Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART

Round 1

Reviewer 1 Report

The article by Mens H et.al highlights the risk of developing pan-integrase resistance in patients with non-complacence and non-optimal NRTI.

This study uses a case to show that no-complacence to NRTI leads to developing G118R pan-integrase resistance.

This study has many plus points such as the authors have thoroughly analyzed the treatment history and HIV status with HIV-1 RNA in copies/ml and CD4 cell counts in cells/mm etc.

Figure no. 1 is presented very well.

However, I have some major concern

1. I failed to understand if this is a brief communication with one case sample or just another case report to show that non complacence to ART leads to developing G118R pan integrase resistance. Please clarify.
2. I also failed to understand the title especially “in a non-compliant HIV-1 subtype B positive individual”. Please redraft it.
3. Please briefly explain how three genotypic drug resistance test were performed and how they are analyzed (circulating virus or proviral DNA).
4. Please also include the amino acid and DNA sequences if possible for April 2003 in figure no 2.

Author Response

Dear Reviewer 1.

We thank you for the great comments to improve the manuscript. Below you will find our point by point  response

1. good point - yes this is a case report documenting the emergence of the G118 in a treatment experienced individual infected with HIV-1 subtype B with a history of low compliance.  Although case reports have previously documented the emergence of G118 on dolutegravir - it has mostly been in a HIV-1 non-B context. We recocnize your point but regard it important to inform collegues that dolutegravir may not be first choise in a patient with this profile.
2. Ok - yes agree The title has been changed to "Emergance of the G118R pan-integrase resistance mutation as a result of low compliance to a dolutegravir based cART"
3. The method has been added to the manuscrpt p.2 line 50-52
4. We appology but the sequence from 2003 were obtained in Norway where the patient resided at the time. We only have the DRM available. Integrase was not amplified and sequenced at that time

Reviewer 2 Report

This brief case report describes one Person Living with HIV (PLWH) with a history of antiretroviral therapy (ART) non-adherence. This PLWH was switched to a WHO-recommended second line HIV therapy, which includes the second generation integrase inhibitor (InSTI), dolutegravir (DTG). During the DTG combination ART (cART), the person developed a rare viral pan-integrase inhibitor mutation, G118R, that had mainly been described in non-subtype B HIV infection, while this individual had an HIV subtype B infection. The person also had a nucleoside RT inhibitor (NRTI) mutation, M184V/I, which limits efficacy of the cART 3TC, and authors state this drug resistance may have played a role in the development of G118R. The authors suggest that for certain individuals, such as those with a history of ART non-adherence, dolutegravir regimens may support the development of pan integrase inhibitor escape mutations, and this should be evaluated more closely.

Based on the case report, the authors think that some individuals with a history of non-adherence and the M184V/I mutation, may be more susceptible to the G118R pan-integrase mutation, which severely limits downstream therapy options.

While the authors say that there is a wealth of large-scale clinical trials using second line cART dolutegravir treatment with success, the authors recommend factors such as prior adherence be considered when DTG is used as a second-line therapy for PLWH.

From the literature, there are certain PLWH populations where adherence is concern, such as in resource-limited settings, where access to cART regimens may be a factor and non-adherent populations do not seem to be a rarity, so this observation could be impactful.

The greatest limitation in the report, is that only one individual is reported. The manuscript would be significantly enhanced were other cases included.

While the report here is only from one patient, a correlation between a DTG cART second line regime and the emergence of the G118R mutation is made. For this reason, PLWH with a history of nonadherence and the M185V/I mutation should be evaluated more closely, argue the authors; and serve as the basis for a larger study aimed to determine whether nonadherence and the M184V/I be considered before choosing a second line DTG-based cART for an individual PLWH.

The authors make a convincing argument that studies of other PLWH with second line cART DTG, had short post-treatment observation time, and more protracted studies are needed. The authors state that some studies showed virologic failure and more drug resistance emerging after DTG therapy vs. another approved cART drug, darunavir/r.  

While the manuscript only describes one individual, the call for clinicians to evaluate these concerns and expand studies is reasonable.

The case study provides a perspective on cART regimens that could minimize drug escape mutations in certain PLWH groups, a critical public health concern. 

For this reason, I advocate to publish this manuscript/case report.

Author Response

Dear Reviewer 2, 

We greatly appreaciate your positive response. Thank you.

Reviewer 3 Report

The case report description is of great interest in a scenario where many studies have supported the concept that switching to even a dual therapy regimen containing an INSTI such as dolutegravir or bictegravir is safe even if there is an M184 mutation in the viral reservoir. This may not be true in real life in the presence of multi-treated patients, with poor adherence and peculiarities related to the viral subtype (not B)

Author Response

Dear reviewer 3, 

We thank you for the positive evaluation of the case.

Round 2

Reviewer 1 Report

The Authors have addressed my concern.

If possible add the gene bank accession number in the manuscript. 

Author Response

Dear Reviewer, 

We have uploaded the sequences today - we will add the genbank numbers asap.

Thanks, 

Helene