Genotyping and NNRTI Mutations: Where Do We Go From Here As HIV Populations Get Older?

Each year at the HIV Resistance Conference, the issue of non-adherence or (non-compliance) and genotyping surfaces as it relates to HIV treatment regimens. In an effort to vigorously address this issue, resistance or phenotype testing has gained traction.

As genotyping procedures have increasingly become more sensitive and complex, HIV scientists and physicians are finding new clinical approaches to treat compromised patient populations on Non-nucleoside transciptase inhibitor (NNRTI) classes of drugs. Further, as age demographics play a vital role in these populations, understanding phenotype/resistnace panels for regimen changes is paramount.

As many of you may know, genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA chips or beads. The technology is intrinsic for test on father-/motherhood and in clinical research for the investigation of disease-associated genes. Further, the genotype is the specific genetic makeup (the specific genome) of an individual, in the form of DNA (Cohen et al). Together with the environmental variation that influences the individual, it codes for the phenotype of that individual. Non-hereditary mutations are not classically understood as representing the individuals’ genotype. Hence, scientists and doctors sometimes talk for example about the (geno)type of a particular cancer, thus separating the disease from the diseased. While codons for different amino acids may change in a random mutation (changing the sequence coding a gene), this doesn’t necessarily alter the phenotype (Cohen et al, 2006).

NNRTI’s are a class of anti-HIV drugs. When one NNRTI is used in combination with other anti-HIV drugs – usually a total of 3 drugs – then this combination therapy can block the replication of HIV in a person’s blood. NNRTIs, sometimes referred to as “Non-Nucleoside Analogues” – or “non-nukes” (Cohen et al, 2006) for short – prevent healthy T-cells in the body from becoming infected with HIV (AIDSMEDS). When HIV infects a cell in a person’s body, it copies it’s own genetic code into the cell’s DNA. In this way, the cell is then “programmed” to create new copies of HIV. HIV’s genetic material is in the form of RNA. In order for it to infect T-cells, it must first convert its RNA into DNA. HIV’s reverse transcriptase enzyme is needed to perform this process.NNRTIs attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA. In turn, HIV’s genetic material cannot be incorporated into the healthy genetic material of the cell, and prevents the cell from producing new virus (AIDS MEDS.COM)

NNRTI’s such as Atripla, Sustiva, Viramune and Resciptor (brand names) have all been instrumental in the fight of attempting to eliminate tbe replication of HIV in healthy cells of a HIV patient (with combination therapy). The challenges for many clinicians is knowing when to switch treatment regimens, when failure of previous regimens are apparent. The consequences of clinical failure can be significant.

Does the clinician opt for partial interruption or complete treatment interruption? Based on the results (Cohen et al, 2006), the mean change in Viral RNA and the mean change in CD4 count, are two indicators to consider in this decision (3TC Monotherapy vs. treatment interruption). Another issue in understanding resistance panels, determining the Continuous Phenotypic Susceptibility Score (cPSS) is crucial. Elements to consider in this equation: 1. activity of drug defined by relation to clinical cutoff. 2. maximum score. 3. minimum score 4. For drugs where final cutoff is < upper cutoff, get partial score (0 to 1) (Cohen et al, 2006). After the cPSS has been determined, the clinician can ascertain how many new drugs to add to the patient's regimen.

Those of you in the infectious disease community, will hear more of resistance testing in the 21st century. Due to an ever changing and complex environment of drug resistance. Managing patients (particularly, older patients with HIV) will become even more challenging, due to an expanded menu of new classes of HIV drugs and dynamic patterns of resistance.

References

AIDS MED.COM [Online]. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Retrieved from
http://www.aidsmeds.com/NNRTIs.htm on January 10, 2007.

Cohen, J, Haubrich, R.,Zolopa, Z., & Frank, Z. (2006).Consult With the HIV Experts: Optimizing Therapy for Treatment-Experienced Patients. Retrieved from
http://www.medscape.com/viewprogram/6406 on January 10, 2007.

Levin, J. (2003). Genotype Testing Did Not Detect Low Level NNRTI Mutations and Tenofovir Resistance, Single-Drug Treatment Interruption, 3TC Efficacy Persists Despite Resistance. Retrieved from
http://www.natap.org/2003/resistance/day5.htm on January 10, 2007.

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