AIDSWEEKLY Plus; Monday, February 22, 1999
Daniel J. DeNoon, Senior Editor

A daring new treatment strategy hopes that intermittent treatment with highly active antiretroviral therapy (HAART) can lead to permanent immune control of the virus. The strategy comes from several poorly compliant patients whose viral load remained very low after they eventually quit taking the drugs.

Franco Lori, director of Italy's Research Institute for Genetic and Human Therapies, has tested the concept on three human subjects. He reported preliminary findings in a late breaker session at the 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois.

"The implication is that we can generate a new drug - the immune system, maybe the most powerful one," Lori said. "The hope is that people will be able to live with HIV without drugs."

The concept alarms some leading AIDS researchers.

"My concern is that these findings, which are interesting, not be overinterpreted," said Douglas Richman of the University of California, San Diego. "We are not ready to recommend this. I think people who try it are going to be disappointed."

Data are beginning to accumulate that the strategy can work - at least in some people.

The first patient to exhibit the phenomenon, the so-called "Berlin patient," was treated early after infection and before complete seroconversion in an attempt at virus eradication. The patient received hydroxyurea (which Lori thinks may be a vital component), didanosine (ddI), and indinavir. Two baseline viral load tests resulted in measures of 80,041 and 89,390 HIV RNA copies/ml.

The viral load became undetectable, but rebounded during a temporary treatment suspension. After a second temporary treatment suspension, the viral load remained undetectable. On Christmas day, 1996, the patient stopped taking all drugs. His viral load remains undetectable, although continued HIV infection can be confirmed by DNA tests.

Similar findings were reported at the Retrovirus conference by Gabriel Ortiz of the Aaron Diamond AIDS Research Center in New York. Ortiz and colleagues administered a potent HAART regimen (ritonavir + zidovudine [AZT] + lamivudine [3TC]) to 12 patients within 120 days of HIV infection. All were fully compliant for the first month of treatment. Two patients, however, with poor adherence to drug regimens quit therapy. They soon had a rebound in viral load and began taking the drugs again for variable intervals.

When they finally quit taking their medications, their viral load remained undetectable for 21 and 14 months. Analysis of their blood samples showed that both patients had strong cytotoxic lymphocyte (CTL) responses to primary HIV infection that were boosted at the time of first drug interruption. These CTL responses have remained strong.

Two other patients in the study quit taking their HAART regimens more abruptly. One maintained strong CTL responses and low-level viremia for four months, but had viral rebound when the CTL responses faded. The other patient had rapid viral rebound and a weak CTL response.

"It appears that intermittent drug discontinuation can be associated with boosting of HIV-1 specific CTL responses, which may contribute to the prolonged suppression of viral replication when drug therapy is stopped," Ortiz said. "Trials should aim at boosting and maintaining CTL responses during HAART."

In Lori's three-person study, patients with stable HIV viremia received hydroxyurea-containing HAART regimens. They were given three weeks of therapy and one week of treatment interruption followed by two cycles of three months of therapy followed by treatment interruption and initiation as soon as viral load rebounded to 5000 copies/mL.

Each time therapy was re-initiated, viral loads dropped to undetectable levels. The average time without rebound increased during each treatment holiday: seven days for the first, 14 days for the second, and 37 days for the third.

In parallel monkey studies, the animals were allowed to have rebounds in SIV viral load to more than the 5000 copies/mL permitted in the human study.

"Although viral rebound occurred, it was controlled in all three animals and was followed by a reduced steady-state level of virus in the absence of therapy," Lori reported. "This level was less than 5000 copies/mL for six weeks during the first interruption and it decreased to less than 200 copies/mL for at least 10 weeks during the second interruption."

Lori is currently beginning a new primate study with 30 animals and intends soon to recruit 40 to 80 patients for human trials.

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