New Insights Into HIV Resistance Testing: Nursing Guidelines and Implications

Practice Brief

New Insights Into HIV Resistance Testing: Nursing Guidelines and Implications Carl A. Kirton, RN, MA, APRN, BC Don Kurtyka, ARNP-BC, MS, MBA, David J. Sterken, MN, CNS, CPNP

The detection of resistance by HIV drug resistance assays has become an important management tool for use in the HIV-infected patient. Because of its important role in management of HIV disease, it is important for the nurse to understand the mechanism of HIV resistance, the appropriate use of resistance tests, and how to use this information to improve or maximize patient outcomes. The purpose of this review is to increase the nurse’s awareness of the problem of resistance, to describe the available resistance tests, and to develop a model whereby the patient collaborates with the health care team in understanding, implementing, and monitoring resistance-related actions. The use of combinations of antiretroviral (ARV) drugs to treat HIV infection has proven to slow the progression of HIV disease and reduce the number of deaths caused by HIV infection. Despite these advances, most patients will develop some degree of resistance. The detection of resistance by HIV drug resistance assays has become an important management tool for both the acute and chronically ill patient. Because of its important role in management of HIV disease, it is important for the nurse to understand the mechanism of HIV resistance, the appropriate use of resistance tests, and how to use this information to improve or maximize patient outcomes.

Nursing guidelines for resistance testing were developed by a consensus committee consisting of nurses from both clinical practice and academia across the United States who are experts in the management of patients with HIV/AIDS. A major goal of this committee was to increase the nurse’s awareness of the problem of resistance, to describe the available resistance tests, and to develop a model whereby the patient collaborates with the health care team in understanding, implementing, and monitoring resistance-related actions.

Mechanism of HIV Drug Resistance Adaptation and change is an inherent and essential property of all living things. Generally speaking, the ability of organisms to mutate allows them to adapt to different environments. Without this ability to adapt, organisms cannot survive when confronted Carl A. Kirton, RN, MA, APRN, BC, is administrative director and a nurse practitioner at AIDS Center, North General Hospital, New York, and a clinical associate professor at New York University. Don Kurtyka, ARNPBC, MS, MBA, is director, HIV services, Tampa General Hospital; a nurse practitioner at Hillsborough County Health Department; and an instructor at University of South Florida College of Medicine. David Sterken, MN, CNS, CPNP, is a pediatric clinical nurse specialist at Helen DeVos Children’s Hospital, Grand Rapids, MI.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 18, No. 3, May/June 2007, 74-86 doi:10.1016/j.jana.2007.03.003 Copyright © 2007 Association of Nurses in AIDS Care

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with anything that threatens their survival, such as a drug. It is this simple principle that forms the basis for understanding HIV mutations and resistance and that will be explored in this review.

these drug-resistant viruses. However, these viruses may soon become the predominant species in the viral population and result in loss of viral suppression and an increase in the viral load.

Evolution of Viral Mutations

Epidemiology of HIV Drug Resistance

Viral mutations can occur in two ways: naturally, without the presence of drugs (random mutations) or as a result of selective pressure exerted on the virus by the human immune system (escape mutations) and of pressure that occurs as a result of selection by insufficient ARV therapy (drug-resistant mutations). All mutations, regardless of whether they occur randomly or as the result of adaptation to a particular environment, involve changes in HIV proteins or their building blocks, amino acids. These slightly different copies of HIV are known as quasispecies and generally are an altered shape or a change in the biochemical property of the viral protein. Recall that HIV contains viral RNA and several copies of reverse transcriptase (RT) (also known as RNA-dependent DNA polymerase). After infecting a cell, the RT is used to make the initial copies of viral DNA from viral RNA. Mutations may occur naturally during the transcribing of viral RNA into viral DNA because of the lack of a mechanism to check for mistakes that may occur during this process. This results in a different amino acid sequence and may lead to a quasispecies that is generally not viable and quickly dies. Alternatively, as a result of these amino acid changes, the quasispecies becomes a more fit virus, is viable, and can replicate without difficulty.

Selection of Mutations During Therapy When a potent ARV combination regimen is added to the virus’s environment, viral replication is impaired and as a result the viral burden (or viral load) is often reduced. Some quasispecies will be produced that enable the virus to replicate despite the presence of the ARV drugs. When this occurs, it is said that the virus has been, in a sense, selected by the regimen to survive (selective advantage). A potent regimen with adequate drug levels and high levels of adherence may delay the emergence of

Prevalence of Resistance in Acute Infection One of the challenges facing HIV care providers is the problem of continued transmission of HIV to others, and in particular the transmission of a drugresistant strain of HIV from one person to another. Detectable resistance in an individual who is naive to ARV therapy is called primary drug resistance. Worldwide, the rates of primary drug resistance are increasing. Little et al. (2002) evaluated drug resistance patterns in patients in 10 North American cities between May 1995 and June 2000 before starting treatment with ARV therapy. Over this 5-year period, the prevalence of primary resistance increased significantly. The frequency of high-level resistance to one or more drug was 3.4% between 1995 and 1998 and increased to 12.4% during the period of 1999 to 2000. The frequency of multidrug resistance increased from 1.1% to 6.2%. Similarly, Grant et al. (2002) examined 225 cases referred to a San Francisco Hospital with recent HIV infection from 1996 to 2001. The prevalence of nonnucleoside RT inhibitors (NNRTIs) resistance increased from 0% in 1996 and 1997 to 13.2% in 2000 and 2001. Whereas one mutation (2.5%) associated with protease inhibitors (PIs) was identified between the years of 1996 and 1997, PI resistance increased to 7.7% between the years 2000 and 2001. Over this time period, nucleoside RT inhibitor (NRTI) resistance decreased and then returned to prior levels. Primary resistance has important clinical implications. Transmitted drug-resistant virus impairs treatment response and the continued transmission of drug-resistant virus limits the potential for future success with ARV therapy. The median time to viral suppression was 56 days for individuals without drug-transmitted virus and 88 days in individuals with drug-resistant virus. The time to virologic failure was shorter in individuals with drug-resistant

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Resistance Testing in Clinical Practice

Figure 1. Prevalence of estimated HIV drug resistance in represented population. From “The prevalence of antiretroviral drug resistance in the United States” by D. Richman, S. C. Morton, T. Wrin, N. Hellmann, S. Berry, M. Shapiro, and S. A. Bozzette, 2004, AIDS, 18(10), pp. 1393-1401.

virus compared with those without drug-resistant virus (Little et al., 2002). Prevalence of Resistance in Patients With Chronic HIV infection The prevalence of resistance in patients with chronic HIV infection is hard to quantify. Among viremic patients (VL ⬎ 500 copies), an estimated 76% had resistance to one or more ARV drugs (see Figure 1) Drug resistance in two classes was detected at 48%, and resistance to all three drug classes in this cohort was 13% (Richman et al., 2004). Depending on the type of resistance obtained at the time of infection, the drug-resistant virus may be detected between 4 months and 3 years (Little et al., 2002). Beyond this time period, drug-resistant virus may be difficult or impossible to detect because the transmitted virus may represent only a small percentage of the total viral population as wild-type virus may now be the dominant species. Given the rates of transmitted virus and the potential for drug resistance to affect clinical outcomes, resistance testing is recommended to guide clinical decisions.

Resistance tests are valuable tools that have been well-integrated into the standard of HIV care. These tests assist clinicians in making therapeutic decisions regarding ARV agents by selecting drugs that have therapeutic activity. Genotypic, phenotypic, and computer-assisted “virtual” phenotypic HIV drug susceptibility tests are the principal assays commercially available to measure drug resistance. Genotypic and phenotypic assays are performed on HIV-1 extracted from plasma. After being extracted, the protease and RT genes are reverse transcribed to cDNA and then amplified using polymerase chain reaction to produce sufficient DNA for genotypic or phenotypic testing. It usually takes a minimum of 1,000 RNA copies/mL to perform these tests. Genotypic HIV drug resistance assays identify specific mutations in the gag-pol (the genes responsible for the virus’s structure) region of the HIV-1 genome that are associated with reduced susceptibility to specific ARVs. A genotype refers to the DNA sequence in which the coding region of genes is organized in codons. Each codon codes for a single amino acid. Genotyping is the methodology that detects resistance by comparing the specific gene sequences of the patient’s virus compared with that of a reference wild-type virus. For example, an M184V mutation means that the amino acid methionine is replaced by valine at position 184 in the RT enzyme (see Figure 2). Once this comparison is made, the genotypic changes (the mutations) are reported. Almost all labs provide the clinician with some degree of analysis of the identified changes. The most common method of interpretation is the rules-based algorithm generated by an expert panel such as the International AIDS Society–USA or the European HIV Drug Resistance Guidelines Panel. These groups determine which mutations or combinations of mutations are associated with resistance to specific drugs and establish an algorithm for interpreting the genotype. The rules are then applied to classify the genotyped virus as having resistance, no resistance, or possible resistance. The disadvantage to this approach is that algorithms need regular updating, and because expert panel algorithms are not subjected to rigorous validation, there is the

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potential for error. The second method for reporting uses special software to compare the patient’s protease and RT sequences to a large database of phenotypes and genotypes and report results as a virtual phenotype. Phenotypic HIV drug resistance assays identify how well clinical isolates grow in the presence of selected drugs relative to a wild-type reference virus. Phenotypic testing provides a quantitative analysis of the drug concentration needed for inhibition of HIV replication in vitro. Drug susceptibility results are reported as inhibitory concentration 50% (IC50) (or IC90) of the drug being tested for the patient’s virus divided by the IC50 (or IC90) for the reference virus. This result is commonly reported as a “fold change” in susceptibility. In the clinical setting, phenotypic data are interpreted by evaluating the values known as biological cutoffs and clinical cutoffs. Biological cutoffs are derived from in vitro susceptibility experiments with clinical isolates from drug-naive patients and are a good reflection of the resistance that is circulating in the general population. Because the biological cutoff defines what is resistant and nonresistant based on how virus responds in treatment-naive patients, it does not indicate individual clinical response. Clinical cutoffs define what is resistant and nonresistant based on how well an individual patient’s virus responds to a drug in vivo. Clinical cutoffs represent the correlation between actual patient’s virologic response and phenotypic susceptibility. Using clinical cutoffs provides a more accurate estimation of the potential contribution of any one drug to the response of a multiple drug regimen. Because clinical cutoffs are based on the actual observed correlation between viral susceptibility and response to treatment, they provide a more realistic indication of potential response. A virtual phenotype is a relational genotypic-phenotypic database that provides a quantitative predic-

4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Figure 2. The top figure represents transcription of RNA into DNA with normal amino acid sequences. The bottom figure represents an error in transcription, resulting in a point mutation with an abnormal amino acid sequence. This is a virus with the M184V mutation.

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tion of ARV drug resistance. The database will select genotypic isolates with similar patterns of resistance. The phenotypes of these database isolates are averaged to provide a prediction of the fold change in IC50 relative to a reference wild-type. The database is continually updated as known genetic mutations, associated phenotypes, and new drugs are made available. Studies have shown that the virtual phenotype performs as well as a directly measured phenotype (Emery et al., 2003; Graham, Peeters, Verbiest, Harrigan, & Larder, 2001; Perez-Elias, Garcia, & Munoz, 2002). Advantages and Disadvantages of Genotypic and Phenotypic Resistance Tests Both genotypic and phenotypic resistance tests have a variety of limitations that clinicians must be aware of that can impact test selection and interpretation of test results. In an effort to preserve the patient’s immunologic cells and limit viral replication, appropriate regimen changes must be made swiftly. In the case of treatment failure, regimen changes are often guided by resistance assays, and one of the major limitations is the turnaround time for test results. Genotypic assays can be reported within 1 to 2 weeks, whereas phenotypic assays require several weeks to be reported. Genotype results are sufficient for treatment-naive individuals or for regimen changes in individuals whose initial regimen may be failing. Genotypic tests can be difficult to interpret when the client has been on several regimens with a large number of mutations. Although genotype testing may be helpful, phenotypic testing is the preferred assay to guide therapeutic changes. Drug resistance is only detectable by current commercial genotypic or phenotypic assays if resistant virus is present in at least 20% to 30% of quasispecies. No current commercially available assay can identify low-level minority drug-resistant variants. With a regimen change, minority species can be selected for by drug therapy and can rapidly lead to regimen failure. Interpretation of complex resistance patterns needs further study to understand interactions between various mutations and effect on phenotypic sensitivity and response to therapy. Tests’ advan-

tages and disadvantages are further listed and described in Table 1.

When Should Resistance Testing Be Used? Guidelines for the use of resistance testing have been developed by expert panels and are updated and published regularly as new knowledge develops. The EuroGuidelines Group for HIV Resistance, the International AIDS Society–USA Consensus Panel on Resistance Testing, and the Panel on Clinical Practice for Treatment of HIV infection of the U.S. Department of Health and Human Services (DHHS) have each published recommendations on the use of resistance testing in specific clinical settings. These are summarized in Table 2. All expert panels recommend resistance testing for newly diagnosed patients who have been infected within the last 2 years. The rationale for performing resistance testing in primary infection is based on evidence of increased levels of transmitted resistant virus in the population. It is estimated that drugresistant virus is present in 5% to 10% of patients and seen in about 25% of recently infected patients (Grant et al., 2002; Little et al., 2002; Richman et al., 2004). After the initiation of ARV therapy, there is an expected 10- to 100-fold reduction in HIV RNA levels within 2 to 4 weeks. A suboptimal response may be caused by the presence of low-level resistance mutations that were undetectable in the majority pretreatment viral population in the pretreatment genotype. With the selective pressure of ARV therapy, these mutations may emerge. When a suboptimal response occurs, resistance testing is indicated to guide the selection of an appropriate regimen. Resistance testing may be beneficial during pregnancy, pediatric infection, and chronic infection. It is important to remember that the value of resistance testing is a complement only to a patient’s medical history, immunologic status, viral load, medication tolerance, and adherence. Resistance guidelines are continually updated and often published first in widely circulated medical journals.

Kirton et al. / New Insights into HIV Resistance Testing: Nursing Guidelines and Implications Table 1.

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Advantages and Disadvantages of Genotypic and Phenotypic Resistance Assays Advantages

Genotypic assay

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Disadvantages

Shorter time requirement for assay (a few days) Less expensive than phenotyping Proven utility in predicting shortterm virologic outcome Ability to identify emerging mutation before onset of phenotypic drug resistance Quality control measures can help detect sample contamination Widely available

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Phenotypic assay

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Direct measurement of susceptibility to ARV drugs: measures concentration of drug required to inhibit viral replication by 50% (IC50) or 90% (IC90) Can be used to test viral susceptibility to any drug (including newly available agents) Provides direct information on cross-resistance and multidrug resistance Tests net effects of all mutations (“averaging” of mutational interactions) Can be used to evaluate non-B clade HIV-1 strains not commonly found in the United States

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Indirect measurement of drug resistance Results regarding mutations must be translated into conclusions about viral resistance to drugs Interpretations can vary Identifies mutation in the predominant viral quasispecies only; not able to detect minority viral species (⬍25% of viral population) Clinical relevance of many mutations remains unclear Resistance to certain drugs (e.g., A2T) does not correlate well with gene mutations Can be difficult to interpret when numerous mutations present Inability to detect linkages between mutations Lack of standardization of cutoff values for drug resistance: Not all drugs show the same range of IC50 values Differing cutoff values between assays Level of resistance that translates to clinical drug failure not fully understood Identifies phenotype in the predominant viral quasispecies only: not able to detect minority viral species (⬍25% of viral population depending on the assay) Long-term response to active drugs cannot be determined Does not take into account activity of drugs used in combination More complex testing platform requiring longer time to complete in most centers More expensive than genotypic assays

SOURCE: Zolopa (2004). NOTE: ARV ⫽ antiretroviral, IC ⫽ inhibitory concentration.

Provider Knowledge of Specific Mutations Interpretation of HIV resistance is perhaps one of the most challenging aspects of HIV care because of the complexity that is often associated with moderate and highly resistant viral mutants. Knowledge related to HIV resistance continues to emerge in terms of new resistance mutations and new patterns of resistance. Although it is important for nurses to stay

current with HIV resistance information, it may be a daunting task because new information is presented frequently at national and international meetings and publication and dissemination of the information frequently lags behind. It is important for nurses and other health care providers to have a basic understanding of HIV resistance patterns. In most instances, physicians, nurse practitioners, and physician assistants will be respon-

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Table 2.

HIV Drug Resistance Testing Guidelines: A Comparison of 3 Expert Panels

Primary/acute Postexposure prophylaxis Chronic, treatment naive Treatment failure Pregnancy Pediatric

IAS-USAa

DHHSb

Recommend — Recommendd Recommend Recommend —

Recommend — Recommend Recommend — —

EuroGuidelinesc Recommend Recommend Strongly consider Recommend Recommend Recommend

a. Hirsch et al. (2003). b. Department of Health and Human Services (2006). c. The EuroGuidelines Group (2004). d. For individuals who have been infected for up to 2 years and perhaps longer. Table 3.

Expert Resources on Resistance Testing Group

Internet Address

International AIDS Society–USA Stanford University HIV Drug Resistance database Los Alamos HIV Drug Resistance database

http://www.iasusa.org/resistance_mutations/index.html http://hivdb.stanford.edu http://resdb.lanl.gov/Resist_DB/default.htm

sible for making clinical decisions regarding therapy based on resistance test results. It is not uncommon for even the most experienced HIV clinicians to consult HIV resistance experts, Internet-based interpretation guidelines, and other sources for assistance in interpreting resistance test results. Even HIV resistance experts do not consistently agree on genotypic test results, as evidenced by the GUESS study (Zolopa, Lazzeroni, Rinehart, & Kuritzkes, 2002). A number of tools and resources are available to assist in the interpretation of resistance test information. Several Internet sites provide comprehensive information related to drug-resistant mutations including the International AIDS Society–USA, the Stanford University HIV Drug Resistance Database, and the Los Alamos database (See Table 3). Several rule-based algorithms and decision trees have also been developed and published to assist clinicians with interpretation of genotypic data. The following section provides a brief overview of mutations that are commonly reported as of this writing. Nucleoside Reverse Transcriptase Inhibitor Resistance The most important mutations associated with resistance to NRTIs include M184V, V118I and

E44D/A, L74V, K65R, and thymidine analog mutations (TAMs). An important consideration in the assessment of NRTI resistance is not only the presence of one or more of these key mutations, but the combination and/or patterns of mutations that accumulate. For this reason, interpretation of genotypic results for the NRTI class is often complicated, especially when heavily treated individuals accumulate multiple mutations. It is beyond the scope of this report to discuss in detail the interpretation of resistance assays. Rather, a summary of important key mutations and patterns is presented. Nucleoside and nucleotide RT inhibitors are generally classified into two subclasses: thymidine analogs (zidovudine and stavudine) and nonthymidine analogs (didanosine, lamivudine, emtricitabine, abacavir and tenofovir). Mutations that develop under the selective pressure of the thymidine analogue agents are frequently termed TAMs or NAMs (nucleoside-associated mutations). These mutations occur at positions 41, 67, 70, 210, 215, and 219 on the HIV genome. The accumulation of multiple TAMs is usually necessary to significantly reduce the susceptibility of thymidine analogs. An accumulation of certain TAM combinations can also confer cross-resistance to other NRTIs as well as to the nucleotide RT inhibitor tenofovir. For reasons that are not com-

Kirton et al. / New Insights into HIV Resistance Testing: Nursing Guidelines and Implications

pletely understood, TAMs usually follow one of two pathways in the development of resistance. The more common pathway contains mutations at positions 41, 67, 210, and 215. This pattern usually leads to a greater degree of resistance. The second pathway contains mutations at positions 67, 70, 215, and 219 (Wainberg, 2004). The M184V mutation is unique in that alone it can cause significant reduced susceptibility to lamivudine and emtricitabine. This mutation can also antagonize the actions of TAMs with the potential to increase susceptibility to zidovudine, stavudine, and tenofovir. Mutations at points 44 and 118 often appear together and can confer resistance to lamivudine. The L74V mutation may impact resistance to didanosine and abacavir. Multinucleoside resistance can occur with the K65R or Q151M mutation as well as the T69 insertion mutation. Multidrug resistance to NRTIs may also occur with an accumulation of multiple TAMs. In the presence of multiple NRTI mutations, many clinicians prefer a phenotype assay or combination phenotype and genotype over a genotype because the interactions between multiple mutations may be difficult to predict based on genotype alone. Nonnucleoside Reverse Transcriptase Inhibitor Resistance NNRTIs have a low genetic barrier to the development of mutations. The most important mutations associated with resistance in this class are K103N and Y181C. Although there is no cross-resistance between NRTIs and NNRTIs, several TAMs may cause hypersusceptibility to NNRTIs. Two major patterns of NNRTI resistance have been described. The K103N mutation frequently confers resistance to all the currently approved NNRTI agents. A second pattern involves an accumulation of multiple mutations including L100I, V106A, Y181C, G190S/A, and M230L (Hirsch et al., 2003). Hypersusceptibility to NNRTIs has been described in association with the presence of multiple NRTI mutations (Haubrich et al., 2002). Hypersusceptibility can be seen only with phenotypic testing. Although the clinical relevance has not been established, there may be biologic significance with an enhanced response to efavirenz-based regimens. It

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has been hypothesized that NNRTI hypersusceptibility may help explain the value of these NNRTI agents in salvage regimens for patients naive to NNRTIs (Haubrich et al., 2002). Protease Inhibitor Resistance The major mutations resulting in PI resistance occur at positions 30, 50, 46, 50, 54, 82, 84, and 90. Whereas resistance to PIs most frequently occurs with a step-wise accumulation of mutations, single mutations can also confer resistance to some agents. Some PI agents select for unique primary resistance mutations that are not associated with significant cross-resistance with other agents in the class. Examples include the D30N mutation seen with nelfinavir and the I50L that may occur when atazanavir is used in first-line PI therapy (Hicks et al., 2004). Entry Inhibitor Resistance Entry inhibitors have a different mode of action than the protease and RT inhibitors, and subsequently a different array of resistance-associated mutations can be seen. Mutations are typically located in the gp41 gene at points in the 36 to 45 region. Mutations identified at codons 36, 38, 38, 39, 42, and 43 have been associated with resistance to enfuvirtide, the only approved fusion inhibitor (Johnson et al., 2004). Resistance testing of this region of the HIV genome recently became commercially available.

Viral Fitness and Replication Capacity The term viral fitness refers to the ability of HIV to replicate in a defined environment and thus is used to describe the viral replication potential in the absence of an antiviral drug (Buckheit, 2004). Viral replication capacity (RC) can be defined as the ability of a virus to multiply in a given environment, usually compared with a reference or control (wild-type) virus (Haubrich et al., 2002). It has been shown that RT and protease inhibition mutations can affect the RC of HIV compared with wild-type virus. The D30N and M184V are examples of two mutations that have the ability to reduce RC.

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Haubrich (2004) suggests that the “cost” to the virus of acquiring such resistance is the reduced ability to replicate in the presence of the drug selected for the resistance mutation. This phenomenon may help explain the ongoing benefits of ARV therapy despite the presence of resistance. An RC assay is currently available from only one commercial lab in the United States and is included as part of its routine phenotypic testing procedure. The RC test compares the rate of viral replication for a patient isolate with the median rate of replication for a drug-sensitive, wild-type strain. The result is reported as a percentage compared with the median wild-type RC. As knowledge related to viral fitness and RC evolves, it is likely that RC measurement will be used in guiding therapy to improve treatment outcomes.

Resistance Testing in Nursing Practice The nurse as part of the HIV care team should apply the nursing process to ensure the appropriate use, collection, and interpretation of HIV resistance tests. The goal is to improve or maximize clinical outcomes for the HIV-infected individual through assessment, planning, intervention, and evaluation. Assessment It is important to document a complete and accurate ARV history including a detailed record of current and previous therapies as well as the drug side effects that the patient may have experienced. The patient history is important to the interpretation of the resistance assay. It is also important to assess the patient’s perceived barriers to adherence, because lack of adherence is known to increase the patient’s risk of developing resistance. Barriers to adherence may be physical (e.g., diarrhea, pain, difficulty swallowing pills, inadequate absorption) as well as psychosocial (e.g., financial concerns, lifestyle, homelessness, fear of taking the drugs, fear of drug side effects, admitting they are sick, being “outed” to family members/friends, lack of a support system). Resistance testing should be incorporated into patient management when appropriate (see Table 2). The nurse ensures that resistance testing is performed

when warranted by clinical indicators such as primary infection, chronic infection, and treatment failure. Research has shown an increasing rate of new infections with strains of HIV that are already resistant to one or more ARV agents. Current guidelines on resistance testing recommend testing for patients with a new HIV infection as one means of determining the best therapy options. It is important for the nurse to ensure that the patient understands that a regimen may not be selected until the results of the resistance test (the genotype) return. A patient with chronic HIV infection may also have HIV resistance testing performed, particularly in regions where resistant viral transmission is greater than or equal to 5%. Treatment failure is another indicator for resistance testing. Virological failure is defined in terms of viral load greater than 500 to 1,000 copies/mL. Resistance testing should be performed as soon as virological failure is confirmed and before ARV therapy is stopped in treatmentexperienced patients. The nurse ensures accurate documentation of treatment failure in the medical record, indicating the treatment regimen and the corresponding genotypic/phenotypic results. Resistance testing is also indicated for pediatric patients and pregnant women. Many HIV-positive patients keep a personal record of laboratory values and treatment regimens. Nurses play a vital role in helping the patient maintain accurate personal records. During clinic visits, laboratory data, current medications, medication side effects, and complications as a result of therapy (e.g., resistance to medications) should be recorded in the patient’s personal record (see Figure 3) The patient’s personal record is useful to the health care team because it provides a brief summary of the patient’s medical history and may prove useful in anticipating the patient’s educational needs. A patient with no documented history of treatment failure or previous resistance testing will require an explanation of the HIV resistance testing in the planning phase of the nursing process. Planning When the patient’s provider determines that resistance testing is necessary, the nurse may be involved in education, investigation of issues related to reim-

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Figure 3. The patient personal record is used to record the patient’s past and current medical history.

bursement of HIV resistance testing, and specimen collection. Education regarding resistance testing begins with an assessment of the patient’s knowledge regarding HIV resistance testing, the reason for testing, and an explanation of the benefits of testing. The patient who has no history of previous HIV resistance testing should receive education that explains how resistance occurs, how to prevent resistance through maximal ARV adherence, how HIV resistance testing is done, and the expected time period before results will be available. The nurse should investigate institutional policies regarding reimbursement. Knowledge of reimbursement issues is helpful because resistance testing is expensive. In some cases, alternative funding sources may need to be considered to help cover the cost of the tests. It may be important to determine how often the test may be ordered and what criteria must be met for the test to be reimbursed. The nurse should work

with other members of the treatment team to assure that the test that is ordered (genotype, phenotype, or virtual phenotype) will provide the data that are needed to make treatment decisions. The patient’s ARV history and previous resistance patterns are key for determining appropriate resistance testing. The nurse must also assure that resistance-testing specimens are correctly obtained. Samples should be obtained while the patient is on ARV therapy. If the patient’s ARVs have already been stopped, the sample should be obtained no later than 1 to 2 weeks after stopping ARVs. Samples should be obtained in a plasma preparation tube or ethylene diamine tetraacetic acid– containing tube (most commonly found in purple-top tubes) and never in a heparinized tube. A total of 7 mL of whole blood should be drawn to allow for at least 2 mL of plasma to be extracted during aliquotting (the process of separating red cells from the plasma). Care should be taken during the

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collection process to prevent the lysing of red blood cells (e.g., never vigorously shake the tube) because this may interfere with test results. Ideally, specimens should be transported immediately to the lab for processing. If specimens must be stored in the clinic unit, it is recommended that the specimen be aliquotted within 4 to 6 hours after the specimen is taken from the patient. If the nurse must perform this procedure in the clinic or office setting, it is best to collaborate with laboratory professionals to ensure that the appropriate equipment is obtained and that all staff involved are properly trained. Aliquotted plasma should be frozen as soon as possible and remain frozen during the transport of the sample for analysis. If specimens cannot be immediately aliquotted, do not freeze the whole blood specimen.

the need for resistance testing, the benefit of resistance testing, and the decisions that have been made regarding his or her ARV regimen. Changes in behavior may impact adherence to ARV therapy. Determine the lifestyle changes that were made and the impact of these changes on adherence and prevention. The nurse should also document the adherence behaviors/methods that worked, as well as those that did not work for the patient. The nurse should assist the patient to establish a method of personal record-keeping in regard to health status and management that can be used by other health care providers to evaluate care.

Intervention

The Association of Nurses in AIDS Care Expert Panel on Resistance Testing recognizes the importance of partnering with patients to monitor and manage their health status. To assist patients and to help all providers have an accurate record of past and present health status, the panel advocates that all HIV nurses assist patients with establishing personal resistance records (see Figure 3). These personal records are available from the Association of Nurses in AIDS Care.

The nurse acts as an advocate for the patient. Decisions regarding initiation or change in therapy should always be patient-driven in collaboration with the entire care team. Changes or modification in therapy may be indicated based on the resistance test results. The nurse begins by helping the patient to understand the reasons why a change in therapy is indicated. Nurses work with the patient to assure that the action taken as result of the test provides better control of replicating virus. Generally, three options exist in regard to ARV therapy: first, continuing the current ARV therapy; second, boosting the current ARV regimen with additional ARVs; or third, changing the entire or individual components of the ARV regimen. All of these options require patient education regarding how making or not making changes could impact the patient’s lifestyle. Careful documentation of these discussions should be included in the medical record. Evaluation The effectiveness of nursing interventions is evaluated by patient outcomes. Several important patient outcomes related to HIV resistance testing need to be considered. The patient should receive education regarding resistance testing and the potential changes in treatment that may result. Confirmation of this knowledge is shown when the patient can verbalize

Patient Personal Record

Summary Resistance testing in clinical practice has greatly expanded. Genotype testing is typically preferred in treatment-naive patients who have either acute or chronic infection or for cases of early virologic failure. By contrast, phenotype testing is preferred when patients have high-level resistance to NRTIs or PIs on genotype or when they have had multiple regimen failures with limited treatment options and are those for whom interpretation of resistance tests has become too complex. The optimal selection of subsequent regimens requires integration of resistance data with the patient’s treatment history as well as with results from clinical studies. Nurses play an important role not only in appropriate specimen collection, handling, and storage, but in the assessment and interpretation of test results. Patients must be educated about the impact of adherence on resis-

Kirton et al. / New Insights into HIV Resistance Testing: Nursing Guidelines and Implications

tance, and nurses must work with clients who have adherence issues to minimize the emergence of drugresistant virus. The nurse also works toward helping the client amass critical information about his or her regimen and resistance patterns because all previous information is useful in test interpretation. ANAC has developed the patient personal record, which is one tool that nurses can use to assist clients in recording key elements of their present and past significant mutations.

The Association of Nurses in AIDS Care Expert Panel on Resistance Testing Lyn Stevens, MS, NP, ACRN Syracuse, NY Paul Alfieri, RN San Antonio, TX MaryAnn Andrews, BSN, ACRN Voorhees, NJ Christine Brennan, RN, MSN, FNP, ACRN New Orleans, LA Cynthia Harrison, FNP-C Los Angeles, CA Jody Gilmore, MSN, CRNP Philadelphia, PA Mary Hermanns, CNS Montclair, NJ Carl Kirton, MA, RN, APRN, BC Clifton, NJ Wayne Morra, RN Greenwood, DE David Sterken, MN, CPNP, CNS Grand Rapids, MI Deb Trimble, RN, MS, FNPC, ACRN Houston, TX Adele Webb, PhD, RN, ACRN, FAAN Akron, OH

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