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Highlights from the First Conference on Human Retroviruses




 

GMHC Treatment Issues 1994 Mar 1; 8(1): 1

The First National Conference on Human Retroviruses and Related Infections was held on December 12-16, 1993 in Washington, DC. The conference provided an impressive array of researchers in a somewhat intimate surrounding. Much of the program focused on HIV antivirals, immune therapies, and basic science. More limited attention was focused on HIV- related opportunistic infections. With the International Conference on AIDS being held in Japan this year and scheduled to become a biannual affair thereafter, many believe that this annual conference will become increasingly important. In this issue, Treatment Issues provides an overview of the conference. Next month, we will provide comprehensive analysis of the oral ganciclovir studies that were reported at the conference.

AZT Resistance: A Marker for Progression? Resistance to AZT may predict more rapid disease progression. In a subset of ACTG 116B/117, which studied the effects of ddI in patients with less than 200 CD4 cells who had taken AZT for more than sixteen weeks, it was found that those who had entered the study with a high level of AZT resistance were three times more likely to progress to another opportunistic infection (OI) or death.[1] In addition, those who had a high level of AZT resistant virus also did not seem to benefit from switching to ddI.

This poor showing was of great concern to conference participants. It gave a clear indication that the presence of AZT-resistant HIV in the body really translates into poorer physical health, even when an individual switches to another drug. But the reason for this observation eluded the experts. A two-and-a-half hour roundtable discussion on the issue could only conclude that AZT-resistance must somehow be a sign that the virus has gained other abilities, such as greater mutability, that help it to quickly respond to challenges posed by drug therapy or immune defenses.

Benefits Seen in Switching to ddI Switching from AZT to ddI did cause a significant increase in CD4 cells in a study conducted by the Canadian HIV Trials Network. Two hundred thirty two patients who had been on AZT for greater than six months were randomized to either ddI (334 mg daily if body weight less than 60kg, 500mg daily if more) or continued AZT (600 mg daily).[2] Sixty percent of those enrolled were asymptomatic, the balance had either ARC or AIDS. Patients given ddI had an average increase of 47 CD4 cells at four weeks and 90 CD4 cells at 24 weeks, compared to those given AZT. This statistically significant increase lasted for greater than 36 weeks. Interestingly, benefits in switching to ddI occurred in patients with both syncytium inducing (SI) or non-syncytium inducing (NSI) stains of virus. SI virus promotes a "clumping together of immune cells" that causes cell death and has been linked to more rapid disease progression.

Searle's HIV Protease Inhibitor One way to get around the problems posed by resistance to AZT and related drugs is to find a therapy that attacks a different, more vulnerable point in the virus's lifecycle. A new class of treatments that received considerable attention at the conference is protease inhibitors. Protease inhibitors block the assembly of HIV particles as they bud out from an infected cell. A comprehensive report on protease inhibitors will appear in next month's Treatment Issues. Companies currently developing protease inhibitor include Hoffmann-LaRoche, Merck & Co. and Searle/Monsanto. Researchers at the Retrovirus Conference presented data on SC-52151, Searle's lead HIV protease inhibitor compound.[3] They reported that SC-52151 is estimated to have a "single- dose oral bioavailibility of greater than 20 percent." In a press conference , Martin Bryant of Searle compared this to Hoffmann-LaRoche's lead protease inhibitor compound, RO-31- 8059, which he reported is 4 percent bioavailable. He also characterized the Roche drug as "at the cusp of the dose response curve," implying that higher doses of Roche's drug may be more beneficial than those now being tried. Dr. Bryant further reported that, in terms of toxicity from animal studies and single-dose safety studies in humans, SC-52151 is "very safe." In regard to viral resistance, Bryant thought that simultaneous resistance to different protease inhibitors may be more difficult for HIV to achieve. Test tube studies of other protease inhibitor compounds have reported that viral resistance may develop at a slower pace than with nucleoside analogues such as AZT, ddI and ddC.[4] A dose escalating study, using a 100mg, 300mg, 500mg, and 1 gram single dose of SC-52151 is underway. The company expects to begin enrolling 60 patients in a Phase I trial in the Spring of 1994. In terms of production, Searle's drug requires ten to twelve steps compared to Roche's 24 steps (we hope that this means that the drug is so much easier to produce and that trials will be quicker and more forthcoming).

Measuring HIV Viral Load Significant attention was focused on new methods to measure HIV viral load. A rapid, accurate, and relatively inexpensive means of measuring viral burden is critically important to the study of new anti-HIV therapies. Such a test would also provide physicians with guidance as to whether existing therapies are benefiting individual patients. One particular test which caused some excitement was the branched DNA assay (Quantiplex) developed by Chiron Corp., a California-based biotechnology company. This test measures HIV RNA using branched DNA signal amplification technology.

Researchers at San Francisco General Hospital and Chiron reported that this test is precise and amenable to routine laboratory use for measuring HIV RNA in plasma.[5] Using the branched DNA assay, levels of HIV were found to be significantly higher, in general, in HIV-infected patients with low CD4 counts. Another study suggested that the branched DNA assay may be useful in predicting progression to AIDS.[6] In this study, researchers examined 62 gay men from the Multicenter AIDS Cohort Study (MAC) in whom HIV seroconversion had been documented. They then compared those who had progressed to AIDS rapidly (median 3.8 years) with 44 non-progressors (median of 5.6 years of follow-up). It was found that persistently high levels of HIV during the first two years after seroconversion, as measured by the branched DNA assay, strongly predicted both rapid CD4 decline and progression to AIDS.

If these results are confirmed by other studies, the branched DNA test is likely to be a considerably simpler and less expensive means of measuring HIV viral load than the PCR test (Polymerase Chain Reaction). In addition, Chiron researchers reported that branched DNA technology can be used to detect TB bacteria in sputum samples within 24 hours.[7] Of 74 TB culture positive samples, 73 or 98.7 percent were also positive with the branched DNA test. Moreover, the assay does not cross react with other mycobacteria, such as MAI. The researchers conclude that branched DNA assay is a rapid, sensitive and specific method for direct detection of TB bacterium in clinical specimens.

Underestimating Herpes Infections Herpes Simplex (HSV) infections among HIV-infected gay men may be substantially underestimated, according to researchers from the University of Washington in Seattle.[8] A total of 45 HIV-positive/HSV-positive and ten HIV-negative/HSV-positive gay men were followed with daily viral cultures of the mouth, rectum and urethra for 60 days. Among HIV-positive patients the median CD4 cell count was 364. Overall, 68 percent of HIV-positive people and 40 percent of HIV-negative people had evidence of reactivated HSV infections. Among HIV-positive patients, Herpes Simplex Virus 2 (HSV-2) was cultured on 9.7 percent of the days, compared to less than 1 percent of the days in HIV-negative patients. The authors conclude that herpes reactivation, especially of HSV-2, is frequent and has been seriously underestimated in HIV-positive individuals.

Acyclovir for HIV Acyclovir use was associated with a survival benefit in patients with AIDS, according to a retrospective study conducted as part of the Multicenter AIDS Cohort (MAC) Study.[9] In the study, researchers looked back at 786 HIV- positive gay men who began AZT prior to an AIDS diagnosis. Of these, 515 subsequently took acyclovir, an anti-herpes therapy. These patients were followed semi-annually. It was found that the reported use of Acyclovir did not correlate with progression to AIDS). However, the drug was significantly associated with a survival benefit. This survival benefit was seen in patients who began acyclovir therapy after an AIDS diagnosis. Dose, constancy, and timing of acyclovir were also examined. The median dose used was 600 to 800mg per day. Higher doses of acyclovir did not seem to effect survival, but the use of the drug for a longer, uninterrupted period of time was associated with longer survival. The researchers concluded that acyclovir was significantly associated with survival, if used after an AIDS diagnosis, but not if taken pre-AIDS. Interestingly, acyclovir use did not seem to prevent development of cytomegalovirus (CMV), a type of herpes virus.

It should be noted that this study was not designed to determine whether acyclovir can be of benefit as a treatment for HIV-disease. It was a retrospective ("look back") study and participants were not randomized to receive either acyclovir or placebo. Another conference presentation, by the Houston Immunological Institute,[10] described a small study that directly compared AZT to AZT plus acyclovir. Over twelve months time, three out of five of those taking AZT alone (average T-helper cell count: 154) began to test positive for HIV core protein (p24) in their blood compared to none of the thirteen people taking the two drug combination (average T- helper cell count: 166). Testing positive for p24 is considered a sign of disease progression.

An earlier British study showed that acyclovir provided a survival benefit in people with AIDS. In addition, ACTG 063, a controlled study comparing AZT with and without acyclovir, is ongoing. Preliminary data from this trial may be available sometime in the first quarter of 1994.

Human Herpes Virus-6 and HIV A number of presentations discussed Human Herpes Virus-6 (HHV-6) and how it may interact with HIV. In a plenary talk focusing on many aspects of HIV disease. Dr. Robert Gallo of the National Cancer Institute reported that HHV-6 may play a role in HIV disease progression.[11] According to Dr. Gallo, HHV-6, is one of the few viruses that like HIV, binds to the CD4 receptor. Dr. Gallo suggested that Foscarnet, an anti-CMV therapy, should be evaluated as a therapy for HHV-6. In addition, researchers from The Medical College of Wisconsin reported that HHV-6 is more destructive to macrophages than HIV, that HHV-6 and HIV show synergistic destruction of cells.[12] Based on these findings and on reports showing that HHV-6 can cause pneumonitis and bone marrow suppression in bone marrow transplant patients, the researchers conducted autopsies of nine patients who died of AIDS in order to see whether HHV-6 could be identified. They were able to quantify HHV-6 in one patient with CMV pneumonitis and one with HHV-6 pneumonitis. They suggested that HHV-6 may be more common in the tissues of PWAs than CMV and may appear later in disease. Like Dr. Gallo, the Wisconsin researchers believe that HHV-6 is susceptible to antiviral agents. However, they concluded by stating they were still unsure as to whether HHV-6 is "just another viral infection that jumps on the bandwagon" or, perhaps, pathogenic "co-factor" which significantly enhances HIV disease progression.

Expanding HIV-Specific "Killer Cells" Dr. Judith Lieberman of New England Medical Center in Boston discussed preliminary results about an immune therapy which seeks to use large numbers of the patients own cytotoxic lymphocytes (CTL) or "killer cells" to fight HIV.[13] The therapy, known as "autologous ex vivo expanded HIV specific cytotoxic T-cells," involves taking CTL cells from the patients own blood and selecting for their ability to kill HIV-infected cells ("HIV-specific T-lymphocytes"). The cells are then cultured in the laboratory and added to agents which stimulate proliferation of these cells. These agents include PHA, a sugar which activates T-cells by attaching to T-cell receptors, and IL-2, (see box). The activated cells are then reinfused into the patients. Dr. Lieberman noted in her presentation that HIV-specific T-lymphocytes increase in response to HIV infection and then usually drop as disease progresses.

A total of 14 patients, all with 100 to 400 CD4 cells and no AIDS-related opportunistic infections, were enrolled in the study. HIV specific cells were expanded over a ten-day period. Of the fourteen patients, eleven had CTL's that reacted to parts of the virus (viral proteins, such as gp160, nef 7, nef 17). These patients were given one infusion of their expanded, HIV-specific CTL's and then evaluated at one, two, four, eight and 24 weeks. Dr. Lieberman presented data on the first five patients. Two of these five had "significant and sustained increases in CD4 cells" and a sustained decrease in viral load. No patients had significant decreases in CD4 levels or significant increases in HIV replication. Four of five patients had an increase in circulating HIV-specific CTL response that peaked at one week after infusion. It is important to note that these are preliminary results, based on a very small number of patients. Dr. Lieberman has told Treatment Issues that all patients currently in the trial will be retreated with an additional infusion. In addition, a new group of five patients will receive a series of three infusions (one every five to eight weeks).

Passive Immunotherapy Researchers from France reported that passive immunotherapy reduced the number of opportunistic infections in patients with advanced AIDS (less than 50 CD4 cells). Passive immunotherapy is a process in which individuals with advanced disease (who have low levels of HIV antibody production) are infused with plasma rich in HIV antibodies. Plasma is obtained from asymptomatic HIV-positive individuals with high levels of HIV antibodies. In the double-blind, placebo- controlled trial, a total of 86 patients were randomized to receive either plasma high in HIV antibodies or placebo (plasma from HIV-seronegative individuals). Infusions were given every two weeks and then every four weeks over a one year period. Participants who received placebo had three times the number of new AIDS defining infections as those who received passive immunotherapy. There were seven deaths in the treatment arm and eleven in the placebo arm. The statistically significant difference in new opportunistic infections led the investigators to stop the trial and provide all participants with treatment. The difference in survival did not, however, reach statistical significance.

Few Menstrual Irregularities in HIV-Positive Women Relatively few menstrual irregularities were seen in 207 women who had been HIV-positive for at least one year, according to a study by researchers from the Centers for Disease Control and Prevention (CDC) and Columbia University in New York City.[14] In the study, the women were compared with 215 HIV-uninfected women who were recruited from STD, methadone and HIV clinics. Both groups were interviewed about menstruation patterns. There were no significant differences in terms of likelihood of monthly menses over one year, length of menses, likelihood of no menstruation for 90 days, or difficult or painful bleeding (dysmenorrhea). The only reported differences were bleeding between periods (intermenstrual bleeding) and, possibly, in postcoital (after sexual intercourse) bleeding. Among HIV-infected women, there were no apparent differences in menstrual patterns based on levels of CD4 cells.

Saliva May Inhibit HIV Researchers at the University of Pennsylvania reported that when human saliva is combined with HIV, a sharp reduction in the infectivity of HIV occurs.[15] The researchers studied the saliva of fifteen HIV-negative individuals and found that ability of the saliva to inhibit HIV varied by individual, with a range of inhibitory activity from 0 to 95 percent. In addition, the study suggested that the inhibitory effect of saliva may be HIV-specific, meaning that it may stop replication of HIV to a greater extent than other viruses such as Human Herpes Simplex 1 or Hepatitis B.

HTLV-1 and HIV in Gay Men Two cases of dual infection with HIV and HTLV-1 among gay men who did not use injection drugs were reported.[16] One of these patients developed cutaneous T-cell lymphoma. The researchers from New York University Medical Center report that the two viral infections, not previously seen together in patients without a history of injecting drugs, may act synergistically. They conclude that dual infections with HIV and HTLV-1/2 are no longer rare among homosexual and drug abusing populations.

References: 1 D'Aquila RT, et al. Abstract 460.

2 Montaner JSG, et al. Abstract 2.

3 Bryant M, et al. Abstract 261.

4 Chin -Ming Chen, et al. Astract 265.

5 Pachl C, et al. Abstract 312.

6 Mellors J, et al. Abstract 274.

7 Kolberg J, et al. Abstract 294.

8 Schlacker T, et al. Abstract 519.

9 Stein DS, et al. Abstract 527.

10 Thompson C, et al. Abstract 426.

11 Gallo R. Oral Presentation, Session 3.

12 Knox KK, et al. Abstracts 544, 545.

13 Lieberman J. Oral presentation, Session 47.

14 Ellerbrock TV, et al. Abstract 251.

15 Malamud D, et al. Abstract 653.

16 Pluda JM, et al. Abstract 31.

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Copyright © 1994 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in March 1, 1994. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.