Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 8 - September 1994
David Gold

New Ways to Measure Viral Burden

Diagnostic techniques that measure the amount of HIV in the blood were a major focus at this year's International Conference. The two products receiving the greatest attention were Hoffmann-LaRoche's HIV RNA polymerase chain reaction (PCR) and Chiron's "branched- chain DNA" (bDNA). These two assays measure the same thing - the RNA that forms HIV genes in free virus particles.

Both methods may be useful in clinical trials, where they could provide a quick assessment of the effectiveness of anti-viral therapies without having to wait for clinical endpoints (the onset of opportunistic infections or death). For individual patients and their physicians, these tests ultimately may provide a way to track disease progression more clearly. An increase in someone's HIV population might indicate that their current treatment had lost its effectiveness and thus point to the need to alter antiviral therapy. Both Roche's PCR and Chiron's bDNA are now available for use by physicians, but these assays are not approved by the FDA for diagnostic use in HIV disease, and "research or scientific use" must be claimed. The price of these tests is steep for now -- at least $200.

Analyzing Viral Load Decreases

Currently approved anti-HIV therapies (AZT, ddI, ddC, d4T) can decrease HIV levels in the blood, at least temporarily. It is hoped that these decreases will translate into slower disease progression and increased survival for patients. This relationship has yet to be demonstrated, though.

In Yokohama, several studies did suggest that a drop in viral load caused by anti-viral therapy predicts clinical improvement in human beings. The NIH-sponsored trial ACTG 116B/117 produced data indicating that individuals whose HIV levels go down by 50 percent or more during the first month of therapy also experience a reduction in new opportunistic infections. A 254-person Veterans Affairs (VA) study similarly found evidence that decreases in viral load after starting AZT correlate with improved health.

HIV in the Lymph System

The new viral burden tests so far have been used almost exclusively to measure HIV levels in the blood. Yet, researchers have come to realize over the past few years that much of the early HIV replication occurs not in the blood but in the lymph system. Dr. Ashley Hasse presented data suggesting that approximately 25 percent of the CD4 cells in the lymph nodes are infected by HIV. This is a much larger portion than previously thought. Using a new type of molecular technology, Hasse detected a "staggeringly large" amount of HIV-infected CD4 lymphocytes and macrophages in the lymph system.

Yet, a small study by NIH researchers suggested that current antiretroviral therapies may have a very minimal impact on HIV levels in the lymph system. When asymptomatic, HIV-positive individuals were given AZT monotherapy, the amount of HIV found in lymphoid tissue remained largely unchanged. In more advanced patients who added ddI to AZT therapy, there was a "temporary reduction" in HIV replication in the lymph tissue in four of six patients.

Protease Inhibitors

Much of the discussion about new antiviral therapies centered around HIV protease inhibitor compounds. Approximately twenty of these compounds are now under development, but most are not yet in human trials. Of those that are in human trials, virtually no new data were reported. Hoffmann-LaRoche presented previously released data on saquinavir from ACTG 229 (see Treatment Issues, June 1994). Researchers from Merck discussed the company's overall development program in only general terms. Preclinical data measuring antiviral effect in test tubes and bioavailibility (how much of the drug gets into the bloodstream) in animals were presented by at least eight companies.

Viral Resistance to Protease Inhibitors

The most important new information about protease inhibitors came from the Third International Workshop on Resistance, held in Kauai, Hawaii immediately preceding the International Conference. There, researchers from Wellcome Research Labs presented viral resistance profiles based on test-tube studies of five protease inhibitor compounds under development. Of concern, similar resistance patterns were seen in many of the compounds. In fact, two key mutations were associated with resistance to four of the five compounds.

Interestingly, HIV resistant to Merck's compound, L-735,524, was still sensitive to Roche's saquinavir, though. Dr. Emillio Emini of Merck Research Laboratories reported that after six to eight months, the HIV in most patients on L-735,524 is resistant to the protease inhibitor compounds created by Abbot and DuPont-Merck, but not to saquinavir. However, one patient, among the first given L-735,524, eventually developed virus that was ten times more resistant than normal to all protease compounds tested, including the Roche, Vertex and Searle compounds.

Roche researchers reported that after one year of treatment with saquinavir at 600 mg three times per day, 50 percent of patients showed evidence of harboring resistant HIV with a mutation at one of two points in the virus's genes. Stefano Vella, M.D., summarized data indicating that the combination of saquinavir and AZT delayed the emergence of resistance to both drugs.

Little Benefit to "Early" Use of AZT, again

New data was released from ACTG 019, a long running, placebo- controlled study of AZT in over 3,200 HIV-positive patients. Paul Volberding, M.D., of the University of California San Francisco presented data on 1,637 individuals who began the study with over 500 CD4 cells and were randomized to either AZT or placebo. After a median follow-up of five years, patients randomized to AZT had higher median CD4 cells, but there was no significant difference in disease progression or death. The results of this study, which will be discussed in greater detail next month, appear to be consistent with results from the Concorde study announced last year. In that study, the use of "early" AZT in asymptomatic HIV-positive individuals provided measurable increases in levels of CD4 cells but no significant advantage in terms of disease progression or survival.

A More Promising NNRTI?

Some have already written off the class of drugs known as non- nucleoside reverse transcriptase inhibitors (NNRTIs). Yet, a number of reports at Yokohama suggested that these compounds may still be promising, especially when used in combination with two nucleoside analogs. Although resistance seems to develop rapidly with both nevirapine and delavirdine, a European study reported that resistance may develop less quickly with loviride, an NNRTI manufactured by Janssen Pharmaceuticals.

Other New Anti-HIV Drugs

Aside from the reports about the protease inhibitor compounds, there was little data about new anti-HIV therapies. Dr. Robert Gallo reported that hydroxyurea, a drug already approved as a treatment for some forms of chronic leukemia, inhibits a cellular enzyme necessary for HIV to reproduce. Hydroxyurea seems synergistic with AZT. Burroughs Wellcome reported that it is developing three new nucleoside analogs, all now in clinical trials, and an immunomodulator compound known as "Tucaresol," which should begin phase I trials by the end of 1994. A small study of interleukin- 4 suggested that the compound, although unimpressive as a Kaposi's sarcoma therapy, increased CD4 levels and decreased HIV levels.

Mono, Combo or Sequential Therapy

A number of small studies suggested that switching (sequential) therapy from AZT to ddI may be more beneficial than continued long- term AZT monotherapy. An retrospective analysis conducted by the U.S. Multicenter AIDS Cohort Study (MACS) found that men with intermediate stage HIV infection and on long-term AZT had a one- third better survival rate if they added ddI or ddC to the AZT. Men who exchanged monotherapies did no better than those who stayed on AZT. Yet, the issue of combining versus switching drugs remains unsettled and probably awaits the results of larger trials now underway (ACTG 175 and the Delta trial). For more advanced patients with very low CD4 counts, combination therapy still has not proven better than monotherapy and may be associated with more toxicity.

Opportunisitic Infections

The leading story in terms of OI treatment was data about Serrano Labs' human growth hormone (see below). Unfortunately, no data was presented about the use of oral ganciclovir for CMV prophylaxis. Shortly before the conference, Treatment Issues reported that a placebo-controlled study of oral ganciclovir had been halted after initial results indicated a significantly lower level of CMV disease and a "trend toward increased survival" in patients given the drug. The drug's manufacturer, Syntex, was unable to put together the data quickly enough to be presented at the international conference as late-breaking news. The data are now scheduled for release at a U.S. conference in October.

Long Term Survivors

"Long-term nonprogressors" (individuals infected with HIV for at least seven to twelve years with no decline in CD4 counts) elicited a flurry of reports this year. David Ho, M.D., of the Aaron Diamond Research Center in New York, reported that the long term nonprogressors he is observing have extremely low levels of HIV in their blood and that their CD8 cells may be playing a critical role in suppressing HIV replication. Neutralizing antibodies to HIV also remained high, indicating some continued viral replication in nonprogressors. The viral strains from two of Dr. Ho's subjects grew poorly in cell cultures and seemed defective in some way.

Reducing Maternal-Fetal HIV Transmission

While the conference was in session, the Food and Drug Administration approved the use of AZT to reduce perinatal transmission. Guidelines were issued in the CDC's Morbidity and Mortality Weekly Report (August 5, 1994; vol. 43, no. RR-11). A presentation by Yvonne Bryson, M.D., reported that HIV-positive mothers with higher viral burden, lower CD4 counts and more advanced disease were more likely to transmit HIV to their infants. Efforts are now underway to initiate trials using Merck's protease inhibitor to see whether this drug's comparatively large initial reduction in viral load further reduces mother-to-child transmission.

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