ARV regimen change for 27 y.o. with congenital HIV

Mutations: I5I, I5V, K20K, K20R, V35I, M41L, E53D, K101Q, Q102K, K122E, I135K I135R, C162S, S163T, F171F, F171V, Q174N, V179I, T215E, V245T, A272P, V276I, R277K, Q278H, Q278N, K281K, K281R, D324E, G333E, Q334N, K358R, G359S, A371V, K374K, K374R, I375V, A376T, K385R, K390R, A400T, L10V, I13V, K14K, K14R, I15V, D30N, E35D, M36I, N37D, L63P, I72V, V75I, N88D, D6E, K14R, N27G, N27S, V32I, L45Q, V72I, L101I, V113I, K136Q, I204I, I204V, D253D, D253N
Comorbidities: Diarrhea and GI Symptoms, Peripheral Neuropathy, Depression
Comedications: Dapsone
Treatment history: LPV/r (Lopinavir-ritonavir/Kaletra) , FPV/r (Fosamprenavir-ritonavir/Lexiva and Norvir) , ATV (Atazanavir/Reyataz) , DRV (Darunavir/Prezista) , RAL (Raltegravir/Isentress) , DTG (Dolutegravir/Tivicay) , BIC (Bictegravir/Biktarvy) , TDF/FTC (Truvada) , ABC/3TC (Epzicom) , EVG/c/TAF/FTC (Genvoya)
Current regimen: None
Adherence: No options selected
CD4: ≤ 100
Viral load: High (100,000 - 500,000)
HLA-B5701: Negative
Tropism: Unknown
View results
Submitted by Ncwhelan3 on Thu, 07/22/2021 - 16:20

27 year old female not taking ART's for the last 5 months. The last ART Genvoya caused excessive nausea. She was well controlled on Bictegravir prior however developed apraxia of speech and right-sided muscle weakness. Although neurological symptoms have improved she refuses to take Bictegravir.  Intermittent medication adherence since 2015. 

Regimen Weighted Score Active Drugs Total Pills Frequency (x/day)
BIC/TAF/FTC 1.35 2 1 1
DTG+TAF/FTC 1.35 2 2 1
DRV/r+BIC/TAF/FTC 3.4 2.67 5 2
DOR+BIC/TAF/FTC 3.55 3 2 1
DTG+DRV/r+TAF/FTC 3.6 2.67 6 2
Ask on the National Clinical Consultation Center

Comments

Submitted by nicky.mehtani on Wed, 07/28/2021 - 17:34

I'd be curious to hear more about the potential reaction she had to Biktarvy with apraxia and right-muscle weakness. What was the temporal relationship to Biktarvy and how long did the symptoms last? Did they resolve completely after discontinuation of the drug? In any case, given her heavy level of treatment experience and limited ART options, it would be helpful to better understand what has been causing her poor med adherence the last 6 years since 2015? Are there any concerns for co-morbid substance use disorder or mental health conditions that we could treat (which would also likely improve her adherence to ART)? If so, this may be paramount to getting her HIV under control. 

Some initial thoughts:  
- If using a PI, given she has a darunavir-resistance associated mutation (V32I), the patient ought to be on DRV/r bid (not once daily, thus DRV/c cannot be used) 
- The HIVASSIST algorithm predicts that she may have developed potential archived INSTI resistance due to her treatment experience and difficulties with adherence in the past (even though there is no evidence of ressistance on the genotypes), which is why it is suggesting DTG be given bid. This can be considered on a case by case basis, though not always necessary. In this particular case, given her low CD4, high VL, dwindling ART options, and likely need to be taking DRV/r bid anyway (for the simplest of regimens), I would favor DTG bid. 
- It's interesting that she has had no known NNRTI exposure given long standing history of HIV. 
- Do we know if she had any AZT monotherapy exposure? 

Here are some options that could be considered: 
- DTG bid + DRV/r bid (+/- DOR qd) - Most robust option. The biggest downsides here are 6-7 total pills daily and need for twice daily dosing. This would be a relatively robust regimen, but she would really need to be adherent. If she is not going to do BID dosing, would have to go with another option. 
- DTG qd + DOR/TDF/FTC qd - This would be potent and simpler to take than the above; however, I would be a bit concerned in using it for this patient, not only due to the possibility of archived DTG resistance as noted above, but also given the possibility of low-level TDF and/or FTC resistance concurrent with the relatively lower barrier to resistance of DOR. (Per the Stanford DB, she has minimal FTC resistance based on mutations reported, but could imagine there may be archived mutations we aren't seeing). That said, this regimen would still likely confer the equivalent of nearly 3 fully active drugs and would be relatively easy to administer with just two pills dialy. If she has food security and able to take ART with meals, you could alternatively do DTG/RPV qd + TAF/FTC qd. 
- Given her lack of current INSTI or NNRTI resistance (at least on genotypes), she could be a good candidate for injectable CAB/RPV if it is accessible in your community or if there are ongoing clinical trials in your area (which generally provide heavy financial incentives for the oral lead-in therapy).

Nicky Mehtani, MD MPH - On behalf of National Clinician Consultation Center 

Submitted by Ncwhelan3 on Tue, 08/10/2021 - 16:27

Thank you for your input. I was able to access some records prior to 2008 and it appears as if there was no AZT monotherapy; however she had been on NFV; 3TC, and AZT around 95-98 and possibly D4T and DDI at some point. The apraxia and right muscle weakness occurred about 2 weeks after starting Biktarvy. Her neuro work-up noted left-sided white matter lesions and CSF was negative for JV virus. We had suspected inflammatory PML as part of IRIS. Her symptoms resolved and subsequent MRI noted resolution of white matter lesions. The depression as a barrier to her HIV adherence has been her most prominent obstacle to care and many attempts to address this have been refused by this patient. 

In terms of the injectable CAB/RPV, does she need to have an undetectable viral load prior to starting the oral lead-in therapy? 

thank you

Colleen Whelan, DNP,APRN-BC

Hi, Colleen, 

Yes, she would have to have an undetectable VL prior to oral-lead in therapy for CAB/RPV under current guidelines and, as Maunank has noted, this regimen would thus be off-guidelines at this time. At this point, the most simple regimen to switch would likely be DTG + DOR/TDF/FTC but adherence will be important. I would consider CAB/RPV at this point only if she could access it through a study in which they can offer financial incentives to help patients with historical difficulties with adherence reach viral suppression prior to beginning the oral lead-in and injectable (LATiTUDE study: https://clinicaltrials.gov/ct2/show/NCT03635788). It seems as though there may potentially be several sites recruiting in the NJ/NY area if that is where you are located? Contact info is here: https://clinicaltrials.gov/ct2/show/NCT03635788#contacts. Please let us know if you have any additional questions, either here or via phone at NCCC: (800) 933-3413. Best, 

Nicky Mehtani, MD MPH 

UCSF, National Clinician Consultation Center HIV Warm Line 

 

Submitted by maunank on Wed, 08/11/2021 - 10:48

Dear Colleen, Thank you for submitting your case to HIV-ASSIST.  We wanted to alert you that the tool's recommendations have changed somewhat based on a recent update.  In particular, the current version of the tool is more cautious about presence of any PI mutations (and suggests BID DRV), and is no longer automatically assuming the presence of INSTI mutations after prior exposure to RAL or EVG/c (the system used a very conservative approach previously, which has been relaxed somewhat after discussion with our scientific panel).  Consequently, the tool recommendations now include once/daily DTG and BID DRV as part of the considerations. 

Notably, in light of some of the discussions with the NCCC that I see, I will just note that the tool's algorithms do not yet allow for CAB/RPV in viremic patients, as its approval and DHHS recommendations are currently restricted to "people with HIV with sustained viral suppression for 3 to 6 months (optimal duration is not defined), who have good adherence and engagement in care, no baseline resistance to either medication, no prior virologic failures;".  We certainly appreciate that there may be reasons to consider off-label usage and the tool does not account for some potential individual level nuances, but wanted to provide the explanation for why CAB/RPV does not show up in the tool's recommendations. 

Maunank Shah MD PhD

Johns Hopkins