Immunity study could help stop HIV before it starts
One day, clinicians may be able to help patients prevent HIV disease if they can identify their infection during the first bout of flu-like symptoms, occurring within a few weeks of exposure to the virus.
Researchers at Massachusetts General Hospital in Boston have been studying the use of aggressive antiretroviral therapy to treat patients who have recently been exposed to the virus. Their work shows that early drug treatment triggers an immune system response that could prevent the disease from progressing.
The concept is based on what clinicians already witness with a variety of other viruses, such as herpes viruses like chicken pox, Epstein-Barr, and cytomegalovirus.
"Once we’re infected with chicken pox, our body never clears it; we have it for life, and it’s the same with Epstein-Barr," says Eric S. Rosenberg, MD, instructor of medicine at Massachusetts General Hospital and Harvard Medical School in Boston.
"These cause chronic infection, but our immune system keeps them in check," he adds. "HIV also causes a chronic viral infection, but in most individuals the body cannot effectively contain HIV."
However, some individuals’ immune systems do effectively keep the lid on HIV for years, even for more than a decade. The Boston researchers began by asking why most HIV-positive people’s immune systems do not respond to HIV, while for a few people the immune systems do. They found that everyone’s immune systems develop a response to HIV within weeks after they’re infected. This response coincides with the person becoming sick with acute retroviral syndrome (ARS). However, for most people, the immune system quickly loses its ability to defeat HIV, Rosenberg explains.
"So we started identifying people with ARS, first checking to see if this immune response is present," he says.
Once they found evidence of the immune response, investigators studied the hypothesis that they could generate a longer-lasting immune response by treating these newly infected HIV patients with potent antiretroviral therapy.
"We think what happens is [that] when an HIV-infected person’s CD4 cells are colonially expanding against HIV, they’re also getting infected with HIV because the CD4 cells are the target of the virus," Rosenberg says. "So if someone is just infected with HIV and their CD4 cells are trying to expand, the more they expand, the more they are infected by HIV and [CD4 cells] get knocked out of the immune repertoire before they can generate a response."
Researchers theorized that if they could find newly infected people and treat them with anti retrovirals, then the drugs could shoot down the viral replication before HIV infected all the CD4 cells. This would permit the person’s immune system to expand in response to the virus and perhaps keep HIV in check once the drugs were discontinued.
The theory proved sound. In 25 newly infected individuals, researchers discovered an immune response that was generated after early initiation of highly active antiretroviral therapy (HAART).
Therapy interruption stimulated immune cells
"They were on HAART and generated this immune response which only people who are long-term nonprogressors have," Rosenberg says. "Then we wanted to know what would happen with these people if we took away their HAART, and that’s the basis for the structured treatment interruption."
At the Infectious Diseases Society of America conference held in Philadelphia in November 1999, Rosenberg presented data that showed that the first time patients were taken off therapy, their virus rebounded.
"But what was interesting was when we started therapy back, their immune responses blossomed and got much stronger," Rosenberg explains. "So we think that by showing the immune system a very limited amount of virus by taking them off medicine and then putting them back on, that stimulates the immune system to mature and withstand HIV."
After patients were taken off HAART a second time, their immune systems worked, and for four months their viral loads remained less than 5,000 copies/mL.
The research team identified the study participants based on cases presenting with mononucleosis symptoms, including fever, sore throat, and rash. If the patients had HIV risk factors, they were tested for the virus. If the standard HIV antibody test was negative or weakly positive, they made a diagnosis through a viral load test.
"Viral load in these patients is sky-high early on, with 12.5 million copies/mL," Rosenberg says. "For most people, if they’re not treated, the viral load will go up high and then the immune system kicks in and drives it down to as low as it can, and that low point is different for everybody."
For long-term nonprogressors, the viral load will settle at a very low point. For others, it might stop at a high viral load, and that person would progress to AIDS quickly unless treatment is initiated.
Clinicians could use the Boston research as evidence that they need to make a diagnosis of acute HIV infection with a viral load test whenever HIV infection is probable, and then start early treatment. But until more research results are in, it’s too soon to talk about starting treatment interruption in the clinical setting, Rosenberg advises.
"We clearly show that early treatment is very effective, and individuals develop immune responses they wouldn’t normally develop with HIV," Rosenberg says. "But it’s too soon to make any decisions about structured interruption."
The only drawback is that the clinician would be starting a patient on therapy much earlier than they would otherwise, he adds.
The Boston study will continue as researchers test the concept of structured treatment interruption, and they’ll try to identify which immune responses work and which won’t control HIV.
Using hydroxyurea as booster for HIV drugs
The retroviruses conference also featured data, presented by an Italian researcher, demonstrating the success of an antiretroviral regimen with hydroxyurea serving as a booster to the HIV drugs.
While the hydroxyurea research offers a less clear objective with regard to controlling the virus through improving immune response, there are seven years of studies that show hydroxyurea added to didanosine (ddI) regimens can greatly enhance ddI’s effectiveness in suppressing HIV.
However, there are some major drawbacks. One problem is that hydroxyurea cannot be used with certain antiretroviral drugs, including AZT, because both medications have a bone marrow toxicity profile and they do not have synergy, says Franco Lori, MD, director of the Research Institute for Genetic and Human Therapy (RIGHT) in Pavia, Italy, and Washington, DC.
Lori’s studies have looked mainly at a treatment combination of hydroxyurea and ddI. Researchers monitored three patients who were treated for three weeks and then had their treatment interrupted for one week. Then they were treated again until their viral load was undetectable, and again treatment was stopped. When viral loads rose above 5,000 copies/mL during interruptions, treatment was started again. One of the three patients maintained good control of the virus for six months during the second interruption. A second patient’s virus rebounded quickly during each interruption. The third patient’s virus also rebounded, but more slowly.
Hydroxyurea inhibits HIV replication
Researchers theorize that hydroxyurea works against the virus by decreasing the level of HIV replication. "But the real mechanism of action that we’re exploiting is probably another one, and that has to do with the combination of hydroxyurea and ddI," Lori notes.
"What hydroxyurea does is it inhibits a cellular enzyme called ribonucleotide reductase, and this enzyme is responsible for the synthesis of dioxynucleosides, the building blocks of DNA," he explains. "So if hydroxyurea inhibits it and reduces the level of dioxynucleosides and those dioxynucleosides are needed for cell synthesis, then the cell can’t be divided."
The antiretroviral ddI then is incorporated, ultimately stopping HIV from completing its synthesis. Lori says when hydroxyurea is added to the ddI treatment, it gives ddI a boost because hydroxyurea reduces the number of ddI’s competitors being incorporated into the cell.
Another drawback to hydroxyurea is its poten tial for bone marrow toxicity. But when it’s combined with ddI, there is a small potential for a higher frequency of peripheral neuropathy, hair loss, fatigue, and hyperpigmentation among black patients.