As effective vaccines against HIV remain elusive, Johns Hopkins researchers have completed the first tests to see if a drug already used to treat HIV infection might one day be used to prevent sexual and blood-borne transmission of the virus that causes AIDS.
Reported in the March 7 issue of the journal AIDS (available online now), the 12-week study of nevirapine in Baltimore is believed to be the first in the United States to evaluate a pre-exposure, drug-based prevention strategy for adults at high risk, say the researchers. Previous strategies have focused on behavioral changes such as condom use and clean needles.
"This is a new concept for prevention of HIV infection," says J. Brooks Jackson, M.D., M.B.A., director of pathology and leader of the study. "A combination of drugs is used to treat HIV infection, but we want to see if long-term, low doses of one of these drugs can prevent new HIV infections in people at high risk. HIV infection rates are fairly steady in the United States, but skyrocketing elsewhere. We can't afford to wait for a vaccine."
When taken twice a day, nevirapine is one part of routine anti-retroviral therapy to keep HIV infection from resulting in AIDS. In small, one-time-only doses, the Johns Hopkins researchers already have proven -- overseas -- that nevirapine cuts in half the risk an HIV-infected mother will pass the virus to her baby during childbirth.
The new study tested the safety of three different doses of nevirapine -- all just a fraction of the treatment dose -- in 33 people at high risk of contracting HIV because of sexual practices or injection drug use. No serious adverse side effects related to nevirapine were seen in any participants, and none contracted HIV during the study period, the scientists report.
"This study wasn't designed to test whether nevirapine could in fact prevent HIV transmission, but it would have been bad for the future of this effort if we'd detected significant side effects or new infection," notes Jackson. "The important thing is that the treatment doses were well tolerated, and now we feel comfortable moving forward."
While it can take as long as six months after exposure for HIV to appear, today's HIV tests (which detect antibodies created to battle the virus) can reliably catch a new infection within four to six weeks of exposure, notes Jackson.
At treatment-level doses of 200 milligrams twice a day, the risk of liver damage is serious enough when used with other anti-retroviral drugs that nevirapine is not used to prevent HIV infection after suspected exposure (such as in health care workers or rape victims). The three much-lower doses tested were chosen to spare the liver, yet keep blood levels of the drug high enough to potentially provide a benefit.
Participants were divided into three groups: the first 12 received one tablet (200 milligrams) of nevirapine once a week for 12 weeks, the second group of 12 received one tablet twice a week, and the third group of nine took one tablet every other day. The scientists tested for HIV and hepatitis B and C infection and measured participants' liver function throughout the study period.
No clinically severe or life-threatening side effects were seen at any dose, says Jackson. However, participants susceptible to liver damage for reasons other than nevirapine (hepatitis C infection, excessive alcohol consumption, or exposure to toxic chemicals) were more likely to have slightly elevated liver enzymes (a measure of liver function) while taking the drug, regardless of dose.
Importantly, the researchers discovered that at all doses, blood levels of the drug seemed high enough to potentially prevent HIV infection. While the necessary blood level of nevirapine to prevent HIV infection in people is unknown, in the lab 10 nanograms of the drug per milliliter is enough to inhibit the virus.
"We decided on a blood level of drug 10 times that as the lowest desirable level in our study, but we don't know yet whether that will prevent infection," notes Jackson. That determination will begin with a large clinical trial, currently in the planning stages.
Tested just before getting their next dose of nevirapine, almost all participants had at least the desired level of nevirapine in their blood. While no new infections were noted, one participant with longstanding hepatitis B infection no longer tested positive after two weekly doses of nevirapine, a finding worth pursuing, says Jackson.
A few participants had blood levels of nevirapine as high as those typically seen with treatment-size doses, which could possibly contribute to liver damage over time. Another concern is that chronic use of nevirapine or another medicine might make the drug less useful if HIV infection does occur, notes Jackson. However, if the drug is well tolerated and prevents infection, that may be a risk worth taking, he adds.
The study was funded by the Johns Hopkins School of Medicine Department of Pathology. Authors on the report are Jackson, Scott Barnett, Estelle Piwowar-Manning, Linda Apuzzo, Charles Raines, Craig Hendrix, Fayez Hamzeh and Joel Gallant, all of Johns Hopkins.
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