HIV Resistance Testing in Clinical Practice: A QALY-fied Success

Despite the significant advances in HIV therapy over the past 5 years, failure of highly active antiretroviral therapy (HAART) remains a significant problem. In a meta-analysis of 21 treatment groups from randomized clinical studies, only 46% of patients were able to reach the targeted HIV RNA viral load (<50 copies/mL) by 48 weeks (1). Because of virologic rebound or toxicity, the initial regimen ultimately fails even in most patients who are at first treated successfully. Therefore, HAART failure is common and should be anticipated by all clinicians caring for HIV-infected patients. The management of HAART failure depends on the reason for failure and the availability of alternative therapies. The most common causes of HAART failure are difficulties in adherence, short-term intolerance, long-term toxicities (such as lipodystrophy, insulin resistance, and hyperlipidemias), insufficient drug levels, and development of virologic resistance. Management of adherence and treatment-related toxicities involves detailed discussions with the patient and identification of an acceptable new regimen. Evaluation of insufficient drug levels is challenging and requires formal pharmacologic testing, a procedure not available in most clinical settings. The determination of virologic resistance is also a challenge. In the past, when viral resistance was suspected, it was assumed that resistance had developed to all drugs in the failing regimen (2); similarly, it was assumed that the virus would still be susceptible to drugs not previously used. Unfortunately, the strategy of designing new regimens that contain virgin agents while avoiding drugs used in previous regimens is often unsuccessful (3), mostly because the virus frequently does not become resistant to all of the drugs in the failing regimen and some virgin drugs may not be effective because of cross-resistance. With the availability of resistance testing, clinicians can now determine more precisely which drugs the virus has developed resistance to and, conversely, which drugs are more likely to be effective. Over the past 3 years, several studies have demonstrated the clinical benefits of resistance testing, establishing a strong rationale for its routine use in clinical practice (4). Indeed, three expert panels recently recommended such routine use (4-6). However, several researchers have questioned the true costbenefit of this approach and have been critical of these recommendations (7). In this issue, Weinstein and colleagues (8) provide evidence demonstrating the costbenefit of resistance testing. The authors used a standard measure, the quality-adjusted life-year (QALY), to determine costbenefit (9). In general, any intervention that results in a cost of $25 000 or less per QALY gained is deemed to be very cost-efficient. Other interventions in HIV patient management have cost values of $16 000 per QALY gained (Pneumocystis carinii pneumonia prophylaxis), $35 000 per QALY gained (prophylaxis against Mycobacterium avium complex using azithromycin), $58 000 per QALY gained (prophylaxis against Mycobacterium avium complex using clarithromycin), $100 000 per QALY gained (routine fungal prophylaxis using fluconazole), and $314 000 per QALY gained (cytomegalovirus prophylaxis using oral ganciclovir) (10). Using models based on data obtained from two prospective studies (11, 12), as well as data from natural history cohorts (13), Weinstein and colleagues determined that the cost per QALY gained would be $16 100 for a resistance test that cost $400 and $17 000 for a test that cost $1000. The costbenefit remained below $25 000 per QALY gained even if resistance testing cost up to $10 000 per year. These findings are consistent with the cost-effectiveness data for three-drug HAART therapy itself (14, 15). The two clinical trials used by Weinstein and colleagues were prospective studies of genotypic analyses (9, 10). Each study defined virologic success as achieving a viral load less than 500 copies/mL, and each study demonstrated roughly 25% improvement in virologic outcome over 3 months. Although this benefit was truncated at 3 months, Weinstein and colleagues were able to demonstrate a significant costbenefit associated with resistance testing. These findings remained consistent under a wide range of assumptions, including a model in which the incremental benefit of genotypic testing was only 5% (cost-effectiveness ratio, $24 000 per QALY gained). Several other assumptions used in the study suggest that even greater benefits might be realized in the real world. For example, the two studies used in the model evaluated genotypic testing in the setting of first failure. In practice, resistance testing is likely to be of greater benefit among patients who have experienced failure of many regimens (although the effect of multiple failures in the study by Weinstein and colleagues did not change the cost-effectiveness ratio). Furthermore, in the setting of many regimen failures, most clinicians use a different definition of success. They try to sustain an HIV viral load that is more than three times lower (0.5 log) than at baseline, rather than setting an absolute target of less than 500 copies/mL. If a less stringent definition of success is used, the benefit from resistance testing will probably last longer and therefore be more cost-effective. Finally, the two studies used in the model were based on genotypic testing, which is limited by the need for detailed interpretation of the test results in the face of an ever-expanding list of resistance-conferring mutations. Phenotypic resistance tests use an in vitro testing system that evaluates the growth characteristics of the virus in the presence of antiretroviral drugs; they cost roughly twice as much as genotypic tests ($800 to $1000 per test vs. $400 per test). In highly experienced patients, phenotypic test results are generally easier to interpret and may result in improved outcomes in certain clinical settings. In the study by Weinstein and colleagues, the cost of phenotypic testing (approximately $1000 per test) did not dramatically change the estimated costbenefit. Despite its demonstrated benefits, resistance testing has several limitations. The tests identify only the predominant viral populations in circulation. Minority species, representing less than 10% to 50% of the viral population, may be missed. For the test result to be interpreted properly, the patient must be taking the failing regimen when blood is drawn for testing. Results of genotypic resistance tests may vary from laboratory to laboratory and require intricate, often expert interpretation to yield the best outcome (16). Phenotypic tests have ill-defined cutoff values for resistance, which can be problematic. As with antimicrobial therapy, the determination of susceptibility depends on both the 90% inhibitory concentration of the organism and the achievable plasma and intracellular concentration of each drug. In the current HIV treatment environment, in which drug-level boosting (for example, with low-dose ritonavir) is a common practice, achievable drug concentrations may be substantially higher than published values, making it difficult to determine the true susceptibility cut-point in vivo. In addition, neither existing phenotypic nor genotypic tests account for in vivo synergy between drugs, adding to the complexity of interpretation. Nonetheless, on the basis of numerous clinical trials, virologic outcome studies, and now a detailed cost analysis, resistance testing is warranted in clinical practice. The optimal use of resistance testing has not yet been fully defined. Most experts agree that the tests are of benefit for virologic failure after many regimens, during pregnancy (to ensure use of the best regimen), and after failure of the first regimen (when tests can help assess adherence or the ability to continue certain drugs from the initial regimen). The use of resistance testing before initiation of the first regimen depends on the relative prevalence of resistance in the community. In the analysis by Weinstein and colleagues, the prevalence of resistance before the first regimen was assumed to be 20%. In reality, the observed percentages of high-level resistance in most communities are between 1% and 10%, underscoring the need to make this decision on a community-by-community basis. In the future, to determine susceptibility cutoff values on an individual basis, resistance testing may be augmented by plasma drug levels obtained at precise times after the last dose of medication, a practice called therapeutic drug monitoring. Some studies have demonstrated improved outcomes when these two tests are performed in tandem (12). However, therapeutic drug monitoring is associated with many logistic issues that make its use in practice premature. Therefore, as with viral load testing 7 years ago and resistance testing 3 years ago, we await further virologic, clinical, and QALY-fication data before implementing therapeutic drug monitoring in routine practice. Stay tuned.