drugs) over sequential therapy (adding drugs to an existing regimen). These data also point out the continuing efficacy of the triple combination; for many, in this study at least, this combination has proved a durable antiviral regimen.

Twice Daily Indinavir

The current dosage of indinavir is 800 mg three times a day. For some, this has proved to be a difficult dosing schedule to follow. Thus, researchers are looking at the efficacy of taking indinavir only twice a day. At ICAAC, there was a report on a pilot study of 87 individuals who had never taken either 3TC or a protease inhibitor prior to the start of the study. All were given AZT+3TC+indinavir. One third of the study subjects followed the standard dosing schedule of indinavir (800 mg three times a day). One third took 1000 mg of indinavir twice a day and another third took 1200 mg twice a day. After four months, about 75% of the subjects tested at less than 400 viral copies/mL of blood.

Researchers noted that there was no evidence that the twice daily dosing of indinavir was less effective than the three times daily dosing. In fact, they noted that more on the three times per day schedule dropped out of the study. It should be noted, however, that those on the higher twice-daily dosage of indinavir did show somewhat higher incidence of kidney stones. This study only has a four-month follow-up, so there is no way to gauge long term efficacy. And the study population is quite small. Most physicians would agree that the three times daily dosing should remain standard for now. Larger studies of twice daily indinavir are being planned so we should have more data on efficacy in the future.

Invirase Becomes Fortovase

Hoffman-LaRoche has reformulated saquinavir (brand name Invirase) and given this new formulation the brand name of Fortovase. This new drug is a soft gel capsule that has 4-5 times greater absorption in the blood than Invirase. A study that compared the combination of AZT+3TC+Crixivan (brand name for indinavir) to AZT+3TC+Fortovase included 44 subjects with no prior therapy. All had CD4 counts less than 500 and viral loads greater than 10,000. After six months, there did not appear to be any difference in efficacy between the two combinations. Both reduced viral load and boosted CD4. There did, however, appear to be greater GI intolerance with the Fortovase combination.

Hydroxyurea Boosts Efficacy of ddI

Hydroxyurea is not an antiviral, but it does appear to make the antiviral ddI work better in the blood. An AmFAR study, reported at ICAAC, followed a small group on ddI alone and another group on ddI+hydroxyurea. They found that 32% of those taking both drugs had viral loads of less than 500. In contrast, only 20% of those on ddI alone tested at below 500 viral copies/mL. Clearly, ddI, with or without hydroxyurea, is not adequate therapy by itself. But for those taking ddI as part of their antiviral regimen, the supplemental use of hydroxyurea may prove beneficial. Researchers caution, however, that the ddI+hydroxyurea combination works best when both drugs are started at the same time. Simply adding hydroxyurea to an established regimen that includes ddI does not seem to be as efficacious.

Ritonavir Boosts the Concentration of Other Protease Inhibitors Researchers are reporting that ritonavir appears to enhance the blood concentrations of other protease inhibitors. Because of this, the drugs stay in the blood longer and thus have more beneficial effects. A dose-ranging study that combined ritonavir with saquinavir found that after three months, 80% had undetectable viral loads when only using the two-protease inhibitors. In another pharmokinetic study that combined ritonavir with indinavir, study subjects took only 400 mg of indinavir twice a day. By using with ritonavir, the hope is that indinavir levels will be boosted and only twice daily dosing will be required. Neither of these studies were clinical trials; clinical trials that combine ritonavir with another protease inhibitor are now being planned.

Protease Inhibitor Rescue Therapy

At ICAAC, there was a report on a small study conducted at St. Vincent's Hospital in New York City. Twelve individuals whose viral load was going up on a regimen of nelfinavir and two reverse transcriptase inhibitors were switched to another protease inhibitor and to two other RTIs. Of the twelve, three (25%) had undetectable viral loads after switching their regimen. Four had a partial reduction in viral load and for five of the twelve (about 40%), there was no response to the new regimen. The researchers stressed that as long as there are new drugs to take, they should be tried in the hopes of triggering a response.

What About Prophylaxis For Opportunistic Infections?

Now that more and more people with AIDS in the U.S. and Europe are on HAART and the incidence of opportunistic infections (OIs) is dropping, there is not nearly as much research into the causes and treatment of OIs as has been reported at previous ICAAC gatherings. However, for those on HAART and doing well, whether to continue on their prophylactic drugs is an issue. The consensus today continues to be that, regardless of a rise in CD4 count, you should remain on any prophylactic regimen. The decision to take prophylaxis for OIs should be based on the lowest CD4 count of the individual, not the possibly rebounded count after triple combination therapy.

This consensus is based on what we know about the immune system. There are two kinds of T-cells: na ve cells which can fight any infection and memory T-cells which have been programmed to fight specific infections. As HIV attacks the immune system, more na ve than memory cells are lost and these na ve cells are slower to come back. Memory T-cells with their limited functions seem to hold on longer and come back quicker. Thus, even with a rise in CD4 count, not all the cells may be fully functional and may not fully protect from opportunistic infections.

The good news from ICAAC is that there is very preliminary data that show some evidence of the rebuilding of na ve T-cells after prolonged viral suppression. It may be that if we keep HIV suppressed long enough, there will be no need to continue OI prophylaxis. However, we do not yet have the data to support such a suspension of prophylaxis. Until we do, the old adage proves true: better safe than sorry.

Information On CMV

One study presented at ICAAC reported on individuals that had CMV retinitis in one eye. Researchers treated the individuals with one of three therapies: an eye implant of ganciclovir plus a regimen of oral ganciclovir, an eye implant plus a placebo, standard intravenous therapy. Anyone who had drug implanted in the eye had a longer time to recurrence of CMV than anyone on IV therapy. In addition, those who added oral ganciclovir had less breakthrough to disease, less disseminated CMV and less incidence of KS than those not taking the drug orally.

Researchers from the University of California, San Diego, reported on eight individuals with CMV retinitis who had a mean CD4 count of 39. All were put on triple combination antivirals that included a protease inhibitor. After a year, mean CD4 count had risen to 272. At that point, all went off maintenance therapy for their CMV and six months later there has been no disease progression. Many might think that these eight individuals are skating on thin ice. Going off CMV maintenance therapy after T-cells rise is not generally recommended.

Two small Italian studies address this same issue and provide contradictory results. Individuals begin on HAART and remain on maintenance therapy for CMV. In one study, the mean CD4 count of the 17 subjects rose from 13 to 156. Yet, in just three months, 9 of the 17 had recurrence of CMV. In contrast, the other study of only seven people reported that after three months for all subjects, CD4 count had risen to over 150, viral load had fallen to below 200 and CMV PCR tested negative. After 8 months, there was no recurrence of CMV.

Bactrim As Prophylaxis for PCP and Toxoplasmosis

A Spanish study reported that Bactrim, commonly used as prophylaxis for PCP, can also be used as prophylaxis for toxoplasmosis. However, in order to have this effect, the individuals must be taking greater than four double strength tabs of Bactrim a week. A large study in New York City looked at whether Bactrim needed to be taken daily in order to provide effective prophylaxis against PCP. Study subjects either took one double strength tab each day or one double strength tab three times a week. After three years, there was a trend toward greater efficacy on the daily dosage, though the results were not statistically significant.

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