HIV Genotype and Phenotype Testing

HIV Genotype and Phenotype Testing

Development of drug resistance to antiretroviral therapy

HIV Genotype and Phenotype Testing- Human immunodeficiency virus (HIV) replicates rapidly, particularly in response to antiretroviral (ARV) therapies.

These replications are a result of substitutions in the viral protease, reverse transcriptase, or integrase enzymes which are targeted by various ARV drugs that can lead to drug-resistant mutations (quasi species). These mutations lead to virologic treatment failure.

Because of the rapidity of these replications, highly active antiretroviral therapy (HAART) has been designed to use treatments with multiple mechanisms of action in order to reduce mutations and the development of drug-resistant variants. The drug included in this regimen include, but are not limited to, nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, and fusion inhibitors.

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Effectiveness of HAART

The effectiveness of HAART in suppressing HIV replication for prolonged periods has allowed HIV to be considered a chronic, rather than a fatal, disease.

However, drug failure continues to occur because HAART regimens do not completely suppress replication in all cases. Other factors, such as nonadherence, inadequate potency of treatment, or suboptimal drug levels may play a part in drug failure.

Historically, the initiation of, or a change in, ARV therapy has been based on HIV ribonucleic acid (RNA) levels and CD4 cell counts, both of which are essential components of the clinical management of HIV. Because treatment decisions can irrevocably alter an individual’s response to future therapy, clinicians can also utilize genotypic or phenotypic assays as additional clinical tools for selecting safe and efficacious treatment regimens.

Test information


HIV phenotype and genotype testing may include genotypic resistance assays, phenotypic resistance assays, or virtual phenotyping.

Genotypic resistance assays

Genotypic resistance assays look for mutations that are present in HIV genes (e.g., reverse transcriptase [RT], protease, fusion, or integrase enzymes). Some assays sequence the entire gene, while others use probes to detect mutations that are known to produce drug resistance.

Advantages of genotyping over phenotyping are a shorter turnaround time (1-2 weeks compared to 2-3 weeks) and lower cost.

Phenotypic resistance assays

Phenotypic resistance assays measure the ability of the virus to replicate in vitro in the presence of an ARV drug. The medical literature, the federal government and medical society guidelines all support the use of HIV genotyping and/or phenotyping to identify drug-resistant viruses and assist with selecting the most appropriate ARV drugs for an individual.

Virtual phenotyping

Virtual phenotyping is a modified genotypic test that looks for mutations in the genetic structure of the HIV virus. When mutations are found, the information is entered into a database that contains data on thousands of HIV samples. If the genotype of the virus being studied matches a genotype in the database, the assumption is that the phenotype will also match.

Virtual phenotyping is not a direct measure; rather, it is a prediction based on genotypic analysis and database matching. Current clinical practice guidelines do not provide specific guidance about the role of virtual phenotyping in HIV resistance testing.

However, based on current clinical practice, it appears there is correlation between genotypic interpretation and virtual phenotypic results—particularly when the drug(s) used in HAART have been on the market long enough for the correlative database to garner enough matching genotypes and phenotypes to provide accurate phenotypic results.

As a result, the value of virtual phenotyping is limited when evaluating newer and experimental drugs because there are fewer matching genotypes and phenotypes in the correlative database.

Infectious Diseases Society of America

Infectious Diseases Society of America (IDSA, 2013) guidelines agree that HIV resistance testing should be done routinely upon initiation of care and/or at the start of

ART therapy initiation as well as in patients experiencing virologic failure:

  • “Because drug-resistant virus can be transmitted from one person to another, all patients should be assessed for transmitted drug resistance with an HIV genotype test upon initiation of care.” [Strong recommendation, high quality evidence].
  • “If therapy is deferred, repeat testing at the time of antiretroviral therapy (ART) initiation should be considered because of the potential for superinfection.” [Weak recommendation, low quality evidence]
  • “Resistance testing is also indicated for patients who are experiencing virologic failure to guide modification of ART.” [Strong recommendation, high quality evidence].


Medically Necessary

HIV genotyping is considered medically necessary and, therefore, covered for any of the following:

  • For resistance testing at baseline for individuals with acute HIV infection, regardless of whether ARV therapy is initiated or deferred.
  • To guide therapy in ARV-naive individuals with chronic HIV infection, regardless of whether ARV is initiated or deferred.
  • For all pregnant women prior to initiation of therapy and for those entering pregnancy with detectable HIV RNA levels while on therapy.
  • To assist in the selection of active drugs when changing ARV regimens in individuals with virologic failure or suboptimal response on their first or second regimens.
  • For individuals with known or suspected complex drug-resistance patterns.

HIV phenotyping is considered medically necessary and, therefore, covered when genotypic results do not allow for drug selection in either of the following instances:

  • To assist in the selection of active drugs when changing ARV regimens in individuals with virologic failure or suboptimal response on their third and subsequent regimens, or if the individual had initially acquired a multidrug-resistant virus.
  • For individuals with known or suspected complex drug-resistance patterns. Virtual phenotyping should be used with discretion as a testing option with respect to newer drugs used in antiretroviral therapy (ART) because there are typically fewer matching genotypes and phenotypes in the correlative database.
  • Standard phenotyping should be used in these circumstances.

Not Medically Necessary

HIV genotyping and phenotyping performed at the same time is duplicative and is considered not medically necessary and, therefore, not covered.

For more information about HIV Genotype and Phenotype Testing, please visit WHO

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