Special Coverage: 12th Conference on Retroviruses and Opportunistic Infections
Growing number of drug resistant strains dominates at retroviruses conference
Drug resistance is an 800-pound gorilla
While some researchers, AIDS advocates, and public health officials still debate the wisdom of publicizing the recent New York City case of multidrug resistant HIV that progressed rapidly to AIDS, the one thing everyone can agree upon is that multidrug resistance in newly diagnosed patients is a major problem.
HIV experts also note that the case highlights the need for more effective prevention messages, substance use treatment, and surveillance of new HIV infections.
Several studies presented at the 12th Conference on Retroviruses and Opportunistic Infections (CROI), held Feb. 22-25 in Boston, showed how common HIV drug resistance has become, even in newly infected individuals.
North Carolina researchers were shocked to find that of 127 people identified as having become infected with HIV within the past few months, nearly 20% had virus mutations associated with drug resistance.1
"I thought I made a mistake because the number was so much higher than I expected," explains Charles Hicks, MD, an associate professor at Duke University Medical Center in Durham, NC.
Using the International AIDS Society list of mutations associated with resistance that are significant, 19.7% of the North Carolina subjects had some HIV drug resistance, Hicks says.
"That stunned me — one out of five," he points out. "And no matter how we looked at them, different ethnic groups, whether we had used the detuned assay vs. identifying truly acute infection or whether they were men who have sex with men [MSM] or heterosexual, there were no big differences."
The Centers for Disease Control and Prevention (CDC) presented 2003-2004 surveillance findings at CROI. These showed a 114.5% prevalence of at least one drug resistant mutation in 787 drug-naïve, newly diagnosed patients at 89 diagnostic sites in six states. The same group had a 3.1% prevalence of resistance to two or more drug classes, and less than than 1% had resistance to three drug classes.2
One of the more surprising findings in the CDC data is the HIV drug resistance rate is relatively consistent among all newly diagnosed, drug-naïve participants. This is a change from previous studies that showed less resistance among African American patients, says Diane Bennett, MD, MPH, coordinator of the CDC’s Antiretroviral Drug Resistance Surveillance and Monitoring. "In some ways, that probably reflects the fact that the [public health care] system is getting more people into treatment in all of these categories," she says.
The CDC is expanding a resistance surveillance program that began in July 2004 for the purpose of providing drug resistance testing routinely on blood samples from all newly diagnosed people, Bennett notes. "We’re planning for this to be a national system, the way tuberculosis resistance is routinely tested," she says.
Participating states and municipalities will have access to data reflecting trends of resistance in their areas, and individuals newly infected with HIV, along with their providers, will have a baseline resistance profile that could be used when their antiretroviral drug regimen eventually is planned, Bennett explains.
In addition to resistance testing, the samples from newly diagnosed patients will be tested to see if the infection is recent, using the BED public health surveillance tool, which recently received Food and Drug Administration (FDA) approval, she says.
This information particularly is useful to physicians and public health officials because it provides a snapshot of the prevalence of drug resistance among recently infected people at any given time, Bennett notes.
Another study presented at CROI found that resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) may persist for years after NNRTI medication has been discontinued.3
"I think HIV is going to be similar to a lot of other infectious diseases where drug resistance will become more prevalent in the community and that transmission of drug resistance is a concern," says Michael Newstein, MD, an assistant professor of medicine at the Brown University School of Medicine in Providence, RI.
Questions about drug resistance sometimes were heated at a special symposium on resistance presented at CROI in response to the case of the middle-aged New York City man who had been infected recently with HIV that was resistant to 19 of 20 drugs in the three main classes and who also had a dual-tropic HIV-1 that progressed rapidly to AIDS.
The man reported high-risk sexual behaviors while under the influence of crystal methamphetamine a couple of months before his diagnosis.
David Ho, MD, executive director of the Aaron Diamond AIDS Research Center in New York City, presented the latest findings about the NYC case to symposium attendees, and other researchers put the findings in the context of additional research about multidrug resistant virus and rapid progression to AIDS.
Diagnostic evidence suggested the man’s HIV-1 infection was of five to 20 months’ duration, past the acute phase, but recent. A combination of severe fatigue, weight loss, and CD4 T-cell counts consistently below 80 cells were what prompted the diagnosis that he had AIDS.4
Ho’s investigation, thus far, suggests that the man’s CXCR4-tropic or dual-tropic variant of HIV-1 could have contributed to the more rapid disease progression, but genetic studies still are under way.4
The patient’s virus was susceptible to only two antiretrovirals on the market, including the NNRTI efavirenz (Sustiva) and the fusion inhibitor efurvitide (T-20), and a drug regimen that includes those drugs is being used to treat him.4
Investigators continue to trace the patient’s sexual contacts and have not yet determined whether the case is isolated or whether other people have been infected with a similarly resistant and fast-progressing strain.4
The New York City Department of Health issued a health alert that was widely reported in the mainstream media.
"Some people rightly or wrongly question whether it was right to go with a full court press deployment to national media [about the NYC case]," says Jack DeHovitz, MD, MPH, a professor in the department of medicine, division of infectious diseases at State University of New York — Downstate Medical Center in Brooklyn. DeHovitz also is a member of the faculty in the department of community health.
"Resistant organisms are not unique to HIV," he says. "Those of us in infectious disease have been dealing with emerging bacterial resistance for many decades now."
The fundamental challenge with HIV resistance, as with bacterial resistance, is keeping ahead of the disease with new medications, DeHovitz notes.
The CROI symposium tried to put the alarming single case in perspective, focusing on how multidrug resistant virus transmission is not unusual and that fast progression to AIDS also typically occurs in a small proportion of patients, he says.
"Transmission of one-, two-, three-class drug resistant HIV has been detected for many years," according to Andrew Leigh Brown, PHD, a professor at the University of Edinburgh and a convenor of the University of Edinburgh Centre for HIV Research in Scotland.
Brown spoke about HIV drug resistance at the CROI symposium, which was called Transmitted HIV-1 Drug Resistance and Rapid Disease Progression and was held Feb. 24.
"The frequency of transmission has increased, but not continuously," he says.
"There are studies, which are in the literature, and have been for some time that drug resistant virus is frequently less fit than drug-susceptible virus," Brown notes. "And these studies show that some mutations, which are associated with loss of susceptibility, particularly protease inhibitors [PIs], can confer very substantial reductions in compatibility of a virus."
Studies appear to show that the transmission fitness of drug resistant virus with one class resistance is about 20% of the drug-susceptible virus, Brown explains.
Transmission fitness of virus resistant to two or three classes is further reduced, he says.
Fast progression to AIDS also is rare, particularly in the days of HAART, but a small percentage of patients continue to become sick more quickly, Hicks says.
"It’s not at all unique that someone might acquire HIV and get very sick in a year or less; we know that happens," he adds. "The difference here is none of the things that were reported in New York are in and of themselves unique, but the fact that certain things occurred in the same patient has not really been described before."
Speakers at the CROI symposium say the New York City case probably involved unique factors within the patient that accounted for his rapid progression to AIDS, rather than it being a case of transmission of a new and more deadly strain.
The take-home message
What HIV clinicians need to take home from the recent news about multidrug resistance in newly infected patients is the importance of screening all newly diagnosed patients for drug resistance, Hicks notes.
"I’d work really hard to find resources to do resistance testing on every patient you see in your clinic," Hicks says. "It’s time to incorporate that into the standard of care."
At Callen-Lorde Community Health Center in New York City, routine resistance screening already is the standard of care, and the state of New York assists in this effort by covering resistance testing under its AIDS Drug Assistance Program (ADAP) funding, says Dawn Harbatkin, MD, medical director of the health center, which serves HIV patients.
Callen-Lorde also pushes prevention for positives messages routinely and is vigilant in looking for acute HIV infection and seroconversion, both of which are practices Harbatkin would encourage other HIV clinicians to follow, she says.
"I would encourage providers who are not looking for acute HIV infection to start looking for it," Harbatkin notes.
Likewise, providers and public health officials need to improve prevention messages, Harbatkin and Hicks say.
"It’s not good to point fingers and place blame, but the indisputable fact is people are [having intercourse] without using barrier contraception when they have a virus that is transmittable to other people, and that’s wrong. We need to find a better way to diminish the likelihood that that will happen," Hicks adds.
One of the messages that struck home to Harbatkin when she heard about the NYC case of multidrug resistance and fast progression to AIDS was that this patient was a man who had stayed uninfected, despite risk factors, for more than 20 years, and drug addiction played a role in his abrupt behavior change.
"This man had multiple HIV tests that were negative," she adds. "This was someone who clearly was attempting to stay healthy, and yet he became addicted to a drug — crystal methamphetamine. All of those health behaviors and choices he had been making went out the window in the face of his drug addiction."
References
- Hicks C, Eron J, Fiscus S, et al. Transmitted HIV resistance among patients with acute and recent HIV infection in North Carolina: Report of 102 cases. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. Boston; February 2005. Abstract 673.
- Bennett D, McCormick L, Kline R, et al. U.S. surveillance of HIV drug resistance at diagnosis using HIV diagnostic sera. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. Boston; February 2005. Abstract M-120; Poster 674.
- Newstein M, Martin T, Losikoff P, et al. Prevalence and persistence of NNRTI mutations in the female genital tract. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. Boston; February 2005. Abstract 671.
- Markowitz M, Mohri H, Mehandru S, et al. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: A case report. Lancet 2005; 365:1,031-1,038.
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