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Discordant Genotypes - which meds ?
Nov 22, 2008

Dear Doc,

Got a important decision to take (regimen) after getting discordants genotype (accordingly to an EU lab)

1) Basics ##########

Infected Nov 2006. Never been on meds

2) GENOTYPES ############

G1: 2-Dec-2007 ============== SUBTYPE PT/RT: C/C

RT -- K103N V108IV M184V T215FIST T39N S48T V60I K122P D123E I135M S162C D177E G196E Q197K T200A Q207E R211K L228R PR -- T12S I15V G16E L19I M36I L63T H69K I72IV I93L

G2: 13-Aug-2008 =============== SUBTYPE PT/RT: AE/AE

RT -- G51R/G Q102K D121H/D K122E/K D123S C162S Q174L D177E V178I/M L187L D192D H198H T200E E203E/D Q207A R211K K223K K238R V245E/D PR -- T12A I13V I15V E35D M36I S37N R41K L63A H69K L89M

G3: 18-Oct-2008 =============== SUBTYPE PT/RT: AE/AE

RT -- 35T, 39K, 43E, 121H, 121D, 122K, 122E, 123S, 174R, 174L, 177E, 178I, 178M, 195I, 195V, 200E, 207A, 211K, 214F PR -- 3I, 12A, 13V, 15V, 35D, 36I, 37N, 41K, 63A, 69K, 89M

3) VL / CD4 / CD4% / CD8 / CD8% / CD4:CD8 #########################################

DATE LOG VL VL CD4 CD4% CD8 CD8% CD4:CD8

26-Sep-07 3.238 1731 509 18.70% 14-Nov-07 3.702 5031 381 17.20% 17-Nov-07 ? ? 364 24.29% 20-Nov-07 3.528 3371 487 18.03% 2-Dec-07 4.234 17152 608 20.49% G1 10-Dec-07 3.676 4740 595 17.28% 17-Dec-07 3.009 1022 577 17.96% 4-Feb-08 3.761 5763 704 17.23% 3-Mar-08 3.446 2793 710 16.93% 16-Mar-08 3.443 2771 635 17.80% 18-May-08 2.935 862 812 16.29% 3411 68.45% 0.24 15-Jun-08 3.029 1070 678 15.16% 3132 70.00% 0.22 29-Jul-08 3.743 5535 839 12.99% 4543 70.36% 0.18 13-Aug-08 3.522 3327 712 14.80% 3399 70.67% 0.21 G2 18-Oct-08 2.775 595 310 15.20% 1450 72.00% 0.21

4) The problems ###############

A) Discordant genotypes

The first 2 genotypes have been made in a developping country, while the 3rd in the EU. The labs in charge of doing the 3rd lab made the following comments:

i) The subtype they found (AE) in G3 is the same as the one found in G2 but is different from the one found in G1, which was the subtype C. ii) The polymorphisms found in G3 and G2 are almost the same, but they are differents from those find in G1.

Based on these observations, they concluded the 2 possible hypothesis below, the first being the most probable.

Hypothesis 1 ------------ G1 is not mine

Reasons : The presence in G1 of the mutation M184V, absent in G2 and G3

This mutation appears and remains only under the drug pressure of 3TC or FTC. Few months after interrupting such drugs, this mutation disappear (become undetectable) This mutation can then reappears if the 3TC or the FTC is taken again.

But:

- I have never been on treatment. - I have been infected very probably in Nov 2007, so G1 have been made 13 months after my infection.

Lab Conclusion

We shouldn't have found the mutation M184V in G1 (as I have never take any drugs, and as, if this virus have been transmitted to me, it should have disappears from my blood in the next few months following this infection).

Hypothesis 2 ------------ I have been superinfected by a virus AE, while I was already infected by a virus C. This is possible, but extremely rare. If it was the case, we should have found at least some mutations of the virus C in G3. But there are very only very few similitudes, and none of the major mutations mentioned in G1 have been found neither in G2 or G3.

Lab conclusions --------------- It is very likely that G1 is not my genotype. However, there is a very little chance that it is mine.

I made some reading on the internet and it seems that when superinfection occurs, the VL increase in most cases. Looking at my VL history, such increase isn't visible.

Maybe have I been coinfected ?

5) Questions ############

I asked the labs who did G1 and G2 to see if they can find a genotype made around the date I made G1 that is harboring the subtype AE and having comparable mutations with G2/3

Waiting their answers, if any, I was wondering what should I conclude in terms of meds (as I got a significant CD4 drop) ?

Many thanks John

Response from Dr. Sherer

First, a caution: This type of single review internet site is NOT a very good way to get ongoing information about a single patient's history and care, particularly in complex cases. I will address your questions, but I urge you to talk to your doctor about them. Your doctor may want to talk to an HIV expert with experience in the management of non-B clades, to ensure that you have the best interpretation of the information you have provided.

Resistance tests are complex, and even more so when the credibility of the laboratory is in doubt. I favor explanation #1, though I agree that it is remotely possible that this is a superinfection.

Even if you did have the M184V, that fact should not dissuade your physician from prescribing lamivudine (3TC) or emtricitabine (FTC), as these drugs still lower the viral load by 1/2 log and provide a fitness advantage.

Although it appears that you have multiple mutations at both the RT and PI locus, most of these mutations are polymorphisms and NOT major primary or secondary mutations. Also, there is no evidence that there are major differences in the response to treatment according to clades, so the question that concerns most of your email would not point me in one or another direction in advising you about treatment.

More persuasive, then, is the sequence of CD4 cells and viral loads. Note that although the absolute # of CD4 cells fell to 310 cells/ml, the percentage did NOT change, and remained around 15%. Therefore, I am not convinced that you have had a real drop in your CD4 cell count, and I'd like to see another value before making that judgment.

Your course and CD4 cell trends suggest slow progression, so you have time to repeat the viral load and CD4 cell count to decide whether treatment is indicated now. At present, I would not advocate ART, though the overall trend is downward, and it may be that you will need treatment in the next year or two. So you should prepare with your physician by choosing the right regimen now, and testing yourself with medication adherence.

As in the US, the EU guidelines now advise treatment for anyone with a CD4 cell count below 350 cells/ml, and for many with higher CD4 cells, if they also have one of the following: 1) pregnancy; 2) hepatitis B; 3) AIDS nephropathy; 4) and consideration should be given to starting ART in anyone with no symptoms, a CD4 cell count above 350 cells/ml, and one or more of the following: viral load > 100,000 c/m, hepatitis C, older age, or cardiovascular disease.

As above, talk to your doctor about these issues.


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