Subtype C and mutations

There is a growing body of research into polymorphisms and resistance mutations seen in subtype C. Studies have reported a higher prevalence of certain secondary protease substitutions, such as K20R, M36I, M46 and I93L among people with subtype C who have never taken antiretroviral drugs.^{1 2}

Subtype C-infected patients in Botswana who were on an NRTI backbone regimen of AZT/ddI used a different thymidine analogue resistance pathway (67N/70R/215Y) than did subtype C-infected patients in India, Malawi, or South Africa.³ 

Subtype C, the predominant form of HIV-1 in southern Africa, is much more likely than other subtypes to develop the K65R resistance mutation. Development of K65R confers resistance to most of the nucleoside (NRTI) drugs except AZT. Further, although K65R is normally seen in patients failing tenofovir, abacavir, or ddI – it is also seen in subtype C patients on failing regimens containing d4T (stavudine).⁴

In subtype C patients in Botswana who failed first-line treatment on d4T/ddI paired with either nevirapine or efavirenz, incidence of the K65R mutation was high (30%).⁵ In Malawi, with an NRTI backbone of d4T/3TC plus nevirapine, incidence of the mutation was 23%.⁶ Occurrence of this mutation was much lower in other studies of subtype C patients in India, South Africa, and Israel.

Subtype C patients failing NNRTI therapy in Israel and India developed the G190A mutation that is not commonly found in subtype B or in therapy-naive patients with subtype C infection.⁷

A study of six Ethiopians also suggested that NNRTI-related resistance mutations may develop more rapidly in the subtype C virus and that people infected with this virus may have a greater chance of being naturally resistant to the NNRTIs.⁸

A retrospective case-control study evaluating 42 consecutive matched pairs of patients with subtype C and subtype B HIV infection found that people with subtype C had an inferior viral load response to treatment at 24 and 48 weeks, with high rates of secondary mutational changes in the protease and reverse transcriptase enzyme.⁹

This confirms several reports of the rapid development of drug resistance among women given nevirapine monotherapy to prevent mother-to-child HIV transmission. There have also been reports of previously unreported mutations in the subtype C virus (103E, 106M, 62V, 75E) in response to efavirenz treatment. ^{10 8}

An analysis of 40 subtype C South African blood samples that had not been exposed to HIV therapy showed that 90% contained polymorphisms M36I and I93L, which have been identified as secondary protease mutations. Nearly half showed the K20R mutation, the L63P/T/V mutation, and five of 40 samples had the V77I polymorphism. A quarter exhibited both K20R and M36I, associated with resistance to indinavir and ritonavir. Three samples showed the V82I polymorphism linked to low level resistance to nelfinavir.¹¹

In 28 Zambians who were subtype C and antiretroviral-naive, an analysis found a high prevalence of polymorphisms.¹² The most frequent secondary mutations in the protease and reverse transcriptase genes were I93L, L89M, M361I, M361V, R211K and S48T; others in the reverse transcriptase gene were M41N and D67A.

Following treatment, key PI-associated mutations such as D30N and L90M may be significantly less common in subtype C than in subtype B virus, although there may be some diversity within C subtypes.¹³ It has also been reported that key reverse transcriptase-associated mutations including D67N, K103N and T215Y are also less common in subtype C as compared to subtype B.¹