Subtypes and resistance mutations

To date, it seems that the majority of antiretroviral resistance mutations are shared by viruses of all subtypes. The major resistance mutations found in subtype B HIV-1 infections are also found in non-subtype B HIV-1 infections, with the addition of some novel mutations.¹  

NRTI and NNRTI resistance mutations are the most similar across subtypes. Less is known about non-B subtype mutations to protease inhibitors, particularly the newer ones.

All HIV subtypes feature naturally occurring genetic variations known as polymorphisms. Generally, polymorphisms do not confer significant resistance; however, they can in the case of some non-B subtypes. There is also some evidence that some natural polymorphisms are more common in people infected with some non-B subtypes.² Additionally, in non-B subtypes, polymorphisms tend to become more frequent and more persistent after antiretroviral treatment.

The genetic make-up of HIV-1 can vary among subtypes by as much as 35%, so it is not surprising that there may be different resistance patterns.³ For instance, when single-dose nevirapine is given to prevent mother-to-child transmission, women with subtype C HIV infection tend to develop resistance more frequently than do women with subtype A or D infection.

A Brazilian study of the timing and number of mutations conferring resistance between subtype B or subtype C individuals showed that 54% of subtype B strains were resistant to NRTIs versus 23% of subtype C. The difference narrowed with protease inhibitors: 26% of subtype B strains were resistant versus 23% of subtype C.⁴ 

Geographic differentiation was also found in subtype C incidence of K65R.¹ In South Africa, Botswana, and Malawi, the K65R mutation occurred more frequently in thymidine-treated subtype C patients than in subtype B patients. This mutation rarely occurred in patients with subtype A virus.⁵

In the UK, one study found confirmed primary resistance to more than one drug class in 20% of patients whose HIV was subtype C versus 15% of those who were subtype B-infected. Primary resistance was found in 35% of the small number of non-B/non-C subtype patients.

In those with confirmed resistance, 38% of subtype B patients had NNRTI resistance as compared to 72% of patients with subtype C and 62% of those who were infected with HIV that was not subtype B or C.^{6 7} 

Another Brazilian study of people infected with either subtype B or C and treated with ritonavir-boosted lopinavir (Kaletra) showed that L63P occurred more commonly in subtype B than C. Other lopinavir-associated mutations such as L10I/V/F, M46I, F53L, I54V, A71V, V82A, I84V, and L90M had roughly similar prevalence rates in the two subtypes.⁸

A more complete understanding of resistance mutations in the non-B subtypes is necessary so that clinically significant resistance is recognised and correctly interpreted and cross-resistance and ineffective drug sequencing are prevented.