Being Alive; January 1994
Mark Katz, M.D., reported by Jim Stoecker

Those interested in participating in clinical trials of new and potentially useful treatments should keep handy two local numbers: the UCLA CARE Center at 310.206.6414 and USC at 213.343.8324. There are usually a variety of trials being conducted at these two sites. Often your physician may not know about them and you may want to initiate your own involvement. If outside the local Los Angeles area, you can get clinical trial information by calling 1.800.TRIALS-A during Eastern time zone business hours.

Antiviral Update

Bristol-Myers has reformulated ddI into a smaller, orange-flavored pill. This new version of the drug should be on the market early in 1994. Expanded access of d4T has shown that this new reverse transcriptase inhibitor is not causing as much neuropathy as first feared. About ten thousand people throughout the US are now included in the expanded access program set up by the manufacturer. So far, 43 cases of pancreatitis have been reported in the trial population and three people have died. What is not clear is the extent to which the use of d4T is responsible for these deaths. If all goes well with current trials, d4T may receive FDA approval as early as the first quarter of 1994.

Some Non-Nucleoside RT Inhibitors

There are two new non-nucleoside reverse transcriptase inhibitors that are currently moving into human trials. These drugs work at the same point in the HIV life cycle as AZT, ddI and ddC, but they use a different mechanism than the currently available antivirals. In the past, non-nucleoside RT inhibitors were prone to develop rapid resistance and thus have little efficacy. When used in combination with AZT, ddI and/or ddC, their clinical usefulness is increased.

Atevirdine is one of the new non-nucleoside RT inhibitors. In the test tube, this drug has been shown to be synergistic with AZT. This means that it enhances the effect of the antiviral. ACTG 199 is a US-wide study of atevirdine in combination with AZT. To qualify for this study, your CD4 should be in the 50-350 range, you need to have been taking AZT for at least three months prior to starting the study, and you have to have at least one symptom of HIV disease. The local site for this study is USC; for more information, call Diane Ramos at 213.343.8324. If outside Los Angeles, you can call Upjohn, the drug's manufacturer, at 800.432.4702 for study details.

This trial might be a good one for people on AZT who are willing to continue with the drug and want to try an additional drug that might enhance AZT's benefit. All participants receive AZT plus high dose atevirdine or low dose atevirdine or a placebo.

Delavirdine is another new non-nucleoside RT inhibitor. It takes much smaller concentrations of this drug than it does of atevirdine to be efficacious. The National Institutes of Health are running an early trial. Locally, UCLA is planning a study of delavirdine and ddI vs. ddI alone for those with CD4 below 300. This is one of the few trials of a combination with ddI rather than with AZT. UCLA is also running a study of delavirdine and AZT for those in the 300-500 CD4 range. For information, call the CARE Center at 310.206.6414.

Antisense Compounds

One of the newest approaches to antiviral therapy is the class of drugs we call antisense compounds. Here sense is used in its biological meaning, i.e. a strand of genetic material used to assemble new viral protein. Sense is a strand of RNA that HIV requires to replicate. Antisense is a mirror image of the RNA that adheres to the sense strand. With the antisense sticking like a glue to the sense, RNA is rendered powerless to make new virus. This is how the antisense compounds fight HIV.

There have been two major hurdles in the development of this class of antivirals. First the antisense has to be made small enough to get into the cell and then stop replication. Second, the antisense must be made resistant to all the other chemicals in the body that could potentially render it useless. Despite these obstacles, drug manufacturers are moving ahead with the development of antisense compounds. GEM-91 is the name of one such compound and there will be others. Human trials of GEM-91 are now in the planning stages in France and at the University of Alabama in the US. Antisense compounds, along with the oft-discussed protease inhibitors, are the "new frontier" of antivirals that we so desperately need.

Reports from the Comprehensive HIV Review

In early November, World Health Communications sponsored a conference in Phoenix for health care providers. A number of experts in the field of HIV were on hand to present what was titled a Comprehensive HIV Review. What follows is information pulled together from this gathering of the experts.

Pathogenesis Issues

We have discussed in previous updates the fact that we now know that the lymph glands harbor HIV for many years during the early course of HIV infection. Researchers are now pointing out the role of follicular dendritic cells in this process. These cells, present in mucosal surfaces, are thought to be responsible for disseminating the virus to the lymph nodes.

HIV researchers are increasingly pinpointing that early HIV infection brings on a hyperimmune response. There is increased immune system activation. Only in late stage infection do we find immune suppression. It may be that in early infection the way to go is to slow down or suppress the hyperimmune activation.

New research hints that when the virus is initially transmitted to someone not previously infected, the mucosal barrier somehow filters out the more virulent strains of the virus. This could explain why someone infected by a person in late stage disease does not immediately develop symptoms. It could be that each new infection starts out with the "simpler," less virulent strains of HIV and that the more destructive strains only appear after a person has harbored HIV for a number of years.

Oral Manifestations of HIV Disease

Deborah Greenspan pointed out that candida in the oral cavity (commonly known as thrush) may not always be the whitish coating that we usually expect to see. Patches of redness in the mouth might also indicate a type of oral candida. Such redness should be treated with antifungals. Dr. Greenspan also recommended that Nystatin oral mouthwash not be used by those with oral candida. This treatment has too little contact time with the fungus to be of value and its high sugar content could in fact promote the growth of the fungal condition.

Finally, Greenspan recommended three possible treatments for oral hairy leukoplakia: oral acyclovir or topical podophylline (commonly used to treat anal warts) or Retin-A.

Skin Problems with HIV

Seborrheic dermatitis is the most common skin condition that people who are HIV+ get. Marcus Conant, a prominent San Francisco dermatologist, recommended treatment including both a steroid cream for its anti-inflammatory effects and an antifungal. Dr. Conant also recommended the use of itraconazole for the treatment of nail fungus. The dosage is 200 mg twice a day for seven consecutive days in each of four consecutive months. Itraconazole is a new and very expensive antifungal.

Comments on the Concorde Study

UCLA's David Hardy discussed some of the fallout from the famous Concorde study. This was the large European study that concluded that AZT offered no benefit for ultimate survival even when antiviral therapy is started early in the course of HIV disease.

Dr. Hardy reported that European physicians have backed off from treating with antivirals those whose CD4 is above 500. If the patient is asymptomatic, they are usually waiting until the CD4 is at 250 or less before beginning antiviral therapy. In the US, there is less consensus on when is the best time to begin a patient on antivirals.

Hardy concluded that the results of the Concorde study offer both good and bad news. The bad news is that AZT offers no benefit for long run survival. Further bad news is that our use of CD4 counts to predict clinical outcome may be in doubt. The good news is that we now know that AZT is time-limited in its benefits even with early intervention which calls for us to move beyond AZT in antiviral development. The Concorde study also shows that AZT clearly preserves CD4 count better than no antiviral therapy, even though we do not fully understand the clinical benefit of higher CD4 counts.

Review of Antiviral Therapy

San Francisco General's Paul Volberding reviewed the current state of antiviral therapy. The big US study of the effectiveness of early intervention with antivirals is ACTG 019. This long range study looks at antiviral use for those in the 500-800 T-cell range, and, it is hoped, will answer the question about whether early use of antivirals really makes a difference in the course of HIV disease. Dr. Volberding said that ACTG 019 data should be available by mid-1994.

Volberding believes that the benefits of antiviral therapy should not be judged by the CD4 level alone. T-cell count does not tell the whole story. Other benefits are occurring; perhaps there is improvement in CD4 function.

From the Concorde data, Volberding extrapolated the notion that the earlier you start antiviral therapy, the longer its period of benefit. Those who started on AZT when CD4 was over 300 had a mean benefit period of 2.5 years. In contrast, those who began antiviral therapy when CD4 was less than 300 had a mean benefit period of only 1.5 years. Ultimately, the efficacy of AZT is time-limited, but that time period may be longer or shorter depending on when antiviral therapy is initiated.

Finally, Volberding suggested that we should rely less on CD4. He offered HIV titer levels as an additional marker of antiviral efficacy.

Update on Combination Therapy

We have been saying for at least three years now that if one drug works, two drugs should work better. This is the basic notion of combination antiviral therapy. Combinations should increase efficacy, decrease resistance and lessen side effects. Now we have some hard data from two studies that were discussed by Dr. Harold Kessler.

The results of ACTG 143 have not yet been published, but Kessler gave an early look at the outcome. ACTG 143 was a large study that looked at AZT alone, ddI alone, and AZT and ddI in combination. When on AZT or ddI alone, there was an average of one log suppression of viral load. (One log is a factor of ten. For instance, 10,000 viral particles are reduced to 1000.) When the combination was used, there was an average of 1.4 log suppression on low dose and 1.8 log on high dose combination. This is definitely encouraging news and confirms what we have long suggested.

Another study was sponsored by Burroughs-Wellcome. AZT was compared to AZT and ddI and to AZT and ddC. Once again, the combination approach proved superior to the single drug approach. Those on the combination therapy showed a sustained CD4 rise even after a year of antiviral therapy.
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