Lazarus’ rising in U.S. but HIV still taking global toll
"When the history of AIDS and the global response is written, our most precious contribution may be at the time of plague we did not flee, we did not hide, we did not separate ourselves." — Jonathon Mann, MD, to whom the 1999 APIC conference was dedicated.
Ongoing advances in antiretroviral drug therapy are dramatically changing the face of the HIV epidemic, yielding a dramatic "Lazarus effect" in some patients that only a few years ago may have been part of mortality statistics. Yet while the death toll has dropped in those with access to new combination-drug therapies, much of the globe has not been invited to the HIV "cocktail" party and the pandemic is still exacting a terrible toll in non-industrialized countries, ICPs were advised recently in Baltimore at the annual conference of the Association for Professionals in Infection Control and Epidemiology.
Delivering an HIV update at APIC was Carlos del Rio, MD, chief of HIV inpatient services at Grady Memorial Hospital and assistant professor of infectious diseases at Emory University School of Medicine, both in Atlanta.
"As antiretroviral therapy has become more commonly used in the United States, mortality from HIV has dramatically gone down," he said. "This is one of the most dramatic events in the history of the epidemic. Any of you who has seen or taken care of AIDS patients can attest to the dramatic Lazarus effect that we have seen. Patients who are very sick — near death — are all of a sudden back to normal. [They are] working, taking their medications, and doing fine. Some hospitals have literally stopped having HIV admissions because HIV has become — for people who can take the medications — essentially an outpatient disease."
As a result, AIDS mortality has fallen from the leading cause of death in 25-to-44-year-olds in the late 1980s and early 1990s to the fifth-leading cause currently, he noted.
The haves and have-nots
In stark contrast to the U.S. situation, the vast majority of the estimated 33 million HIV-infected people worldwide have little or no access to the new drug regimens, particularly those living in sub-Saharan Africa or the Indian subcontinent, he noted. Del Rio invoked the memory of the renowned AIDS researcher and human rights activist Jonathon Mann, MD, to whom the 1999 APIC conference was dedicated, in reminding that the epidemic has become as much a struggle for human rights as to vanquish a disease. Mann, the keynote speaker at the 1993 APIC conference, died in a plane crash in 1998.
"We think we have a large HIV problem in this country, where the CDC estimates half a million to 750,000 [people] are infected with HIV," del Rio said. "Literally, in sub-Saharan Africa it is hard to go to a village and not find a family that has one or two or more members who have either died of HIV or who are infected with HIV."
The result is that life expectancy rates in such countries have fallen dramatically, as HIV infection offsets gains over the last few decades in sanitation and immunizations for other diseases. Every day, 16,000 new HIV infections occur worldwide, most of them in developing countries, del Rio said. "To a great majority of these individuals, antiretroviral therapy — which has dramatically changed the epidemic in this country — is simply not available," he said. "It is estimated that only 5% of the people living with HIV worldwide actually have access to antiretroviral therapy."
There are ongoing efforts to try to improve the situation, for example, by administering drug therapy to interrupt perinatal transmission and break the chain of HIV from one generation to the next, he noted. Antiretroviral therapy has proven effective in blocking perinatal transmission, and some pharmaceutical companies have offered zidovudine at discounted prices for developing countries. The challenge then becomes getting at-risk populations tested so zidovudine can be administered appropriately.
"The problem [then] is not the drug availability, but the testing," del Rio says. "How do you get cheap testing? How do you know who is infected?"
Noting that in some areas of Africa as many as 30% of the pregnant women are HIV-infected, del Rio said the situation is such that public health officials may have to weigh the feasibility of administering therapy to all pregnant women rather than try to discern the truly infected without resources for testing.
U.S. gains undercut by resistance
In addition, even amid the striking successes against HIV in the United States, del Rio reminded that the dramatic improvements seen in many patients are not being realized by all. Many are infected with resistant strains and must keep seeking new combinations of the currently available drugs in an effort to find an effective regimen. Indeed, today’s complex HIV therapy must be administered by highly specialized clinicians who are treating patients on a day-to-day basis.
"We have right now 14 HIV-approved medications, so the combinations are quite numerous," he said. "In 1999, we don’t have one option, we have several options [as] to what to start the patient with. The treatment decision needs to be tailored to the individual needs."
Sometimes patient readiness is key to the drug regimen, he added.
"I have patients who simply tell me [they are] not ready to take 20 pills a day for the rest of [their] life," he said. "Then you are not ready to start therapy. Because if you take it for three days and then you skip two and take it again, your virus is going to rapidly become resistant to those drugs and we are wasting our money and our energies. . . . A lot of patient education is needed before we commit ourselves to anti retroviral therapy."
In a situation similar to emerging antibiotic resistance in bacteria, the AIDS virus has shown the ability to mutate into resistant strains that foil therapy. Resistant strains began to emerge not long after zidovudine began proving effective in reducing viral replication more than a decade ago. The advent of two-drug therapies in 1994 significantly improved the situation, and another dramatic stride occurred with the triple-drug cocktails in 1997, he noted.
"We saw that viral replication was being driven down by more than two logs, and indeed, that has continued," del Rio said. "The virus does not rebound if you continue to take your medications appropriately, and this essentially has led to the changes in mortality that we have seen. If [HIV] is unable to replicate, then it won’t become resistant, because the virus needs to be able to replicate in order to develop resistant mutations."
Viral latency makes adherence crucial
However, adherence to drug regimens can be surprisingly difficult, particularly because some 90% of the medications must be taken for life due to viral latency factors that allow HIV to emerge rapidly when medications stop. New drugs requiring fewer daily pills may help the situation, but side effects are another ongoing concern in maintaining compliance, he notes. About 40% of patients — more if education is heavily emphasized — will still be taking their drugs as part of a successful regimen two years out. But the rest of the patients typically fail antiretroviral therapy because they stop taking the medications, develop liver function abnormalities or other side effects, or the virus becomes resistant to the regimen, he said.
"While you see results in pharmaceutical-sponsored trials saying 96% [success rate] at one or two years, the fact is that happens to be a study setting," del Rio said. "In real clinical practice, we are over and over seeing a success rate of about 40%."
Disease leaves no room for error
Patients on failing regimens are relegated to "salvage" therapies that become increasingly less likely to succeed as successive regimens fail. That makes it all the more important to strictly comply with the initial regimen, he said, underscoring the importance of "compliance nurses" that constantly educate HIV patients about the importance of adhering to therapy. Such efforts are critical because there may be only a scant margin for error between a successful regimen and a failing one. Many of the drugs have a short half-life, meaning a missed dose by a only a few hours can be significant because the virus may be only one mutation away from developing resistance, he said. Compliance is further complicated by such factors as the need to take some medications with food and the need to take others before eating.
"The bottom line is you need to take most of your drugs every day, all of the time," he said. "Again, I remind you, if you have ever taken any medication, it is very hard to take it every day and not to miss doses. They are very unforgiving drugs."
Though HIV — with certain caveats — has evolved from a near uniformly fatal infection to a chronic disease, considerable challenges remain despite the stunning successes.
"It is a manageable [disease], but only for those fortunate enough to acquire a wild-type virus — in other words not a resistant virus — who live where combination therapy is accessible and have no problem taking drugs every day all of the time," del Rio told APIC attendees. "We are a long way from saying that HIV is over."
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