Dr. Ira Shah
Incharge Pediatric HIV and TB Clinic, B.J.Wadia Hospital for Children, Mumbai, India Consultant in Pediatric Infectious Diseases, Nanavati Hospital, Mumbai, India
Development of drug resistance in HIV
infected children with Treatment failure is a major impediment to selection of appropriate therapy. Studies done on Indian population indicate that prevalence of HIV
resistance mutations is around 9.6% in treatment naïve population and up to 81-96% in treatment experienced patients with virological failure. The pediatric population in particular is not only at a higher risk of developing resistance (due to greater viral loads and difficulty in adherence and accurate dosing), but resistance proves a greater challenge as they require longer term therapy than adults. There are 2 types of resistance testing available predominantly.
- Genotype tests : They detect specific genetic mutations. They are based on amplification procedures and can detect mutations in plasma samples with more than 1000 copies/ml of HIV RNA. This involves the nucleotide sequencing of the relevant HIV genes, from which an amino acid sequence of the reverse transcriptase and protease enzymes is predicted. Genotypic testing is cheaper and more widely available compared to phenotypic testing.
- Phenotype tests : Phenotypic assays measure the IC50 of the drug against the virus in vitro. Although, the sensitivity patterns of the virus tested can be determined, it may not detect minor species of resistant viruses.
In patients with HIV, genotypic resistance testing is preferred. Resistance testing should be performed by laboratories that have appropriate operator training, certification and proficiency assurance. Drugs for which the virus requires only one mutation to develop high level resistance (such as Lamivudine and Nevirapine) will in fact generate very rapid resistance when used as monotherapy. For other drugs such as AZT, ABC, TDF and most PIs, high-grade resistance requires the serial accumulation of multiple mutations and is thus slower to emerge. Other drugs such as ddI & d4T are associated only with low level of resistance as measured in phenotypic assays predicting decreased efficacy.
Nomenclature of resistance
The nomenclature used to describe mutations involves one letter followed by a number and followed by another letter e.g. M184V. In this case the first letter refers to a specific amino acid which is present in nonresistant viruses, and the second letter identifies the amino acid present in the resistant virus. The number refers to the position of that particular amino acid within either the protease gene or the reverse transcriptase gene. Thus, M184V signifies that the usual amino acid in drug sensitive viruses, methionine (M), at the 184th amino acid of the reverse transcriptase protein
has been replaced by a V (valine), which leads to high level resistance to Lamivudine.