Integrase Strand Transfer Inhibitor Mutations Research Articles

Virological Failure After Switch to Long-Acting Cabotegravir and Rilpivirine Injectable Therapy: An In-depth Analysis.

Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for human immunodeficiency virus type 1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merit further evaluation. We performed an in-depth clinical, virological, and pharmacokinetic analysis on the reasons behind and the impact of VF during LA CAB/RPV therapy in 5 cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF, and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cutoff (≤Q1) were considered to be low. Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of nonnucleoside reverse transcriptase inhibitor-associated mutations in all cases, and integrase strand transfer inhibitor mutations in 4 cases. All cases displayed low drug levels of either CAB, RPV, or both during the treatment course, likely contributing to the occurrence of VF. In 3 cases, we were able to identify the potential mechanisms behind these low drug levels. This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological, and pharmacokinetic approach in case of failure.

No transmitted drug resistance to HIV integrase strand-transfer inhibitors after their scale-up in Estonia in 2017

In Eastern Europe HIV-1 transmitted drug resistance (TDR) data, especially in integrase (IN) region is limited. In Estonia INSTI (Integrase Strand Transfer Inhibitors) TDR has been studied only prior to the INSTI scale-up in late 2010s. Current study aimed to determine the levels of protease (PR), reverse transcriptase (RT) and IN surveillance drug resistance mutations (SDRMs) among newly diagnosed patients in Estonia in 2017. Study included 216 newly diagnosed HIV-1 individuals from January 1 until December 31, 2017 in Estonia. Demographic and clinical data were obtained from the Estonian Health Board, Estonian HIV Cohort Study (E-HIV) and clinical laboratories' databases. The PR-RT and IN regions were sequenced and analyzed for SDRMs and subtype determination. Seventy-one percent (151/213) of available HIV-positive samples were successfully sequenced. The overall level of TDR was 7.9% (12/151; 95% CI 4.4-13.8%); no dual or triple class resistance was detected. No major INSTI mutations were found. The distribution of SDRMs for NNRTI, NRTI and PI was 5.9% (9/151), 1.3% (2/151) and 0.7% (1/151), respectively. The predominant NNRTI mutation was K103N. CRF06_cpx was predominant variant (59%) in Estonian HIV-1 population followed by subtype A (9%) and subtype B (8%). Although no major INSTI mutations were found, close monitoring of INSTI SDRMs is needed considering the extensive use of the first and second-generation INSTIs. PR-RT TDR is slowly rising in Estonia indicating the need for continuous surveillance in the future. Low genetic barrier NNRTIs should be avoided in the treatment regimens.

Drug Resistance to Integrase Strand-Transfer Inhibitors among HIV-1-Infected Adults in Guangdong, China.

Integrase strand-transfer inhibitor (INSTI)-containing regimens have gradually been administered in Guangdong Province, China beginning in 2016, and INSTI-related drug resistance (DR) may occur and should be monitored among HIV-1-infected patients. To investigate the prevalence of INSTI-related resistance among HIV-1-infected individuals in Guangdong and provide evidence for the optimal administration of INSTIs. This study recruited 1208 HIV-1-infected patients (including 404 ART-naive and 804 ART-experienced patients) between June 2021 and April 2022. The entire integrase gene was amplified from blood plasma. Demographic and epidemiological information were collected. INSTI mutations and susceptibility were interpreted using the Stanford HIV Drug Resistance Database HIVdb program. Of the 1208 enrolled individuals, 2.65% (32/1208) carried at least one INSTI major or accessory drug resistance mutation (DRM), with 1.49% (6/404) being from ART-naive individuals and 3.23% (26/804) from ART-experienced individuals. Among them, seven polymorphic major mutations were detected. Although no INSTI drug resistance was found among treatment-naive patients, seven ART-experienced patients (0.87%, 7/804) carried mutations conferring resistance to INSTIs. The overall prevalence of INSTI DRMs and DR was comparatively low among ART-naive and ART-treated populations in Guangdong; however, INSTI-related polymorphic mutations were observed. Surveillance should be reinforced before transfer to INSTI-containing regimens.

Molecular Epidemiology of HIV-1 in Eastern Europe and Russia.

The HIV epidemic in Eastern Europe and Russia is large and not well-controlled. To describe the more recent molecular epidemiology of HIV-1, transmitted drug resistance, and the relationship between the epidemics in this region, we sequenced the protease and reverse transcriptase genes of HIV-1 from 812 people living with HIV from Ukraine (n = 191), Georgia (n = 201), and Russia (n = 420) before the initiation of antiretroviral therapy. In 190 Ukrainian patients, the integrase gene sequence was also determined. The most reported route of transmission was heterosexual contact, followed by intravenous drug use, and men having sex with men (MSM). Several pre-existing drug resistance mutations were found against non-nucleoside reverse transcriptase inhibitors (RTIs) (n = 103), protease inhibitors (n = 11), and nucleoside analogue RTIs (n = 12), mostly polymorphic mutations or revertants. In the integrase gene, four strains with accessory integrase strand transfer inhibitor mutations were identified. Sub-subtype A6 caused most of the infections (713/812; 87.8%) in all three countries, including in MSM. In contrast to earlier studies, no clear clusters related to the route of transmission were identified, indicating that, within the region, the exchange of viruses among the different risk groups may occur more often than earlier reported.

High-level dolutegravir resistance can emerge rapidly from few variants and spread by recombination: implications for integrase strand transfer inhibitor salvage therapy.

The integrase strand transfer inhibitor (INSTI) dolutegravir is commonly used in combination antiretroviral therapy regimens and retains strong potency even with primary resistance mutations to some other INSTIs. Acquisition of accessory mutations to primary mutations results in significant increases in dolutegravir resistance. Previously, we reported that addition of the secondary mutation T97A can result in rapid treatment failure in individuals with INSTI mutations at positions 140 and 148. Here, we conducted a detailed case study of one of these individuals and find that T97A-containing HIV emerged from a large replicating population from only a few (≤4) viral lineages. When combined with primary INSTI resistance mutations, T97A provides a strong selective advantage; the finding that T97A-containing variants spread by replication and recombination, and persisted for months after discontinuing dolutegravir, has important implications as dolutegravir is rolled out worldwide.

Drug Resistance to HIV-1 Integrase Inhibitors Among Treatment-Naive Patients in Beijing, China.

IntroductionIntegrase strand transfer inhibitors (INSTIs) are important drugs that are currently used as the first line treatment for HIV-1 patients. The aim of this study was to characterize HIV-1 INSTI mutations among ART-naive patients in Beijing from 2019–2021.Methods865 ART-naive patients were enrolled in this study between January 2019 and June 2021 in Beijing. The amplification of the entire pol gene containing the reverse transcriptase, protease and integrase regions was performed using a validated In-house SBS method. HIV-1 subtypes and circulating recombinant forms (CRFs) were determined using the COMET online tool (http://comet.retrovirology.lu). Stanford HIV-1 drug resistance database (HIVdb version 8.9) was used to analyze the mutations.Results865 HIV-1 pol sequences were successfully amplified and sequenced. Among them, no major INSTI-related mutations were identified, but 12 polymorphic accessory mutations were found. Two patients have E138A and G163R mutations respectively and both could cause low-level resistance to RAL and EVG. Furthermore, one patient having S230R mutation resulted in low-level resistance to RAL, EVG, DTG and BIC.ConclusionThe prevalence of INSTIs mutations remains low, which demonstrated that INSTIs have good applicability currently in our city. Nevertheless, it is very important to monitor the INSTI-related mutations in Beijing.

894. Trend of Transmitted Resistance Associated Mutations in People Living with HIV (PLWH) in a Large Southeastern U.S. Ryan White Clinic

BackgroundDepartment of Health and Human Services (DHHS) guidelines recommend integrase strand transfer inhibitors (INSTIs) as the backbone of preferred initial antiretroviral (ART) regimens (1). Baseline mutation rates for the INSTI class is 0.8% compared with an overall rate of 19% for all ART classes, based on Centers for Disease Control and Prevention (CDC) U.S. data from 2013-16 (2). First-generation INSTIs (raltegravir and elvitegravir) have a lower genetic barrier to resistance compared with newer, second generation INSTIs (bictegravir and dolutegravir) (3, 4). DHHS guidelines do not currently recommend routine HIV genotypic resistance testing to INSTIs prior to ART initiation (1). Our study seeks to determine the current prevalence of transmitted INSTI and overall resistance in a large southeastern U.S. Ryan White clinic.MethodsThis was a single-center, retrospective analysis of treatment naïve PLWH presenting for care from January 1, 2017 to December 31, 2020. Of these, 164 had a baseline genotype performed by one of two commercially available assays – Vela Genomics or ViroSeq. Subsequent interpretations were based on Stanford HIV Drug Resistance Database. Results65 patients (39.6%) had at least one transmitted resistance associated mutation (RAMs). Of these, 24 (36.9%) had an INSTI RAM. Baseline PI, NRTI, and NNRTI RAMs declined during the four-year interval (2017-2020), while the rate of INSTI RAMs increased from 11.1% to 19%; all conferred resistance to the first generation INSTIs with one also conferring resistance to second generation INSTIs.INSTI Resistance Associated Mutation Prevalence 2017-2020 Frequency of Antiretroviral Therapy Class Mutations Per Year Trend of INSTI Mutations and Resistance Associated Mutations 2017-2020 ConclusionUnlike the CDC data which showed the overall prevalence of INSTI RAM transmission rates during 2013-2016 to be 0.8%, our data suggests a higher rate of INSTI RAMs (14.6%) with overall ART RAM transmission of 39.6%. This increase in baseline resistance to the INSTI class, which occurred over time, mimics the historical development of RAMs seen in the earlier ART classes. Though suboptimal adherence in the population promotes development of RAMs, increased frequency of INSTI RAMs may be due to a lower barrier to resistance of first generation INSTIs. Should our observed trend continue, routine baseline INSTI resistance testing may need to be considered prior to ART initiation.Disclosures Cheryl Newman, MD, Gilead (Scientific Research Study Investigator)GSK/ViiV (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Janssen (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

High-level resistance to bictegravir and cabotegravir in subtype A- and D-infected HIV-1 patients failing raltegravir with multiple resistance mutations.

The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs. HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells. HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug. Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.

Transmitted Drug Resistance Among Human Immunodeficiency Virus (HIV)-1 Diagnoses in the United States, 2014-2018.

Transmitted human immunodeficiency virus (HIV) drug resistance can threaten the efficacy of antiretroviral therapy and pre-exposure prophylaxis (PrEP). Drug-resistance testing is recommended at entry to HIV care in the United States and provides valuable insight for clinical decision making and population-level monitoring. We assessed transmitted drug-resistance-associated mutation (TDRM) prevalence and predicted susceptibility to common HIV drugs among US persons with HIV diagnosed during 2014-2018 who had a drug resistance test performed ≤3 months after HIV diagnosis and reported to the National HIV Surveillance System and who resided in 28 jurisdictions where ≥20% of HIV diagnoses had an eligible sequence during this period. Of 50 747 persons in the analysis, 9616 (18.9%) had ≥1 TDRM. TDRM prevalence was 0.8% for integrase strand transfer inhibitors (INSTIs), 4.2% for protease inhibitors, 6.9% for nucleoside reverse transcriptase inhibitors (NRTIs), and 12.0% for non-NRTIs. Most individual mutations had a prevalence <1.0% including M184V (0.9%) and K65R (0.1%); K103N was most prevalent (8.6%). TDRM prevalence did not increase or decrease significantly during 2014-2018 overall, for individual drug classes, or for key individual mutations except for M184V (12.9% increase per year; 95% confidence interval, 5.6-20.6%). TDRM prevalence overall and for individual drug classes remained stable during 2014-2018; transmitted INSTI resistance was uncommon. Continued population-level monitoring of INSTI and NRTI mutations, especially M184V and K65R, is warranted amidst expanding use of second-generation INSTIs and PrEP.

A low-cost in-house HIV integrase strand transfer inhibitor drug resistance test for resource-limited settings

Background: HIV-1 drug resistance testing (DRT) is vital for monitoring of individual patient treatment outcomes and for public health surveillance. Access to HIV-1 DRT is limited in resource-poor settings, including Kenya due to its costly nature. Recent inclusion of integrase strand transfer inhibitors (INSTIs) in first-line treatment for all people living with HIV-1 (PLHIV-1) underscores the need for an INSTI DRT. This study aims to validate a cost-effective in-house DRT method to detect HIV-1 Integrase resistance-associated mutations (RAMs) using HIV positive plasma derived samples Methods: Thirty-six plasma derived samples were used to assess the performance characteristics including accuracy, precision, reproducibility and amplification sensitivity of an in-house method in comparison with a reference assay. Cost estimation per test followed an incremental ingredient costing approach. Clinical application of the in-house test was evaluated on a plasma sample from a patient failing an INSTI-based regimen. Results: Comparison of the in-house and reference assay gave mean nucleotide and amino acid sequence identity of 99.49 %, CI [99.21- 99.77] and 99%, CI [98.58, 99.42] respectively. Complete concordance was observed by both assays in detection of the T97TA INSTI RAM. Precision and reproducibility assessment revealed mean nucleotide sequence identities of 100% and 99.14% respectively. The amplification sensitivity was 100% for samples with VL&gt; 1000 copies/mL (n=8) and 50% for samples with VL&lt;1000 copies/mL. Two major (G118R and E188K) and two accessory INSTI mutations (G149A and E157Q) were detected from the clinical sample of a patient failing an INSTI-based therapy. Cost analysis estimated the cost per test at $50.31. Conclusion: The developed HIV-Integrase assay met the validation acceptance criteria and demonstrates the ability to detect clinically relevant INSTI-resistance-associated mutations, highlighting its potential use as an alternative to commercial INSTI tests in resource-limited settings.

The Continuous Surveillance of InSTI Resistance Could be an Important Public Health Tool in the Fight Against HIV Infection.

To evaluate the frequency of the InSTIs mutations in a large cohort of HIV-infected people. The Highly Active Anti-Retroviral Therapy (HAART) allows turning HIV infection from a fatal disease to chronic infection, and Integrase Strand Transfer Inhibitors (InSTIs) represent the cornerstone of this treatment. However, the spread of HIV-1 drug resistance mutations represents an emerging threat to the long-term success of HIV treatment programs. To evaluate the trend of the HIV drug resistance to InSTIs in a large cohort of HIVpositive people in order to assess the risk represented by these subjects in the spread of the HIV infection to the community. A cross-sectional study was conducted analysing all the InSTIs resistance tests performed in HIV positive subjects during 2017-2019 by the HIV Laboratory of the University Hospital "Gaetano Martino" of Messina, Italy. In 2017-2019, 252 InSTIs resistance tests were performed, with 59 (23.4%), 88 (34.9%), and 105 (41.7%) tests respectively in the three considered years. Overall, 28 (11.1%) samples showed resistance to at least one of the four InSTIs. We observed a significant percentage increase of 95% in the resistance to all four drugs. InSTI resistance is not rare. Therefore, continuous surveillance along with incessant health education and a wide offer of the HIV test, can be the most important tools in the fight against HIV infection.

Absence of Integrase Inhibitor-Associated Resistance Among Antiretroviral Therapy-Naïve HIV-1-Infected Adults in Guangdong Province, China, in 2018.

BackgroundAntiretroviral therapy (ART) containing an integrase strand transfer inhibitor (INSTI) plus two nucleoside reverse-transcriptase inhibitors has been recommended as a first-line regimen for ART-naïve HIV-1-infected patients in the latest Chinese Guidelines for Diagnosis and Treatment of HIV/AIDS.ObjectiveTo determine the prevalence of INSTI-related mutations among ART-naïve HIV-1-infected adults in Guangdong, China, in 2018.MethodsThe entire integrase gene was amplified from blood plasma. Demographic and epidemiological information was collected. INSTI mutations and antiretroviral susceptibility were interpreted using the Stanford University HIV Drug Resistance Database HIVdb program.ResultsOf 927 samples, 827 integrase sequences were successfully obtained. Among them, no major resistance mutations to INSTIs were identified, and four accessory mutations, including T97A (0.12%, 1/827), A128T (0.24%, 2/827), E157Q (0.85%, 7/827), and G163R (0.24%, 2/827), were found in twelve individuals. Two patient samples contained the G163R mutation conferring low-level resistance to elvitegravir and raltegravir.ConclusionThe overall prevalence of INSTI mutations remains low. Drug resistance mutation testing for the detection of INSTI drug resistance mutations in HIV treatment-naïve patients should be considered due to the circulation of polymorphisms contributing to INSTI resistance and the expected increasing use of this class of drugs.

Comparable In Vitro Activities of Second-Generation HIV-1 Integrase Strand Transfer Inhibitors (INSTIs) on HIV-1 Clinical Isolates with INSTI Resistance Mutations.

Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC, and CAB demonstrated a comparable activity on a panel of INSTI-resistant strains isolated from patients exposed to RAL, EVG, and/or DTG, with a significantly reduced susceptibility only with the pathway Q148H/K/R plus one to two additional INSTI mutations.

Lack of HIV-1 integrase inhibitor resistance among 392 antiretroviral-naïve individuals in a tertiary care hospital in Beijing, China.

: Reports of resistance to integrase strand transfer inhibitors (INSTIs) are now not uncommon. We analyzed the HIV int gene from plasma of antiretroviral-naïve individuals during acute and chronic HIV-1 infection. No individual with major INSTI mutations was identified. Two individuals harbored INSTI accessory mutations E157Q/T97A were detected for the first time. Our results emphasize the need to consider testing for INSTI resistance at baseline as this class of drugs is increasingly used in clinical routine.

Resistance in patients failing integrase strand transfer inhibitors: a call to replace raltegravir with dolutegravir in third-line treatment in South Africa.

Data on integrase resistance patterns in low- and middle-income countries (LMICs) is scarce. We assessed genotypic drug resistance in 43 patients with virological failure on integrase strand transfer inhibitors (INSTIs) containing regimens as part of the third-line treatment program in South Africa. Of the raltegravir (RAL)-exposed patients 20 of 34 (59%) had ≥1 major INSTI mutation, including 2 (6%) with dolutegravir (DTG) cross-resistance. Dolutegravir resistance was detected in 1 of 4 DTG-exposed patients. Replacing RAL with DTG may reduce the risk of INSTI mutations. We recommend DTG drug resistance monitoring when DTG is introduced at a larger scale in LMICs.

Dolutegravir plus lamivudine dual therapy - a new option for initial antiretroviral therapy.

The current standard of care for treating HIV infection is the use of three antiretroviral drugs: a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a third agent from either the integrase strand transfer inhibitor (INSTI), boosted protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) classes. In an effort to minimize the long-term adverse effects and cost of antiretroviral therapy, the use of regimens with fewer drugs in the combination has been under active investigation. To this end, the combination of dolutegravir (DTG) plus lamivudine (3TC), two antiretroviral drugs with a long track record of efficacy and safety in the treatment of HIV infection, is undergoing clinical evaluation in treatment-naive HIV-infected participants. The promising results of the PADDLE study, with 90% of study participants achieving the primary endpoint of HIV-1 RNA lower than 50 copies/mL, were confirmed by the results of ACTG A5353, a phase II, single-arm, open-label study. Subsequently, GEMINI-1 and -2, two phase III, double-blind, noninferiority studies, compared DTG + 3TC to a three-drug regimen of DTG, tenofovir disoproxil fumarate and emtricitabine in 1,433 antiretroviral treatment-naive adults, and demonstrated noninferior efficacy at 48 weeks with no emergence of NRTI or INSTI mutations and a more favorable safety profile. This dual regimen should be avoided in those patients with existing mutations and chronic hepatitis B virus infection. In addition, data in patients with CD4 counts less than 200/mm3 is limited.

Prevalence of Integrase Strand Transfer Inhibitors Resistance Mutations in Integrase Strand Transfer Inhibitors-Naive and -Experienced HIV-1 Infected Patients: A Single Center Experience.

Integrase strand transfer inhibitor (InSTI) resistance rates are low. However, genotypic resistance test (GRT) is not routinely performed in many centers. The aim of this study is to evaluate the prevalence of InSTI-related mutations in our large cohort. We examined all integrase GRTs performed as part of routine clinical practice at Spedali Civili General Hospital, University of Brescia from 2011 to 2016. Analysis was performed through the Stanford HIV Drug Resistance Database. A total of 341 patients were included. Genotypic resistance assays were performed in naive (48), ART-experienced but InSTI-naive (114), and both ART-experienced/InSTI-experienced (179) patients. No major resistance-associated mutations (RAMs) were detected in patients never exposed to InSTIs. Of 179 samples from patients exposed to InSTIs (mostly to raltegravir [RAL]), the overall prevalence of major RAMs was 11.7%. Among them, 10 harbored N155H, 4 Q148H, 2 Q148R, 2 Y143C/S, and 2 T66A/I/T, respectively. A novel mutation at a recognized resistance site (E92K) was identified in one RAL-experienced patient. The overall prevalence of InSTI mutations in our cohort was low, particularly in naive patients indicating no transmitted RAMs, although in InSTIs-experienced patients the rate of RAMs was high (11.7%). We support an implementation of surveillance of InSTI resistance.

Pretreatment integrase strand transfer inhibitor resistance in North Carolina from 2010-2016.

We sought to define the prevalence of pretreatment integrase strand transfer inhibitor (INSTI) resistance and assess the transmission networks of those with pretreatment INSTI resistance. A retrospective cohort study of HIV-positive patients with genotypic resistance testing sent to a single referral laboratory in North Carolina between 2010 and 2016. We linked genotype and public health data for in-care HIV-positive individuals to determine the prevalence of INSTI resistance among treatment-naive (defined as those with a first genotype ≤3 months after diagnosis) and treatment-experienced (defined as those with a first genotype >3 months after diagnosis) patients. We performed molecular and phylogenetic analyses to assess whether pretreatment INSTI resistance mutations represented clustered HIV transmission. Of 8825 individuals who contributed sequences for protease, reverse transcriptase, or INSTI genotypic resistance testing during the study period, 2784 (31%) contributed at least one sequence for INSTI resistance testing. Of these, 840 were treatment-naive individuals and 20 [2.4%, 95% confidence interval (CI): 1.5, 3.6%] had INSTI mutations; only two (0.2%, 95% CI: 0.02, 0.9%) had major mutations. Of 1944 treatment-experienced individuals, 9.6% (95% CI: 8.3, 11.0%) had any INSTI mutation and 7.0% (95% CI: 5.9, 8.3%) had major mutations; the prevalence of INSTI mutations among treatment-experienced patients decreased overtime (P < 0.001). In total 12 of 20 individuals with pretreatment INSTI mutations were part of 10 molecular transmission clusters; only one cluster shared identical minor mutations. The prevalence of major pretreatment INSTI resistance is very low. Pretreatment INSTI mutations do not appear to represent clustered HIV transmission.

Long-term efficacy of dolutegravir in treatment-experienced subjects failing therapy with HIV-1 integrase strand inhibitor-resistant virus.

This study evaluated the virological efficacy of dolutegravir 50 mg twice daily in 190 HIV-1 failing antiretroviral-experienced patients with previous exposure to first-generation integrase strand transfer inhibitor (INSTI) over a 5 year follow-up using data from clinical practice. This analysis included HIV-1-infected patients who were ≥18 years of age, treatment experienced, had HIV-1 RNA >50 copies/mL, with INSTI-resistant virus, who started dolutegravir 50 mg twice daily plus optimized background therapy (OBT), recorded in the national prospective database PRESTIGIO (www.progettoprestigio.it). Follow-up accrued from the start of dolutegravir 50 mg twice daily + OBT until virological failure (VF) or dolutegravir discontinuation for any reason or the last treatment visit on dolutegravir 50 mg twice daily treatment. VF was defined by the lack of achievement of HIV-1 RNA <50 copies/mL by 6 months and thereafter, or the occurrence of two consecutive HIV-1 RNA ≥50 copies/mL after achievement of undetectable viral load. The estimated VF probabilities were 17% (95% CI = 12%-24%), 28% (95% CI = 21%-37%), 33% (95% CI = 25%-43%), 39% (95% CI = 29%-51%) and 52% (95% CI = 39%-67%) at 12, 24, 36, 48 and 60 months since baseline, respectively. A higher risk of VF was independently associated with baseline viral load >100000 copies/mL (adjusted HR = 4.73, 95% CI = 1.33-16.78, P = 0.016) and with ≥1 INSTI mutations plus Q148H/K/R/N and the G140S/A/C as compared with other subjects (adjusted HR = 4.18, 95% CI = 1.32-13.23, P = 0.015). Our data showed a favourable long-term efficacy of dolutegravir 50 mg twice daily in association with OBT in treatment-experienced failing subjects, with INSTI-resistant virus, in the real world. A close monitoring of adherence is crucial for maintenance of virological response in this fragile subgroup of subjects.

Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan.

Antiretroviral therapy containing an integrase strand transfer inhibitor (INSTI) plus two NRTIs has become the recommended treatment for antiretroviral-naive HIV-1-infected patients in the updated guidelines. We aimed to determine the prevalence of INSTI-related mutations in Taiwan. Genotypic resistance assays were performed on plasma from ARV-naïve patients (N = 948), ARV-experienced but INSTI-naive patients (N = 359), and raltegravir-experienced patients (N = 63) from 2006 to 2015. Major INSTI mutations were defined according to the IAS-USA list and other substitutions with a Stanford HIVdb score ≧ 10 to at least one INSTI were defined as minor mutations. Of 1307 HIV-1 samples from patients never exposed to INSTIs, the overall prevalence of major resistance mutations to INSTIs was 0.9% (n = 12), with an increase to 1.2% in 2013. Of these 12 sequences, 11 harboured Q148H/K/R, one Y143R, and none N155H. Of 30 sequences (47.6%) with INSTI-resistant mutations from raltegravir-experienced patients, 17 harboured Q148H/K/R, 8 N155H, and 6 Y143C/R. Other than these major mutations, the prevalence of minor mutations were 5.3% and 38.1%, respectively, in ARV-naive and raltegravir-experienced patients. The overall prevalence of INSTI mutations remains low in Taiwan. Surveillance of INSTI resistance is warranted due to circulation of polymorphisms contributing to INSTI resistance and expected increasing use of INSTIs.