HIV/AIDS Epi Update - May 2004

Primary HIV Anti-retroviral Drug Resistance in Canada

Introduction

At A Glance

The Canadian HIV Strain and Drug Resistance Program (CHSDRSP) continues to monitor and assess HIV strains and the transmission of HIV drug resis- tance in Canada.

Preliminary observations from the CHSDRSP of HIV drug resistance among treatment-na
ve individuals with newly diagnosed HIV infection in Canada (i.e. primary drug resistance) are as follows:
- The overall prevalence of primary drug resistance to at least one antiretroviral drug is 7%.
- The overall prevalence of multi-drug resistance to two or more classes of antiretroviral drugs is 0.7%. -Primary drug resistance has been observed among both females and males, across different age groups, ethnicities, and exposure categories, in HIV-1 subtype A, B, and C infections, and among recent and older prevalent HIV infections.

The prevalence of primary drug resistance is similar to what has been observed in other countries where highly active antiretroviral treatment (HAART) is widely used.

Drug resistance among individuals receiving treatment (secondary drug resistance) is well documented. Resistance observed in treatment-naive individuals with newly diagnosed HIV infection, in whom resistance is presumably due to the transmission of a drug-resistant variant of HIV-1 (primary drug resistance), is less well understood. However, there is increasing evidence to suggest that transmission of drug-resistant strains of HIV is becoming more widespread in most countries where HAART is used. Drug resistance complicates the treatment of HIV, has important implications for HIV-related morbidity and mortality and may result in increased health care costs.

This Epi Update provides a summary of how drug resistance arises and how it is identified, and an overview of key studies on the prevalence of primary drug resistance in countries where HAART is commonly used.

Why Conduct Primary Drug Resistance Surveillance?

Although HAART has led to a reduction in HIV-1 related morbidity and mortality in Canada and some other countries, there is a concern that its widespread use, the increased number of treatment failures and continuing risk behaviour may result in increased transmission of drug-resistant virus. The first case of primary drug resistance was reported in 1993 with the transmission of a zidovudine-resistant HIV-1 strain.¹ Since then, many reports of transmission of drug-resistant HIV strains have been published, and there is increasing evidence to suggest that the proportion of new HIV infections involving drug-resistant strains may be increasing in countries where HAART is routinely used. (For an overview of these studies see Wainberg and Friedland² and Little.³ )

What is less well understood is the prevalence of primary drug resistance and the variation of this prevalence over time, geographic area and population risk group. The CHSDRSP aims to address these questions, and the resulting information will help inform the development of any guidelines for initial therapeutic regimens and more effective HIV prevention strategies, including the prevention of vertical transmission.

Evolution of Drug Resistance

Viral resistance develops largely as a result of changes (mutations) in the genetic material that codes for the HIV reverse transcriptase (RT) and protease enzymes. Both these enzymes are required for viral reproduction, and current antiretroviral drugs interact with them to impede their activity. Although new drugs are continually being developed, the most commonly used antiretroviral drugs that are approved for treatment of HIV infection fall into three classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). For a review of NRTI, NNRTI and PI resistance see Loveday,⁴ Deeks⁵ and Miller⁶ respectively.

Most mutations are lethal or neutral and are not associated with conferring drug resistance. However, under conditions in which treatment does not completely inhibit viral replication, virus with drugresistant mutations can develop and replicate, resulting in treatment failure. In general, it is theoretically possible for every single drug-resistant mutation to be generated daily.⁷ For some drugs (e.g. NNRTIs), a single mutation is associated with a high level of drug resistance. Such a mutation is referred to as a "major" mutation. For other drugs (e.g. most protease inhibitors), a combination of mutations is often required to confer resistance. Such mutations are known as "minor" mutations.

Methods to Identify Drug Resistance

Genotypic tests identify mutations in the viral genetic material through commercially available probes for particular mutations or through sequencing viral genes of interest. By comparing the generated sequences with databases containing resistance-conferring mutation algorithms, the presence or absence of drug resistance can be identified.

Phenotypic tests determine the enzymatic activity of viral genes or assess viral growth in increasing concentrations of drugs. Resistance is usually defined when, compared with the wild type strain, four or more times the amount of drug is required to inhibit viral growth by 50%. This test is similar in concept to antibiotic resistance testing in bacterial culture.

Note: Genotypic and phenotypic testing and interpretation for patient care are evolving fields that are extremely complex, requiring expert inputs.

Summary of Key Studies on the Prevalence of Primary Drug Resistance

It is difficult to make inter-study comparisons and arrive at firm conclusions because of differences in study design. including study populations, types of resistance testing used, and mutations studied and reported. However, the following observations can be made for Canada:

• Results from the CHSDRSP indicate that between 1998 and 2001, the overall prevalence of major mutations to at least one antiretroviral drug was between 4.5% and 10.5% (Table 1, final column). Pooling results from all years provides an estimate of 7% for overall prevalence of major mutations.
• A BC study in 1996-98 found an overall prevalence of 3.5%, and a Montreal study carried out between May 1996 and December 2001 found that the prevalence of major mutations to at least one antiretroviral drug was between 11.4% and 23.2% (Table 1, final column).
• Primary drug resistance to two or more classes of antiretroviral drugs (multi-drug resistance) has been observed in Canada with an overall prevalence of up to 9.9% (Table 1, column 7).

Table 2 shows the results of studies on primary drug resistance that were conducted in the USA and in Western Europe. Please note that this table is NOT meant for inter-study comparisons: such interpretations are difficult to make because of differences in study design, including study populations, types of resistance testing used, and specific mutations analyzed and reported. The results suggest that the prevalence of major mutations associated with at least one antiretroviral drug is similar to that in Canada. Of note, mother-to-child transmission of zidovudine, nevirapine, or multi-drug resistant HIV-1 has been reported in the USA and in France.^13,14

Comment

The prevalence of primary HIV drug resistance is widespread in most countries where HAART is used. Although the interpretation of results is difficult and evolving, persons infected with drug-resistant variants of HIV may be at increased risk of drug failure despite being therapy-naVve. Surveillance of primary drug resistance is needed not only to develop guidelines for initial therapy but also to better understand and prevent the transmission of resistant variants.

References

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