The New York Times - July 15, 2004
Lawrence K. Altman

The combinations consist of three antiretroviral drugs formulated into one pill that is taken twice a day. The aim is to simplify therapy because experience has shown that the fewer the pills a patient needs to take, the better the compliance.

Doctors Without Borders, the group that carried out the study in 21 countries, bought the pills from two manufacturers in India, Cipla and Ranbaxy Laboratories Ltd.

Fixed-dose generic drug combinations have been controversial. Critics contend that they may be less effective than patented versions and not as safe.

This study expands on a much smaller study with similar results published in the Lancet early this month.

The findings from Doctors Without Borders should assure patients, donors, health workers, governments and others, said Dr. Alexandra Calmy, an AIDS adviser to Doctors Without Borders in Geneva.

When Doctors Without Borders began prescribing the fixed-dose combinations in 2002, "we were convinced they would work or we would not have done it," said Dr. Calmy, who specializes in infectious diseases. "It was common sense."

But to make certain, her group undertook the study reported Wednesday.

"We found a very robust outcome, and the findings are important for the Global Fund and other groups that are recommending" use of generic fixed dose combinations of antiretroviral drugs, Dr. Calmy said in an interview.

The combination that Doctors Without Borders uses for first-line therapy is the same one recommended by the World Health Organization, drugs known as stavudine, lamivudine, 3TC and nevirapine.

Of the 12,058 adults that Doctors Without Borders has treated with antiretroviral drugs in 21 countries in Africa, Central America and Asia since 2002, 6,861 received fixed-dose combinations. Since March, 80 percent of the group's new AIDS patients have received fixed-dose combinations.

Among the fixed-dose combination recipients, the probability of survival after one year was calculated as 82.4 percent, Dr. Calmy reported. About 60 percent of the deaths occurred in the first three months of therapy. The deaths occurred largely among patients who were so ill that they began the antiretroviral therapy too late to protect them from the infections that often kill patients as a complication of AIDS.

Among the 6,861 fixed-dose combination recipients, there was a significant increase in the number of immune cells, known as CD-4 cells, that are destroyed by H.I.V., the virus that causes AIDS. The CD-4 count rose by an average of 137 cells in a year, in about half the patients.

Because of logistical difficulties in treating patients in slums and rural areas in countries like Malawi with poor roads and transportation, Doctors Without Borders does not routinely monitor each patient with the tests that measure the amount of virus in the blood. Doctors in developed countries routinely use such tests, known as viral loads, to determine the effectiveness of therapy.

However, a viral load test in a subset of patients showed that fixed-dose combinations failed in 12 percent of the 477 tested, which is comparable to findings in developed countries, Dr. Calmy said.

Among the 6,861 patients who had been on treatment for one year or longer, 51 had to switch to other drugs because they had suffered side effects to one or more of the drugs in the fixed-dose combination. For those who had to take a new regimen, the number of pills was 13 or more a day.

Nevirapine was the most common cause of the unwanted effects. Of the 51 who suffered reactions such as rashes and liver damage, 23 changed to other regimens. An additional nine patients switched to other drugs because they suffered nerve damage and disfiguring accumulations of fat on the neck, back and abdomen.

The frequency of adverse reactions was comparable to that observed among recipients of patented drugs in developed countries, Dr. Calmy said.

In a separate part of the study conducted in Malawi, Dr. Arno Jeannin's Doctors Without Borders team randomly tested the amount of H.I.V. in the blood of 477 patients who had received fixed-dose combinations there for six months or longer. Of these, H.I.V. could not be detected in 85 percent, showing the overall effectiveness of the fixed-dose combinations.

The annual cost of the fixed-dose combinations was $389 or less.
040715
NYT040715