Characterization of HIV-1 Integrase Gene and Resistance Associated Mutations Prior to Roll out of Integrase Inhibitors by Kenyan National HIV-Treatment Program in Kenya

Abstract

BACKGROUND: Antiretroviral therapy containing an integrase strand transfer inhibitor plus two Nucleoside Reverse Transcriptase inhibitors has now been recommended for treatment of HIV-1-infected patients. This thus determined possible pre-existing integrase resistance associated mutations in the integrase gene prior to introduction of integrase inhibitors combination therapy in Kenya.METHODS: Drug experienced HIV patients were enrolled at Kisii Teaching and Referral in Kenya. Blood specimens from (33) patients were collected for direct sequencing of HIV-1 polintegrase genes. Drug resistance mutations were interpreted according to the Stanford algorithm and phylogenetically analysed using insilico tools.RESULTS: From pooled 188 Kenyan HIV integrase sequences that were analysed for drug resistance, no major mutations conferring resistance to integrase inhibitors were detected. However, polymorphic accessory mutations associated with reduced susceptibility of integrase inhibitors were observed in low frequency; M50I (12.2%), T97A (3.7%), S153YG, E92G (1.6%), G140S/A/C (1.1%) and E157Q (0.5%). Phylogenetic analysis (330 sequences revealed that HIV-1 subtype A1 accounted for majority of the infections, 26 (78.8%), followed by D, 5 (15.2%) and C, 2 (6%).CONCLUSION: The integrase inhibitors will be effective in Kenya where HIV-1 subtype A1 is still the most predominant. However, occurring polymorphisms may warrant further investigation among drug experienced individuals on dolutegravir combination or integrase inhibitor treatment.

Analysis of HIV‐1 integrase genotypes and polymorphisms among integrase inhibitors‐based antiretroviral treatment naïve patients in South Sudan

“…This result might help to inform future arising drug resistance. Multiple polymorphisms, related to INIs resistance in vitro and frequently reported by different studies, 18–23 including K14, V31, I72, T112, S119, T124, T125, K136, V201, T206, T218, L234, A265, R269, D278, and S283 are of unknown impact at sites associated with drug resistance and require further investigation to understand their contribution to viral fitness.…”

“…Polymorphic accessory mutations, M50I and L74I, that contribute to reduced susceptibility to the INSTIs when occurring with major resistance mutations, were also identified. Overall, the M50I mutation has been described in 10%–25% of INSTI‐naïve individuals infected with B or of non‐B HIV‐1 subtypes 23 and, in Sub‐Saharan Africa, it was observed before the HIV‐1 INSTIs treatment program in studies of drug‐naive or first‐line regime‐failing patients from Mozambique, 18 South Africa, 19 and Kenya 20 . Our analysis revealed other two polymorphisms (R and L) at site 50, for a total frequency of 26.6%, of which six samples classified as subtype D, one as subtype G, and one as a recombinant G/A/D.…”

“…Natural polymorphisms in the integrase region may differ according to the subtype, 16,17 Cameroon, Zimbabwe representing the major HIV-1 subtypes. [18][19][20][21][22] Here we identified at least one polymorphic mutation at 78 of 288 possible amino acid sites (27%). These mutations occurred in more than 40% of patients at South Africa, 19 and Kenya.…”

“…These mutations occurred in more than 40% of patients at South Africa, 19 and Kenya. 20 [18][19][20][21][22][23] including K14, V31, I72, T112, S119, T124, T125, K136, V201, T206, T218, L234, A265, R269, D278, and S283 are of unknown impact at sites associated with drug resistance and require further investigation to understand their contribution to viral fitness.…”

Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations

“…It is therefore imperative to screen for the presence of mutations against INSTIs which can affect treatment outcomes. Currently, there is limited data available for INSTI RAMs from studies that focuses on the SSA region, where over two-thirds of the presently infected individuals reside [ 34 , 35 ]. In our previous studies we found low level of RAMSs against INSTIs [ 3 ].…”