October 16 and 17, 2000
Acute HIV infection, along with the research and clinical issues surrounding its diagnosis and treatment, was the topic of a new conference convened by the National Institute of Allergy and Infectious Diseases (NIAID) and the Division of AIDS (DAIDS). The inaugural meeting was held at a time when a lot of attention has been refocused on the treatment of acute HIV infection because of reports in September on the efficacy of structured therapy interruptions in people who begin treatment in acute HIV infection.
Acute HIV infection, also referred to as "primary" HIV infection, is the time immediately following exposure to the HIV virus. The timing of events varies from person to person, but the order in which they occur is fairly uniform. First, there are high levels of viral replication in the blood, leading to a detectable viral load (HIV RNA) within the first week or two following infection. At almost the same time, the p24 antigen (a protein made by the virus) is also detectable in the blood.
Subsequently, a person's immune system begins making antibodies to HIV, and tests for these antibodies will show positive results. This process of detection of antibodies to HIV is often referred to as "seroconversion." The first test is the ELISA antibody test, which would be positive before the other test, called the Western blot HIV antibody test. The Western blot tests for antibodies to several HIV proteins and is called definitively positive when it detects three different antibodies, including those to the HIV protein p31.
Lastly, the "detuned assay," a low-sensitivity ELISA antibody test, shows increasing levels of HIV antibodies over the first six months of infection. This detuned assay is being used to determine if someone who has a positive HIV antibody test was infected within the past six months or so.
The first point to emphasize is that there is no uniform definition of which of the above stages is "acute" HIV infection. Many of the results from research studies that were presented at this meeting included people in various stages of early HIV infection. In order to understand which groups of people the various studies included, and to compare these different data, there need to be standardized definitions of the early phases of HIV infection.
A good example of this need is Eric Rosenberg and Bruce Walker's report on seven people who have been able to discontinue highly active antiretroviral therapy (HAART) for up to a year after one or two treatment interruptions. The people in their study were all treated during "true" acute HIV infection, with symptoms of primary HIV infection, and prior to development of HIV antibodies (seroconversion). Conversely, Marty Markowitz, from the Aaron Diamond AIDS Research Center (ADARC) reported much less impressive results when they followed people who decided to stop HAART when treated during what they termed "early infection." However, the people in the ADARC cohort were not treated as early as were the people in the Harvard cohort, but rather within 90 days of symptoms of acute HIV infection, which may account for some of the apparently different results.
Challenges for Identifying Acute Infection
Probably 70% of people infected with HIV have an "acute retroviral syndrome," characterized by flu-like symptoms: fatigue, diffuse aches, swollen lymph glands in the neck, sore throat, and a rash. However, research centers that are actively recruiting people for acute HIV infection trials have a very difficult time in getting people referred to them. Some people do not see a healthcare provider when they have an acute retroviral syndrome, and most of those who do seek medical care are not correctly diagnosed. An alert healthcare provider needs to take a careful risk history, and order a viral load (HIV RNA) test to make the diagnosis of acute HIV infection. (The HIV antibody test will be negative in most people with acute HIV infection.)
Researchers from Johns Hopkins University reported that they generated only two referrals to their acute infection study despite extensive efforts to test in high-risk communities. But they did find that people were much more willing to get an HIV antibody test when researchers used the urine test, which requires a blood draw only to confirm a positive test. Connie Celum, from the HIVNET Vaccine Preparedness Study, which enrolled thousands of HIV-negative people in preparation for AIDS vaccine trials, reported that only 15% of people who presented to healthcare providers with acute retroviral syndrome were correctly diagnosed. And this was a group identified as at risk for HIV infection! Other researchers noted the failure of extensive outreach programs that were partnered with community-based organizations to help recruit people for acute HIV infection trials, particularly to increase enrollment of women into these trials.
Defining HIV-specific Immunity
One of the most detrimental occurrences in acute HIV infection is the loss of HIV-specific immunity. The term "HIV-specific immunity" is used to refer to the body's natural ability to produce cells specifically targeted at fighting HIV. Once this ability is lost, the immune system can no longer recognize HIV and viral replication can occur almost without interference.
For the most part, participants at the conference agreed that treatment during acute HIV infection may allow for preservation, or recovery, of HIV-specific immune responses, which does not appear to be the case when treatment is started during chronic HIV infection. Also, there was consensus that there is now evidence that in some people enhanced HIV-specific immune responses can control HIV replication without the aid of medication.
Many labs are using different methods to quantify "HIV-specific immunity" in CD4 and CD8 cells, but there is no standardization of assays or techniques. This is because it is not known which is the best available, and clinically relevant, tool or tools to look at HIV-specific immunity. The various tests being used in research labs include lymphocyte proliferation assays, tetramer assays, interferon gamma production assays, cytokine production assays, and ELISPOT-techniques assays. (All too confusing to begin to try to explain.)
Many questions remain regarding HIV-specific immunity. One of the challenges is to define which specific HIV proteins (or antigens) the immune responses are mounted against. Are there critical HIV antigens? Another question is, does the structure of HIV actually change, by mutating, so as to escape immunologic control? One of the major mysteries is why people treated with HAART during chronic HIV infection see their immune response recover to fight infectious agents other than HIV, but not HIV? Answers to these questions may help to define period of time, or window of opportunity, during which HAART needs to be started, if in fact there is a critical period.
Clinical Trials of Acute Infection
[Note: It should be emphasized that most of the clinical series reported at the conference included mixtures of people a various stages of acute HIV infection, from people with very high HIV RNA and negative antibody tests, to people with indeterminate Western Blots, as well as people who were antibody positive, but had documented HIV infection acquired within a three- to four-month period.]
Eric Rosenberg, from Boston, presented experiences with a planned treatment interruption in people treated very early during acute HIV infection. (This study was reported in the STEP Ezine on September 29, 2000.) Of eight people who stopped HAART after being treated during acute HIV infection, seven now have maintained viral loads less than 500 copies/ml without anti-HIV medications. Two people required a second treatment interruption, but now maintain suppression at this level.
Marty Markowitz presented the ADARC's experience with eight people who chose to stop HAART after being treated for acute HIV infection (within 90 days of symptoms). These were voluntary treatment discontinuations, usually due to treatment fatigue. There was an average drop in CD4 cells of 352 while therapy was interrupted, with a range of 123 to 546, and six of the eight people have restarted HAART. These rather disappointing outcomes were observed despite laboratory evidence of good HIV-specific immune responses in six of the eight people prior to treatment interruption.
Perhaps the most sobering issue during this session was the high "lost-to-follow-up" rates in these studies. Participant drop-out and medication side effects and toxicities led to lost-to-follow-up rates of up to 40% for some HAART trials in acute HIV infection. However, one trial at the University of California at San Francisco was able to have 100% follow-up, despite a difficult regimen. People in this study of acute HIV infection were randomized to HAART plus early or late interleukin-2 (Il-2), an immune-modulating compound. The Il-2 was given in a dose of 7.5 MU injected under the skin (subcutaneously), twice a day for five days, every eight weeks, for four cycles. Although there was a significant degree of toxicity from the Il-2 injections, no one dropped out from the study. UCSF has a very aggressive adherence program, under the direction of Margaret Chesney, which may account for this high retention rate.
Transmission of Drug-resistant HIV
The issue of the transmission of drug-resistant HIV may play a major role in selecting therapy options for those treated during acute infection. An alarming increase in the number of people who appear to have been infected with drug-resistant HIV was discussed at the conference. Susan Little, of San Diego, conducted a study involving 171 people from eight North American cities, including Seattle. She found an increased incidence of some drug resistance when comparing people infected in the last year to those infected a few years ago (from 1996 through 1998). There was an 8% incidence of high-level resistance to some drugs in the most recent time period. Luc Perrin, from Switzerland, reported that they have observed a decrease in transmission of drug-resistant HIV recently. He attributed this to the increased number of people with undetectable HIV RNA on treatment. The lower a person's viral load, the lower the risk of HIV transmission.
There was consensus that eradication of HIV with today's drugs is not possible, even when treatment is initiated early in the course of HIV infection. This is because the latent reservoirs of HIV infection are established very early in the course of infection, probably even before a person develops symptoms of acute infection. There is now proof of the concept that you can improve, or preserve, HIV-specific responses, when HAART is initiated during acute HIV infection, and those immunologic processes appear to be able to control HIV replication in some people, without the aid of medication.
Most people agreed that acute HIV infection should be treated in clinical trials, and that people should not be treating acute HIV infection if they are not experienced HIV care providers. It was even suggested that the recommendations of the Public Health Service Treatment Guidelines should be revised concerning the treatment of acute HIV infection. Dr. Jay Levy also emphasized the need for comparative data on people who do not start HAART early.
Looking to the future, Levy also pointed out that using bursts of viral replication, like those induced during strategic interruptions of therapy, to boost HIV-specific immunity was like using leeches to treat people. What are needed, he said, are immunologic agents, both general stimulants and HIV-specific agents, to generate clinically beneficial immunologic responses that can lead to the control of HIV replication.