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A STEP Conference Report

The 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
Toronto, September 17-20, 2000

October 10, 2000

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Contributors

Jeffrey T. Schouten, MD, Brian Coppedge and Erica Didier, STEP Treatment Educators


The 40th ICAAC conference, the largest international meeting of infectious disease specialists, prominently featured HIV/AIDS research. Data was presented in oral presentations, poster exhibits, symposia and state-of-the-art lectures. As at many HIV/AIDS conferences in the past year, there was evidence of incremental scientific gains and more data from ongoing studies, but no major advances in the direct fight against HIV. There was also little increased understanding about the causes or treatment of metabolic complications and body-shape changes observed in people on antiretroviral therapy. There was, however, an encouraging opening session on vaccines, presented by Dr. Gary Nabel, director of the NIH's AIDS Vaccine Development Program. He noted that there are 70 early phase I trials, 5 phase II trials, and 2 large phase III trials of vaccines currently ongoing. Hope also came from the data on Abbott Labs' new protease inhibitor Kaletra™, which was approved for marketing by the US FDA two days before the meeting (see below).

At the opening session, Dr Martin Hirsch, a researcher from Harvard Medical School, took a reflective look back at the first 20 years of the AIDS pandemic. He divided the past two decades into developmental stages:

  • 1980-85 "Conception"
    Initial reports of AIDS and isolation of HIV.

  • 1986-90 "Birth"
    Use of zidovudine monotherapy, beginning of cooperative trials groups such as the ACTG, and initial studies of dual nucleoside analog therapy.

  • 1991-95 "Childhood"
    Studies showed two drugs are better than one, and the first trials of protease inhibitors and NNRTIs began.

  • 1996-2000 "Adolescence"
    Major studies showing the dramatic impact of HAART on the course of HIV infection, but an appreciation of the emerging toxicity issues and problems of multi-drug resistance.

  • 2000-plus "Maturity"
    As we move into the "maturity" phase, as in life, changes seem to occur less often and times goes by faster. But, it is important to look back at the last 20 years, to realize how far we have come, while also realizing how far we still have to go.


The next protease inhibitor in the pipeline?

More data was presented at ICAAC on a protease inhibitor called BMS-232632 (BMS) (in development at Bristol-Myers Squibb) in a slide session titled, "Safety and Antiviral Efficacy of a Once-Daily HIV-1 Protease Inhibitor BMS-232632: 24 Week Results from a Phase II Clinical Trial." BMS has shown potent activity against HIV and a favorable resistance profile in the test tube. Phase I studies have also shown good safety and tolerability of a once-daily dose in people.

This phase II multinational, randomized study compared the safety and antiviral activity of three dose-levels of BMS with nelfinavir (Viracept™, NFV) 750 mg three times a day in a total of 92 treatment-naive people with HIV RNA viral loads greater than 2,000. Each PI was given as monotherapy for two weeks, and then in combination with ddI (Videx™) and d4T (Zerit™). The three levels of BMS studied were 200, 400, and 500 mg, all once a day. BMS was well tolerated both alone and in combination. Common adverse events were diarrhea (29% BMS, 75% NFV) and nausea (24% BMS, 15% NFV). There were no elevations in cholesterol or triglycerides observed. Elevated levels of bile in the blood (unconjugated hyperbilirubinemia) were observed, but were not associated with any other liver abnormalities (this abnormality is not clinically significant, and is similar to that seen with indinavir (Crixivan™).

With two weeks of monotherapy, people on both BMS and NFV had reductions in viral RNA levels of about 1.5 log. Virologic results at 24 weeks of follow-up showed that 65% of those on the 500mg dose of BMS had viral loads below 400 (NFV-67%) and 35% had viral loads below 50 (NFV- 38%). These are encouraging results for a once-a-day PI. Studies are ongoing to determine if this new PI will be active against HIV that has developed resistance to other PIs. (Abstract 691).


The Combine study: Nevirapine versus Nelfinavir

The Combine study is a randomized, open label, multicenter trial comparing nelfinavir (Viracept™, a protease inhibitor) to nevirapine (Viramune™, a non-nucleoside RTI) in HIV-positive, treatment-naive people. A total of 142 participants were randomized to one of two regimens: Combivir™ (ZDV 300 mg/3TC 150 mg, twice a day) with either nelfinavir (1250 mg twice a day) or nevirapine (200 mg twice a day). Statistical analysis showed that the ability of each combination to raise a person's CD4 count was equal (an increase of more than 130 CD4 cells was observed in both groups), but that people taking nevirapine were more likely to have undetectable viral loads. [In an ITT analysis at 36 weeks, 55.7% (nelfinavir) and 70.8% (nevirapine) had HIV RNA viral load < 200, while in an OT analysis 78% vs. 83% had HIV RNA viral load < 200, respectively. At 36 weeks, 38.6% (nelfinavir) vs. 66% (nevirapine) had HIV RNA viral load < 20 by ITT analysis.]

There had previously been some concern that it was not safe to use NNRTIs to treat individuals with high viral loads, but nevirapine worked well for this group, too. At entry, 33% of all the participants had HIV RNA viral load over 100,000 and 20% had CD4 cell counts below 200. Even in people with entry HIV RNA viral load greater than 100,000, a higher proportion of the nevirapine group had undetectable HIV RNA viral loads (< 200 by ITT analysis (85% vs. 61.5%)). About 20% of people switched initial therapy due to adverse effects. Additionally, this study had a high discontinuation rate of 39%. While this is a relatively small trial, with a high discontinuation rate, it is another trial which shows that a non-protease inhibitor combination regimen may be as effective as, or even better, than a protease inhibitor-containing 3 drug regimen at suppressing HIV RNA viral load over the course of almost one year follow up. (Abstract 694).


A symposium on the Human Papilloma Virus (HPV)

The natural history of HPV infection was reviewed as part of a symposium on viral co-infections with HIV. Data from the New York Cervical Disease Study, which has followed both HIV-positive and HIV-negative women since 1991, was presented. They observed that HIV-positive women are more likely to be infected with HPV (60% vs. 35% in HIV-negative women) and are more likely to be infected with the subtypes of HPV that can cause cervical cancer (types 16 and 18). They also noted that lower CD4-cell counts increased women's risk of pre-cancerous cervical disease. Being HIV-positive also appears to increase a woman's risk for cervical cancer. In New York, while there was no overall increase in cervical cancer from 1983-91, in HIV-positive women there was a 2-3 fold increased incidence.

In men, the relationship between pre-cancerous changes in the anal canal and invasive cancer is less clear. While HIV-positive men have a higher rate of HPV infection and abnormal cells in the anal canal, the incidence of invasive anal cancer in HIV-positive men who have sex with men (MSM) does not appear to be higher than the cancer risk of HIV-negative MSM. In two studies, HIV-positive men did show a higher incidence of abnormal findings on anal pap smears(UCSF- 28% vs. 8%; University of Washington- 53% vs. 22%). It is still unclear why the increased risk of cancer in HPV and HIV-positive women does not show up in HPV and HIV-positive men. In both women and men, it appears that improvements in the immune system may help control, or even reverse, some of the abnormal changes seen in the cervix and anal canal. But there is very little data to fully address this issue in the "post-HAART era." Hopefully, in the next year or two, the answer to these questions will become more clear. This information could then be used to make decisions about whether to screen HIV-positive men with anal pap smears, and about the preferred treatment of abnormal anal canal changes. While treatment for women with abnormal cervical pap smears is currently standardized, there is still no similar consensus on how best to treat men with abnormal anal pap smears.


No effect on virologic suppression from Interleukin-2

The potential virologic and immunologic benefits of adding Il-2 to HAART were investigated in a study called CPCRA 059 presented by Donald Abrams. Il-2, short for interleukin 2, is an immune stimulant that is given as an injection under the skin. One of the major problems with Il-2 is that most people get a flu-like syndrome after each injection. The study randomized 511 people who were on HAART to receive either no Il-2, 4.5 MU of Il-2 or 7.5 MU of Il-2. The Il-2 was given twice a day for 5 days, every 8 weeks. This cycle was repeated three times and then as needed to maintain CD4 cell counts at twice the baseline number, or over 1,000. The results showed that after 12 months there was no difference in the control of HIV RNA viral load between the three groups. This large study, like others, shows that while Il-2 does raise CD4 (T helper) cells, it does not appear to affect the control of HIV by HAART. There is currently a large international trial, ESPRIT, which will attempt to follow a large number of people long enough to answer the most relevant question concerning Il-2. Is there a difference in clinical outcomes when Il-2 is added to HAART? (Abstract L-11).





  
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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Ezine.
 

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