HIV Drug Resistance Workshop: Non-B HIV subtypes

Yasmin Halima
Published: 29 June 2004

The mapping of resistance pathways in non-B patients is becoming increasingly important for two main reasons.

Firstly, migration patterns in Europe have resulted in a diverse range of patient demographics with different subtypes. Many clinics in metropolitan cities across Europe now routinely report 25-40% of their patient profile as having non-B clade virus, including London-based hospitals.

Secondly, understanding resistance evolution in the subtypes prevalent in Africa will help to explain and hopefully, redress the current concern for the development of resistance for prophylactic treatment given to pregnant women to prevent transmission of HIV.

Novel resistance profiles

A joint study between Cleveland, Kampala and the Virologic team explored the development of novel mutations rarely observed in patients with subtype B virus, but now increasingly reported in other subtypes. By collecting isolates from treatment-naïve infants all with subtype D, they located a virus (D14-UG) which displayed a high level of resistance to nevirapine (NVP) in PBMCs (>2000-fold). Interestingly, the resistance profile was I135L, T139V and V245T – quite distinct from the usually characterised NNRTI profile of Y181C, K103N and G190A. These findings suggest that with NVP as the drug of choice (or in this case, availability) the prevalence of novel mutations in naïve populations that may confer significant levels of resistance must be heeded (Baird).

Pat Cane and her team from Birmingham (HPA Antiviral Susceptibility Unit, UK) further highlighted the diversity of resistance to NNRTIs in non-B clades in patients on a failing first-line regimen. 164 patients with different subtypes were studies: C 44%, B 32%, A or A recombinant 17%, D or D recombinant 6% and one patient with F subtype. 77% showed resistance to NNRTIs most commonly with M184V, K103N was prevalent for all patients on efavirenz (EFV) treatment but was more common in B compared to A or C subtypes. The G190 mutation was most common for subtype C and A but not for B.

The V106M mutation which has been previously reported exclusively in Clade C and confers 100-1000 fold resistance to all NNRTIs (D Turner et al, Novel Drug Profiles in non-B subtypes, abstract 144, session 27, CROI 2003) was also confirmed here in patients with C virus at a rate of 42%. Similarly, this mutation was seen in patients treated with EFV but not with nevirapine (NVP). The authors conclude that these findings ‘may be of importance for the development of rapid tests for the detection of NNRTI resistance in the developing world’. Perhaps another additional conclusion would be that clinicians should carefully consider genotypic interpretation for non-B patients in light of a growing argument that divergence in resistance pathways may be influenced by subtype and consequently may have serious implications for selecting or switching treatments (Cane).

Ricardo Camacho from Lisbon reinforced this conclusion by reporting on the divergent resistance pathways selected by different HIV subtypes, in this case amongst patients experiencing nelfinavir (NFV) associated failure. His study of 101 patients with subtype B (46 patients) and subtype G (55 patients) illustrated the differences in evolution of resistance mutations dependent upon HIV subtypes, with a transposed prevalence of the D30N and L90M mutations in subtypes B compared to G.

Using a Bayesian Network structure, the researchers found the following patterns of resistance:

In patients with subtype B

Mutation (% of patients)

D30N 66% (strongly associated with N88D)

L90M 28%

N88S 6%

In patients with subtype G

L90M 74%

D30N 12%

N88S 10%

I54V/L 5%

L46I 2%

Whilst D30N is most commonly observed for patients with subtype B virus, in clade G patients, the L90M is most prevalent and D30N is associated with changes at codon 35N/G. Of note, the 54 and 89 mutations were only acquired in patients with G subtype and the V77I mutation in only B patients.

The research also reported changes at L10I/F, A71V/T and a novel NFV mutation at 62V – all were equally distributed across the two subtypes. No mutations were reported at either 82 or 84 in either subtype.

This study categorically confirms the need for clinical virologists and physicians to take care in the interpretation of genotypic resistance results, particularly in geographic regions where non-B subtypes are likely to predominate.

However, the study along with other non-B subtype investigations does raise the broader concern of the existing practice of testing non-B viruses against a reference panel made up of a recombinant genetic background of a B-strain variant. This issue has been raised in the past by several commentators in the field. Whilst these findings are important in our understanding of resistance evolution, it is only once we calibrate and utilise the appropriate diagnostic technologies (with matching genetic backbone) that we can seriously consider the clinical implications of these apparently divergent results (Camacho).

Read related reports from the XIII International HIV Drug Resistance Workshop, June 8-12, Tenerife, Spain

Take home messages

What were the key messages from this year's Resistance Workshop?

Entry and attachment inhibitors

As researchers learn more about the ways in which HIV develops resistance to entry and attachment inhibitors, the future shape of therapy with these new classes of drugs becomes clearer.

New concepts for the clinician

This year's workshop heard more about the clinical relevance of replication capacity and hypersusceptibility, and began to debate the potential therapeutic exploitation of interactions between resistance mutations.

Population surveys of resistance

What sort of resistance is occurring in clinic populations, and what does this tell us about clinical practice today?

Prevention of mother to child transmission

The threat of nevirapine resistance is forcing a rethink of strategies to prevent mother to child transmission. The workshop learnt more about resistance patterns, and why differences in HIV-1 subtype may need to be taken into account when thinking about preventing mother to child transmission.

Non-B HIV subtypes

As treatment access expands and the proportion of patients in Europe with non-B subtypes grows, understanding differences in resistance patterns between B and non-B HIV subtypes becomes more and more important.

References

Baird H et al. Novel mechanisms involved in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance of both the subtype D HIV-1 isolate and reverse transcriptase derived from a drug-naïve Ugandan. (Abstract 29) Antiviral Therapy 2004, 9:S35.

Cane PA et al. Effect of HIV-1 subtype on development of NNRTI resistance mutations in patients failing first line therapy. (Abstract 104) Antiviral Therapy 2004, 9:S115.

Camacho R et al. Nelfinavir resistance in HIV-1 subtype B and G infected patients: evidence for different pathways and novel mutations associated with failure of nelfinavir based regimens. (Abstract 103) Antiviral Therapy 2004, 9:S114.

Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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