What is PHENOSCRIPT™?
What is HIV resistance to antiretrovirals?
Why is resistance to antiviral drugs important today?
What is the point of resistance tests?
What are resistance tests?
When should a resistance test be used?
What are the advantages and the limitations of the two types of resistance tests?
In what way are phenotypic tests complementary to genotypic tests?
What is new about PHENOSCRIPT™?
Who developed PHENOSCRIPT™, and how?
How has the PHENOSCRIPT™ technique been validated?
To order PHENOSCRIPT™
Bibliographic references

 

What is PHENOSCRIPT™?

PHENOSCRIPT™ is a phenotypic antiretroviral resistance test. It is an in vitro assay that measures the susceptibility of the circulating viral population of an HIV-infected individual to a panel of antiretroviral drugs (including all currently available protease and reverse transcriptase inhibitors).

PHENOSCRIPT™ is intended to be used in association with treatment and tolerance records to help healthcare providers to identify the optimal treatment combination for individual patients: that is, the combination that will most effectively inhibit the replication of the virus circulating in the patient and that will also be best adapted to the patient in terms of toxicity and pharmacology.

PHENOSCRIPT™ can also be used as a clinical development tool to aid a better understanding of the mechanisms of viral resistance and to contribute to the advancement of new drugs and new therapeutic strategies.


What is HIV resistance to antiretrovirals?

Unlike many other retroviruses, infection by HIV is characterized by a high rate of virus production and turnover. The absence of proof reading activity of HIV reverse transcriptase means that random mutations are frequently introduced during the replication process resulting in the generation of numerous viral quasi species in the infected individual. While some of these mutations may reduce the competitiveness of the viral quasi-species, others may prove advantageous, conferring improved replication capacity, an ability to escape a component of the immune response, or reduced susceptibility to antiretroviral drugs. Antiretroviral resistance is a reduction in the susceptibility of the virus to a particular agent resulting from mutations in the viral protein that is targeted by that agent (for example, the reverse transcriptase or the protease). Resistance mutations generally alter the shape and the biochemical properties of the viral proteins and are able reduce the activity of the drugs through a variety of mechanisms. Insufficiently suppressive treatment combinations will allow the continuous repetition of cycles of random introduction of mutations and of selection of viruses with decreasing levels of drug susceptibility.

In the clinic, a virus is described as resistant when one or more of the antiretrovirals in use against it cease to effectively inhibit viral replication. Resistant virus can be transmitted from one patient to another and as a result some patients who have been recently diagnosed as seropositive may not respond to one or several drugs owing to their initial infection with resistant virus.

Why is resistance to antiviral drugs important today?

HIV resistance to antiretrovirals is a major public health problem.
A French study published in 2002 evaluated the proportion of treated HIV-infected individuals carrying resistant viruses to be about 60%. In particular, this study stressed that 34% of patients carried virus resistant to one class of antiretroviral, 39% to two classes and 6% to all antiretrovirals1. This 6% of patients in late therapeutic failure (with viral loads higher than 30.000 copies/ml and CD4+ lymphocytes less than 200 cells/mm3) represented a population of 1600 to 2300 individuals. The choice of treatment for these patients requires a detailed knowledge of the resistance profile of the circulating virus, made possible only by using the various resistance tests available.

In a longitudinal study carried out in the United States, more than 75% of treated HIV-infected individuals were shown to be carrying resistant viruses. Half of these patients had acquired resistance to two classes of antiretroviral and 14% carried virus to all three existing classes of antiretroviral 2.
This resistance makes the choice of salvage treatment regimens a complex exercise for which resistance tests are beginning to be seen as an indispensable tool.

What is the point of resistance tests?

Along with information on plasma viral load (a marker of viral replication) and CD4+ lymphocyte counts (a marker of the state of the immune system), antiretroviral resistance tests are important tools for clinicians in the long term monitoring and management of HIV-infected patients.

Resistance tests can identify those antiretroviral agents that are effective against the patient's virus and those which are not. The results of a resistance test, combined with the treatment and tolerance history of the patient, can thus considerably aid the selection of an optimal treatment regimen for the patient.

The interest of resistance tests has been demonstrated by several prospective and retrospective clinical trials. Overall these trials have shown that the use of resistance tests increases the probability of success of new treatments for patients experiencing therapeutic failure (3–11).

Resistance tests are also of considerable use in the clinical trials to monitor the development of resistance and to investigate potential mechanisms of resistance (12,13).

What are resistance tests?

There are two types of HIV antiretroviral resistance test:

Genotype tests identify mutations present in the genes that code for the proteins targeted by antiretroviral drugs (protease, reverse transcriptase). The interpretation of the list of mutations present, using algorithms based on the correlation of genotype with phenotype or with clinical response, results in a list of drugs with potential efficacy in a subsequent treatment regimen.
Phenotype tests are direct quantitative measures of resistance. They consist of an evaluation of the susceptibility of viruses reconstructed from material extracted from the patient’s blood to a panel of antiretrovirals. The results are expressed as the concentration of each antiretroviral that is able to inhibit the growth of the virus in the laboratory by a certain amount (usually 50% or 90%). The results are then interpreted using cut-offs based on comparisons with wild-type viruses and on the correlation of phenotype with clinical response. In the PHENOSCRIPT test each antiretroviral tested is classed as being “likely,” “possible” or “unlikely” to contribute to an effective treatment response(14).


These two types of test provide complementary information and their rational use permits a better understanding of the antiretroviral resistance profile of the viral population studied(15).

When should a resistance test be used?

In an effort to establish the appropriate conditions for the use of drug resistance testing several groups of experts have published recommendations. The Co-ordinated Action (AC11) group of the French National Agency for AIDS Reserach (ANRS) meets regularly to propose an algorithm for the interpretation of genotypic resistance test results. and to update their therapeutic recommendations for the care of HIV-infected individuals (Delfraissy, Flamarion, 2002). The EuroGuidelines Group for HIV Resistance includes experts from different countries and from the pharmaceutical industry and other international organisations(16, 17). In addition groups of experts from Britain, Spain, Germany, Italy, Belgian and Luxembourg also publish regularly updated treatment guidelines. In the United States both the International AIDS Society (IAS)-USA Consensus Panel on Resistance Testing, and the Panel on Clinical Practices for Treatment of HIV Infection of the US Department of Health and Human Services (DHHS) have recently published updates of their resistance testing and treatment guidelines1(8, 19).


A broad consensus exists between all these recommendations, in particular for the use of resistance tests in the following situations:


Prescription of a new treatment following therapeutic failure, a virological response that is too low, or a therapeutic interruption.

Initiation of therapy following recent infection (within 6 months) or in chroniclly infected individuals infected for less than two years. In fact, strains which are resistant to one or several antiretrovirals can be transmitted from one individual to another (10 to 30% of new infections)(20, 21, 22). The choice of the first treatment is critical since the pathway of mutations selected by successive treatment failures can be determined at an early stage and may profoundly affect the possible number of lines of treatment and thus the chances of a prolonged therapeutic response.

Prescription of treatment for women during pregnancy and selection of the best therapy to avoid mother-to-child transmission of the virus.

Treatment of young babies; the options are limited for paediatric patients and the choice of an effective treatment is even more critical than for adults.

Post-exposure prophylaxis, for example, to help define medication following contamination by hypodermic syringe or at birth.


Apart from the French group, which recommends genotyping as a therapeutic tool in the first instance, none of the published recommendations indicates any preference for one type of resistance test over the other.

What are the advantages and the limitations of the two types of resistance tests?

Genotypic tests can be completed in a few days. They yield a list of mutations associated with resistance and permit the identification of sub-populations down to 20% of the total population. Nevertheless, for a reliable interpretation, it is necessary to use well-documented and up-dated interpretative algorithms for all the antiretriviral agents tested. For some drugs, the mutations responsible for resistance have not yet been completely identified and there are cases where the many different algorithms available give contradictory results. In France, virologists and clinicians mainly use the algorithm established by the AC11 of the ANRS.

There are two types of HIV (HIV-1 and HIV-2). Type 1 is much more widespread and consists of two groups (M and O), group M itself being divided into 10 sub-types (A – J).

The algorithms now in use were defined principally from patients infected by sub-type B. New studies show that the mutations involved in the mechanisms of resistance vary according to the sub-type. This implies that determination of the viral sub-type may be essential for the interpretation of genotypic data (23, 24, 25).

Phenotypic tests are independent of sub-type and are easier to interpret, as they provide a direct measurement of the susceptibility of the patient’s viral population to each available antiretroviral. They provide a quantitative measure of resistance (since they evaluate the capacity of the tested virus to multiply relative to a drug-susceptible reference virus in the presence of the drug under study); this is particularly useful, as resistance can have different levels, which are not quantifiable by genotyping (26).

Phenotyping is more time consuming and more complex than genotyping, and consequently more expensive. It is recommended for the definition of salvage therapies and to evaluate the possibility of cross-resistance between drugs – which may be difficult to predict accurately from genotypic results (27). A recent US study has shown that phenotypic tests are associated with long-term treatment benefits (28).

Most international published recommendations insist on the complementarity of the two types of test. In March 2003, the European experts, meeting at a consensual conference at Luxembourg confirmed this complementarity by not pronouncing in favour of either of the two tests.

In what way are phenotypic tests complementary to genotypic tests?


Phenotypic tests may provide a better evaluation of viral susceptibility to protease inhibitors and to more recently approved antiretrovirals, particularly for patients who have failed multiple lines of treatment and carry viruses bearing numerous mutations (29, 30).

Phenotypic tests allow the direct measurement of the corrective effect of certain mutations that are able to restore the susceptibility of a virus carrying other mutations responsible for resistance. For example, it has, been demonstrated that the reverse transcriptase mutation M184V, associated with resistance to lamivudine, restores the zidovudine susceptibility of viruses with the mutation T215Y (31).

Phenotypic tests can measure hypersusceptibility to certain antiretrovirals, such as the non-nucleosidic reverse transcriptase inhibitors, thus allowing for a potential dose reduction and for a reduced risk of side-effects (32).

The results of a phenotypic test can be used to calculate an inhibitory quotient, defined as the ratio between the IC50 of a particular antiretroviral for the plasma derived virus and the plasmatic concentration of the antiretroviral Low-level resistance may allow the clinician to retain the antiretroviral concerned and to attempt to obtain a plasma concentration greater than the IC50 by increasing the dose or by other methods such as ritonavir boosting of protease inhibitors. The measurement of inhibitory quotients could be incorporated into the regular monitoring of plasma antiretroviral concentrations, which has been shown to be a factor in the success of first line treatment regimens (33,34).

Phenotypic tests can also measure the replicative capacity (fitness) of the patient’s virus in comparison to a reference virus. It has been suggested that in patients with few remaining treatment options it may be of benefit to conserve an ineffective therapeutic regimen in order to maintain a resistant virus with a low replicative capacity and thus reduce the impact of viral replication on CD4+ cell counts (35,36).

What is new about PHENOSCRIPT™?

PHENOSCRIPT™ became the first phenotypic resistance test to be made available to patients in France in June 2003.

The test uses the latest technology and innovations in biology and molecular virology, considerably accelerating the turn round time (from 1-2 months to 2-3 weeks) and increasing the sensitivity and reproducibility of the test in comparison with to classic tissue culture based phenotypic tests.

PHENOSCRIPT™ provides a direct measurement of the susceptibility of the patient’s virus to the tested antiretrovirals and may be of particular value for patients experiencing therapeutic failure, for whom genotyping does not always supply a clear answer.

Who developed PHENOSCRIPT™, and how?

PHENOSCRIPT™ is the result of collaboration between VIRALLIANCE and Unit 552 of the French National Institute for Health and Medical Research (INSERM). VIRALLIANCE, a subsidiary of BIOALLIANCE PHARMA created in early 2000, is a biotechnology company with the objective to provide new therapeutic tools for cancer and infectious diseases. INSERM’s Unit 552, specialised in antiviral research, is directed by Dr François CLAVEL, co-discoverer of the HIV-2 virus at the Pasteur Institute. Numerous developments and a considerable number of studies have allowed the test to evolve and to become commercially available.

The test has been validated for the three classes of antiretroviral currently available in France – protease inhibitors and reverse transcriptase inhibitors (nucleosidic and non-nucleosidic) – and evolves continually to integrate the latest antiretrovirals (entry, integrase and budding inhibitors).

How has the PHENOSCRIPT™ technique been validated?

In 2001, the EuroGuidelines group co-ordinated a study to evaluate three available phenotypic resistance tests in parallel: PHENOSCRIPT™, Antivirogram™ and PhenoSense™. The results, presented at the 5th International Workshop on HIV Drug Resistance and Treatment Strategies (Scottsdale, Arizona, USA) in June 2001, show a very good correlation between the three tests (37).

Another study presented at the same Workshop (PROF3020) compared PHENOSCRIPT™ and Antivirogram™. A strong correlation between the results obtained with the two methods was demonstrated (38).

PHENOSCRIPT™ has been performed on more than a thousand plasma samples as part of several clinical studies undertaken for the ANRS (Narval39, Puzzle40, Giga-haartNP) and industrial promoters (Roche, GSK, BMS).

Since its creation, VIRalliance has maintained a quality assurance system that has permitted the characterisation and standardisation of all stages of the analysis. This standardisation has confirmed the robustness of PHENOSCRIPT™ and allowed the technology to be transferred to the highly specialised medical analysis laboratory PASTEUR CERBA. VIRalliance was certified ISO9001:2000 in May 2003.

Bibliographic references

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