Multiclass resistant, salvage therapy, RPR1:16

Mutations: K65R,S68N,Y115F,M184V,R211K,I13V,L63P,A71T,T66A,I_L74I,I_L74L,T97A,I_E138K,S147G
Comorbidities: None
Comedications: None
Treatment history: EVG/c/TAF/FTC (Genvoya)
Current regimen: ETR (Etravirine/Intelence) , DRV/r (Darunavir-ritonavir/Prezista and Norvir) , DTG (Dolutegravir/Tivicay)
Adherence: Patients with intermittent adherence, Increase prioritization of at least 3 active drugs, Penalize regimens with IV/IM dosing
CD4: > 200
Viral load: Suppressed (<50) for less than 6 months or Low Level Viremia (<200)
HLA-B5701: Negative
Tropism: Unknown
View results
Submitted by t.hedley133 on Mon, 07/27/2020 - 02:22

Previously poorly controlled HIV/AIDS due to non-compliance leading to treatment failure. Genotype showed multi-class resistance, including NRTIs and INSTIs. Patient was started on DTG/ETR/DRV/r on 1 year ago. Patient reports compliance with current regimen. Denies missing doses. Undetectable6 months ago but has had low level viremia since. Am concerned with L74I and DTG resistance.RPR positive 1:16 (Most recent) denies any sexual encounters. Treated PCN-G 2.4mu x 1 doseHistory of Syphilis. Treated 2015 PCN-G 2.4mu x 3 doses. Patient is adament that this is syphilis relapse not reinfection. 

  HIV 1 RNA(in-house) HELPER T CELLS CD4 CMIA RPR QUAL TP-PA RPR QUAN
Most recent 40.7 371 R R - 1:16
Recent 46.1 358 - - - -
Recent <20.0 - - - - -
1 year 104 329 R N R -
1 year NOT DETECT - - R - 1:1
1 year 68.8 - - - - -
1 year 90.7 - - - - -
1 year 291 116 Low - N - -
1 year 191000 - - N R -
2 years ago 148000 63 Low        
Regimen Weighted Score Active Drugs Total Pills Frequency (x/day)
DTG+DRV/c+DOR 5.2 2.67 4 2
DTG+DRV/r+DOR 5.4 2.67 5 2
DRV/c+DTG/RPV 5.5 2.67 3 2
DRV/c+DOR+3TC/AZT 5.6 3 4 2
DRV/r+DTG/RPV 5.7 2.67 4 2
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Comments

Submitted by maunank on Tue, 07/28/2020 - 17:23

First, a few quick notes about the results you likely see from the HIVASSIST website. You will notice that all of the scores are generally lower (>3), which indicates that our algorithms don't find strong evidence for any one of these regimens. In these situations, it is worthwhile to actually review the specific 'rationale' for each recommended regimen and see if the various penalties and prioritizations are appropriate to the case; for example, because AZT is hypersensitized and there is no other mutations, it includes AZT containing regimens as part of a regimen of 2 NRTI+ PI (+/- NNRTI or INSTI) as fully active regimens (i.e. inclusion of 3 active drugs) in a patient who has failed 2 NRTI+INSTI. The algorithms do penalize the usage of AZT, but given that all regimens are compromised, the AZT containing regimens are still showing up a bit higher than some other regimens (which each have their own downsides); if one has less enthusiasm for AZT, you can 'penalize' these regimens further and see what other regimens remain--the system attempts to find regimens with at least 3 active drugs in this case so it is allowing older drugs that may be otherwise less favorable. I like DTG, DRV/c, DOR in this case as a regimen perhaps a bit more robust than the one he is on. The persistent LLV could represent smoldering residual viral replication in a patient with suboptimal adherence or just a larger/more active reservoir in someone with a long history of uncontrolled HIV. Given how long it’s been going on without VF, I would favor the latter. I’d also be concerned about AZT-related SEs that may disrupt the pt’s adherence, which is why I generally would exclude such regimens. Due to the presence of the E138K, the current recommendation would be for BID dosing of DTG, which may be something to consider if he is on QD dosing currently. Ultimately, based on the available genotype this person really should suppress with this regimen if he is taking his meds. The L74I is a polymorphism I believe and selected by the prior INSTI therapy, but doesn't seem to be associated with reduced INSTI susceptiblity. You can click on the 'additional information' and 'mutations' and you will see the mutation penalty scores (obtained and updated quarterly from the Stanford HIV Database). The L74I I believe is contrasted from the L74M, which can lead to reduced sussceptibility of DTG if combined with some other mutations. I discussed the RPR's with some of our syphilis experts at Hopkins. He has already been treated for the new RPR rise, which is good. The question I think that is outstanding is relapse vs. reinfection. The response from our team was, "Relapse is definitely possible but there’s no way to tell if it is relapse or reinfection except by history. If there is no way this could be reinfection, then you have to try and figure out why he relapsed (i.e. incompletely treated). I would strongly consider a CSF examination to rule out neurosyphilis. Usually when you suggest an LP, they remember a possible exposure and you treat them for reinfection!" I have shared some of the case details with colleagues and will get back to you if there are additional thoughts. Thank you for sharing your case.

Submitted by t.hedley133 on Fri, 08/07/2020 - 00:43

Thank you for your response, this site is a great resource, I am getting a bit more familiar with it now (hopefully). The E138K mutation you mentioned is the one I was concerned about; I had gotten mixed up and wrote L74I in my submission. I also did not include the current dosage, which is DRV 600mg/RTV 100mg BID, DTG 50mg BID, ETR 200mg BID. &#013; &#010; I was also leaning towards DTG+DRV/c+DOR. The fact that it raises DTG levels is a plus in this patient, especially considering his current regimen lowers DTG levels. &#013; &#010; With the VL not completely suppressed, would you be concerned switching from DRV/r BID to DRV/c QD? The current regimen decreases DTG by 22% and Cmin by 38%, DTG+DRV/c+DOR would increase DTG by 36%. Is that enough to cover switching to QD? &#013; &#010; If I exclude AZT the algorithm places DRV/c+DTG/RPV at the top. That combination would raise the Cmin of both DTG and RPV by 20%. It also might make for an easy transition once (if) we get Cabenuva. &#013; &#010; I am trying to avoid any landmines; can I ask for your thoughts on these two options? &#013; &#010; Now the syphilis, it seems patient was supposed to get PCN-G 2.4 mu weekly x3 doses. The doses are dated 3/11/14, 3/20/14 and 8/28/14 and then still had not cleared it and was given 30 days of Doxycycline Monohydrate 100MG 06/25/2015. The next entry I have is RPR NONREACTIVE 04/17/2017. Given the sporadic treatment history relapse does not seem that farfetched I suppose. Now If his next labs come back nonreactive, that still does not necessarily rule out neurosyphilis, correct? Patient is aware of LP, is concerned and wants to proceed. &#013; &#010; Thank you again for taking the time to read this, and I appreciate any insight or comments you might have.

Submitted by maunank on Mon, 08/10/2020 - 09:05

1.You may wish to re-run your case scenario as we were in the midst of a version update (if you encounter any errors, please check back in a few days as several updates are being implemented), which may more accurately reflect the latest algorithms. When I just re-run your case, DTG+DRV/c+DOR is the top ranked regimen (recognizing that the final score is still suboptimal reflecting some of the uncertainties in underlying available data. 2.Per our HIV pharmacist team, in the absence of known DRV mutations, there was not any real concern with the currently recommended QD DRV/c dosing 3.The DOR-DTG interaction is not sufficiently reliable to count on increased DTG exposures to avoid BID. In this case, with the E138K, the team still favored BID DTG. 4.The team generally favored DOR>RPV due to the lack of food neccessity and absorptions issues. The algorithms try to weigh these issues with the pill burden issues (i.e. ability to combine DTG/RPV) and treats these two factors as somewhat offsetting each other. But many would probably favor the added pill over the necessity to administer RPV with food, and avoiding antacids. 5.There is very limited data on CAB/RPV particularly in the setting of individuals with a history of treatment failure, or any underlying INSTI mutations. In our team discussions, most did not favor a switch to this regimen (with or without additional agents) as a result. We do not yet have tremendous data on CAB mutations, and unclear how E138K or L74I will impact it (no analagous data to using DTG BID for CAB). 6.Our syphilis consultants suggested the following, "To my mind, the history suggests treatment failure, and so you are likely obliged to proceed with the LP, irrespective of the next set of labs. We do not know what a single dose of BPG will do in terms of CSF yield, and probably insufficient if there is truly neurosyphilis. Whether that dose would be enough to compromise results of an LP and warrant repeat LP in the future is unknown." Thank you again for using HIVASSIST.