The Role of Resistance Testing in an Inner City Population

ACRIA Update, Vol. 10, No. 4, Fall 2001
Jason M. Leider, MD, PhD

The introduction of resistance testing technology into the clinical practice of HIV medicine has offered me and my providers at the North Bronx Health Care Network of Jacobi and North Central Bronx Hospitals an opportunity to revolutionize our approach to HIV treatment. In our practice, we provide care to more than 2,000 HIV-positive adults and children. Approximately 40% of these individuals currently maintain viral loads below the limit of detection of the viral load assay. Many of the remainder of our patients are treatment experienced, some extensively so, often having been on multiple previous regimens. Resistance testing has been an extremely helpful tool in guiding our treatment decisions for many of these patients.

Our Choice in Technology for Resistance Testing

As participants in an ambitious resistance research study, we have now performed resistance tests on more than 180 patients. Usually, we have used the genotype assay, rather than the phenotype assay. This preference for genotyping is based on faster turnaround time (1 to 2 weeks versus 2 to 4 weeks for phenotyping), lower assay cost, lack of impressive data to show superiority of phenotyping over genotyping, and a lack of data for the phenotypic resistance tests correlating drug resistance in the lab with actual drug activity in people. Thus, we have used phenotyping for patients who have complex genotype results (for example, unusual NNRTI mutation patterns such as G190A/S, K101E, multiple PI mutations, or multiple NRTI mutations especially for patients with a history of being heavily pre-treated).

The Role of Resistance Testing in Practice

Currently, the Department of Health and Human Services' Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (August 13, 2001) propose that resistance testing be used as follows:

Recommended:

• virologic failure (i.e.. failure to achieve a viral load of less than 1000 copies/mL after more than 16-24 weeks of treatment)
• suboptimal suppression of viral load after initiation of treatment (i.e., less than 0.5-0.75 log10 reduction in plasma HIV RNA by four weeks following initiation of therapy or more than 1 log10 reduction by eight weeks)

Consider:

• acute HIV infection

Not Recommended:

• chronic HIV infection in treatment naïve patients
• after discontinuation of treatment for more than two weeks
• plasma viral load less than 1,000 HIV RNA copies/mL

We follow the recommendations of these guidelines for patients with virologic failure (especially first line failure), suboptimal suppression, and viral loads less than 1000 copies/mL, as resistance testing is not sensitive enough to accurately detect mutations for these patients. In our patient population, people rarely come into care during acute HIV seroconversion, so we have not had the chance to do genotyping for this patient group. Unfortunately, many of our patients first come to us with chronic HIV infection, often with CD4 counts less than 100.

It is for this latter group that we have deviated from the guidelines and performed resistance testing. Our rationale for using genotyping for this population is that many of our patients live in an area where their contacts have been treated with HIV therapy and may have transmitted drug-resistant virus. While we have only performed resistance testing on about ten naïve patients with chronic HIV infection, we have already seen one patient with a significant mutation in the protease inhibitor class prior to ever taking HIV medication. This patient had been HIV infected over five years ago and had maintained a CD4 count more than 500 and a viral load of about 50,000. However, he had fallen out of care for the past three years and now came back into care due to the development of severe rash, itching and weight loss. His CD4 had decreased to 3, while his viral load was now greater than 750,000. This serious decline in his health prompted us to send for a genotype, which revealed the mutation associated with loss of activity to Viracept (nelfinavir). The patient has now started HIV treatment, and the results of his genotype test definitely impacted on our choice of his initial HIV regimen.

We have also differed from the guidelines in performing resistance testing on pre-treated patients who have discontinued therapy for more than two weeks. We have found that at least 30% of our patients harbor significant resistance mutations despite the interruption in therapy. Many of these patients have retained the K103N mutation associated with resistance to all of the medications in the NNRTI class. In fact, we have seen that NNRTI resistance tends to be persistent, with many patients showing this mutation despite having discontinued NNRTI treatment for more than six months. In light of this, we have found genotyping to be especially useful in helping us avoid prescribing inactive medications. At our medical centers, we also care for many HIV-positive pregnant women. For these patients, we routinely perform genotype testing before starting HIV medication as it is imperative to design treatment regimens that offer the greatest chance of decreasing their viral load and avoiding maternal-fetal transmission of HIV. The following patient illustrates the value of using resistance testing in this situation. One of our heavily pre-treated patients is now twelve weeks pregnant. Her genotype, done six months ago when her CD4 was 31 and her viral load was 3,496, revealed many significant mutations to virtually all of the medications in the NRTI class as well as high level resistance to medications in the NNRTI and PI classes. Despite this result, she decided not to change her regimen and continued taking Zerit (d4T), Epivir (3TC), Norvir (ritonavir) and Crixivan (indinavir). In the interim, she has had several hospitalizations for psychiatric causes, fragmenting her HIV outpatient care. She returned to care with a CD4 count of 9 and a viral load that had increased to 22,000. We repeated her genotyping and have discovered a genotype showing less severe mutations in the NRTI class, the same NNRTI mutations and no mutations in the PI group. The patient later revealed to us that she had a problem obtaining her HIV medications and has not taken them for more than two weeks. Without the genotype from six months ago, we may have designed a regimen of inadequate NRTI or PI potency. Having serial genotypes for this patient is invaluable as we can now design a regimen with the greatest potential for virologic success.

Conclusion

In conclusion, we have found resistance testing to be a welcome addition to our clinical practice. Due to the need for rapid results, we have used genotyping initially for resistance evaluation and have reserved phenotyping for interpretation of the most complex patients. The extensive penetration of treatment into our community has made genotyping a helpful tool for guiding treatment decisions for patients who are failing current therapy as well as for chronically infected naïve patients. Pregnant women are a group of patients in which we feel genotyping definitely has a niche for ensuring intelligent treatment decisions. Of note, as NNRTI therapy becomes a more common treatment option for HIV+ pregnant women - specifically the use of Viramune (nevirapine) - we anticipate that many women treated with Viramune during pregnancy will eventually develop NNRTI resistance. Repeat resistance testing of these women, should they experience future treatment failure, will be of increasing importance to guide treatment decisions. As can be imagined, it will also be necessary to genotype these same women who in the future have subsequent pregnancies should they have detectable viral loads.

Jason M. Leider, M.D., Ph.D., is Director of the Adult HIV Service for the North Bronx Health Care Network of Jacobi and North Central Bronx Hospitals.

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