STUDIES SUGGEST EASIER DOSING SCHEDULES POSSIBLE FOR SOME PROTEASE INHIBITORS

A number of studies released over the past few months have suggested that easier dosing schedules for protease inhibitors may be on the way.

At the Fourth International Congress on Drug Therapy in HIV Infection, Agouron Pharmaceuticals presented forty-eight week data from their ongoing study comparing twice-daily dosing of the company's protease inhibitor Viracept brand nelfinavir to the standard dosing schedule of three times daily. Two hundred and eighty-three patients were randomly assigned to receive either 750mg of Viracept TID in combination with AZT/3TC or 1250mg Viracept BID in combination with AZT and 3TC. After forty-eight weeks of treatment, 66% of patients in both groups had plasma HIV RNA levels of <400 copies/mL.

Hoffmann-La Roche also presented data recently comparing twice-daily administration of its protease inhibitor Fortovase brand saquinavir. Two hundred and forty-two patients were randomly assigned to receive 1600mg of Fortovase BID or the standard dose of 1200mg of Fortovase TID in combination with nucleoside analogs. After twenty-four weeks of treatment, 69% of patients in the BID group had plasma HIV RNA levels that were below the assay limit, as compared to 74% of patients in the standard-dose group.

Merck, however, has had greater difficulty converting their protease inhibitor, Crixivan brand indinavir sulfate, to a twice-daily drug. The company suspended two ongoing studies of Crixivan administered twice-daily when preliminary results suggested a significant advantage to thrice-daily dosing.

One of the ongoing studies compared the combination AZT, 3TC, and twice-daily Crixivan to AZT, 3TC, and Crixivan three times daily in antiretroviral naive patients. Following an interim analysis of 87 patients who had reached 24 weeks Merck decided to discontinue the Crixivan twice-daily arm based on a finding that a significantly smaller number of patients in the twice-daily arm sustained reductions of viral load to <400 copies as compared to the regimen using Crixivan three times daily. At week 24, 91% of patients treated with the thrice-daily regimen had undetectable viral load as compared to 64% of patients treated with the twice-daily regimen.

The other study randomly assigned patients with stable, undetectable plasma HIV RNA levels during treatment with AZT, 3TC and Crixivan to continue Crixivan three times-daily or to switch to Crixivan twice daily.

The company is continuing to evaluate twice-daily regimens of Crixivan in combination with other protease inhibitors.

GOOD NEWS IN THE FIGHT AGAINST HEPATITIS C

(sidebar) about forty percent of HIV-infected patients are also infected with hepatitis C.

People who suffer from chronic hepatitis C got some good news as the US Food and Drug Administration granted approval to pharmaceutical giant Schering-Plough to market a combination of interferon alpha and ribavirin for the treatment of the life-threatening liver disease. The combination was approved for use in patients who have already failed to effectively suppress or clear the virus using monotherapy with interferon alpha.

Hepatitis C is a major world-wide concern for both HIV-positive and HIV-negative people. The Centers for Disease Control and Prevention estimates that 4 million to 4.5 million Americans suffer from chronic hepatitis C. The infection contributes to the deaths of more than 12,000 Americans every year and is a principal cause of chronic liver disease, cirrhosis and liver cancer. American Liver Foundation researchers say that liver failure due to hepatitis C infection is the leading cause of liver transplants in the U.S.

Studies suggest that about forty percent of HIV-infected patients are also infected with hepatitis C. "In general, we know that people with HIV progress [with hepatitis C] more rapidly than people without HIV," said Dr. Douglas Dieterich, a New York AIDS specialist who is currently studying the combination in patients who are co-infected with HIV and hepatitis C.

In a study recently published in the New England Journal of Medicine, 345 patients who had relapsed during treatment with interferon were given either interferon or the combination of interferon and ribavirin. After twenty-four weeks of treatment, eighty-two percent of patients on the combination treatment had undetectable plasma hepatitis C viral load counts (<100 copies/mL), as compared to forty-seven percent of patients treated with interferon alone. Patients were then followed for twenty-four weeks after treatment, at which point forty-eight percent of patients on combination therapy had undetectable plasma viral load counts, as compared to five percent of patients treated with monotherapy.

Another clinical trial was recently reported in the The Lancet, using the interferon/ ribavirin combination in 832 patients with previously untreated chronic hepatitis C. In these treatment-naive patients, results were also positive: forty-one percent of patients treated with the combination therapy for forty-eight weeks showed sustained virologic response to undetectable levels, while only nineteen percent of patients treated with interferon alone had undetectable virus levels.

Side effects of the combination can include fatigue, fever, and flu-like symptoms. According to Dr. Dieterich, "With the doses used, people are likely to feel something. Generally it is not terrible; patients can usually control most of the symptoms with over-the-counter medicines."

LEADERS IN GLOBAL AIDS FIGHT WARN OF RISK TO WOMEN, YOUNG PEOPLE

On World Aids Day, the United Nations AIDS Program (UNAIDS) released new statistics on the global AIDS epidemic. According to Dr. Peter Piot, President of UNAIDS, "There is continuing spread of HIV nearly everywhere at the same rate as last year: 16,000 new infections per day, and 5.8 million total infections last year. The estimated number of people infected by HIV world-wide has now risen to 33.4 million, with all but five percent of the infections occurring in Asia, Africa and Eastern Europe. The death toll from AIDS is increasing. Two and a half million people died this year from HIV/AIDS, putting it second only to tuberculosis in terms of infectious causes of death in the world. The epidemic has not been overcome anywhere." According to Dr. Piot, the disease is increasingly focused in young people. According to UNAIDS numbers, "Persons aged 15-24 years old are experiencing 50 percent of all new infections." He explained that these are the years when most young people become sexually active, and are also peak productive and reproductive years.

High rates of HIV infection in young women also mean high risks of vertical transmission. In the capital of Botswana, HIV infection rates in pregnant women twenty-four years of age or younger rose from 17 percent in 1992 to 37 percent in 1997.

However, Dr. Piot noted, "HIV prevention programs have a much bigger impact on young people than adults we know that now from studies in Thailand, Uganda, Senegal, Chile, and Switzerland." When asked if explicit sex education and condom promotion efforts targeted to young people would be as controversial world-wide as they have been in the United States, Dr. Piot responded: "It's probably controversial in all countries, but not necessarily a problem. We're pushing that very hard. We also know that early sex education is beneficial, but doesn't lead to increased sexual promiscuity. We hear the same argument for needle exchange programs; everyone will start using drugs. There is scientific proof that that's not the case."

In addition to behavioral prevention efforts, UNAIDS is also directly funding and coordinating a multi-national study of the effectiveness of nonoxynol- 9, a topical microbicide. However, Dr. Piot warned, "We don't have enough funding to support these kinds of trials extensively."

However, Piot summed up, "convincing the people working on global development that AIDS should be a central concern is probably the most important priority: "Poverty and AIDS are very intrinsically linked. It's not by chance that Africa is so very much affected by this epidemic. Poverty drives men into immigration for economic reasons. In addition to poverty, Africa has conflicts from Rwanda to West Africa to the Congo. Third, because of poverty there is illiteracy, and prevention campaigns are much more difficult. Fourth, the resources needed for education campaigns are much fewer. On the other hand, what we're seeing is that AIDS is making this situation that much worse. So all of this is a vicious circle they are mutually reinforcing phenomenons. One of our goals is to put HIV on the development agenda. Today, when we are dealing with development assistance in these countries, we have to include HIV as a part of what we are doing."

NEW DDI FORMULA TWO YEARS AWAY

Bristol-Myers Squibb is developing a new enteric-coated version of Videx brand didanosine, the company's nucleoside analog, that should reduce gastronintestinal toxicity. However, representatives of the company say that the new version will not be marketed for another eighteen to twenty-four months.

The new ddI formula will come in a capsule "about the size of a Contac," according to BMS spokesperson Angela Saffo-Daniel, and will be manufactured in both 200 and 400mg capsules.

Videx has performed well in a number of large-scale studies, but the current formulation of the drug must be taken on an empty stomach and includes a phosphate buffer, which can cause diarrhea and flatulence. The enteric coating will eliminate the need for administration of a buffer with ddI, which should improve the drug's overall tolerability.

Although Videx is currently labeled for twice-daily administration, several studies have indicated that once-daily administration is probably equivalent. The new formulation will be administered once-daily. In February, the company plans to start a multi-national study comparing the old and new formulations of Videx. Depending on FDA requirements, the company expects to obtain approval in approximately two years.

ZIAGEN APPROVED DESPITE CONCERNS

Despite some concerns over the safety and efficacy of Ziagen brand abacavir, a new nucleoside analog manufactured by Glaxo-Welcome, the US Food and Drug Administration recently approved the drug for the treatment of HIV when antiretroviral therapy is warranted.

In a blinded phase III study comparing the combination of AZT, 3TC and Ziagen to the standard regimen of AZT, 3TC and Crixivan, the treatment arms were equivalent at weeks sixteen and twenty-four, with approximately sixty percent of patients in both arms having achieved undetectable plasma HIV RNA levels (<400 copies/mL).

In the recently-completed ACTG 359 study of 94 patients who had experienced virologic rebound while being treated with AZT, 3TC and indinavir, abacavir was as effective as approved nucleosides in salvage therapy regimens also containing various combinations of efavirenz, adefovir and nelfinavir. This finding suggests that the drug may have some activity in AZT/3TC pre-treated patients; although because the number of patients in the comparison is small, the relative benefit of using abacavir as opposed to other approved nucleosides is difficult to assess.

Abacavir has demonstrated activity in combination with all marketed protease inhibitors and amprenavir, reducing viral load to undetectable after sixteen weeks using both the standard assay and the ultrasensitive assay respectively in 54-85% of patients and 40-60% of patients depending on the protease inhibitor used. It should be noted that this study included very small numbers of patients, averaging 12 patients per arm. An open-label study of abacavir in combination with amprenavir in 40 antiretroviral-naive patients suggests that the combination is active for as long as twenty-four weeks.

The FDA warned that these were, in general, small studies, and that definitive proof that the drug contributed to significant and durable suppression of HIV was still being developed.

In addition, a small percentage of patients treated with Ziagen have experienced a severe hypersensitivity response. In studies of the drug, hypersensitivity resulted in therapeutic discontinuation in about three percent of patients. Symptoms may involve a low-grade fever, nausea (with or without vomiting), malaise and rash. Intensity tends to increase with duration of therapy, and resolves upon therapeutic discontinuation. When patients have been rechallenged with abacavir following a hypersensitivity response, potentially fatal hypersensitivity has developed. Glaxo-Welcome warns that patients who develop a hypersensitivity response during Ziagen therapy should discontinue treatment and not re-challenge.

REPORTS OF CARDIOVASCULAR DISEASE DURING HIV TREATMENT

Researchers at the 4th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland, presented additional data adding to concerns that the metabolic changes that have been reported in patients taking anti-HIV therapy may increase risk of cardiovascular disease.

A variety of metabolic changes have been noted in patients treated with HIV protease inhibitors, including redistribution of fatty tissues, high blood sugars, and elevated lipid levels. The long-term consequences of these changes are not known, but could include serious cardiovascular disease. In June of 1998, The Lancet published several letters on these complications, including reports on three patients who developed coronary artery disease after initiating protease inhibitor treatments. Two additional cases were reported in Glasgow.

However, Jeffrey Lawrence of Cornell University warns that premature cardiac disease can be caused by both HIV infection and by opportunistic diseases. During the course of the AIDS epidemic, cardiac disease as a cause of mortality in HIV-positive patients has risen from 1.1 percent of deaths to 9.1 percent. Lawrence asserts "there is no direct evidence that any anti-HIV drug, including protease inhibitors, augments an already substantial frequency of HIV-1 linked cardiac disease."

UNRESOLVED ANEMIA MAY INCREASE RISK OF DEATH IN PEOPLE WITH HIV

In addition to the immediately obvious clinical complications of HIV disease, anemia can substantially reduce quality of life for HIV-infected people. Now a new study has suggested that anemia alone, if not corrected, can significantly increase the risk of death in people with HIV/AIDS.

Anemia is a deficiency in the number of red blood cells, which transport oxygen to the body's tissues. The condition may be caused by a number of factors, ranging from improper diet, to certain drugs, to autoimmune diseases, to infections including HIV. Symptoms can include fatigue, paleness, unusual bleeding, and increased susceptibility to bacterial infections. According to experts, the condition affects up to 95% of people living with HIV at some point during their illness.

Richard Moore, M.D., Associate Professor of Medicine and Director of the Program in Pharmacoepidemiology and Pharmacoeconomics at the Johns Hopkins University School of Medicine, said, "The symptoms of anemia can be so severe that individuals can become bedridden and unable to perform even basic daily activities." In the Sept. 1 issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, a group of researchers from Johns Hopkins reported that they observed 2,343 patients between 1989 and 1996 and found that 498 (21 percent) had some degree of anemia. Patients treated with erythropoietin had longer survival time, while treatment of anemia using blood transfusions was found to diminish survival time.

"Although anemia frequently is viewed as affecting the patient's quality of life," Dr. Moore added, "Our research found it also can be linked to early death." Dr. Moore recommends that patients and physicians educate themselves about the symptoms of early anemia, and seek medical attention when appropriate.

RESISTANCE TESTING: UP AND COMING

The development of several commercial assays for HIV drug resistance is one of the most exciting and promising new areas of HIV treatment.

Although the clinical utility of these assays has not yet been proven, recent preliminary studies have produced encouraging news about the relationship between genotype, phenotype and clinical outcome. Several recent retrospective studies have suggested that baseline viral genotype and phenotype can predict response to reverse transcriptase inhibitors, protease inhibitors, and combination therapies.

In general, experts say baseline resistance is more predictive of virologic failure than is baseline sensitivity at predicting success.

In one recent study, baseline phenotypic and genotypic resistance profiles were generated in eighty-four nucleoside analog-experienced patients, who were then treated with the combination of ritonavir and saquinavir with or without additional nucleosides. People with phenotypically sensitive virus before therapy were twelvefold more likely to achieve an undetectable virological response (defined as less than five hundred copies on the standard Roche Amplicor HIV RNA PCR assay). People with genotypically sensitive virus were four times as likely to achieve a virologic response.

In another study, genotype and phenotype were heavily correlated with virologic outcome in sixty-five heavily antiretroviral-experienced persons participating in the United States program, providing expanded access to Viracept brand nelfinavir. Eighty-four percent (16/19) of patients with no more than one genotypic resistance mutations experienced at least a one-half log reduction in viral load or a reduction to undetectable levels, while only one-third (3/9) of patients with two or more mutations responded. Phenotypic analysis also correlated drug resistance with clinical outcome: lack of phenotypic resistance at baseline correlated with a response in 74 percent of treated patients. Baseline resistance correlated with lack of response in 80 percent of patients.

Other studies have suggested that genotpyic analysis could predict short-term virologic response to abacavir, a new nucleoside analog, and to adefovir dipovixil, an experimental nucleotide analog.

The proper clinical role of resistance testing is not yet defined, and formal prospective validation studies are clearly needed. However, with more than seven different assays in development, clinicians say they have high hopes that these tests will significantly improve efforts at identifying effective salvage regimens for patients.