Antiretroviral Rx: Resistance

Case 1: Discussion

Testing for HIV resistance to antiretroviral medications has become an important component of the clinical care of HIV-infected persons. Resistance assays can assist the clinician in selecting a maximally effective HAART regimen by identifying the level of resistance, if any, to antiretroviral agents. The December 2007 DHHS guidelines for the use of antiretroviral therapy guidelines in adults and adolescents provided specific recommendations regarding HIV drug resistance testing (Figure 1Resistance Testing RecommendationsRating Scheme for Clinical PracticeAcknowledgments)[1]. The January 2008 DHHS antiretroviral therapy guidelines did not make any changes in the 2007 recommendations for resistance testing.

Resistance Testing for Virologic Failure

The December 2007 DHHS antiretroviral therapy guidelines recommend resistance testing in the setting of virologic failure or suboptimal viral suppression in patients receiving HAART[1]. The term "virologic failure" refers to the development of a rising HIV RNA level in a patient on HAART who previously had excellent virologic control (HIV RNA levels less than 50 copies/ml) (Figure 2). Unless the patient has simply stopped taking his or her medications, this clinical scenario suggests the development of resistance. Several randomized controlled trials have demonstrated the clinical benefit of resistance testing among patients with virologic failure[2,3,4]. "Suboptimal viral suppression" or "failure to suppress" describes the patient who initially shows a favorable initial response to HAART with a decrease in HIV RNA level, but is not able to drive the HIV RNA level below the level of detection (less than 50 copies/ml) (Figure 3). Suboptimal viral suppression can result from the rapid development of resistance, inadequate potency of the regimen, or both. As disccussed below, resistance testing in the setting of virologic failure is usually not recommended when the HIV RNA level is less than 1,000 copies/ml, mainly because it is hard to obtain an accurate result at very low levels of viremia.

Resistance Testing with Acute HIV Infection

In the setting of acute HIV infection, the 2007 DHHS antiretroviral therapy guidelines recommend obtaining resistance testing, regardless of whether the decision is made to initiate antiretroviral therapy[1]. The recommendation to obtain resistance testing even when the decision in made to defer therapy is based on the greater likelihood of detecting transmitted resistant early in the course of HIV infection. If therapy is deferred, the guidelines suggest considering repeat resistance testing prior to initiating antiretroviral therapy, since the patient may possibly acquire resistant HIV in the interim[1]. In a retrospective study that involved 10 North American cities and 377 patients with acute HIV infection, investigators reported that high-level phenotypic resistance increased in each of the major antiretroviral drug classes when comparing isolates obtained during 1995 to 1998 with those from 1999 to 2000 (Figure 4)[5] . Moreover, the frequency of multi-drug resistance in these patients increased from 1.1-6.2% between these two time periods. More recent studies suggest that 6-16% of newly infected patients have acquired HIV with resistance to at least one drug[1]. Among patients infected with a drug-resistant strain of HIV, time to viral suppression after initiation of therapy was longer and time to virologic failure shorter when compared with patients who did not have evidence of having resistant HIV. In a separate study that involved 225 patients diagnosed with acute HIV infection in the San Francisco Bay Area from 1996 to 2001, drug resistance among newly HIV-infected individuals increased, predominantly in the non-nucleoside reverse transcriptase class (Figure 5)[6] . This study also found patients who acquired resistant strains of HIV had a longer time to virologic suppression when treated with HAART compared with those individuals without evidence of resistant HIV (12 weeks versus 5 weeks).Taken together, these studies show a significant proportion of new HIV infections involve drug-resistant virus, the resistance rates have increased since the mid-1990's, and acquisition of resistant HIV has an impact on response to antiretroviral therapy[1,5,6].

Resistance Testing with Chronic Infection

Because most HIV-infected individuals are diagnosed with HIV long after their acute HIV illness, the first opportunity for resistance testing typically occurs years after initial HIV infection. The December 2007 DHHS antiretroviral therapy guidelines recommend performing resistance testing in the setting of chronic HIV infection at the time a patient enters into care for their HIV disease[1] . Some controversy exists regarding whether or not resistant HIV strains acquired during initial infection will persist at a high enough level to be detected if resistance testing is performed in a chronically HIV-infected person who has never received antiretroviral therapy. Among those with acute HIV infection who acquire resistant HIV strains and who do not receive antiretroviral therapy, several possible scenarios exist regarding subsequent detection of resistant HIV strains. First, in the absence of any antiretroviral selective pressure, those resistant strains of HIV may back-mutate to more fit wild-type strains, or be overgrown by wild-type virus (Figure 6). Alternatively, if particular resistant stains of HIV do not cause a loss in viral fitness, the strains could persist indefinitely and this could involve multiple distinct resistant mutations (Figure 7). Last, it is possible that some resistant mutations will revert to more fit wild-type whereas others that do not cause a significant loss in fitness could persist (Figure 8). One study that involved relatively few patients found that some multi-drug resistant strains acquired during initial infection persisted for up to 5 years as the dominant quasispecies, despite these strains being less fit than wild type strains. Regardless of whether or not resistance testing will detect transmitted strains of resistant HIV, most experts would agree that these transmitted drug-resistant variants persist in cellular reservoirs, such as latently infected CD4 cells, and thus could reemerge upon the selective pressure of antiretroviral therapy.

Resistance Testing after Discontinuation of Therapy

The December 2007 DHHS antiretroviral therapy guidelines state that drug resistant assays are usually not recommended when patients who have taken antiretroviral agents in the past, but have been off therapy for more than 4 weeks[1]. Among chronically-infected persons who develop resistance in response to antiretroviral therapy, populations of wild-type and resistant strains of HIV may co-exist, but upon discontinuation of antiretroviral therapy, replication of the more fit wild type strain generally outpaces that of the resistant strain (Figure 9). Accordingly, the resistant strain will likely become a minority species in the overall viral population. Because currently available resistance assays do not reliably identify strains of HIV that constitute a low percentage (generally defined as less than 10-20%) of the overall viral population, minority resistant strains often evade detection by resistance assays in chronically infected persons who discontinue therapy. The speed at which resistant strains become overgrown by wild type strains will likely vary from patient to patient, but available data suggest most wild-type strains predominate over resistance strains within 12 weeks of stopping antiretroviral therapy (Figure 10)[8,9] . Although in this setting resistant strains may not be evident on resistance testing, they remain archived in the host[8] and thus would presumably play a role if the patient reinitiated antiretroviral therapy that included medications to which the patient had previously developed resistance.

Resistance Testing with Low HIV RNA Levels

The 2007 DHHS antiretroviral therapy guidelines do not recommend resistance testing in the setting of a patient experiencing apparent virologic breakthrough with an HIV RNA level less than 1,000 copies/ml[1]. This recommendation exists because of technical aspects of most currently available resistance assays that require HIV viral levels of approximately 1,000 copies/ml or more to accurately identify resistant HIV. As the technology of resistance assays improves, these tests may become more accurate at detecting resistance at HIV RNA levels significantly less than 1,000 copies/ml.