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Issue #145: October 5, 1997
FASTFAX is available by fax in the 215 and 610 area codes at no cost, or by mail anywhere for $20.00 per year, by calling 215-545-6868, and by E-mail by contacting and type the message SUBSCRIBE in the message section. Sources for some information in this issue include Reuters, San Francisco Examiner, The Lancet, Morbidity and Mortality Weekly Report, UPI.
Protease cocktails fail 53% in study; "two epidemics" predicted
Birth control pill linked to higher HIV risk
AIDS said "very rare" when viral load is under 5000
Draft of pediatric HIV guidelines released
Progress seen in protease use for children
Delavirdine+Crixivan hailed as "salvage therapy"
NIAID awards $11.8 million for vaccine study
Gonorrhea up 74% among gay/bisexual men
Warning issued on Seldane and protease drugs
Protease cocktails fail 53% in study; "two epidemics" predicted
by Lisa M. Krieger
San Francisco Examiner
There is disappointing new evidence that the highly acclaimed potent AIDS medicines are failing those who need them most.Slightly more than half of the patients in a San Francisco General Hospital-based study developed evidence of drug failure after six months of treatment, and saw their HIV levels rise, according to a study released this week.
More optimistic are the results from the rest of the patients in the study: One year after the initiation of treatment, their virus remains persistently undetectable, suggesting long-term good health.
"In our clinics, we appear to be seeing the epidemic split in two," said Dr. Steven Deeks, assistant professor of medicine at UC-San Francisco, who presented his findings at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto.
"About half of our patients will see a long-term, possibly permanent, response to these drugs while the other half may begin to exhibit disease progression again," said Deeks.
The 53 percent of patients who had evidence of failure after at least six months of therapy tended to be people who already had very advanced HIV disease, defined by researchers as a low immune system CD4 cell count and high levels of virus. Most had tried multiple anti-viral drugs in the past.
The 47 percent of patients who obtained lasting benefit from protease inhibitors used in combination with one or more other anti-viral agents, were those who were more recently infected and who had not been treated with earlier generations of anti-viral medicines.
Until this S.F. General-based study, no one knew what proportion of "average" patients taking the drug combination was benefiting from it. Doctors generally do not track a therapy's success the way researchers do in the clinical studies that first document its results.
Clinical trials showed unqualified success with the drugs, which offered bright hope in a dark time. The often-disappointed AIDS community was told that things were different now - that the triple-drug combinations might turn AIDS into a chronic, manageable disease, a lifelong affliction rather than a fatal illness.
The news was so compelling that people at all stages of disease rushed to seek treatment.
But these latest findings show that for some people, lasting benefit is as elusive as ever.
While drug combinations can delay disease and death, they have serious limitations. Keeping HIV at bay, even with the most potent three-drug cocktails now available, is not always possible.
For many patients, combination therapy is another in a long list of bitter disappointments.
The irony is that those less likely to be helped by the new drugs tend to be highly educated and engaged patients - often AIDS activists - who were infected long ago and conscientiously tried each of the AIDS drugs individually as they were introduced over the years. Now, this early conscientiousness may have worked against them, because they are resistant to the entire combination.
The failure of current therapies demands new and better drugs, said Deeks. "The pharmaceutical industry, the government and all researchers need to remain vigilant and continue to develop new therapeutic options for HIV-positive patients."
Unlike the patients selected for well-controlled, industry-sponsored clinical trials, "real world" San Francisco AIDS patients, particularly those treated in a public clinic like that at S.F. General Hospital, arrive with the odds stacked against them.
They tend to have been infected a long time, have tried a litany of other agents, and may have trouble complying with the complicated treatment regimen. So while clinical trials show a success rate of 80 to 90 percent, the more typical patient population may have only a 50-50 chance of enduring benefit.
"Clinical trials tend to enroll patients who are healthy, who haven't been on much therapy in the past and who are highly motivated; they are not the typical patient," explained Deeks.
The 136 patients in the study had, on average, a low CD4 count of 169. A normal CD4 count ranges from 500 to 1,000 and AIDS is defined by a CD4 count of under 200. They had a high viral load of 70,000 copies of HIV per milliliter of blood. They were treated with a protease inhibitor, such as indinavir or ritonavir, in combination with at least one and often two other anti-viral drugs, such as AZT and 3TC.
There is a biological basis for the problems encountered by this population: A virus that is exposed to sub-optimal doses of inferior drugs learns to sidestep treatment. Because early treatments offered only partial suppression of the virus, HIV survived and rebounded, with a genetic diversity that then made it resistant to all available agents.
Limited success after switching PIs
A companion paper, also presented by Deeks, offers the disappointing news that people who fail one treatment with a protease inhibitor have only limited success with a second. In this second study, 16 patients who failed one protease inhibitor were treated with an aggressive combination of two powerful protease inhibitors and two other anti-viral drugs. Most of the 16 had a limited and short-lived response to the drugs, Deeks said."This finding suggests that there is cross-resistance among protease inhibitors and that patients may have only one shot at achieving long-term viral suppression," he said.
But those patients who succeed in combination treatment may have a bright future.
"For those who made it past six months and have stayed undetectable for as long as they continue to take drugs, I predict they will stay undetectable," said Deeks. "If people fail (treatment), failure comes early," usually within six months.
Researchers at the conference heard results from a trial by Dr. Roy Gulick of New York University, which showed that the same 27 out of 30 people whose viral levels were undetectable after six months of three-drug therapy remained undetectable two years later.
Another study, from France, suggested a dramatic new approach to treatment: "Maintenance therapy" for patients in whom the virus is consistently undetectable. Rather than keeping patients on three drugs for many years, perhaps decades, researchers there say they have had success in withdrawing the potent protease inhibitor, while maintaining anti-viral benefit.
Most researchers have abandoned the idea, at least for now, of attempting to stop treatment entirely, said Deeks. The terms undetectable and eradication may be chimera. Just because HIV can't be found doesn't mean the virus isn't there - or that it isn't replicating. HIV insinuates itself into the DNA of the body's cells and when treatment stops, the virus surges back without so much as a pause, experts now believe.
Birth control pill linked to higher HIV risk
HIV-infected women who take birth control pills are much more likely than other HIV-infected women to have detectable virus in the cervix or vagina, according to a new study. Other risk factors for viral shedding include vitamin A deficiency, gonorrhea infection, or yeast infections.Increased shedding of virus could mean a greater risk of transmission to either a sexual partner or to an infant during delivery.
"Heterosexual transmission of HIV is the predominant mode of infection among adults worldwide," reported Dr. Sara Mostad in the current issue of The Lancet. "Of children who acquire HIV-1 from their mother, 40% to 80% are estimated to become infected during delivery."
"For both heterosexual and mother-to-child transmission, factors that affect shedding of HIV-1 in cervical and vaginal secretions may be important determinants of transmission risk," said Mostad, of the University of Washington in Seattle. The study was conducted with researchers at the University of Nairobi and Coast Provincial General Hospital in Mombasa, Kenya.
In the study of 318 HIV-infected women in Kenya, 51% had detectable HIV in their cervix and 14% had HIV in vaginal secretions. Those who took low dose birth control pills were nearly four times as likely and those taking high dose pills were 12 times as likely to have detectable virus. And the risk was at least five times higher for women deficient in vitamin A, two to three times higher for those with yeast infections, and three times higher for those with gonorrhea.
The study "reinforces the importance of detecting and treating gonococcal infection in HIV-1 infected individuals," the authors wrote. Other sexually transmitted diseases, such as Chlamydia trachomatous or Trichomonas vaginalis, did not appear to increase viral shedding, though the study may not have been large enough to show an association.
It's not clear why birth control pills, which contain synthetic estrogen and progesterone, should increase shedding of HIV in the genital tract. It's possible that the hormones influence immune system function or they may change local factors in the vagina, such as thickening cervical mucus -- which may enhance shedding of the virus.
And as for vitamin A, it "has long been recognized to have a central role in maintenance of epithelial surfaces and normal function of the immune system," the authors wrote.
FDA approves 3TC/AZT combo
The U.S. Food and Drug Administration (FDA) has approved the first tablet to contain two antiretroviral drugs for the treatment of HIV infection, lamivudine (Epivir) and zidovudine (Retrovir), Glaxo Wellcome has announced.The availability of the new lamivudine/zidovudine tablet, sold under the name Combivir, "...is the first major step toward simplifying highly effective HIV combination-drug regimens," according to a press release from the company.
Combivir, which contains 150 milligrams (mg) lamivudine and 300 mg zidovudine, can be taken twice daily by HIV-positive people who receive the two drugs as a part of a combination regimen.
This reduces the number of pills that must be taken each day, which it is hoped will make it easier for people living with HIV/AIDS to keep up the often burdensome combination therapy treatment regimen. Combivir does not require refrigeration and can be taken with or without food.
"There is little question that patient adherence to complicated combination therapy regimens is a critical issue today in the treatment of the people with HIV and AIDS," Dr. W. David Hardy of the University of California in Los Angeles commented. "Nonadherence to therapies, which are designed to provide maximal suppression of HIV, result in less than optimal antiviral effects and, more importantly, the emergence of drug-resistant virus."
AIDS said "very rare" when viral load is under 5000
Findings from a German study, presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy, indicate that when HIV RNA levels are detectable but no higher than 5,000 copies/mL, progression to AIDS is "very rare."The focus of the session was the correlation of clinical outcomes with various levels of HIV suppression. Dr. Schlomo Staszewski of J.W. Goethe University in Frankfurt studied data on 1593 HIV-positive patients participating in six trials of various therapies.
Of the 195 patients who developed AIDS within 1 year, 188 (96%) did not have a reduction in viral load to less than 5,000 copies/mL. On the other hand, among the 323 patients who sustained a viral load of less than 5,000, only 7 (2%) had an AIDS defining event. "The HIV RNA level required to prevent progression to AIDS," Dr. Staszewski concluded, "...may be higher than that required to delay the emergence of drug resistance."
When asked if this meant that untreated HIV-positive patients with viral loads below 5000 may not require treatment, Dr. Staszewski could not concur. "We are not talking about natural history here," he said. "The aim of treatment is still clearly to reduce RNA to undetectable levels."
During the same ICAAC session, Dr. Joan Romeu presented data on the clinical significance of several HIV threshold values. Dr. Romeu, of Germans Trias i Pujol University Hospital in Badalona, Spain, found that maintaining a viral load value below 150,000 copies/mL is associated with higher short-term survival and maintenance below 35,000 copies/mL reflects short-term clinical stability.
Those conclusions were based on an analysis of more than 1,300 HIV RNA measurements made in 444 HIV-positive patients. During a mean follow-up of nearly 2 years, 132 patients developed AIDS and 117 died.
Before those encouraging data were heard, Dr. Julio Montaner of St. Pauls' Hospital, Vancouver, presented more daunting figures showing that unless HIV RNA is suppressed to 20 copies/mL, a durable response is unlikely. Included in his talk, however, was a hint that highly complex antiretroviral regimens may not be necessary to maintain suppression once the 20 copies/mL level is achieved. In five such patients who periodically discontinued some drugs in their regimen, no rebound in viral load occurred.
Draft of pediatric HIV guidelines released
Donna E. Shalala, secretary of Health and Human Services, has announced the release of draft guidelines for the treatment of pediatric HIV infection, which will be published in the Federal Register and open to public comment for 30 days, according to a Health Resources and Services Administration press release.The guidelines, developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, recommend that children receive potent combination antiretroviral regimens similar to those administered to adults. Two protease inhibitors, ritonavir and nelfinavir, currently are approved by the FDA for pediatric formulations.
"These guidelines will fill an important gap in our knowledge by recognizing the unique treatment needs of infants, children and adolescents living with HIV," Secretary Shalala said. The "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection" were developed by 64 specialists in pediatric HIV care, federal agency representatives and family members of HIV-positive children.
Most working group participants recommend that all HIV-positive infants under 12 months of age receive combination antiretroviral treatment as soon as HIV infection is diagnosed. "Adult guidelines are more appropriate for older adolescents," Dr. James Oleske, group co-chair, commented, "...but youth in their growth spurt or younger may be more appropriately treated using the pediatric guidelines."
The national AIDS Policy Center for Children, Youth and Families applauded the release of the pediatric treatment guidelines. "Today represents a massive step forward in the battle against AIDS among the nation's most vulnerable citizens -- children and youth living with HIV and AIDS," David Harvey, executive director of the center said in a press release.
Mildred Williamson, center president, added that patient access to the expensive antiretroviral drugs will be needed. "Congress, the president and the federal government must maintain a commitment to fund the federal AIDS Drug Assistance Program, comprehensive family HIV care under the Ryan White CARE Act and other services, to ensure that everyone gets access."
For a copy of the guidelines, call the National AIDS Clearinghouse at 1-800-458-5231 or the HIV/AIDS Treatment Information Service at 1-800-448-0440. The HIV/AIDS Treatment Information Service also has a website at http://www.hivatis.org.
Progress seen in protease use for children
Combination antiretroviral therapy containing the protease inhibitor ritonavir can safely suppress HIV RNA to undetectable levels in children, a multicenter group reported at the ICAAC conference. At 12 weeks, the superiority of this regimen prompted members of the Pediatric AIDS Clinical Trials Group 338 to halt the arm of the study that did not contain a protease inhibitor.The trial involved about 300 stable HIV-positive children -- none of whom had opportunistic infections or AIDS -- who had "reasonable" T-cell levels, Dr. Sharon A. Nachman of the SUNY Health Science Center at Stony Brook, New York, said.
The children were randomly assigned to one of three treatment arms: AZT and 3TC, d4T and ritonavir, or AZT, 3TC and ritonavir. Although the clinical condition of the pediatric study subjects did not deteriorate during the study, significantly more of the children who received ritonavir had undetectable HIV levels and larger increases in CD4 T-cell concentrations.
At 12 weeks, the researchers found that the children on AZT/3TC had only a mean drop in viral load "...of about a third of a log (0.33%)," Dr. Nachman said. The children in ritonavir-containing arms had a mean drop in viral load "...of about 1.8 log." Because this was a difference of more than 50%, the protocol team felt it reasonable to terminate the AZT/3TC arm of the study, according to Dr. Nachman. Children in the AZT/3TC arm can switch to another regimen.
"We're very, very excited about [the results]," Dr. Nachman said prior to presentation of the findings at the ICAAC meeting. "No. 1: We didn't know if children could take protease inhibitors. We were of course worried about the toxicities, but we were also worried about whether they would take them by mouth -- they are not good tasting medications.
"It turns out that there were no unexpected toxicities. Ten percent of the children who were in a ritonavir-containing arm stopped therapy because of toxicity, and that includes taste and nausea from the ritonavir." There were very few problems, she continued. "I thought [the side effects] would be a lot worse."
"The children that I have on proteases, both in the trial and out of the trial, are doing incredibly well," she said. However, protease inhibitors aren't for everyone, she cautioned. Not all patients response to or can tolerate these drugs.
Dr. Nachman anticipates that FDA approval for the new treatment combination for children will be issued within the next few weeks.
Delavirdine+Crixivan hailed as "salvage therapy"
Adding the recently approved non-nucleoside reverse transcriptase inhibitor delavirdine to the multidrug regimen of HIV-infected patients experiencing "failure" of protease inhibitors can produce a "remarkable" decrease in viral load and significant clinical improvement. The effect is most pronounced, Dr. Paul Bellman said, when the regimen includes the protease inhibitor indinavir."This therapy has reproduced the magic of protease inhibitors for some of the patients for whom protease inhibitors have not worked," he said.
Dr. Bellman, of St. Vincent's Hospital, New York, entered 46 of his patients for whom antiretroviral therapy was not working into Pharmacia & Upjohn's expanded access program for delavirdine (Rescriptor). "This represents a group of patients who are extremely treatment experienced," Dr. Bellman said, "...including all of the available protease inhibitors." He noticed very early that some of the patients "...were getting really extraordinary benefits."
During follow-up, there was a rapid decrease in HIV RNA of about 1 log10 copies/mL, overall. "But that obscures the fact that actually a fair number of patients have gone to 'undetectable'," Dr. Bellman noted. While some patients responded minimally or not at all, 12 of the 46 patients have maintained viral levels below the detection threshold for 6 to 10 months.
The efficacy of delavirdine in this setting exceeds expectations based on its intrinsic virologic potency, which Dr Bellman attributes to its synergistic effect with indinavir. Notably, nearly all the patients in the group of complete responders had been on indinavir in combination therapy, had initially responded but had lost viral suppression. The addition of delavirdine "increases indinavir levels, particularly trough levels" by inhibiting the p450 enzyme system in the liver that metabolizes indinavir. Hence, drug levels are increased sufficiently to allow any partial resistance to indinavir to be overcome.
"I believe that indinavir and delavirdine in combination therapy is, at this particular point, the best demonstrated salvage therapy for protease-experienced patients who are breaking through virologically," Dr. Bellman stated. "In my mind, it often has a better response than changing indinavir to ritonavir and saquinavir, or any other combination that has been studied," he added.
Another new non-nucleoside reverse transcriptase inhibitor, DMP 266, also has potent activity in combination with indinavir, at least in relatively treatment-naive patients. That's according to data presented at the ICAAC conference by Dr. Douglas Mayers of National Naval Medical Center in Bethesda.
Some 100 asymptomatic HIV-positive patients with a history of nucleoside treatment (but not protease inhibitor or non-nucleoside therapy) were randomized to indinavir plus DMP 266 (efavirenz, Sustiva) or to indinavir alone for 24 weeks. The mean baseline HIV RNA level was 5.06 log10 copies/mL. In the first group, viral levels became undetectable in 94% of the patients, in the second group the figure was only 47%.
"The regimen is actually very well tolerated, because you only have to give the DMP at bedtime," Dr. Mayers said. Side effects such as insomnia that do occur can be overcome by dividing the dose. Some patients do develop a rash in the second week of therapy, Dr Mayers added, "but you give a nonsedating antihistamine and treat through it, so it's not something that has caused us to withdraw anyone."
DuPont Merck has announced an expanded access program for Sustiva. People with CD4 counts below 50 and who are failing therapy are eligible. More information is available by calling 1-800-998-6854.
NIAID awards $11.8 million for vaccine study
The National Institute of Allergy and Infectious Diseases has announced the first recipients of the new "INNOVATION Grant Program for Approaches in HIV Vaccine Research," according to an NIAID press release.More than $11.8 million in 1-year or 2-year grants will go to 49 recipients at institutions nationwide who were selected from more than 100 applicants. "The 49 grants we are funding will explore creative approaches to vaccine designs and involve many investigators new to AIDS research," Dr. Anthony Fauci, NIAID director, commented.
"Traditional killed vaccine or live attenuated vaccine development methods are being pursed, but may not be the most successful for HIV," Dr. David Baltimore, head of the AIDS Vaccine Research Committee added. "To discover the best way to tame HIV infection, we need also to focus on the newer biomedical technologies and approaches that depart from the conventional."
The major areas of study include the structure and function of the HIV envelope, improvement in animal models and mechanisms of antigen processing in vivo to maximize immune response.
Michael S. Marks, Ph.D., of the University of Pennsylvania, is one of the recipients of the grants. The complete list of grant recipients is available on the NIAID home page on the Internet at http://www.niaid.nih.gov.
Feds say most know HIV status
AIDS researchers say a majority of HIV- infected people in the United States have already been tested."It's great news," said Patricia Sweeney of the Centers for Disease Control and Prevention in Atlanta, because it means that most infected people know their status and can seek treatment.
But, at an infectious diseases conference in Toronto sponsored by the American Society for Microbiology, Sweeney said "a large number of people (at risk from AIDS) still have not been tested and we need to encourage early testing for those people."
She noted that her study may only be counting those who are already known to the health care system, and may miss an unknown number of HIV+ people who don't routinely seek health care. The spread of HIV infection among substance abusers, the uninsured and low-income people who are not in contact with health care providers could well mean that the CDC numbers are unreliable, she admitted.
If the numbers are correct, she said, that would mean about two- thirds of HIV-infected people already know about it and can begin to seek treatment. But getting accurate figures is hard, she said, because not all states require doctors to report HIV. As well, some people are tested anonymously. So, Sweeney says, the estimate "is likely a minimum of persons... known to the health care system."
Sweeney said her study indicates that between 509,000 and 545,000 infected people know about their disease, out of an estimated 650,000 to 900,000 people who have HIV infection.
Gonorrhea up 74% among gay/bisexual men
An increased incidence of gonorrhea seen among men who have sex with men "may signal a return to high-risk sexual behaviors in this population," according to CDC officials.In the Morbidity and Mortality Weekly Report, government epidemiologists report a 74% increase from 1993 to 1996 in new cases of gonorrheal infection in this population. In
1993, 5.0% of all gonorrhea cases were in men who have sex with men, but by 1996 this rate rose to 8.7%. The data are from the Agency's Gonococcal Isolate Surveillance Project, which tracks the number of gonorrhea cases reported by sexually transmitted disease (STD) clinics in 26 US cities.
In the early 1980s, the number of new cases of gonorrhea "declined substantially" among men who have sex with men, a trend that paralleled decreases in sexual risk behaviors prompted by the AIDS epidemic. However, recent reports in the US and Europe point to a reversal in this trend, an Editorial Note in the MMWR points out.
The increase in incidence of gonorrheal infection in men who have sex with men documented in the current report "cannot be explained by such factors as improved case ascertainment or increase screening in this population." CDC officials point out that these data highlight "the need for innovative approaches to achieving and maintaining safer-sex practices among [men who have sex with men]."
Warning issued on Seldane and protease drugs
The list of drugs that are unsafe to mix with the antihistamine Seldane has gotten longer.New labels will warn people against mixing Seldane and Seldane-D with a variety of medications including protease inhibitors, the recently approved blood pressure drug Posicor, and the class of antidepressants that includes Zoloft and Serzone.
Drug maker Hoechst Marion Roussel has already warned people not to take Seldane with certain antibiotics and antifungals because the combination sometimes triggers a potentially fatal heart causes.
The Seldane antihistamines may be nearing the end of their marketability anyway. In January, the FDA proposed removing them from shelves because the agency has approved a safer
alternative, called Allegra. The agency said it is continuing with the process to remove Seldane and Seldane-D from the market.
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