Nucleoside Reverse Transcriptase Inhibitors (NRTI)-associated Mutations in the RNase H Region in South African Adults and Children failing Highly Active Antiretroviral Therapy (HAART)

Sinaye Ngcapu, Michelle Gordon

Abstract


South Africa is currently one of the most affected countries by the AIDS epidemics in the world. Approximately over 5.7 million people are living with HIV-l and over 1000 AIDS related deaths are occurring everyday since the introduction of a national treatment program in 2004. According to HIV & AIDS and STI Strategic Plan for South Africa 2007 to 2011, there has been a significant growth in numbers of South African patients receiving HIV combination therapy, or HAART with over 370, 000 people on treatment by the end of 2007, in the public sector alone. The subtype-C epidemic is the major circulating HIV-1 subtype in Southern African countries where HIV- 1 prevalence is the highest in the world (South African Department of Health et. al, 2007).

The South African national treatment program includes 2 NRTIs (D4T and 3TC) and 1 NNRTI (‘NVP or EFV) in the first line regimen and 2 NRTIs (AZT and ddl and 1 P1 (Kaletra) in the second line regime (Pillay et al., 2008). The efficacies of these drugs are limited by HIV- 1 drug resistance, which is usually. caused by mutations in the protease and RT regions. Mutations in the DNA polymerase domain of RT as well as in the RNase H domain are some of the factors associated with resistance to NRTIs. Mutations in the RNase H domain could disturb the interactions of RT with its nucleic acid substrate and that leads to both RNase H and polymerase activity to be affected which has an impact on replication. For example, some of the mutations (T473A) can rminate HIV- I replication whereas others can either reduce the virus concentration (N474A, K476A and Q500A).