HIV drug resistance testing: data be damned.

HIV's ability to develop drug resistance, through rapid turnover and high rates of mutation, has been the Achilles' heel of antiretroviral therapy. On a molecular level, HIV's mechanism of replication is error prone and given to genetic infidelity. But on a therapeutic level, haphazard viral reproduction is the bane of anti-HIV drugs.

In May 2000, a panel of the International AIDS Society-USA (IAS-USA) endorsed the use of drug resistance testing.[1] Although it relied on relatively limited surrogate marker data, and although it acknowledged the technical deficiencies of resistance tests, the panel nevertheless recommended the use of these assays in a variety of clinical scenarios. While citing measurements of plasma viral load as the primary basis on which decisions about therapy should be made, the panel concluded that the "... available data support a role for HIV drug resistance testing in selecting drugs in many clinical situations."[1] These situations include, according to the panel, the use of resistance assays in treatment naive patients with chronic infection, even as the panel concedes that the absence of selective drug pressure in this population means that drug-resistant mutants "... might not be detected by current assays."[1]

Written by some of the most respected experts in HIV clinical care and research, the panel's recommendations are rarely questioned. Unfortunately, its recommendations also dash any hope that industry or government will ever conduct the studies that could determine the true clinical utility of resistance assays. Late last year, the US Food and Drug Administration lowered the regulatory hurdle for kit-based genotypic tests, making it easier for them to get approved. Now, with their products accepted as integral to the standard of care, the makers of all drug resistance tests have no regulatory or financial incentive to investigate these products more rigorously. Moreover, with resistance testing adopted as standard of care, it becomes ethically impossible to conduct longer, definitive clinical trials since most institutional review boards will not allow volunteers to be randomized to receive anything less than the prevailing standard. Normally, a standard is established by its validation. But in this case, the standard has both preceded and precluded its validation.

The recommendations of the IAS-USA panel are made in the context of other recommendations from yet another group of experts, namely the Panel on Clinical Practices for Treatment of HIV Infection. For 4 years, that panel has lent its considerable influence to the early, aggressive use of antiretroviral therapy in patients who have relatively high CD4 T cell counts, even as evidence supporting the long-term clinical benefit of that practice has remained lacking, and even as observational data have shown that early therapy offers no disease-free survival benefit.[2] Thus, a conscientious clinician, by following the recommendations of experts, could prescribe expensive antiviral regimens to patients who have not been shown to benefit clinically from the intervention and then adjust the regimen when necessary with the use of expensive assays. Stockholders in drug and biotechnology companies can take heart. But the rest of us should wonder if there is a field of modern medicine other than HIV in which evidence-based practice is taking so severe a beating.

The IAS-USA panel's premature endorsement of resistance testing is also not without opportunity costs. In the short-term, monies that will go to resistance testing cannot be spent on measures to decrease nonadherence, the most common cause of drug failure.[3] In the long-term, endorsement of resistance testing now diverts attention from what should be a potent sense of urgency to end the era of highly active antiretroviral therapy (HAART) in favor of novel, safer, more effective agents for the treatment of HIV infection.

Of course, HAART is all we have for the moment, and healthcare providers are ethically obligated to make the most of it. But the surrogate marker data on which the panel relied for its recommendations show that even when drug choices are guided by resistance tests, two thirds of patients fail to achieve an optimal virologic response to therapy.[4] Moreover, in 2 of the 3 studies cited by the panel, the mean difference in viral load between those whose treatment decisions were influenced by resistance testing and those whose decisions were not was less than 0.50 log, which is within the margin of error for viral load assays. Since measurements of viral load lose some of their prognostic utility under therapy anyway,[5] the clinical significance, if any, of these modest changes in plasma viremia is unknown. Finally, the premise of resistance testing is that a reduction in viral load is the most crucial determinant of the clinical benefit of therapy. But new data show that changes in CD4 T cell count, and not viral load, are a better predictor of a drug regimen's clinical effect.[6]

The IAS-USA's panel has, in the words of Charles Flexner, MD, issued recommendations that cover "... every HIV-infected patient except those who refuse therapy or are already fully suppressed on an established regimen."[7] We hope clinicians take a less enthusiastic view of resistance assays and confine their use to treatment experienced patients with advanced disease. But the damage is already done. The appropriate controlled, prospective trials will never be undertaken; a potential focus on technologies of adherence is clouded; and a sense of urgency for something better is diminished. Moreover, as the cost of HIV-related care continues to grow, the inevitable day of resource rationing draws closer. When that day finally arrives, we will find ourselves in an environment where expert panels have committed a substantial portion of the AIDS dollar to clinically unproven assays and management strategies. Such an inefficient use of finite funding is both irrational and unethical. The recommendations of the IAS-USA panel, like the recommendations of its sister panel, almost always coincidentally further the commercial interests of industry. But even more importantly, recommendations of this nature demonstrate powerfully the need for studies of long-term clinical effectiveness and the costs, both financial and human, of expert opinion unsupported by the facts.

REFERENCES

[1.] Hirsch MS, Brun-Vezinet F, D'Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection. JAMA. 2000;283(18):2417-2426.

[2.] Miller V, Sabin CA, Phillips AN, et al. The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load. AIDS. 2000; 14(14):2129-2136.

[3.] Bonhoeffer S. Models of viral kinetics and drug resistance in HIV-1 infection. AIDS Patient Care STDs. 1998; 12:769-774.

[4.] Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomized controlled trial. Lancet. 1999;353:2195-2199.

[5.] Deeks SG, Barbour JD, Martin JN, et al. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis. 2000;181(3):946-953.

[6.] Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med. 2000; 133:401-410.

[7.] Flexner C. HIV genotype and phenotype -- arresting resistance? JAMA. 2000;283(18):2442-2444.