Low Prevalence of Pre-Treatment and Acquired Drug Resistance to Dolutegravir among Treatment Naïve Individuals Initiating on Tenofovir, Lamivudine and Dolutegravir in Zimbabwe

Round 1

Reviewer 1 Report

The combinational antiretroviral therapy (ART) is very effective in controlling HIV replication, and preventing the clinical onset of AIDS.  However, the development of viral mutations potentially poses a major challenge to the long-term effectiveness of ART.  

In this study, the authors investigated PLWH that were either ART-naïve or ART-defaulted, and determined the mutations in pol (PR, RT and IN), by monitoring the surveillance drug-resistance mutations (SDRMs).  They found that SDRM did not differ significantly between ART-naïve and ART-experienced participants.  The integrase strand transfer inhibitor (INSTI) was not significantly altered by ART treatments. SDRM for mutations to non-nucleotide reverse transcriptase inhibitors (NNRTIs) was slightly higher than to NRTIs.  Therefore, drug resistance to Tenofovir, Lamivudine and Dolutegravir appears to be low in these PLWH from Zimbabwe.

This study is very interesting and adds to our understanding of development of drug resistance in PLWH. It will be very helpful to draw a diagram with the alignment of HIV sequence, and show the sites of mutations in the HIV genome (SDRM).

In summary, it is an interesting study of HIV mutations in ART naïve and ART-defaulted PLWH. Drawing a diagram to highlight sites of mutations in the HIV genome in Table 2 will be helpful. 

OK

Author Response

We thank the reviewer for this suggestion. The authors have now added a diagram highlighting all the sites of mutation found in this study.

Reviewer 2 Report

In this study, the authors present the results of pre-treatment HIV drug resistance analysis in patients receiving care at an HIV clinic in Zimbabwe and undergoing treatment with dolutegravir (DTG) combined with tenofovir and lamivudine (TLD). The study was conducted between October 2021 and April 2023, involving 172 HIV-positive antiretroviral therapy (ART)-naïve adults who initiated DTG-based ART or re-initiated first-line TLD after a default of at least 3 months.

Participants were followed for a median duration of 27 weeks (IQR: 25-30) while on  TLD. Among them, 98% achieved virological suppression with VL < 1000 copies/ml, and only two participants with VL > 1000 copies/ml showed no baseline SDRMs (Surveillance Drug Resistance Mutations). Additionally, they did not develop acquired drug resistance to DTG.

Informed consent was obtained from all participants. For the enrolled patients, the protease (PR), reverse transcriptase (RT) (150), and integrase (IN) (137) regions of the HIV-1 pol gene were sequenced through Sanger sequencing. The mutations and subtypes were then analyzed. After a comprehensive review of sociodemographic and clinical characteristics of the participants, a detailed analysis of individual mutations and classes of inhibitors was conducted.

All sequences were confirmed to be HIV-1 subtype C. The prevalence of SDRMs was found to be 19%, with 15% of them associated with NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors). This prevalence is broadly consistent with many other findings. No SDRMs to INSTIs (Integrase Strand Transfer Inhibitors) were observed among both ART-naïve and experienced patients, though some accessory mutations were identified.

The authors draw an optimistic conclusion that "DTG is more likely to address the problems of HIVDR in Africa."

Indeed, the article contains all the necessary and sufficient information regarding the presented work and the appropriate conclusions. Only minor remarks are provided below.

Comments:

·       Line 50: "…knowledge of major INSTI-DRMs and polymorphisms remains very limited in this geographical context." Since the analysis of polymorphisms is promised, the results section should specify the polymorphic mutations identified, especially given the 100% subtype C homogeneity.

·       Line 63: "…obtained written informed consent before participant recruitment." It is essential to include the approval date and number from the ethics committee.

·       Pages 2-3: detailed procedures for viral load determination, nucleic acid isolation, and amplification are outlined, when involving commercial laboratory kits. This section could be more concise by stating that all tests were conducted in accordance with the manufacturer's instructions. This approach can be chosen at the authors' discretion.

Author Response

  Line 50: "…knowledge of major INSTI-DRMs and polymorphisms remains very limited in this geographical context." Since the analysis of polymorphisms is promised, the results section should specify the polymorphic mutations identified, especially given the 100% subtype C homogeneity.

Response: All polymorphic mutations found in this study have now been added in the result section.

Line 63: "…obtained written informed consent before participant recruitment." It is essential to include the approval date and number from the ethics committee.

Response: This information had been provided on page 9 under Institutional Review Board Statement.

Pages 2-3: detailed procedures for viral load determination, nucleic acid isolation, and amplification are outlined, when involving commercial laboratory kits. This section could be more concise by stating that all tests were conducted in accordance with the manufacturer's instructions. This approach can be chosen at the authors' discretion.

Response: The authors have clarified that all detailed procedures were conducted in accordance with the manufacturer's instructions.