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Susman, Ed

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Notes from the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 2002

Once daily HAART treatment for viral control

A low pill burden and convenient once-daily HAART dosing can be used to achieve viral control similar to that of gold-standard treatments, researchers in Italy reported. The once-a-day therapy that includes lamivudine, didanosine and efavirenz, was described by Dr. Franco Maggiolo, MD, of the division of infectious diseases at Ospedale Rinuniti, Bergamo, as the first thymidine analogue-sparing regimen tested in a controlled trial. In the prospective study, the efavirenz-based therapy was compared with one using nelfinavir, zidovudine and lamivudine and another that included zidovudine, lamivudine and efavirenz. The latter two trials required twice-a-day dosing.

`‘A simple, effective, user-friendly, once-a-day regimen, allowing pill intake just at bedtime, may limit interference with a person's lifestyle, with his need to privacy, with his personal everyday schedule and this may positively influence adherence and therefore improve treatment outcome’’ Dr. Maggiolo said.

He and his colleagues enrolled 102 patients previously naive to antiretroviral therapy and assigned them to one of the three HAART regimens. After 1 year of treatment, the proportion of patients whose HIV RNA was below level of detection was 76% in the once-a-day cohort; 77% in the efavirenz twice-a-day cohort, and 50% in the patients on the nelfinavir twice-a-day regimen.

HAART and protease inhibitor GW433908

Almost three-quarters of HIV-infected patients were able to achieve an undetectable viral load when treated with HAART based on the investigational protease inhibitor GW433908 compared with just over half the patients on a nelfinavir-based therapy.

Dr. Jeffrey Nadler, MD, professor of medicine at the University of South Florida College of Medicine, Tampa, said the study, which enrolled 249 patients, ‘‘was generally reflective of the changing demographics of the HIV epidemic and is representative of patients with relatively advanced immune deficiency.’’ About 31% of the patients were women; 44% were Hispanic; 31% were black; and more than 50% were heterosexual.

In the study, 166 patients were assigned to a HAART regimen of GW433908 – a pro-drug of the protease inhibitor amprenavir – and 83 patients were assigned a protease regimen with nelfinavir. The patients were given 1400 mg of GW433908 twice a day as well as 300 mg of abacavir and 150 mg of lamivudine twice a day. The same dosages of abacavir and lamivudine plus 1250 mg of nelfinavir twice a day were given to patients on the comparative regimen.

Dr. Nadler said that when the 24-week results were analyzed it was found that 73% of the patients on the investigative compound had achieved undetectable viral loads when measured with the 400-copy assay as compared with 54% of patients on the nelfinavir-based regimen.

Emtricitabine (FTC) treatment option

Doctors said that replacing stavudine with the investigational nucleoside analogue emtricitabine – formerly known as FTC – resulted in superior safety, efficacy and tolerability.

`‘FTC represents an attractive new treatment option for patients with HIV infection,’’ said Dr. Michael Saag, MD, associate professor of infectious diseases at the University of Alabama at Birmingham.

In addition to performing better, the emtricitabine regimen allows for once-daily dosing, while the stavudine therapy requires twice-a-day dosing. Among the key findings of the study in which 286 patients were randomized to receive emtricitabine and 285 received stavudine was that more patients on the investigational drug achieved an undetectable viral load using both the 400- and the 50-copy assays. In addition to either emtricitabine or stavudine, all the patients were also treated with didanosine and efavirenz.

Dr. Saag said that 87% of the patients on emtricitabine achieved an undetectable viral load using the 400-copy assay compared with 79% of the patients on the other HAART in which stavudine was the second nucleoside analogue. He said that 81% of the emtricitabine patients compared to 70% of the stavudine patients achieved undetectable HIV levels when the 50-copy assay was used.

Enfuvirtide (T-20) treatment benefit

Patients across a wide variety of treatment groups appear to benefit from adding the investigational fusion inhibitor enfuvirtide to a therapy that already includes an optimized background regimen. ‘‘Enfuvirtide added to an optimized background regimen provided additional viral suppression compared to those patients on an optimized background regimen alone in highly antiretroviral experienced patients as well as among a variety of subgroups based on baseline characteristics,’’ said Dr. Julio Montaner, MD, professor of infectious diseases at the University of British Columbia, Vancouver, Canada.

Dr. Montaner said patients treated with the injectable enfuvirtide, more commonly know as T-20, did better with the fusion inhibitor regardless of whether they were male or female, white or non-white, had high CD4 cell counts at baseline or had lower baseline figures.

Nelfinavir safety

Doctors looking at treatment of patients co-infected with hepatitis C and HIV reported that the protease inhibitor nelfinavir appears safest as far as increases in liver function tests are concerned. Overall, Grade 3 or Grade 4 increases in the liver tests occurred in about 4% of patients on highly active antiretroviral therapy with nelfinavir compared to 8% of patients who were taking other protease inhibitors.

`‘I think a fivefold increase – Grade 3 – in these liver tests is alarming,’’ said Dr. Douglas Dieterich, MD, vice chairman and chief medical officer at Mt. Sinai Medical Center, New York. ‘‘And a Grade 4 increase, I believe, many people would think is a time to panic.’’ Dr. Dieterich and colleagues reviewed treatment history of 1052 patients co-infected with HIV and hepatitis C who had received protease inhibitor-based HAART therapy for at least 3 months.

Using HIV research to fight cancer

The knowledge gained through intensive research into the genetic and molecular makeup of HIV may help doctors defeat cancers that occur in the eyes and elsewhere in the body.

Dr. J. William Harbour, associate professor of ophthalmology at the Washington University School of Medicine, St. Louis, Mo., said that the use of the HIV Tat protein helps slide a key receptor blocker into cancerous cells.

`‘We have identified a key molecular feature of eye cancers that prevents the cancer cells from dying,’’ said Dr. Harbour said in Washington, DC, at a symposium sponsored by New York-based Research to Prevent Blindness.

That molecule, HDM2 turns off the tumor suppressor, p53. The cancer cell overproduces HDM2 and blocks the ability of p53 to initiate the apoptosis cascade. Dr. Harbour and colleagues developed a small fragment of p53 that attaches to HMD2, preventing the inhibitor from turning off the normal p53 gene. By flooding the cell with the therapeutic molecule, doctors believed that p53 would be available to attack the cancer, but they were stymied as to how to get the tiny p53 fragment into the cell. So the research team attached the p53 fragment to Tat. Then the Tat protein enters the cell, taking the hitchhiking p53 fragment with it.

In experiments in the laboratory, Dr. Harbour said that once the Tat–anti-HMD2 fusion molecule enters the cancer cell, it binds the HMD2, freeing p53 molecules to turn on the apoptosis cycle. Cancer cells begin dying within hours. In other laboratory tests in animals, Tat–anti-HMD2-treated tumors were 95% destroyed within 3 days, while tumors in rabbits treated with a Tat sham molecule were unaffected.

Ed Susman, Florida

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© 2003 Lippincott Williams & Wilkins, Inc.