Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia
, Zsófia Ilona Szojka 3, Kidist Zealiyas 2,†, Atsbeha Gebreegziabxier 2,†, Fekadu Adugna 4, Sviataslau Sasinovich 1, Per Björkman 1,5 and Patrik Medstrand 1,6
Round 1
Reviewer 1 Report
This research paper investigated pre-treatment integrase resistance and natural polymorphisms among people living with HIV-1 subtype C in Ethiopia. The topic is highly relevant, as the World Health Organization in 2019 recommended that dolutegravir (in combination with 2 nucleoside reverse transcriptase inhibitors) be the first-line treatment of all adults and adolescents. The methods were extensive and the population included both ART-naive and ART-experienced patients (non-DTG). The authors have acknowledged the limitation of Sanger sequencing.
Minor questions/comments are as follows:
- A viral load of >1,000 was used as a cutoff for virological failure and genotyping. The CDC defines 'detectable' >200 copies/ml. Please clarify the cutoff used or provide citation
- Although the authors have indicated that majority of studies were on subtype B, it would be interesting to see the results of integrase resistance and polymorphisms and other subtypes.
- In the Statistical methods, the authors state that Fisher's exact test was used. Please clarify whether it was both Fisher's exact test and Chi-squared test of proportions, given the relatively large sample size of the study.
- Results: In Line 557, "but INSTI native patient" seems misplaced. Please clarify the sentence.
Author Response
Please see the attachment.
Reviewer 2 Report
In this study the authors aimed at the analysis of genetic polymorphisms in HIV-1 integrase (IN) of subtype C dominating in Ethiopia. The study included 460 HIV-1 sequences obtained both from ART-naïve and ART-experienced (NRTI/NNRTI) patients.
Ethical approval was in place.
The main aim of the study was to assess the prevalence of INI resistance mutations in patients with no experience of DTG treatment, and to look for the possibility of the influence of drug resistance mutations acquired after the experience of previous therapy.
The methodology used was based on an adequate and modern set of methods for genomic analysis, including genotyping, phylogenetic analysis, drug resistance analysis, genetic barrier studies and docking analysis. The description of the methods is exhaustive.
The polymorphism of HIV-1 subtype C INI is described in great detail and includes all functionally important regions of the genome. The authors obtained very convincing data on the low prevalence of INI major drug resistance mutations that can limit the use of second-generation IN inhibitors.
Data on the impact of NRTI/NNRTIs mutations differ from previously obtained data from other authors, but they also look very serious and well-supported. In addition, the data obtained by the docking analysis method and confirming the conclusion that there is no relationship between the presence of NRTI/NNRTIs mutations and IN polymorphism look especially appropriate.
Information about differences in the INI genetic barrier for different HIV subtypes is very important.
In fact, I do not see any shortcomings in the article and obstacles to its publication. There are a few typos that should be corrected, for example:
Page 8, Line 280. “Among the HIVDR-groups and no-HIVDR, 4.7% (11/234) and 4.7% (11/234) accessory mutations were detected respectively (p=0.8)” – should be “Among the HIVDR-groups and no-HIVDR, 3.2% (3/93) and 4.7% (11/234) accessory mutations were detected respectively (p=0.8)”.
Page 9, Line 308. “Figure 4. Distribution of variant among HIV-1 subtype C integrase sequence”. Some word is missing. The text in the next paragraph needs to be combined with this one so that it is clear that this is a figure caption.
Page 10, Line 334. integrase: integrase oligomerization at the dimer: dimer interface.
Author Response
Please see the attachment
Author Response File: 
Author Response.docx
