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Johns Hopkins Medicine
Office of Corporate Communications
Media contact: David March
February 15, 2005
SMALL INCREASES OR “BLIPS” IN HIV LEVELS DO NOT SIGNAL MUTATIONS LEADING TO DRUG-RESISTANT HIV
Researchers at Johns Hopkins have concluded that sudden, temporary spikes in the amount of HIV in the body, commonly called “blips,” generally do not mean the virus is developing resistance to AIDS drugs and gaining strength in numbers.
“These results should provide relief to hundreds of thousands of HIV-positive patients in the United States currently taking drug therapy, called highly active anti-retroviral therapy, or HAART, and reassure them that their medications have not failed,” says senior study author and infectious disease specialist Robert Siliciano, M.D., Ph.D., a professor at The Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator. “Physicians and patients now have a much better idea of when to worry about these blips and when not to worry.”
Because HIV mutates very rapidly, physicians and patients have worried that even small, temporary increases in the amount of virus could indicate the virus had mutated to evade anti-viral drugs being taken.
Instead, the Hopkins team has shown that these so-called blips are mathematical artifacts, or variations, that stem from the test used to gauge the amount of virus in the body, a measurement known as viral load.
According to the Hopkins findings, to be published in the Journal of the American Medical Association online Feb. 16, unless the blip is higher than 200 copies per milliliter of blood, or persists upon repeated testing, it does not signal that the virus has mutated, or changed form.
True drug resistance requires changes in therapy which can be very difficult for the patient, says Siliciano. Different combinations of medications can have toxic side effects, such as lipid abnormalities and diabetes, and can be considerably harder to tolerate than the originally prescribed drug cocktail. Today’s anti-HIV drug treatments quickly suppress the virus to nearly undetectable levels, but blips are a frequent problem. Earlier studies suggested that blips occur in 11 percent to 46 percent of patients, while the Hopkins study, which used intensive sampling, found blips in nine-tenths of patients.
To see whether or when blips mean possible mutation, the Hopkins team conducted a detailed genetic analysis of multiple blood samples from 10 HIV-positive patients, taking samples every two to three days for a period of three months between June 2003 and February 2004. All patients had their infection under long-term control, on HAART, and with viral loads of less than 50 copies per milliliter for at least six months. In total, 36 blood samples were taken from each patient.
Statistical analysis of the results showed that blips occurred in nine of the 10 patients with a median viral load of 79 copies per milliliter. The duration of the blips was typically less than three days, and blips were not related to any demographic factors, such as gender or age, nor to any clinical factors, such as illness, vaccination, or differences in antiretroviral drug regimens.
For every blip, the researchers conducted genetic tests on the samples before, during and shortly after the blip, to uncover any mutations in the virus. Measures of viral load were confirmed by using two independent laboratories to test each sample.
No new mutations were found in an analysis of nearly 1,000 viral clones for mutations in HIV’s two key enzymes which are blocked by drug therapy, protease and reverse transcriptase. The authors also found that blips were not, again, detected when blood samples were assayed twice in independent laboratories.
“The lack of any consistency among the tests performed on blood samples confirms that there is no danger from these blips in viral load,” says study lead author and infectious disease specialist Richard Nettles, M.D., an assistant professor at Hopkins. “These blips can be attributed to random statistical artifact inherent in measurements of very low amounts of virus.”
Siliciano warns that drug resistance is a growing problem in AIDS therapy, as the virus can mutate faster than medical research can develop new drugs. When HIV becomes resistant to one drug, it may also become resistant to other drugs in the same class. With only four classes of HAART drugs - for a total of 20 drugs - the number of available combinations is limited for people who have developed drug resistance.
Funding for this study, conducted solely at Johns Hopkins, was provided by the National Institutes of Health, the Doris Duke Charitable Foundation and the Howard Hughes Medical Institute. Other researchers who took part in this study were Tara Kieffer, Ph.D.; Patty Kwon, B.A.; Daphne Monie, Ph.D.; Yefei Han, B.S.; Teresa Parsons, Ph.D.; Joseph Cofrancesco Jr., M.D.; Joel Gallant, M.D., Ph.D.; Thomas Quinn, M.D.; Brooks Jackson, M.D.; Charles Flexner, M.D.; Kathryn Carson, Sc.M.; Stuart Ray, M.D.; and Deborah Persaud, M.D.
Currently, there are more than 40 million people in the world living with HIV, including an estimated 950,000 in the United States and 23,000 in the state of Maryland. Nearly half of all HIV-infected patients in the United States develop resistance to one or more classes of treatment medications.
- JHMI -