HIV AIDS drug resistance

Overview

The ability of HIV to mutate and reproduce itself in the presence of antiretroviral drugs is called HIV drug resistance. HIV Drug Resistance occurs when microevolution causes virions to become tolerant to antiretroviral treatments. Drug resistant virus will continue to replicate in the presence of the drug to which it has become resistant.

Contributing Factors

As ART continues to expand, the emergence of some drug resistance is inevitable. Many factors leading to treatment failure and eventually drug resistance are as follows:

• HIV biology: Human Immunodeficiency Virus replicates at a high rate, with more than 10⁹ virions produced daily. The absence of DNA polymerase give rise to mutations in the progeny. The combinations of high replication rate and repeated introduction of mutations produces randomly generated mutatant stains that give rise to drug resistance.
• Variable response to mutation: Resistance can develop against certain drugs with a single mutation, while some require multiple mutations for resistance to take effect. Example: A single mutation can lead to high-level resistance in lamivudine, efavirenz and nevirapine. On the contrary, it takes multiple mutation to develop resistance against Protease inhibitors.
• Insufficient knowledge among patients and health workers.
• Suboptimal adherence to treatment regimens.
• Drug stock-outs.
• Inadequate patient monitoring mechanisms.

Historical Perspective

• Over the past decade, access to ART for HIV has dramatically increased in low- and middle-income countries. From preliminary data, more than 6 million people were receiving ART in these countries at the end of 2010, as compared to just 400 000 at the end of 2003.
  • Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), was first administered in 1987, and until 1995, monotherapy or dual therapy with NRTIs were the only treatments available.
  • The first protease inhibitor (PI), saquinavir, was approved for treatment in 1995, followed closely in 1996 by a nonnucleoside reverse transcriptase inhibitor (NNRTI), nevirapine. These new drugs generated a major change in the treatment strategy against HIV—highly active antiretroviral therapy (HAART).

Types

HIV drug resistance may be transmitted or acquired.

1. Acquired drug resistance: Drug resistance could develop if patients interrupt their treatment or do not take it according to prescription.
2. Transmitted drug resistance: If people are infected by others who had HIV drug resistance, it is called transmitted drug resistance.

Current scenario

• Nearly all drugs currently used to treat HIV eventually stop working when patient develops resistance to ART. HIV develops resistance when it evades the effects of these treatments. A recent study estimated the percentage of the American HIV positive population with some form of drug resistance to be 76.3%.
• The extent of HIV drug resistance resulting from recent ART scale up in resource-limited countries has not systematically been quantified due to the lack of reliable data and information.

Mechanism of drug resistance

• As a retrovirus, HIV uses the enzyme reverse transcriptase to synthesize DNA from its RNA genome but it lacks a mechanism for correcting errors made while reproducing its genome. As a result, HIV replicates its genome with the highest known mutation rate of any living organism. This creates an ideal situation for natural selection to act on the HIV population, as genetic variation is the raw material for natural selection.
• These mutations accumulate over generations in the HIV infected population, resulting in great genetic variation and an increased probability of a virion developing an evolutionary selective advantage over other virions. Natural selection then acts on HIV by selecting for virions with higher fitness, as all others are eventually killed off by drug treatments. The virions that are able to escape the harmful effects of the drug then create an entirely new, drug resistant population.
• With HAART, at least 3 drugs are administered at the same time, which substantially reduces viral load and, compared to results of earlier regimens, increases the life expectancy of patients. These advantages follow because the mutations necessary to confer resistance to HAART are generated at a slower rate and are lost more rapidly than those conferring resistance to monotherapy or dual therapy. Moreover, viral strains resistant to HAART are not as efficient at completing their own life cycle (e.g., their replication rates are lower), they may generate less illness and lower proportion of deaths among infected persons, and the viral strains are less likely to be transmitted to other persons.

Consequences of drug resistance

The consequences of drug resistance include

1. Treatment failure.
2. Increased direct and indirect health costs associated with the need to start more costly second-line treatment for patients.
3. The spread of resistant strains of HIV.
4. The need to develop new anti-HIV drugs

Strategies against HIV Drug resistance

WHO and its HIV ResNet group of experts and organizations have developed a Global strategy for prevention and assessment of HIV drug resistance. The strategy aims to build evidence on the scale of HIV drug resistance and equip and prepare countries with knowledge, skills and systems to respond should drug-resistant HIV epidemics emerge.

Resistance Testing

Resistance testing is usually performed for the management of patients with established HIV disease but can also be done before starting therapy. It is also recommended during pregnancy to optimize treatment selection and to decrease the risk of perinatal transmission.

There are 2 main methods to detect antiretroviral resistance in HIV:

1. Genotypic testing.
2. Phenotypic testing.

1. Genotypic Testing

• Underlying Concept: Drug-resistance mutations have been well known and characterized from patient specimens and in vitro work. Rapid detection of probable resitance mutation to different ART can be detected by amplification and sequencing.

• Limitations:
  • Low viral load
    • It not only decreases the sensitivity of the test but also make this test redundant.
    • Low-level resistance can be lost in the mixed population of viral pseudospecies, which often exists in HIV infected persons.

2. Phenotypic testing

• Underlying Concept: It also test the virus’s ability to replicate in the presence of antiretroviral drugs.
• Limitations:
  • Low viral load limits the test.
  • Labor intensive.
• Advantages: It is better than genotypic testing at detecting mixed populations of resistant and sensitive pseudospecies.