Treatment Issues, Vol. 9, No. 2 - February, 1995
Dave Gilden, David Gold, and Gabriel Torres, M.D.

Viral Dynamics

Viral dynamics -- the rate of HIV particle production and clearance within the body -- was a key issue dominating the Second National Conference on Human Retroviruses and Related Infections. Two leading AIDS researchers, David Ho, M.D., from the Aaron Diamond AIDS Research Center in New York and George Shaw, M.D., from the University of Alabama started off the proceedings with oral presentations on this topic. Their findings -- that production of HIV virions and CD4 cells both can exceed a billion per day -- indicate the massive struggle occurring during HIV infection. Those findings also indicate the difficulties involved in relying on antiviral drugs to eliminate the virus, especially given the number of mutant, drug-resistant variants that viral production of this magnitude makes possible.

Dr. Ho reported on twenty patients with high viral loads (over one million copies of HIV RNA per milliliter of plasma) who received Abbott Laboratories' protease inhibitor. This compounded lowered study participants' plasma HIV levels by 98 percent within two weeks. The virus's exponential rate of decline indicated that the half-life of virus particles was on average approximately 2.1 days. This means that one-half of the HIV in an infected person is renewed every two days, for a daily production of 680 million HIV particles per day. This rate of renewal appears relatively constant throughout all stages of chronic HIV infection.

This is a conservative estimate of viral turnover, since all virus production is not shut off by the Abbott drug. Residual virus may be due to inadequate drug penetration of tissues, drug-resistant virus, long-lived virus-producing cells and gradual activation of latently infected cells. Using a similar model, Dr. Ho calculated the rate of CD4 production and clearance based on the CD4 responses to the Abbott drug. He estimated that each day anywhere from 35 to 53 million new CD4 cells appear in the blood. Given that the lymph system contains nearly 50 times more CD4 cells than the blood, approximately 1.8 billion CD4 cells are produced in the human body per day during HIV infection.

Dr. Ho's group inferred from these figures that even in persons with low CD4 counts, the loss of CD4 cells is not due to lack of production, but rather to excess destruction. He concluded from these experiments that the continuous high viral replication is the engine driving the pathogenesis of AIDS.

In experiments by Dr. Shaw's group, patients were treated with the Merck or Abbott protease inhibitor, and similar viral and CD4 kinetics were seen. The Shaw team also used nevirapine, an antiretroviral agent that leads to the rapid emergence of resistant HIV. The researchers noted the appearance of mutant, nevirapine-resistant virus within two weeks.

In the Ho and Shaw studies, resistance to both the Abbott and Merck protease inhibitor were observed, although some patients still had sensitive virus after six months of therapy. Also, cases of marked, although usually short-lived, CD4 increases were seen, with one patient who received the Abbott compound going from a CD4 count of 68 to 680. The implication of both of these studies is that aggressive treatment with a combination of more than one drug should be started as early as possible. Keeping HIV levels and replication at a minimum would delay the emergence of resistance to particular therapies. Dr. Ho plans to conduct a study of aggressive combination therapy, including protease inhibitors, for people experiencing initial, acute HIV infection. His goal is to assess whether lowering viral load as early as possible may alter the course of, or even eradicate, HIV infection.

Protease Inhibitors

ABT-538: Abbott's compound, ABT-538, continues to appear the most potent protease inhibitor now being tested in HIV- positive individuals. Dr. Martin Markowitz from the Aaron Diamond Research Center in New York presented phase I data on ABT-538. At week four, viral load reductions had decreased by an average of two logs (99 percent), and by week twelve, HIV levels were still an average of 70 percent below baseline. CD4 counts were 75 to 95 percent above baseline at week twelve in the higher doses. The maximum antiviral effect occurs within weeks of beginning therapy. It was not clear from the data how long viral load reductions are maintained on ABT-538.

Australian researcher David Cooper presented additional data from a 21-patient study of ABT-538. As reported in Treatment Issues last month, two patients in this study had short-term remissions in Kaposi's Sarcoma lesions after beginning ABT- 538. Other reported clinical improvements included: regression in oral hairy leukoplakia (two patients) and weight gain of over fifteen pounds (two patients). One patient had remission of thrombocytopenia (low platelet count), and one patient experienced a clearance of cryptosporidiosis. The current formulation of ABT-538 is a cherry syrup which, company officials admit, "tastes terrible." Reported side effects include headaches, diarrhea and a cluster of symptoms including lightheadedness and fatigue, which were most common at the higher doses. According to researchers, some patients on the highest doses of ABT-538 "felt real lousy" for the first week.

In a meeting with community activists, Abbott officials described two placebo-controlled trials of ABT-538 that will begin enrolling within a month. One study will enroll 250 AZT-naive patients and will measure surrogate markers (viral load and CD4 cells). The other will look for clinical benefits (differences in progression or survival) in 700 patients with less than 100 CD4 cells. In this trial patients will be allowed to take the standard of care (i.e., whatever nucleoside analog therapy they wish). The dose will be 600 mg twice a day.

Abbott researchers hope to file for FDA approval of ABT-538 within four months after beginning these studies. Another study, of 900 AZT-experienced, asymptomatic people, will begin at a later date. Abbott is also doing a dose escalating study using 700 mg twice a day at Duke Medical Center in North Carolina. Some suggest that drug interactions may be a problem with ABT-538 (particularly with rifabutin and fluconazole).

Saquinavir: Stanford University researchers reported preliminary data from a phase I/II study of 40 people treated with higher doses of saquinavir (3,600 and 7,200 mg per day). The findings indicated greater reductions in HIV levels and increases in CD4 levels than the 1,800 mg dose being used in phase III studies of the drug. Even at the higher doses, saquinavir was reasonably well tolerated and there was a direct relationship between blood level of saquinavir attained and greater reductions in HIV levels. The anti-HIV effect is still probably less potent than the Abbott protease inhibitor, though. Interestingly, the Stanford researchers noted that resistance to saquinavir seemed to develop at a point after HIV RNA levels had already started to rebound. Roche representatives claim that they are confident that the 1,800 mg dose of saquinavir taken in combination with nucleosides analogs will provide a "meaningful antiviral effect." The company plans to file for FDA approval of the drug by December of 1995.

AG-1343: Agouron researchers presented early phase I data on AG-1343 in HIV-negative volunteers. The results showed that the drug was extremely well absorbed and well tolerated. In a meeting with activists, company officials outlined plans for a phase I study including 25 HIV-positive people in London. In the study, patients will be randomized to 100 and 300 mg three times per day for four weeks.

If all goes well, a phase II study will begin in the US shortly thereafter. Agouron's data was considered reasonably impressive, but activists are concerned that the company is moving too cautiously and that the company has not outlined studies to determine the optimum dose of AG-1343.

Agouron is also working on developing protease inhibitors for CMV, hepatitis C and rhinovirus (the common cold).

Resistance to Protease Inhibitors

Dr. Markowitz also presented work by Aaron Diamond researchers on resistance to protease inhibitors. The test tube studies suggest HIV can develop cross-resistance to the Abbott, Agouron, Roche and Merck compounds with long term use. But the resistant HIV is still susceptible to the Upjohn's protease inhibitors and a novel compound from Searle. While this study provides some more sobering news about drug resistance, it should encourage drug companies to focus more effort on developing protease inhibitors which require unique viral mutations to create resistance.

New Data Provides a Second Look at 3TC

Previous studies: The December, 1994 edition of Treatment Issues reported extensively on antiviral therapy with 3TC and AZT. We noted that this two-drug combination did seem to produce a "comparatively robust" effect, with HIV levels in blood plasma falling off dramatically and CD4 counts rising significantly. But questions remained as to how long-lasting and profound this response was. The conclusion that benefits from 3TC/AZT still existed a year after therapy began or that adding 3TC to preexisting AZT monotherapy preserved the latter's effect turned out to be based on meager information.

Newly presented studies: At the Washington retrovirus conference, US researchers presented new data from two large studies conducted in North America. Joseph Eron, M.D., of the University of North Carolina-Chapel Hill reported on a trial of 364 persons without prior experience on AZT (oral presentation no. LB34). The group was divided into four arms: 93 were on AZT alone, 85 were on 3TC alone, and 186 received AZT/3TC combination therapy with two different doses of 3TC (150 and 300 mg twice daily). The median initial CD4 count was 351. At week four, both combination therapies had triggered a 98 percent reduction in plasma HIV levels whereas AZT alone decreased virus levels by 70 percent and 3TC alone resulted in a 95 percent drop. By week 24, virus levels in the monotherapy groups had climbed back considerably toward their original values. The combination therapy groups, in contrast, retained an 84 to 90 percent viral load decrease. The pattern was similar as far as CD4 counts go, although there was a time lag between changes in HIV levels and CD4 cell numbers in the blood. By week 24, the AZT and 3TC monotherapy groups had fallen on average almost back to their initial CD4 count while the combination therapy groups were still above baseline: People on AZT plus high dose 3TC had an average CD4 count of 58 over baseline (at week eight they averaged 66 over baseline) and the low dose 3TC combination group had an average CD4 count gain of 37 at week 24 (compared to 70 over baseline at week eight). This 40 to 60 cell superiority may be modest in the overall scheme of things (especially compared to some of the first data coming out of protease inhibitor trials), but it seemed to persist out to one year. As Dr. Eron pointed out, though, no firm conclusion can yet be drawn beyond six months because information on study participants after that point is still largely lacking.

The second trial (oral presentation LB35) involved 254 people with an average of two years' prior experience on AZT and a median CD4 count of 211. The trial compared AZT plus 3TC therapy to AZT plus ddC. The results, described by John Bartlett, M.D., of Duke University, were much more disappointing in this population, which had more advanced disease than the first trial. Despite some initial superiority, AZT plus 3TC performed little better than the more traditional AZT/ddC combination. Decreases from baseline virus load were nearly the same by week 24 (and were almost below the sensitivity of the PCR assay). CD4 cell count differences were marginal: Up 32 for the low dose 3TC combination, up fifteen for the high dose 3TC combination and down fifteen for AZT/ddC. All these CD4 values were reduced somewhat from their peak values early in the trial.

Analysis: The data comparing AZT/3TC and AZT/ddC in AZT- experienced individuals is particularly puzzling in that there are strong theoretical reasons, based on laboratory experiments (oral presentation no. LB33), to think that the AZT/3TC combination should represent a therapeutic breakthrough. In persons treated with 3TC, HIV becomes resistant to the drug within a matter of weeks, through a single amino acid change in the reverse transcriptase enzyme. This single mutation appears to reverse other changes in the enzyme that enable it to resist the effect of AZT. In the laboratory, it is impossible for HIV to be resistant to both drugs at the same time.

Yet, giving 3TC to people on long-term AZT proved little better than adding ddC to the regimen. In the first study, 3TC alone actually performed at least as well as AZT alone even though developing resistance to AZT seems to be a longer, more drawn-out genetic process than for 3TC. High- level resistance to AZT takes months to develop and requires several genetic mutations.

It would be interesting to further test combination nucleoside analog therapies such as AZT /ddC against AZT/3TC, especially in AZT-naive persons, to check if the latter combination really possesses any special magic. But theory aside, the final proof is whether combinations including AZT and 3TC provide added clinical benefit (i.e., fewer opportunistic infections) than other combinations. A one-year trial looking at these issues is now starting up in Europe. It includes 1,200 people with CD4 counts of 50 to 250, and will compare the clinical effect of remaining on current treatment (either AZT or AZT/ddI or AZT/ddC) to current treatment plus 3TC or current treatment plus 3TC and loviride (an experimental compound under development by Janssen Pharmaceuticals that blocks reverse transcriptase but is not a nucleoside analog). The problem here is that the "current treatment" rubric obscures the differences between the various regimens that do not include 3TC. Also, adding loviride, a second drug of uncertain effect throws a wild card into the proceedings.

In the meantime, the 3TC expanded access program (call 800/248-9757 to register ), continues to enroll patients at the rate of 2,000 per month. Since the studies showed no additional benefit to the 300 mg dose, all patients will be given the 150 mg dose. Glaxo plans to file for FDA approval of 3TC by June of this year.

Other Reports

Acyclovir for HIV: While a number of studies have suggested a survival benefit from continual acyclovir (Zovirax) therapy in HIV-positive individuals, two studies presented at the conference, a placebo-controlled ACTG study (oral presentation 383) and an observational study conducted by Johns Hopkins University (oral presentation no. 382), failed to find such a benefit. A more detailed analysis of the acyclovir results will appear in the March Treatment Issues.

Flu vaccinations and HIV: A number of poster presentations reported that influenza or pneumoccocus vaccines can temporarily increase the levels of HIV in HIV-positive individuals. Researchers from the University of Nebraska said that pneumoccocus vaccines resulted in a rapid, and in some cases profound increase in viral burden (poster 240). A consortium of medical centers in San Francisco reported that "a substantial, yet transient increase" in HIV RNA was observed in 78 percent of 30 HIV-positive individuals who were given influenza vaccines and then closely monitored for changes in viral load (poster 151). It is still unclear whether these transient increases in HIV levels have any clinical meaning at all. Moreover, the possible risks from vaccination have to be weighed against the serious dangers that influenza or pneumonia may cause in HIV-infected individuals.

Saliva's anti-HIV protein: Researchers from the National Institute of Dental Research said they have identified a protein in saliva that inhibits HIV (poster 165). The test- tube studies suggest that the protein, called SLPI (secretory leukocyte protease inhibitor), attaches to white blood cells and prevents HIV from infecting those cells. Amgen, a California based biotech company, is studying whether SLPI has application as an anti-HIV treatment or as a viricidal adjunct to safer sex.

Good news for gym queens: An observational study at the Naval Medical Center in San Diego suggested that HIV-positive individuals whose workouts consisted primarily of weight- lifting lost fewer CD4 cells over a 24 month period than those whose exercise came mostly from running (poster 544).

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