Extensive HIV Treatment Failure Found Rare


LONDON, Dec. 6 -- Complete failure of HIV treatment on the basis of the three original drug classes is much more the exception than the rule, researchers here said.
Action Points --->
Explain to interested patients that for several years therapy for HIV was limited to drugs from three classes, with the risk that patients could develop resistance to many of them and have few treatment options.
Note that this study suggests that few patients in that period developed so much resistance that they were completely without treatment options.
The finding may be encouraging for clinicians and patients in developing countries, where in most cases only drugs from the three original classes are available, according to Andrew Phillips, Ph.D., of the Royal Free and University College Medical School, and colleagues.
In a cohort of 7,916 HIV patients in the United Kingdom, only 167 ever developed "extensive" failure to respond to the three classes, Dr. Phillips and colleagues reported in the Dec. 8 issue of The Lancet.
And even among those, Dr. Phillips and colleagues said, there was enough residual drug activity so that 60% had an undetectable HIV viral load at least once after they were classified as having extensive virological failure.
"Extensive" failure was defined more strictly than the usual category of "triple-class failure," which is defined simply as failure to respond to at least one nucleoside reverse transcriptase inhibitor (NRTI), one non-nucleoside reverse transcriptase inhibitor (NNRTI), and one protease inhibitor (PI).
"Extensive" failure was defined as:
For nucleoside reverse transcriptase inhibitors, a lack of response to at least one drug each from three subclasses -- zidovudine or stavudine; lamivudine or emtricitabine; and didanosine, tenofovir, or abacavir.
For the non-nucleoside reverse transcriptase inhibitors, lack of response to efavirenz or nevirapine.
For the protease inhibitors, failure of at least one ritonavir-boosted protease inhibitor.
Lack of response -- or "virological failure" -- to a given drug was defined as a viral load higher than 400 copies of HIV RNA per milliliter of blood despite four continuous months of therapy with the medication.
Over 27,441 person-years of follow-up, the researchers found extensive triple-class failure in 167 patients, 90% of them with a lack of response to seven drugs or more, and 58% of them who went on to fail second-line therapies.
The only drug outside the three original classes that was available during the study period was the fusion inhibitor enfuvirtide, but only five of the 167 patients with extensive triple-class failure used it. (Three new drug classes are currently available -- fusion inhibitors, integrase inhibitors, and CCR5 antagonists.)
Despite their relative lack of other options, the five-year risk of death for patients with extensive triple-class failure was 10.6%, with a total of nine deaths over the follow-up period.
Over the whole cohort, the 10-year risk for extensive triple-class failure was 9.2%, but the researchers said that appears to have decreased over time by roughly 14% per year, which was significant at P=0.006.
Two factors of importance in the developing world appear to affect the risk of developing extensive failure, the researchers found in a multivariate analysis of baseline factors:
Being heterosexual was associated with a doubling of the risk. The odds ratio was 2.26, with a 95% confidence interval from 1.50 to 3.40, which was significant at P<00001.
Having a higher CD4 cell count decreased the risk by 32% for every 100 cells per microliter of blood. The odds ratio was 0.68, with a 95% confidence interval from 0.60 to 0.77, which was also significant at P<00001.
Starting treatment with more than 200 cells per microliter gave a cumulative 10-year risk of extensive triple-class failure of 5.5%, compared with 12.1% for those who started therapy with a lower CD4 cell count.
Both factors may affect therapy in the developing world, where the pandemic is largely heterosexual in nature and where a level of 200 CD4 cells is often considered an upper limit for starting therapy.
The good news in the study is that extensive failure was rare, according to Edward Mills, Ph.D., of the Center for Excellence in HIV/AIDS in Vancouver, and Jean Nachega, M.D., of Johns Hopkins Bloomberg School of Public Health, writing in an accompanying commentary.
But, they said, the bad news is that many patients then went on to fail further regimens -- options that are usually not available in the developing world.
The study "underscores the need for access to alternative, less toxic, and more affordable first-line, second-line, and now third-line antiretroviral drugs in developing countries," they argued.
The study was supported by the Medical Research Council of the United Kingdom. Dr. Phillips reported financial links with Boehringer Ingelheim, Roche, Abbott, GlaxoSmithKline, Gilead Sciences, Tibotec, and Janssen-Cilag.
Primary source: The LancetSource reference:Phillips AN, et al "Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study" Lancet 2007; 370: 1923-28. Additional source: The LancetSource reference: Mills E, Nachega J, "A wake-up call for global access to salvage HIV drug regimens" Lancet 2007; 370: 1885-87.