Protease and gag diversity and drug resistance mutations among treatment-naive Mexican people living with HIV

Abstract

Introduction In Mexico, HIV genotyping is performed in people living with HIV (PLWH) failing their first-line antiretroviral (ARV) regimen; it is not routinely done for all treatment-naive PLWH before ARV initiation. The first nationally representative survey published in 2016 reported that the prevalence of pretreatment drug mutations in treatment-naive Mexican PLWH was 15.5% to any antiretroviral drug and 10.6% to non-nucleoside reverse transcriptase inhibitors (NNRTIs) using conventional Sanger sequencing. Most reports in Mexico focus on HIV pol gene and nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI) drug resistance mutations (DRMs) prevalence, using Sanger sequencing, next-generation sequencing (NGS) or both. To our knowledge, NGS has not be used to detect pretreatment drug resistance mutations (DRMs) in the HIV protease (PR) gene and its substrate the Gag polyprotein. Methods Treatment-naive adult Mexican PLWH were recruited between 2016 and 2019. HIV Gag and protease sequences were obtained by NGS and DRMs were identified using the WHO surveillance drug resistance mutation (SDRM) list. Results One hundred PLWH attending a public national reference hospital were included. The median age was 28 years-old, and most were male. The median HIV viral load was 4.99 [4.39–5.40] log copies/mL and median CD4 cell count was 150 [68.0–355.78] cells/mm3. As expected, most sequences clustered with HIV-1 subtype B (97.9%). Major PI resistance mutations were detected: 8 (8.3%) of 96 patients at a detection threshold of 1% and 3 (3.1%) at a detection threshold of 20%. A total of 1184 mutations in Gag were detected, of which 51 have been associated with resistance to PI, most of them were detected at a threshold of 20%. Follow-up clinical data was available for 79 PLWH at 6 months post-ART initiation, seven PLWH failed their first ART regimen; however no major PI mutations were identified in these individuals at baseline. Conclusions The frequency of DRM in the HIV protease was 7.3% at a detection threshold of 1% and 3.1% at a detection threshold of 20%. NGS-based HIV drug resistance genotyping provide improved detection of DRMs. Viral load was used to monitor ARV response and treatment failure was 8.9%.

Genetic diversity in the partial sequence of the HIV-1 gag gene among people living with multidrug-resistant HIV-1 infection

“…In addition to the mutations associated with resistance to PIs, more than half of the samples presented deletions and insertions in the protein-coding region of the matrix (p17), presenting greater sequence variation compared to the capsid. This pattern is consistent with similar studies that have also reported more quasispecies diversity, polymorphisms, deletions, and insertions in the matrix p17 21 , 22 .…”

“…Mutations at cleavage sites can directly affect the interaction with PI, whereas mutations at non-cleaved sites can contribute to restoring viral fitness, thus improving the access of the viral protease to the cleavage site 11 , 20 . Comparatively, a study conducted in Mexico showed a higher prevalence of the R76K and H219Q mutations and lower prevalence of the V128I and Y132F mutations among treatment-naïve individuals 21 .…”

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

“…Additional articles were identified by experts in the field. We screened out 1330 studies after removing duplicates, and 140 articles were downloaded for full-length screening, of which 39 articles were kept [ 6 , 17 , 24 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

HIV-1 Low-Frequency Variants Identified in Antiretroviral-Naïve Subjects with Virologic Failure after 12 Months of Follow-Up in Panama

“…Not surprisingly, we observed very few mutations to PIs, an expected result due to the high genetic barrier of this class of drugs. However, we identified the M46I as the most common mutation to PIs, also reported at a low frequency in ART-naïve individuals in Mexico, which is associated with reduced susceptibility to ATV and LPV [ 16 ]. The N88S mutation, conferring high-level resistance to ATV, was detected in one subject.…”