Treatment Issues: Newsletter of Current Issues in HIV/AIDS - Volume 19, Number 1 & 2, January / February 2005
Bob Huff

A group of HIV/AIDS community doctors and organization leaders gathered at the New York City Department of Health and Mental Hygiene on a Friday morning in early February 2005. They had been summoned by Health Commissioner Thomas Frieden to attend a press conference about a newly diagnosed strain of HIV. In a briefing to the group before the press was ushered in, the commissioner explained that a gay New Yorker in his 40s had become infected in October 2004 after bingeing on crystal methamphetamine and having sex with hundreds of people over a period of several months. The man started feeling sick in November and went to his doctor. By December he was confirmed HIV-positive and had already experienced a dramatic loss of CD4+ T cells, which pushed him into the range of AIDS. By February his CD4 count was well below 50. Furthermore, the group was told, he had a particularly aggressive strain of HIV that was resistant to every antiretroviral (ARV) drug except Fuzeon. Frieden concluded these facts were so unusual and alarming that they warranted issuing an alert to doctors and holding a press conference to announce that a new, highly virulent strain of HIV was on the loose in New York City.

Frieden targeted gay men in particular: "It's a wake-up call to men who have sex with men, particularly those who may use crystal methamphetamine. Not only are we seeing syphilis and a rare sexually transmitted disease — lymphogranuloma venereum — among these men, now we've identified this strain of HIV that is difficult or impossible to treat and which appears to progress rapidly to AIDS."

The press reaction was swift and predictable: "AIDS Super Bug," blared the New York Post; "rare and deadlier form of AIDS," announced The New York Times. Soon it was on CNN and the nightly news. "A frightening, never-before-seen 'superstrain'... full-blown AIDS sets in with lightning speed." The report sped around the globe: "New AIDS Peril Puts America on High Alert," announced The Hindu and other international papers. Yet behind the headlines, accounts of the "supervirus" were mostly superficial.

Hotlines at AIDS service organizations began buzzing with anxious questions: "Does this mean my HIV test was no good? Does this mean my drugs won't work anymore?" People were certainly talking, but what was the hubbub about? Chatter on the e-mail networks of people who follow AIDS research immediately zeroed in on one glaring detail: There was only one case. An unusual and tragic set of circumstances, no doubt, but, so far, found in just one person. If there had been a cluster of several cases where people were progressing to AIDS with a highly virulent strain of untreatable HIV, that would have been big news. But did a single case warrant a press conference that launched headlines around the world? As the story filtered out and the personalities behind the news became known, some pieces began to fall into place.

Super Ego
The next red flag went up when it was learned that the patient had been referred by his doctor to a special research group at the Aaron Diamond AIDS Research Center (ADARC) known for studying people in the earliest stages of HIV infection. The director of ADARC is Dr. David Ho, Time magazine's Man of the Year for 1996 for his role in helping usher in the era of highly active antiretroviral therapy, or HAART. Dr. Ho was also a chairman of the Retrovirus Conference, the most important AIDS science meeting of the year, which was due to open in Boston in two weeks. Many observers became suspicious because Dr. Ho has a history of announcing dramatic findings to the press around the time of scientific conferences. He also has a history of being wrong and overhyping his findings. In 2002 he announced, to much ballyhoo, that he had discovered a long-sought natural defense against HIV produced by CD8 cells. That finding was recently retracted in Science magazine. And at the 1996 International AIDS Conference in Vancouver, Ho grabbed hopes and headlines when he posed the possibility of complete eradication of HIV from the body using the new protease inhibitors. Those dreams were dashed within the year. Upon hearing of his involvement in this new sensation, many AIDS insiders immediately suspected the "supervirus" was Ho's "conference surprise" for 2005.

Super Script
To others, the story simply seemed queer on the face of it. Although very rapid progression to AIDS is rare, a quick literature search will turn up several cases where individuals had become infected, developed AIDS, and died within six months. The average time to AIDS in untreated persons is usually put at around 10 years. But, as with any bell curve, there are a few people at each end of the spread. Some never develop AIDS, while some go quickly. Rapid progression on its own was not news.

But this patient had a virus that was resistant to drugs in three of the four classes of antiretrovirals. Wasn't that alarming? Well, it should be, but it is not uncommon. Studies have found resistance to at least one drug in 6 to 15 percent of recently infected people. Even triple-class drug-resistant HIV was found to be transmitted in about 1.3 percent of new infections, according to one study. In the corridors of the 12th Retrovirus Conference, in Boston, several clinicians confided that they had a number of patients with this extent of drug resistance.* Among people already on therapy, studies have found at least one resistance mutation in nearly 80 percent of those with detectable viral load.

Frieden claimed it was the unprecedented combination of rapid progression with transmitted multidrug resistance that justified the alert. But even this was not unique. In 2001, Julio Montaner of Vancouver, Canada, reported on two cases of multidrug resistance in patients who had rapidly progressed to AIDS. Clearly this situation had been seen before — and the sky didn't fall in — so what possessed Frieden to unleash a torrent of fear and confusion over this case? Had he been duped by the fame and authority of Dr. Ho? Was it all orchestrated by Dr. Ho's public relations firm? Was Frieden, who has worked in India, so naïve as to think the global press wouldn't whip this story into a superheated frenzy far beyond the boroughs of New York? Or did the aggressive commissioner simply spy an opportunity to advance his own agenda of shaking up New York's complacent gay community about the unabated AIDS crisis among them?

New Yorkers could use a wake-up call. Gay men continue to lead the categories of the newly infected in New York, and alcohol and methamphetamine use have been shown to strongly increase one's risk of infection. Take this individual — by all accounts a successful business executive: How can it be that a gay man with an active sex life remains uninfected until his mid 40s, then stumbles in such a dramatic way? Unfortunately, there is nothing unique about this aspect of his case. Not enough attention has been given to midlife gay men and they stress they experience. But with shrinking federal funds for HIV prevention efforts and a shifting emphasis toward secondary prevention (prevention efforts aimed at reaching infected people in a medical context, an approach lately promoted by the CDC as it retreats from funding prevention in high risk groups) and away from primary prevention education for people at risk (youth, women of color, and amphetamine users, etc.), men like this are less likely than ever to have somewhere to turn for help.

Super Vision
Commissioner Frieden has been admirably successful in his campaign to curb smoking in New York. Most agree that the quality of life in the city has improved (although health benefits may take longer to show up). He has a reputation as a public health activist but also for being a bit of a Napoleon when it comes to going after his goals, harboring little patience for criticism or community input. A look at the medical articles he has authored shows a long-standing concern with the need to control outbreaks of disease without trampling civil rights. Frieden made his bones by fighting tuberculosis — specifically, an outbreak of multidrug resistant TB that appeared in New York in the early 1990s. TB is a highly communicable disease and is easily spread in institutional settings such as hospitals and shelters. Conceivably, you could get it from standing next to someone in an elevator. The TB treatment model is classically authoritarian. When a TB outbreak occurs, the health department swoops in with medical detectives who track down everyone who may have been exposed and puts the infected on directly observed therapy (DOT), where a medical professional watches each pill go down. It's a very effective way of dealing with an isolated outbreak of TB. But can such an approach work for HIV?

HIV is relatively difficult to transmit sexually, although certain practices, such as unprotected anal intercourse, can increase the risk greatly. Once acquired, HIV is normally a slow-moving disease. A person who is newly infected may not realize it, or may have symptoms of acute infection that range from muscle aches to a dramatic rash and flu-like symptoms. After the initial stage of infection, an individual's immune system usually kicks in to bring the HIV under partial control. But HIV replicates rapidly — a new generation is born nearly every day — so within a few weeks of settling into its new host, the virus is evolving and beginning to escape immune control. By the time a year has passed, the dominant virus may be quite different from the virus a person received at infection, having gone through the equivalent of 6,000 years of human evolution. Antiretroviral therapy can knock down the HIV replication rate to nearly — but not quite — zero. There are always a few cells hanging around that hold some virus in reserve. If the drugs are interrupted or stretched too thin, these few viruses will start to increase in number. The longer the virus is allowed to replicate in the presence of the drugs, the more likely it becomes that a random mutant capable of thriving despite the medication will be generated. Before long, if this keeps up, a drug-resistant strain is born. The fact is: Most people with multidrug resistance have made it themselves.

The best guard against resistance is to maintain strict adherence to effective medication, but it's hard to do. The DOT approach, from the TB world, has been successfully used to administer HIV drugs as well. But TB is curable within months, while HIV requires lifelong treatment. Studies of ARV therapy in prisons have produced excellent levels of adherence and viral suppression. But it should be obvious that such means are not solutions for this situation.

The terms "superbug" or "superstrain" are sensational words invented by the media to sell newspapers. But there are a couple of other "super" terms that have been conspicuously missing from discussions about the New York patient. One is "superspreader," an informal epidemiological term used to describe an individual who is responsible for a high number of transmission events in a population. Recently infected people typically have extremely high viral loads. They may also have a virus that is well-adapted to transmission — after all, it was recently transmitted to them. Put this person in a social setting where he is bingeing on drugs and unprotected sex with multiple partners in weekend-long parties and he will be much more likely to infect other people than a party pal with a relatively tame chronic infection. The Hollywood horror angle to this scenario is that the "superspreader" may have no idea he is infected.

Maybe this is who Tom Frieden really wants to reach. If you can diagnose people when they are most infectious, then perhaps the unrelenting cycle of HIV transmission among gay men can be arrested and reduced. For someone who has tackled outbreaks of TB, it makes sense. But will it work for HIV? By the time someone has visited a doctor with symptoms of primary HIV disease and has been confirmed positive, the most infectious phase may be nearly over. So the disease detectives from the Department of Health hit the streets to find anyone our superspreader may have infected (they also want to find out who infected him and trace those contacts as well). If they can reach one of his infected contacts early enough, then maybe the superspreader cycle can be broken. It's certainly worth a try. But when partners are anonymous or dimly recalled after drug-fueled lost weekends, it may be tough to make the connections. In the case of the New York patient, the word is that two of the people who may have infected him have been contacted, and one is cooperating with the health agency.

Super Trooper
Contact tracing in New York is voluntary, but notorious cases like this one always revive fears of more draconian measures. There is a long list of reasons why compulsory contract tracing is a bad idea, but some minds naturally run to coercive solutions. First, any approach that increases HIV stigma or applies the taint of criminality to people's sexual desires will likely drive them further away from doctors and support. A better idea is to get people out of dark, anonymous situations and into testing and care — not leave them cowering in fear as their health and sanity deteriorate. But within days of Frieden's announcement, conservative blogs and talk radio were crackling with calls for the quarantine and criminalization of drugged-up, gay-sex-crazed superfreaks. It seemed like 1985 all over again. This is not to say that frustration over the never-ending epidemic and irresponsible behavior hasn't riled folks within the gay community too. Syndicated gay columnist Dan Savage proposed treating viral donors like deadbeat dads, holding them responsible for the financial burden of antiretroviral therapy for the people they infect. A letter to the San Francisco Bay Area Reporter, a gay weekly, simply recommended locking them up and throwing away the key.

But HIV-negative people are not the only ones at risk. Another unspoken "super" in all of this is "superinfection." This is a much misunderstood medical term for acquiring one HIV infection on top of an existing infection (super, in Latin, means "above," not "faster than a speeding bullet"). Reinfection might be a less loaded term. Some people in the HIV community absolutely deny the possibility of superinfection, probably because it threatens a perceived freedom to have unprotected anal intercourse with other positive people, a practice called serosorting. There are theories and a few persuasive studies that say having HIV is protective against infection with a different strain of HIV. Nevertheless, there is incontrovertible proof that superinfection does occur. The worst-case scenario, of course, is if a person on ARVs with fully suppressed HIV becomes reinfected with an untreatable, multi-drug resistant strain of HIV that takes over and plunges him into AIDS. Superinfection has been convincingly detected in several individuals and in a few longitudinal studies. The question now is how often, how likely, and how clinically relevant these events are. One study described at the 12th Retrovirus Conference calculated that reinfections may occur as often as initial infections. So a multidrug-resistant strain of HIV being passed around is a potential problem for both negative and positive people.

One new tactic Frieden is using to tackle resistance is to demand that every diagnostic laboratory in the country notify his department whenever a multidrug-resistant specimen turns up that has originated in New York City. They have asked labs to be on the lookout for not only the specific strain that caused the panic but also for every instance of HIV with a more broadly defined set of resistance mutations. So far nothing has turned up, although it is not clear if the labs are taking his request seriously.

To some it seems the commissioner is chasing a utopian fantasy of monitoring the care of every HIV-positive New Yorker from his downtown command center. But how will this help prevent new infections? Frieden's department currently collects HIV viral load and CD4 count reports from the labs, but this information is rarely reported to the community, where it might make a difference. The city's HIV testing reports are still running a year behind real time. If the disease detectives are not swamped with processing these new resistance reports, they may occasionally hit upon a recent seroconverter and make an effective intervention. But these are likely individuals who should be the focus of prevention efforts anyway, whether they have acquired a drug-resistant strain or not. A better way to reach these people, it seems, is to create more opportunities to access medical care, train more doctors to suspect HIV, take better sexual histories, and perform more tests. This will require resources and education.

Increasing the rate of HIV testing within the city is another top agenda item for Frieden. The number of newly diagnosed people with HIV reported by the city has dropped by 38 percent from 2001 to 2003. But it is not clear whether this reflects a real drop in new infections or merely a failure to offer HIV testing outside of the easiest-to-reach populations. The large proportion of individuals (28 percent) who are diagnosed with AIDS at the same time they find out they have HIV suggests that HIV tests are either unavailable or not offered to far too many people. But Frieden has been heard to opine that the way to increase testing is to lift the barriers, particularly the requirements for thorough pre-test counseling and informed consent. While testing procedures could certainly be streamlined, many would see testing without consent as an unacceptable erosion of privacy in a land that still bars infected foreigners from entering the country. As demonstrated by the reaction to Frieden's announcement, stigma lives in the United States, and mistrust of government and insurance companies, plus the increasingly insecure health care situation leave many ill at ease. Unfortunately, there are still good reasons why testing for HIV is not like testing for anemia.

Strained Logic
So was this strain of HIV really that special? Almost all transmitted viruses use the CCR5 coreceptor to gain entry to a new host cell. CCR5-using HIV is most commonly found during the early years of infection, but in some people, the virus eventually switches and begins to use another coreceptor, CXCR4. The switch to using CXCR4 is associated with a much more rapid loss of CD4 cells and progressive disease. Ominously, the New York patient appeared with a virus that could use CXCR4 only a few weeks after his infection. Also, it is generally thought that drug-resistant HIV is less capable of replication than the wild type and therefore more difficult to transmit. But this virus had a replication capacity equal to or better than the average wild-type virus. These facts, more than the drug resistance, make this a curious and unsettling case.

While Frieden put most of the emphasis on the viral "strain," many HIV scientists who heard about the patient that Friday afternoon immediately suspected the explanation likely lay with the individual: "More often than not, [rapid progression] has something to do with the person infected; not the virus itself," said Anthony Fauci, perhaps the only AIDS scientist better known than Dr. Ho. Some people are genetically more susceptible to HIV and disease progression than others. Yet of the 20 or so immunological characteristics known to be associated with AIDS onset, this person had none. That does not mean that some other factor wasn't responsible. New interactions between the host and the virus are reported almost every month. One telling aspect to this case was that the patient apparently failed to mount any significant immune challenge to the infection and that his CD8 cell count fell along with his CD4 count. But again, there is no way of knowing if this was due to the virus or the person.

Some people initially speculated that crystal meth had played a role in wearing down the man's immune system or somehow revving up the virus. But there is nothing solid in the medical literature that points to this, although the patient's reported 20-pound weight loss during that period might just as well be attributed to crystal meth use as to AIDS.

So, agendas aside, there were some strikingly unusual and alarming aspects to this case. It certainly must have seemed that way to Martin Markowitz, the researcher at Aaron Diamond who evaluated the patient. After the story broke and criticism began swirling about the decision to go public, Markowitz spoke before a group of New York physicians, where he described the patient and distributed a draft of an op-ed piece he had written about the new strain, which he compared to "a silent tsunami." An attendee at the meeting recalled that the researcher was adamant about the significance of the case and accused the doctors of "looking for a horse" when faced with a stampeding "herd of zebras." Markowitz subsequently attended the Retrovirus Conference, where a special session had been called to discuss the case, but left the presentation to Dr. Ho, who, it became clear, had been unaware of many details of the case (such as whether the individual had ever injected methamphetamine — we were later told he hadn't). So the question remains: Is this case the tip of the iceberg of some new, highly virulent strain of HIV that is spreading even as you read this? Or was it a perfect storm involving an unusual (but hardly unique) case that became supersized by runaway imaginations, inflated egos, political opportunism and a gullible press? Was the brouhaha over this individual simply a heavy-handed way of getting the attention of New York's doctors and at-risk communities? Dr. Frieden and other health department representatives have repeatedly said it would have been irresponsible not to announce the case.

Whatever the merits of the decision to launch this story around the world, the fact is that, in New York at least, a few more people are talking about HIV and the reality that gay men still become infected every day. Hopefully, some are learning that adherence can prevent drug resistance and that condoms can prevent new infections. But with all the noise about this virus, how many have learned to recognize the symptoms of primary HIV infection?

One wonders: If this particular virus of mass destruction does not exist, did it have to be invented as a pretext for a renewed war on AIDS? If the only way to get the gay community's attention is by hitting us in the head with the two-by-four of an imaginary supervirus, then do the ends justify the means? I suppose it depends on what comes of all this. Fear has never been demonstrated to be a sustainable prevention aid. Most agree that clear information and enlightened self-interest work better. Dr. Frieden has stimulated some discussion here in New York, and he may uncover some interesting facts about drug-resistant HIV in the city as well. Over the coming months he will roll out his plan for tackling HIV in New York City. Hopefully, all this will result in a net reduction of new infections when his department reports its estimated HIV incidence numbers next year.

* It turned out that his virus was phenotypically susceptible to efavirenz and delavirdine. At last word, he was being treated with a multidrug combination and his viral load had dropped.

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