The most recent revision of the Guidelines for the Use of Antiretrovirals in Adults and Adolescents from the US Public Health Service (February, 2002) discusses the use of resistance testing. These guidelines support resistance testing as a tool to assist with appropriate antiretroviral selection.

There are two types of resistance testing: genotype and phenotype testing. Genotype testing measures patterns of genetic mutations in HIV that are associated with reduced drug susceptibility. Phenotype testing measures ability of HIV to replicate in the presence of individual antiretroviral drugs. The virtual phenotype extrapolates resistance by comparing results of genotype testing to data bases in which certain mutations are known to be associated with drug resistance.

Two studies have shown that resistance testing improves outcomes. The French study of genotypic adapted therapy, the so-called ADAPT trial,1,2 and the genotypic antiretroviral-resistance testing trial (GART)3 compared virologic responses to antiretroviral treatment regimens when genotypic resistance tests were available to help guide therapy with the responses observed when changes in therapy were guided solely by clinical judgment.

The results of both studies indicated that the short-term virologic response to therapy was significantly greater when results of resistance testing were available. Similarly, a recent prospective, randomized, multicenter trial has shown that therapy selected on the basis of phenotypic resistance testing significantly improves the virologic response to antiretroviral therapy compared with therapy selected without the aid of phenotypic testing.4 Thus resistance testing is becoming a useful tool in selecting drugs when one is changing antiretroviral regimens in the setting of virologic failure.

In the past, treatment guidelines have recommended changing at least two drugs in a failing regimen to avoid "sequential" monotherapy. It should be noted that virologic failure in the setting of HAART, in some instances, is associated with resistance to only one component of the regimen.5 In this situation, the availability of resistance testing may allow us to substitute individual drugs in a failing regimen, rather than two or more. This strategy requires further study.

There are currently no prospective data to support the use of one type of resistance assay over the other (genotypic versus phenotypic) in different clinical situations. According to the PHS guidelines, one type of assay is generally recommended per sample; however, in the setting of a complex prior treatment history, both genotype and phenotype assays may provide important and complementary information.

A more recent study has added to our understanding of the value of resistance testing. Tural and colleagues examined the potential roles of genotyping and expert advice in HAART-experienced patients in a 24-week analysis of a prospective, multicenter, randomized trial of 274 treatment-experienced patients.6 At baseline, subjects had mean CD4 cell counts of 388/µL and viral loads of 4.04 logs (approximately 11,000 copies/mL). At week 24, there was a significant difference in the percentage of patients below the level of detection (less than 400 copies/mL) among the following groups:

"     Genotype and nongenotype arms

(57.5% vs 42.4%, respectively; P =.01)

"     Expert-advice and no-expert-advice arms

(59.1% vs 41.1%, respectively; P = .003)

"     Genotype/expert-advice and nongenotype/no-expert-advice arms

(69.2% vs 36.4%, respectively; P = .001)

The authors concluded that at the 6-month end point, both genotyping with interpretation and expert advice improved virologic outcomes in very heavily antiretroviral-experienced patients.

The US Public Health Service guidelines support resistance testing in treatment-experienced patients who are not fully suppressed or who show evidence of treatment failure. The guidelines are equivocal on the use of resistance testing before treatment in antiretroviral-naive patients.

However, as more newly infected patients with resistance to one or more antiretrovirals are identified, many experts recommend that resistance testing be done for treatment-naive patients before initiating antiretrovirals. Resistance testing makes sense in this case when one considers that a surprising number of newly infected patientsÑranging from 16% to 26%Ñare infected with strains of HIV-1 that are resistant, genotypically and phenotypically, to at least one antiretroviral drug.7,8

Reimbursement for viral load and resistance testing is variable. Some health plans and managed care organizations limit the number of tests reimbursed per year. However, limitations on testing need to be flexible in order to accommodate individual patient needs and emerging technologies. In addition, changes in our understanding of the value of these important tools require that policies for reimbursement of new technologies be reviewed on a regular basis.

See Dr. Valenti's bio on page 66.

References

     1.   Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet. 1999;353:.

     2.   Clevenbergh P, Durant J, Halfon P, et al. Persisting long-term benefit of genotype-guided treatment for HIV-infected patients failing HAART: the Viradapt study, week 48 follow-up. Antiviral Ther. 2000;5:65-70.

     3.   Baxter JD, Mayers DL, Wentworth DN, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS. 2000;14(9):F83-F93.

     4.   Cohen C, Hunt S, Sension M, et al. Phenotypic resistance testing significantly improves response to therapy: a randomized trial (VIRA3001). In: Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, CA. [Abstract 237.]

     5.   Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000;283:.

     6.   Tural C, Ruiz L, Holtzer C, et al. Utility of HIV genotyping and clinical expert advice. In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago, IL. [Abstract 434] Available online at: <http://www.retroconference.org/2001/abstracts/abstracts/abstracts/434.htm>. Accessed April 24, 2002.

     7.   Little S, Daar E, D'Aquila R, et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA. 1999;282:.

     8.   Boden D, Hurley A, Zhang L, et al. HIV-1 drug resistance in newly infected individuals. JAMA. 1999;282:.

Internet Resources

US Public Health Service Guidelines for the Use of Antiretrovirals in Adults and Adolescents

[Accessed April 24, 2002] <www. hivatis.org>

HIV Resistance Web: Includes a summary of available genotype and phenotype tests and their status with

the US Food and Drug Administration.

          <http://www.hivresistanceweb.com>

          <http://www.hitatis.org>

Virco <http://www.vircolab.com>

Virologic PhenoSense

          <http://www.phenosense. com>

Visible Genetics <http://www.visgen.com>

Guidelines for the Use of Antiretroviral Agents in

HIV-Infected Adults and Adolescents February 4, 2002 Developed by the panel on Clinical Practices

for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation