A revised version of HIV treatment guidelines issued Feb. 5 takes a less aggressive approach on when to start therapy. The changes reflect what has become common practice among the most experienced physicians treating HIV. They will have the greatest impact on those doctors who treat only a few cases of the disease and who rely upon such documents to shape their practice.
The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents is a joint effort of the U.S. Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The first version was published in 1998, with revisions coming at least once a year.
The new version recommends that therapy not be started until a person's CD4+ T-cells fall below 350, or the blood plasma viral load passes a certain minimum level [ 30,000 copies as measured by the branched DNA test, 55,000 copies as measured by the RT-PCR test ] with a higher T-cell count.
The previous guidelines set an earlier standard for intervention of 500 T-cells and viral load levels of 10,000 or 20,000 copies as measured by those same respective tests. A normal immune system has 800-1,000 T-cells on average and no virus in the blood. At the other end of the progression, serious illness begins to appear once T-cells sink below the level of 200 and accelerates below 100. Viral load at this point, absent therapy, can be well above 100,000 copies.
The initial guidelines were developed soon after protease inhibitors came into widespread use. They were based on the hope that by using these drugs to "hit it early, hit it hard," in the mantra of noted researcher David Ho, head of the Aaron Diamond AIDS Research Center in New York, the virus could be eradicated.
All too soon it became apparent that this was a false hope, virus quickly took up residence in certain tissue and cell compartments beyond reach of the drugs. Even when virus was cleared from the blood, it could trickle back in from these reservoirs to re-infect those portions of the body that had been cleared of virus. Drug associated toxicities also became more apparent.
"We are very concerned about a number of toxicities associated with the long-term use of antiretroviral drugs," said Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. This is one of the primary reasons for pushing back when to start therapy under the Guidelines.
THE EXCEPTION
One major exception on when to start is acute or primary HIV infection. That is a brief window of perhaps 90 days or so from the time one is exposed to HIV to the time one exhibits antibodies to the virus. Many people experience flu-like symptoms during this period.
The only way to determine the presence of HIV during acute infection is with a PCR assay that measures the virus itself. And even that is not likely to work in the first two weeks, as there may not be enough virus in your blood for the test to measure effectively. The common elisa test used to screen most people for HIV infection will not work because the body has not yet generated those antibodies that the elisa assay measures.
Very limited research in a small number of people who began therapy during acute infection strongly suggests that this may be the best time and the best way to help train the immune system to fight back against HIV before it gets overwhelmed by the virus. This seems to be the group of patients who are best able to eventually stop all therapy and have their immune system control the virus at very low levels of replication.
REACTIONS
At a Feb. 4 news conference at the 8th Retroviral Conference, activist Mark Harrington charged that the organizers of the Conference refused to allow a news conference for release of the Guidelines. He is a member of the Treatment Action Group ( TAG ) in New York City and has participated in shaping the Guidelines.
"No, it never came to that point," said Constance Benson in a testy exchange with Harrington. She is Conference co-chair and a researcher at the University of Colorado Health Sciences Center in Denver. She explained that the executive committee had "lengthy discussions" about the matter and decided the Guidelines were not part of the meeting, nor something they wanted to "highlight."
Later Harrington called Benson's response "all spin." If the Guidelines advocated "hit it early, hit it hard," a position the Conference organizers had championed in the past, he thought their response would have been different. He said the organizers "had their tails between their legs."
"I've been one who has been urging caution [ in starting therapy ] for a long time," said Donald Abrams. He is an AIDS doc at the University of California, San Francisco and former president of the Gay and Lesbian Medical Association.
"I think that most [ experienced AIDS physicians ] know that when you are taking care of a patient, what the patient wants is very much a driver of what kind of therapy you are going to prescribe," he said.
Douglas Ward, an AIDS doc in Washington, D.C., echoed that view. He said, "The frontline people are already doing it, being a lot less aggressive with higher T-cell counts."
Both physicians were uneasy saying what they would recommend to a patient who had started therapy some time ago at around 500 T-cells and had an undetectable viral load. Should the patient continue on therapy or stop? There is little data to support either position.
The more experienced patient advocates seem to be the ones urging caution in the use of therapy. Harrington fought the initial draft guidelines in 1998 that virtually demanded an early start of therapy. The community gained a change in language that made such intervention an option instead of a requirement.
"The people who are [ medically ] screwed right now started AZT monotherapy and went along the route of jumping into every one of the latest things that came out," said Terje Anderson, executive director of the National Association of People With AIDS. He believes this revision "will mark some kind of turning point, a change in emphasis." But he feels the impact "may take a year or two to ripple through."
Taking a Break: How to Stop Therapy
by Bob Roehr
Physicians realize that there are times when it makes sense to stop therapy, when toxicities are so extreme the regimen is no longer tolerable, or when the drugs are no longer working. They are very much divided over stopping for lesser reasons.
One thing they do agree on is that if a patient is going to stop, it should be a clean break, so as to minimize the opportunity for drug-resistant virus to develop on a less than optimal regimen.
Douglas Ward, a Washington, D.C., physician with more than 300 active HIV patients under his care, has very clear procedures for those who do decide to stop therapy. First to go are non-nucleoside analogs [ Sustiva/efavirenz, nevirapine, delavirdine ] , about two days before the other drugs, so that their long half-life in the blood does not unnecessarily promote the emergence of drug-resistant virus.
He runs a genotypic test on the patient to use as a benchmark when restarting therapy. If the patient has a viral load above 1,000, he will draw blood for test soon after stopping. If the patient's viral load is undetectable, he will wait about two weeks after stopping therapy. That allows the virus to replicate to great enough quantities to show up well on the assay, but it is not so long that mutant virus recedes into the background as wild type reemerges.
In addition, "What I generally do is viral load at one month, viral load and T-cells at two months, and then every two months until we follow the pattern of what is happening," says Ward. He will repeat the genotype test at 4-6 months to see if the virus of highly experienced patients has reverted to wild type.
He has one highly experienced patient who had boosted his T-cells to about 800 on an IL-2 protocol, but was on a double protease regimen and still had a viral load of 20,000, plus bad lipodystrophy. The patient stopped therapy for about six months, then restarted, said Ward. "He had reverted to wild type [ during the time off therapy ] and for the first time ever he is undetectable."
More on HIV therapy, page 10
The Prevention Conundrum
by Bob Roehr
Newspaper headlines scream of increasingly risky sexual behavior among gay men and very high rates of HIV infection among young gay Black men. All are based upon studies funded or conducted by the Centers for Disease Control . Reading those reports, one gets the impression that HIV is again exploding across America.
Yet at the same time, the CDC estimates 40,000 new infections of HIV a year—the same number it has used since 1992. What is happening here?
At the 8th Retrovirus Conference, in Chicago Feb. 4-8, the CDC's Robert Janssen expressed "particular concern" with reports of increased risk behavior by HIV-positive men who have sex with men and with rises in sexually transmitted diseases ( STDs ) in gay men in Seattle and San Francisco. STDs traditionally have been used as a surrogate or marker for HIV transmissions.
Boston activist David Scondras asked if there was any evidence that there was increased transmission of HIV in the last few years. Janssen restated the evidence of increases in risky behavior and in the number of STDs but concluded, "At this point we do not have data on HIV incidence that demonstrates an increase, but we are concerned."
Two facts may explain why STDs may no longer be a good marker for HIV transmissions. First, HIV is a lifetime infection where a new infection is counted only once. A person can have STDs such as gonorrhea or syphilis numerous times in their life or even within the same year.
Second, people who are HIV positive may be having unsafe sex primarily with other people who are already infected with the virus. This could result in news STD transmissions but no new HIV transmission. Janssen himself mentioned data that supported this conclusion. In the Seattle "outbreak" of syphilis, 75 percent of the cases are in HIV-positive men who seem to be passing it among themselves.
VIRAL LOADS
Janssen pointed to new data from Amsterdam showing that HIV-positive men had "an increase in unprotected sex with casual partners after their viral loads became undetectable and their CD4 counts increased" while on therapy.
"While lower viral load in the plasma is associated with lower risk of transmission, cell-associated virus is still found in the semen and it is not well understood how infectious that is," though animal models suggest it is much less infectious, he said.
"The focus on HAART and the way it affects transmissibility is important but somewhat academic. What is really important is to focus on behavior. At this point we don't know the answer about whether HAART reduces infectiousness in sexual transmission. There is no question that it does in perinatal situations, but it is much less clear in sexual and injection drug use situations."
Janssen tried to downplay a study by Johns Hopkins University researchers in Uganda, funded in part by the CDC, showing that there were no new infections of HIV among heterosexual couples if the viral load was under 1,500 copies. He seems to believe that semen and transmission vary between continents and acts until proven otherwise.
What about the sky-high rate of viremia during acute infection, those first few weeks after exposure to HIV where one group of patients had an average viral load of 12 million? Some researchers have speculated this is a major factor in the continued spread of HIV in the U.S.
Janssen said the only data comes from the Options Project in San Francisco, where about 40 percent of the 17 examples were linked to the acute infection of a partner.
SAFE
The CDC is launching the first prevention program targeted to those who are infected with HIV. Evidence shows that those who know their HIV status are more likely to change their behavior and adapt less risky practices in order to protect their sexual partners.
SAFE—Serostatus Approach to Fighting the Epidemic—has two principle goals. "The first is to increase the proportion of HIV-infected people in the United States who know they are infected, from the current estimated 70 percent to 95 percent by the end of 2005," said Janssen. The second is to link 80 percent of these to appropriate services.
SAFE will be launched later this year with a "Know Now" media campaign launched in Detroit, New Orleans, Houston, Miami, and Jackson, Miss. If fully implemented, the program will cost $300 million of federal and local funds. The CDC currently has $100 million and is "looking for additional public funds."
But SAFE is based upon the standard antibody test to identify HIV. And antibodies become detectable only at seroconversion, at the end of acute infection, about 90 days or so after exposure. The program will do little to address the issue of HIV transmission during acute infection when viral load is in the millions.
Homophobia, HIV, and Prevention in the Black Community:
Phill Wilson speaks
by Bob Roehr
"By definition, to be gay is to be white" within the mindset of many African Americans. "So what happens for Black gay men, not only do you deal with the stigma of sexual orientation, you deal with the betrayal of race," says Phill Wilson, director of the African American AIDS Policy and Training Institute at the University of Southern California.
The sense is that "being gay is not a Black thing. Somehow by expressing your sexuality, you are denying your blackness."
"We have never gotten to the point of having an explicit discussion around stigma, homosexuality, and AIDS in the Black and Latino communities," says Wilson. "Part of what is driving these men and their relationships with women is the need to be accepted in our community. And to, quite frankly, create plausible deniability around their sexuality.
Wilson says that Blacks are no more or less homophobic than are whites but they do have "a whole set of issues around shame. We don't want outsiders to know that there are drug users, and homosexuals, anything that might be perceived to be a prejudice.
"You have the urban myth that all of the members of the choir and the choir director are gay. Well, to some extent that myth exists because there is some truth to it. These people often are honored within the church environment, people know they are gay, but they don't talk about it. And if an outsider were to come in and attack that person, they would rally behind that person inside the church. He is a part of us, and an outsider cannot come in and do that. If that person were to explicitly say that it is so, then the church would come back and force him out.
"So a lot of the stigma really is about an understanding that there is a conspiracy of silence. If I am silent, then I maintain the support of my community. And so this notion of Blacks being more homophobic than whites doesn't come from the reality of homophobia but comes from the intensity of the experience.
"If I am Black and gay, I believe or know that I am dependent upon my Black community for sanctuary on the race question. So I am not willing to do anything to jeopardize that sanctuary. When I disclose that I'm gay and lose that sanctuary, it has a more devastating impact on my life."
Wilson says that the traditional AIDS organizations often do not have much of a history of providing services for Black gay men. "And when you look at minority initiative programs funded by the CDC, rarely do they explicitly address gay men of color in ways that directly deal with issues of sexual orientation."
He believes that it is legitimate for organizations like the CDC to support building infrastructure to "create a cultural environment for gay and bisexual men who are in the closet, to take more ownership within their community. ... We need to strengthen organizations so that we have the wherewithal to do this work."
