HIV i-Base

Appendix 6: Stanford Drug Resistance Database online tables

The Stanford Drug Resistance Database is one of several online research resources that contain a vast amount of support information about drug resistance.

One page in the resource includes links to each drug family (Drug resistance mutation tables) and the related mutations and individual pages for each HIV drug (Antiretroviral drug summaries):

http://hivdb.stanford.edu/DR

Notes and comments on mutations by drug class are linked from the HIV drug resistance summaries page.

For example the link to NRTI-associated mutations has a link for notes that includes the table below and a link for comments that describes each mutation.

This table looks complicated but just needs explaining (see Table 4).

Table 4: Nucleoside RT inhibitor (NRTI) resistance mutations (Stanford database)

Cons stands for consensus sequence which means wild-type non-resistant virus. The letters in the Cons row refer to the amino acids that should be at those junctions (codons).

The line of numbers above the ‘Cons’ row are the positions or junctions where important changes occur:

41  67  70  210  215  219          65  70  74  75  115          69  151  62  75  77  116

Each of these junctions in RT is linked to resistance to different members of the family of HIV drugs called ‘nukes’ (reverse transcriptase inhibitors). They are arranged in three sections.

The first section is for mutations linked to AZT (ZDV, zidovudine) or d4T (these drugs are both thymidine analogues). The second section relates to other nukes (non thymidine analogues, ie 3TC, ddI, tenofovir, abacavir  etc). The third section includes mutations that have broad cross resistance to all nukes (multi-drug resistance).

Each row next to a drug name then shows the mutation at each junction that is associated with drug resistance.

So reading across from 3TC the letters V and I mean that M184V or M184I both indicate resistance to 3TC. Red letters indicate the resistance is high level (it will have a big impact on stopping the drug form working). Letters in black indicate lower level resistance, showing that the drug may still work a little,  but less than if it was wild-type.

The letters in black (representing K65R, K65N, K70E, K70G, T69Ins, Q151M and A62V) list other mutations that all reduce how well HIV works.

Although this looks like a lot of mutations, amino acid changes at all the junctions not listed are not associated with resistance. For example changes at 1, 2, 3, 4, 5 etc or 42, 43, 44, 45, 46 etc in RT are not clinically relevant.

‘Ins’ refers to insertion, which is a type of mutation where instead of one base switching to another (technically called a ‘point mutation’), an additional base in inserted.

If you look up K65R in the comments page it states “K65R causes intermediate/high-level resistance to tenofovir, ddI, abacavir and d4T (2 to 3-fold reduced susceptibility) and low to intermediate-level resistance to 3TC and FTC (5 to 7-fold reduced susceptibility). K65R increases susceptibility to AZT.”

This shows the complexity of interpreting HIV drug resistance….Time for a break to let this information settle :)

The link to 3TC (lamivudine) drug summary explains the implications for each of the mutations that have been associated with 3TC resistance AND includes references for the studies which show this:

http://hivdb.stanford.edu/pages/GRIP/3TC.html

For example:

M184V or M184I

M184V causes high-level resistance to 3TC (more than 300-fold reduced susceptibility). In patients with viruses containing M184V, there is some benefit in continuing 3TC because viruses with M184V replicate less well than wild-type viruses and because this mutation increases susceptibility to ZDV, d4T, and tenofovir. However, the benefit of continued 3TC will be less than the benefit of 3TC in patients with wild-type virus.

This explanation includes new terms which relate to phenotype resistance including ‘fold changes’ and ‘reduced susceptibility’.

It also refers to an unusual feature of the M184V mutation that is important enough to be used as a treatment. If you keep the M184V mutation by continuing to take 3TC or FTC, viral load stays a little lower. This is because the virus is let fit. It reproduces less well so there is less virus. Although other mutations also reduce fitness, this effect is usually overcome by new mutations that compensate for this.

>> Appendix 7: IAS-USA resistance mutations and cross resistance

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