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The 35Th Interscience Conference
on Antimicrobial Agents and Chemotherapy. (ICAAC)
Can we still be hopeful?

Part I

by Moisis Agosto

San Francisco was the host of one of the most important conferences in the area of infectious diseases. The 35th ICAAC meeting served as a scientific and clinical forum for researchers and infectious disease specialists from all over the world. This year the meeting included an interesting portfolio on the latest development in AIDS research and the complications related to it, as well as the emergence of new pathogens and antibiotic-resistant pathogens. This conference was a very critical one for AIDS researchers, clinicians, and advocates.

This article will be the first of a series of articles about the conference. Future articles will cover the development of prophylaxis and treatments for AIDS opportunistic infections, pediatrics, immune based therapies and diagnostics. The purpose of this specific article is to provide a summary of the most critical issues presented at the conference that are related to AIDS pathogenesis and antiretroviral treatments. This summary must not be taken as a medical advice. The main goal is to provide information that should be shared and discussed with the doctor or health care provider in order to develop well-informed therapeutic strategies.

I. HIV/AIDS Pathogenesis

a. Viral Diversity

The conference started with an opening symposium that focused on "AIDS viral diversity" and what viral diversity mean for individuals infected with HIV, a virus that replicates in big amounts and quickly.

Following are some of the main points that were made about viral diversity:

HIV has shown a chameleon-like nature. Which means that HIV is able to develop considerable diversity due to it rates of replication and also because reverse transcriptase is prone to introduce errors into the viral genome. Beatrice Hahn, of the University of Alabama at Birmingham, described the potential classification for HIV viruses. This classification consists of two groups . These two groups include a diverse group of subtypes. Also she has found recombinant subtypes in several AIDS patients. The question is: Do the groups or subtypes related to HIV variants correspond to a particular disease course?

John Coffin, of Tufts University in Boston, focused his discussion on the viral diversity found within HIV infected individuals. He believes that disease progression and the development of drug resistance relates to the HIV viral diversity and dynamics. Drug resistance variants are present in high numbers even before any antiviral treatment is started. Understanding the issue of viral diversity would provide clinicians and researchers with a better way to monitor patients and develop new therapies. Based on these observations Coffin stated that the only effective way to control this virus will be with the use of multiple drug regimens.

How HIV changes over time in particular infected individuals has been the question that Steven Wolinsky of Northwestern University Medical School in Chicago has been working on. He observed that subtle differences can affect the development of HIV diversity in HIV infected individuals. Based on this HIV diversity argument the two most important factors to study would be how this variety affect viral replication and the immune system. He pointed out that individuals can be superinfected by strains that belong to different subtypes. In some individuals in whom HIV is not particularly variable, the infection can progress to AIDS relatively quickly. In others, the virus seems to become quite variable, and disease develops more slowly.

The diversity of HIV has critical implications for the pathogenesis of AIDS as well as for the development of effective drugs and the prevention of infection. More research must be implemented. Knowing about the viral diversity in patients may help the clinician understand pattern of disease progression and the application of effective treatment strategies. Because there is a correlation between the subtypes and replication of the virus in vitro it is important to have more research that addresses the impact of these viral variations on virus pathogenicity and immunity.

b. Pathogenesis Based-Clinical Studies

Another interesting symposium was "Pathogenesis-Based Clinical Studies in HIV." This session suggested how can we might learn about HIV pathogenesis through clinical studies. Dr. Richman D. Douglas, from the University of California talked about the Genotypic and Phenotypic characteristics of HIV and how these relate to the pathogenesis of AIDS. He explained how SI phenotype is a CD4 decline factor. He said that changes in clinical markers based on therapy doesn't relate with SI phenotype. He also said that SI phenotype emerges during the course of infection and accelerates disease progression.

Dr. William Powderly from the Washington University in St. Louis talked about how the pathogenesis related to opportunistic infections can be a factor in disease progression. He articulated how there are specific immune responses to specific pathogens. Therefore it is important to be aware of diseases that are reactivated when the immune system isn't working properly. He suggested that quantitative blood culture could be a good marker of disease progression and therapeutic response. For example quantitation of CMV DNA in peripheral blood may predict CMV retinitis. Some of the questions Dr. Powderly posed were: How does Acyclovir affect survival?; How does the presence of TB is relate to disease progression; Why does the presence of opportunistic infections predict the development of other opportunistic infections (CMV, MAC)?

The symposium ended with a presentation by Dr. Schooley from the University of Colorado, about HIV pathogenesis and how much we can learn from immune-based therapies. He focused on issues related to Virus-Host interaction presented at the conference.

c. Immunopathogenesis of HIV

Immunosuppressive Acidic Protein (IAP) is a marker for progression of HIV disease based on results presented by Dr L Sacks. The Immunosuppressive Acidic Protein is an immunosuppressive serum glycoprotein, that becomes elevated under inflammatory and neoplastic conditions. This group of researchers wanted to determine the clinical implications of IAP. They measured the levels of IAP as well as disease progression or CD4 counts in 94 HIV infected individuals. This group concluded that levels of IAP correlated with the laboratory and clinical progression of HIV disease and has proven to be a useful predictor of survival.

A poster presented by a group of researchers from Columbia University in New York City suggested that Interferon-gamma may not have any antiviral effect against HIV infection of human CD4+ T cells. Based on long-term cultures of CD4+ T cells and the preliminary results, the group concluded that not only is Interferon-gamma ineffective as an antiviral agent, but they can even enhance HIV replication in these T cells. These results may have critical implications for immunotherapies against HIV.

d. Pathogenesis and Natural History of HIV-1 infection.

The use of HIV RNA PCR is proving to be a very useful tool to predict HIV disease progression. Various posters in this conference are trying to define the correlation between the levels of plasma RNA and the development of opportunistic infections and how this translates to the clinical use of the HIV RNA measurement.

A poster presented by CE Bush from the Henry Ford Hospital in Detroit found that there was a striking and significant increase in the level of plasma RNA with the development of an opportunistic infection in patients with detectable levels of RNA. They also found a significant decline in the level of RNA with the recovery of the patients. In contrast there was no consistent or significant change in p24 antigen levels or CD4 counts with either the development of the opportunistic infection or the recovery.

In conclusion they found that there was a consistent burst of HIV plasma RNA during an opportunistic event, while plasma p24 antigen levels and CD4 counts were unchanged. A poster from the University of Washington in Seattle suggested that the reactivation of Herpes Simple Virus-2 (HSV-2) in HIV infected people is associated with increased levels of plasma HIV RNA.

Based on a study that looked at four groups of patients representing different disease progression stage populations (>500 CD4+ to individuals with opportunistic infections) a group of researchers from the Long Island Jewish Medical Center in New York found that the HIV load in the long-term non progressors was low and not significantly different from that of the stable treated patients with lower CD4+ counts, while the patients with progressive HIV infection and opportunistic infection had significantly higher viral loads. This may suggest that viral loads distinguish the pattern of disease progression.

A study from France may suggest the predictive value of progression of free and disassociated circulating p24 antigen, in a subpopulation of HIV-1 infected black patients, does not appear to be a useful surrogate marker of progression.

II. Development of HIV Antiretroviral Treatment

During the conference participants were able to obtain a significant amount of information on the latest developments in HIV antiretroviral therapy. In this session we won't be able to cover every single presentation, therefore we will try to summarize the most critical presentations.

The results of the ACTG 175 study, the objectives of which were to compare the relative efficacy of combination therapy with monotherapy among HIV infected individuals with CD4 200-500 and to compare immediate versus deferred combination therapy, were presented on one of the late breaker sessions. This study was a randomized, double blinded placebo-controlled clinical trial of four treatment arms. The four arms were as follow:

The study population involved individuals with CD4+ T cell counts of 200 to 500 and the total amount of participants was 2,467: 1067 naive; 1400 experienced (individuals that used antiviral therapy prior to the study); 82% asymptomatic. The median treatment duration was 118 weeks (apprx. 2 years) and the overall median follow up was 143 weeks (apprx. 2 years). The premature discontinuation of study drug was a significant 53% and the loss to follow up was 20%.

The study results were summarized by Scott Harmmer of Harvard Medical School. Hammer reported that each of the other three arms was significantly superior to the AZT arm in preventing death, progression to AIDS, or a severe drop in CD4+ Tcell count. He said that this superiority proved to be true whether or not individuals have received antiretroviral therapy or not. In the group of participants taking AZT alone the rate of progression to AIDS or death or a 50% CD4+ T cell decline was 32 %. While the in the other three arms was 18-22%. For patients that never had antiretroviral treatment before the combinations of AZT+ddC and AZT+ddI or ddI alone were found to be more effective than AZT alone in preventing CD4+ T cell decline, AIDS and death. For those experience individuals(those that did antiretroviral therapy before) treatment with AZT+ddI, and AZT+ddC or ddI alone was found to be more effective than AZT alone in preventing CD4+ T cell decline, AIDS and death.

Even though these results may be encouraging for the validation of combination therapy over AZT monotherapy we still have to be cautious. The non-compliance in this study was more than half. Which mean less statistical power to the study. Also, these results conflicted with results from the ACTG 155 on combination drugs. This study suggests that combination therapy may be better than monotherapy but we still need more studies that take into consideration the new line of HIV drugs coming down the pipe line.

Protease inhibitors are a new family of antiretroviral drugs that inhibit HIV-protease, an enzyme that plays a critical role in the replication of HIV. AG1343 is a new compound under development by Agouron Pharmaceuticals, Inc. and Japan Tabbaco Inc. Results from a pilot phase II study with 30 HIV infected subjects were presented. In all 30 patients, significant reductions in HIV detectable in blood were observed. The reduction went from 90-94%. Significant increases in CD4+ T cells counts were observed. The drug seems to be safe and well tolerated.

Based on a Saquinavir (Hoffman LaRoche Protease Inhibitor) Monotherapy Trial preliminary results suggested that 7200mg/day dosage of Saquinavir has a superior impact on surrogate markers with a more sustained suppression of viral load, increase in CD4+ T cell counts and reductions in key resistance mutations.

A study sponsored by ABBOT pharmaceuticals suggested that the combination of two protease inhibitors, in this case Ritonavir and Saquinavir, along with a nucleoside analogue, in this case AZT seem to delay the development of resistance for the three drugs. The Merck Research Lab in West Point, Pennsylvania presented results from a study in which patients received Indinavir (Merck's Protease inhibitor) alone or in combination with AZT or AZT alone in naive patients. The preliminary results suggest that Indinavir in combination with AZT cause a sustained 99% decline of viral RNA. Indinavir alone also reduced the amount of virus more than AZT alone, but not as effectively for as long a time as the two drugs in combination.

Learning about the latest in pathogenesis and the latest developments on HIV treatments is critical for researchers, clinicians and patients in order to have a better understanding of treatment strategies and options. You must share this information with your doctor and see how these new findings may impact your primary care decisions. The second part of this series of articles will address opportunistic infections and immune based therapies.




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