Currently, appearance of drug resistant viruses is an inevitable consequence of prolonged exposure of HIV-1 to antiretroviral therapy. Drug resistance is a serious clinical concern in treatment of viral infection, and it is a particularly difficult problem in treatment of HIV. Resistance mutations are known for all approved NRTIs.
Two main mechanisms are known that cause NRTI drug resistance:  Interference with the incorporation of NRTIs and excision of incorporated NRTIs. Interference with the incorporated NRTIs involves a mutation in the p66 subdomain of the RT. The mutation causes a steric hindrance that can exclude certain drugs, for example lamivudine, from being incorporated during reverse transcription. In case of excision of incorporated NRTIs the resistant enzymes readily accept the inhibitor as a substrate for incorporation into the DNA chain. Subsequently, the RT enzyme can remove the incorporated NRTI by reversing the polymerization step. The excision reaction requires a pyrophosphate donor which RT joins to the NRTI at the 3´primer terminus, excising it from the primer DNA.
To achieve efficient inhibition of HIV-1 replication in patients, and to delay or prevent appearance of drug resistant viruses, drug combinations are used. HAART, also known as highly active antiretroviral therapy consists of combinations of antiviral drugs which include NRTIs, NtRTI, non-nucleoside reverse-transcriptase inhibitors and protease inhibitors.