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Being Alive
Report on the Second National Human Retroviral Conference
Jim Stoecker
March 5, 1995
Being Alive 1995 Mar 5: 1

The Second National Human Retroviral Conference, sponsored by the American Society of Microbiology in collaboration with the National Institutes of Health and the Centers for Disease Control, was held in Washington, DC, late in January. The importance of this conference for HIV/AIDS researchers has grown, now that the International Conference on AIDS is being held every other year (the next is scheduled for the summer of 1996 in Vancouver). The National Conference provides an annual forum for a clinically oriented review of the latest in HIV/AIDS research, and over two thousand participants were on hand in Washington.

As at past conferences, the epidemiological data presented provide little reason for optimism. Contrary to popular belief, the AIDS epidemic is not leveling off. Today, in the US, AIDS is the leading killer of men and women between the ages of 25 and 44. And even as the epidemic grows, it appears that recent political changes may result in a curtailment of funding for fighting the epidemic. People at the conference were concerned about cutbacks in research funding, as well as reductions to the Ryan White Care Act funds. Many did not consider AIDS to be a partisan issue, but the current political climate in Washington seems to be making it one.

Along with the pessimism about the extent of the epidemic and about the current political situation in the US, there was also optimism about where we now stand in fighting HIV disease. Indeed, some participants reported that such optimism had not been seen since the approval of AZT in 1987. This optimism is based on breakthrough thinking about how HIV works in the human body, the importance and increasing availability of viral load tests, and the reasonably good news about the effectiveness of the protease inhibitors as monotherapy and 3TC in combination therapy.

HIV Dynamics The conference began with a presentation by Dr. David Ho on his recently published research on how HIV works in the human body (see Walt Senterfitt's report on page 3 for more complete information). HIV works fast in the human body, creating some 110 million viral particles each day. In response, the body's immune system also works fast, producing some two billion CD4 cells every day. This dynamic continues throughout infection. Thus, there is a war going on between the immune system and HIV from day one of infection. And the body might be called the "best antiviral," because for a number of years it does a good job of controlling the virus. At some point, however, HIV gets the upper hand and the response of the immune system becomes inadequate.

The Leukemia Model This new understanding of HIV dynamics has implications for treatment of HIV disease. Some researchers point to how leukemia is treated as a possible model. When a person is diagnosed with leukemia, he or she is immediately and aggressively treated with chemotherapy. A medical provider would not tell a leukemia patient to wait until symptoms appear before treating the disease.

Now that we understand that there is no "latency" period for HIV, researchers are questioning the wisdom of waiting until T-cells drop or symptoms appear to begin antiviral therapy. They look to the leukemia model of "hitting hard and hitting early" as the way to effectively treat HIV disease. The theory is that such early and aggressive treatment might suppress viral activity for a long time. When viral load again goes up, as measured by the new viral load test, other drugs could be tried to again suppress viral activity.

The problem with this theory is the reality of current drug availability. We don't yet have the drugs to do the long term job effectively. Yes, we should start early, but the effects of the current generation of antivirals don't last long. And would this leave the patient resistant to antivirals in late stage disease? At the moment, early antiviral intervention remains practically if not theoretically problematic.

Viral Load Tests We now have tests that measure the amount of virus in the blood. These tests do this by measuring the amount of HIV genetic material or viral RNA. The two currently available viral load tests are Q-PCR, developed by Roche, and b-DNA, developed by Chiron. These tests are not yet FDA-approved and are not yet widely available. Nonetheless, their development is very important in research, as well as in treatment.

Up to this time, we have used changes in CD4 count as a measure of a drug's effectiveness in slowing viral activity. CD4 count, however, is a surrogate marker. It does not directly measure viral activity, but rather tells us the effect of that activity on the immune system. If the CD4 count stays level or rises, we assume that less virus is being produced. Viral load tests, however, measure virus directly. They tell us how much virus is in the blood stream at a given time.

The widespread commercial use of these tests will allow physicians and patients to make better informed decisions about when to start antivirals, when to change antivirals, and when to start prophylaxis for opportunistic infections. T-cell counts, to some degree, are useful for determining when OI prophylaxis is called for, but they don't tell us enough for decisions about antivirals. For that, we need to know what the virus is doing. For people with over 200 T-cells, it is often difficult to determine if antiviral therapy is called for; viral load tests will give these people a much clearer picture of the state of their HIV disease. And changes in viral load can tell us quickly whether an antiviral (or a combination of antivirals) is working for the individual. This means not only quicker drug development, but also more individualized antiviral regimens. Providers will be better able to tell what works for an individual and what does not. Viral load has predictive value; it correlates with the stage of HIV infection. The less virus measured in an individual, the less chance that individual has of getting sick. Conversely, the higher the viral load the shorter will be the time to clinical symptoms.

Both the Q-PCR and b-DNA express their results in terms of how many genetic copies of HIV are found in a milliliter of blood. A "low" value would be less than 10,000 copies per ml; a "high" value would be more than 100,000 copies per ml. As with CD4 counts, one test is not the full story; one needs to look at the trend over time.

Combination Therapy The AIDS Research Consortium of Atlanta (ARCA) reported on a study of over 5000 people treated in Atlanta over the past few years. The group was broken down into those who only took one antiviral (monotherapy), those who took one drug and then switched to another (sequential monotherapy), and those who took two or more antivirals at the same time (combination therapy). The researchers found that the sequential monotherapy group had a 21% survival advantage over the monotherapy group; the combination therapy group had a 43% survival advantage over the monotherapy group. The researchers conclude that adding a second drug has a clear advantage over switching from one drug to another.

In some research circles, combination therapy is now looked upon as the optimal approach to treating HIV. These researchers believe that one should start out with a combination of antivirals; they see no point in the monotherapy approach.

Update on AZT Plus 3TC Two US studies of AZT plus 3TC confirm the antiviral efficacy reported by a French study and by a German study last fall (and covered at length in last month's Newsletter). One multicenter study compared AZT alone to 3TC alone to a combination of the two drugs. Everyone in this study started with a CD4 count between 200 and 500. All participants had no prior AZT therapy. At 24 weeks, those on the combination had greater drops in viral load than those usingmonotherapy, as well as higher increases in CD4 count. In comparing the two monotherapies, 3TC alone appeared to have some benefit over AZT alone in terms of reduced viral load and increased CD4 count. Researchers report that CD4 and viral load differences are holding steady after 52 weeks of treatment.

The second US study compared two different doses of AZT plus 3TC to AZT plus ddC. All participants were on combination therapy. The starting CD4 counts for this study were between 100 and 300, and everyone had been taking AZT for at least two years prior to the study. The results were less clear than those seen in the French, German and other American studies. The high dose combination of AZT/3TC was somewhat more effective in reducing viral load than the low dose combination. The AZT/ddC combination was equally effective as the low dose AZT/3TC combination in lowering viral load. After 24 weeks, both the AZT/3TC groups showed a mean CD4 cell increase (32 for low dose and 15 for high dose), while the AZT/ddC group had a mean CD4 cell decrease of 15.

What continues to impress researchers is the durability of the antiviral effect offered by the AZT/3TC combination. The response at 48 weeks is greater, both in terms of decreased viral load and increased CD4 count, than has been seen with any other antiviral therapy. And 3TC does not appear to have significant side effects associated with its use.

Protease Inhibitor Update Protease inhibitors continue to show more promise than fulfillment. The promise is that we will at long last have an antiviral that works at a point in the HIV life cycle that is different from AZT, ddI, ddC and the like. The currently available antivirals are all reverse transcriptase inhibitors and only work in "virgin" cells, i.e. cells that have not yet been infected with HIV. Protease inhibitors, on the other hand, work in chronically infected cells, cells already infected by the virus. The long range hope is that protease and reverse transcriptase inhibitors in combination will truly be able to fight off HIV by stopping viral replication in both acutely and chronically infected cells. Some refer to this as "stomping out fires" wherever they are found.

Today we are still at the point of small dose-ranging studies of a number of protease inhibitors. Merck's L-735,524 and Hoffman-LaRoche's saquinavir both appear to work best at the higher doses studied. Both show promise of being potent antivirals. Some believe that Abbott's ABT-538 may be the most potent of all. In a twelve week dose-ranging study, CD4 counts more than doubled at all doses tested; researchers also noted equally impressive reductions in viral loads. The optimal dose of ABT-538 has been set at 600 mg/day for future studies.

To date, the protease inhibitors appear to be well tolerated. Relative few side effects were reported in the early studies of L-735 and saquinivir. Some diarrhea, headaches and nausea were reported in the ABT-538 studies. The problem with the protease inhibitors, as we have seen with other antivirals, is the rapid development of viral resistance to the drug. This is why higher doses of the drug were needed in the dose-ranging studies. At the lower doses, rapid resistance rendered the drug ineffective.

Researchers have also noted some cross resistance with protease inhibitors. If a person is resistant to L-735, he/she will also be resistant to AB-538. Such cross resistance has not been seen with the reverse transcriptase inhibitors. That is why RT inhibitors seem to be more effective in combination. Current research suggests that this may not be true for protease inhibitors.

Hoffman-LaRoche is currently planning to study saquinivir in combination with other, non-protease inhibitor antivirals to see if resistance can be stopped or delayed. Researchers also hope that combinations with other antivirals will allow for lower doses of protease inhibitors. Because of the cross resistance problems, combination studies must proceed with great caution so as not to induce even faster resistance.

The other problem with protease inhibitors is that they are not easily absorbed by the body. Their bioavailability is low and thus a high dose is required. Agouron has developed a protease inhibitor, AG1343, that has bioavailability as high as 80%. The promise of high concentration in the blood could result in reduced viral resistance. AG1343 has not shown cross resistance to the other protease inhibitors in the test tube. Other test tube studies show AZT and AG1343 working well together and enhancing each other's antiviral activity. Human studies of AG1343 are currently in the planning stage.

The promise of protease inhibitors is a more effective antiviral, but significant problems in fulfilling that promise still remain to be resolved. Researchers expect that there will be different generations of protease inhibitors. The first generation may receive FDA approval sometime late this year or early next year.

New Formulations of Ganciclovir The oral form of ganciclovir was recently approved by the FDA as maintenance therapy for CMV disease (see R. Scott Hitt's article on page 6). This form of ganciclovir also has potential as prophylaxis for this opportunistic infection. At the conference, researchers reported on a study that compared 1000 mg of oral ganciclovir a day to a placebo. To be eligible for this study, a person needed to have less than 100 T-cells and an AIDS-defining OI (other than CMV) or less than 50 T-cells. As it happened, the average T-cell count of the study group was less than 25. During the course of the study, 24% of those on ganciclovir had a CMV event, and the time to the first event was 270 days. In contrast, during the same period, 47% of those on placebo had a CMV event, and the time to first event was 240 days. Researchers did not find a survival benefit, but did note that the drug was relatively well tolerated.

This study shows, as other early studies have, that prophylaxis with oral ganciclovir can cut the incidence of CMV almost in half. There are, however, some problems. About 2% of the study participants became resistant to the drug. And some researchers are concerned that prophylactic use of ganciclovir may increase ganciclovir resistant strains of CMV.

The other new form of ganciclovir is implants, peppercorn-size pellets that hold 6 mg of ganciclovir. These pellets are surgically placed directly into the eye, and the drug is then released over time to fight CMV retinitis, one of the terrible scourges of late-stage HIV disease. Researchers argue that such an approach ensures that the drug gets where it is needed, and thus offers superior therapy to the current standard treatment of IV ganciclovir or foscarnet.

In a study of over one hundred patients with CMV retinitis, the two treatments were compared. Those that received ganciclovir implants had a median time to disease progression of 190 days, while those receiving IV ganciclovir had a median time to progression of only 72 days. However, the occurrence of CMV in other parts of the body was less common for those on IV ganciclovir.

Side effects of the implants centered on post-operative complications; about 10% had a problem with retinal detachment and some 8% experienced hemorrhaging in the eyeball.

Clearly, there are serious risk/benefit issues when considering ganciclovir implants. The studies do show greater efficacy in fighting off CMV retinitis. On the other hand, there is greater risk of developing CMV elsewhere in the body, since the drug is not being taken systemically. High dose IV ganciclovir does have toxicities and these appear to be avoided with the use of the implants. Finally, without the central line required for IV ganciclovir, there is decreased risk of bacterial infection and increased quality of life.

Treatment for Microsporidiosis Microsporidiosis is one of the causes of HIV-related diarrhea, and, to date, there has not been an effective treatment. At the conference, the CDC reported on a small (eight patient) study that used Mepron as treatment for microsporidiosis. Mepron, as you may know, is approved as a second-line treatment for PCP. In this study, participants saw reduced diarrhea after two weeks of therapy with Mepron. Study participants also reported an average weight gain of 8-10 lbs.

(The main source of information for this article was the February 27 panel discussion, co-sponsored by Being Alive and LA Shanti. Panel participants were Mark Katz, MD, R. Scott Hitt, MD, David Hardy, MD, and Peter George. Additional information was taken from Martin Majchrowicz's report in the March 1995 issue of Positive Living and Mark Mascolini's report in the March/April 1995 issue of Positively Aware.)