Important note: Information in this article was accurate in January 2002. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, January 2002
Dave Gilden
The widespread prevalence of treatment failure and drug resistance was underscored by an observational cohort study conducted by Douglas Richman, Sam Bozzette and colleagues from the University of California San Diego (UCSD) and the RAND Corporation. (This study was presented later in the month at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy.)
The group looked at blood samples taken in 1999 from a cohort established by Bozzette in 1996 to be representative of Americans then receiving [quote]any sort of medical care for HIV. This was the year that highly active antiretroviral therapy (HAART) became standard treatment for HIV. Researchers initially interviewed 2,864 patients, out of an estimated quarter million Americans receiving HIV-related care.
In 1999, blood samples were taken from 1,906 of these people. Only about two-thirds of the original group were still surviving and locatable. And of the group available for follow-up, a mere 37% had viral loads under 500 copies/mL. The researchers then checked for drug resistance in the HIV infecting those with viral loads above 500. (They used the phenotypic (cell culture) assay performed by ViroLogic at its laboratory in South San Francisco, California.) Of the 1,080 samples checked, 79% had HIV that resisted at least one of the standard HIV medications - 70% of the samples exhibited resistance to nucleoside analogs, 42% to protease inhibitors and 31% to NNRTIs.
Assuming that there was no drug resistance in those with viral loads under the 500 copies/mL threshold, half the total cohort had acquired drug-resistant HIV after three or more years of medical management of their HIV.
It is no wonder, then, that a separate study presented by Richman found a continuing increase in transmission of drug-resistant HIV: In 1999 to 2000, a national survey found that 14% of newly acquired HIV was highly resistant to at least one HIV drug and 5.5% highly resisted two or more drugs. In the 1995 to 1998 period, the corresponding figures were 3.5% and 0.4%.
At least in the U.S., drug resistance is now commonly spreading as uninfected people acquire HIV from persons with drug-resistant virus. Some people have acquired an instant history of past drug exposure and failure along with their new infection.
The record for HAART looks dismal here, but the UCSD-RAND cohort's overall experience may not be completely representative. Persons, even in poor countries, who now start HAART as their first-ever anti-HIV therapy could do significantly better through improved medical management.
The beginning of 1996 marked an end of an era in HIV treatment: 60% of the people enrolled in this treated cohort already had an AIDS, when response to therapy is reduced. Also, 79% had used anti-HIV drugs previously, almost entirely single or dual nucleoside analogs. During the course of 1996, protease inhibitors and NNRTIs were added aggressively to the nucleoside analogs. At the start of the year, only 16% were taking an NNRTI or protease inhibitor. By the end, 55% were doing so.
Three years before this, Stanford University pharmacologist Gary Nolan presciently warned in an interview, "If theoretically you need three things to stop HIV, we've already wiped out the ability to use nucleoside analogs due to resistance. Every time you try out one inhibitor, you develop a patient pool with resistance." The evolution of further drug resistance is a foregone conclusion when HIV is not fully suppressed.
Serial addition of new drugs to failing regimens may have foredoomed the experience of the UCSD-RAND group when it encountered HAART. Many of the new treatment combinations failed because they contained less than three fully active drugs - and frequently only one or none.
One of the contributors to the current study, Nick Hellmann, who is ViroLogic's Director of Clinical Research, commented, "We did find a lot of resistance. But we all expected this in the back of our minds."
Aside from serial adoption of new drugs, poor adherence to dosing schedules has been a major factor in treatment failure. One presenter at the NCI symposium, Roy Anderson, of the Imperial College Faculty of Medicine in London, described the results of his study of adherence in 129 patients. These results were built into a mathematical model. "Adherence is critical when viral load is high early in treatment," Anderson said. The same goes for any time that there is still substantial HIV replication in the presence of drugs.
Adherence is particularly crucial for drugs like 3TC or nevirapine, which HIV can counter with one simple mutation. But even more complicated resistance patterns can quickly emerge with less than full adherence. Anderson cited the example of a regimen containing a protease inhibitor that requires three HIV mutations to lose its effect. Even if near-perfect adherence with that regimen would successfully suppress HIV, Anderson's model predicts that missing 15% of required doses allows HIV to evolve and then rebound within 130 days.
Anderson further argued that "multiple drug holidays inevitably lead to the accumulation of [drug resistance] mutations." Members of the UCSD-RAND cohort frequently went on and off therapies. By the end of 1997, 71% had tried an accepted HAART combination, but only half were then on one.
HIV's tendency to mutate and evolve drug resistance is relentless. Still, Hellmann noted a "silver lining." He remarked, "There were high rates of drug resistance in '98 and '99, but we have not seen a dramatic increase in mortality and morbidity. Either there will be in next year or two, or resistant virus may not be as bad for individual as wild type. It may not be as pathogenic or replicate as well."
The silver lining may already be darkening. New AIDS cases were up slightly in the year 2000. In early January, the Centers for Disease Control and Prevention revealed preliminary figures for 2001 indicating a further 8% increase in the number of AIDS cases nationally. New York City was especially hard-hit. There, the AIDS rate increased 47%. These increases come after a period of sharp decline in the nineties that nearly halved the AIDS incidence compared to the pre-HAART era.
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