Integrase Inhibitor Resistance Research Articles

Transforming HIV prevention: the promise of long-acting preexposure prophylaxis in high HIV burden settings.

Recent research on efficacy and safety of long-acting preexposure prophylaxis (PrEP) holds the promise to transform HIV prevention in high HIV burden settings. We review emerging findings regarding early end-user acceptability of long-acting PrEP modalities, feasibility of integrating long-acting PrEP into health systems, and considerations regarding drug resistance and cost. Long-acting PrEP, particularly injectables, was found to be highly acceptable among individuals across key populations in high HIV burden settings. Concerns around use of long-acting PrEP highlight the importance of choice and ability to switch methods. Existing provider-level barriers to oral PrEP implementation (e.g., overburdened staff, training gaps) may impact long-acting PrEP rollout - however, utilization of PrEP implementation strategies such as task-shifting, timely PrEP training for all providers, differentiated service delivery, and integration with sexual health services, may mitigate barriers. Studies modeling injectable PrEP scale-up demonstrate substantial benefits in HIV mortality reduction, outweighing risks of increased integrase inhibitor resistance, but also highlight the urgency of pricing long-acting PrEP to ensure access and affordability. Long-acting PrEP could be a game changer in HIV prevention in high burden settings. There is an urgent need for rapid scale production and price reductions to ensure access in high HIV burden settings. Implementation strategies are needed to address individual and provider-level barriers.

Real-world prevalence of integrase inhibitor resistance and virological failure since adoption as guideline-preferred therapy.

Limited data reporting real-world prevalence of integrase strand transfer inhibitor resistance (INSTI-R) in the USA are available because their recommendation as first-line treatment in 2017. Reported national surveillance data in the USA estimated INSTI-R to be 6.3% as of 2018. This article aims to describe estimated prevalence of INSTI-R within a single clinic network in Chicago, IL, USA, and identify risk factors for resistance and virological failure (VF). This was a retrospective, single-centre study of adults with HIV starting an INSTI-containing regimen between September 2017 and 2020. The primary endpoint was the difference in INSTI-R of the sample population compared with the national prevalence. Other outcomes included VF and documented INSTI-R mutations. Of 948 participants screened, 321 were included. Eight people had baseline INSTI-R testing results available, of which five had INSTI-R at baseline for an estimated prevalence of 1.6%. This estimation was significantly less than the national estimated prevalence of 6.3% (p<0.001). VF occurred in 26 (7.8%) individuals. Because no participants acquired INSTI-R during the study period, investigators were unable to identify risk factors associated with the development of INSTI-R. People with high pre-treatment viral loads had 1.21 (95% CI 1.05-1.39) higher odds of VF. Amongst participants on INSTI-containing regimens, INSTI-R rates were estimated to be lower than the estimated national prevalence. Detectable pre-switch viral loads were more associated with VF than undetectable viral loads.

1518. Prevalence of Integrase Inhibitor Resistance within an Urban Clinic Network After Adoption as First-line Therapy

Abstract Background Limited data outside of randomized controlled trials exist reporting the prevalence of integrase inhibitor resistance (INSTI-R) since the approval and recommendation of INSTIs as first-line treatment for HIV. National surveillance data in 2018 estimated INSTI-R to be 6.3% in people with HIV (PWH) who had never achieved viral suppression, with 0.8% attributed to transmitted drug resistance (TDR). The purpose of this study was to describe the prevalence of INSTI-R in patients from a single urban clinic network on INSTI-containing regimens. Prevalence amongst University of Illinois Chicago Community Clinic Network (UCCN) patients on INSTI-containing single-tablet regimens specifically was previously reported. Methods This was a retrospective study of adult PWH followed at UCCN prescribed an INSTI-containing regimen between September 2017 and September 2020 with &amp;gt; two recorded HIV-1 RNA viral loads collected &amp;gt; 12 months apart. The primary endpoint was the difference in INSTI-R in UCCN patients compared to national data. Other outcomes included development of virologic failure (VF), defined as &amp;gt; 200 copies/mL in two consecutive HIV-1 RNA viral loads, and patient specific factors associated with VF. The primary endpoint was analyzed using a chi-square test. All other data are presented as descriptive statistics. Results Of 948 patients screened, 321 were included and followed an average of 30 months. Baseline characteristics are presented in Table 1. A total of 5 subjects had INSTI-R prior to switch resulting in a prevalence of 1.6%, which was significantly less than the national prevalence of 6.3% (p&amp;lt; 0.001). Of note, all patients with INSTI-R were previously treated with first generation INSTIs and none were deemed TDR. Study-defined VF occurred in 26 subjects (8.1%). Seven subjects (26.9%) were not taking antiretrovirals for &amp;gt; six weeks at the time of study-defined VF. Outcomes of patients with VF are outlined in Table 2. Subjects with a pre-treatment viral load &amp;gt; 100,000 were more likely to experience VF (p=0.0485). Conclusion Among UCCN patients on INSTI-containing regimens, INSTI-R rates were lower than the estimated national prevalence; however, this comparison is limited due to the large proportion of subjects with viral suppression at baseline. Disclosures All Authors: No reported disclosures

Dolutegravir-associated resistance mutations after first-line treatment failure in Brazil

BackgroundSince January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018.MethodsHIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018.ResultsOne hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors.ConclusionsIn marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.

Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV.

Drug regimens containing integrase strand transfer inhibitors (INSTIs) are widely recommended by international guidelines for ART-naive people living with HIV (PLWH).1,2 However, INSTI resistance mutations are uncommon and therefore their surveillance is not suggested before starting ART. The aim of the study was to evaluate the prevalence trend of transmitted INSTI drug resistance (DR) and to assess factors associated with transmitted INSTI resistance among ART-naive PLWH over the past decade. We conducted a time-trend, single-centre study over the period 2009–19 on adult naive PLWH with a genotypic resistance test (GRT) performed before the ART initiation. GRT was determined by Sanger sequencing using an ABI PRISM 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA); we included in the analysis the immediate pre-ART GRT available in people newly diagnosed with HIV infection. The degree of resistance to each INSTI drug was calculated using the Genotypic Resistance Interpretation Algorithm of the Stanford HIV Drug Resistance Database Program (version 9.1.1) (https://hivdb.stanford.edu/hivdb/by-patterns/). The obtained scores were used to classify the presence of low-level, intermediate or high-level resistance to each INSTI drug and to the INSTI drug class. DR within the INSTI class was defined by the presence of at least low-level resistance to ≥1 drug of the INSTI class.

Prevalence of HIV-1 Natural Polymorphisms and Integrase-Resistance-Associated Mutations in African Children.

Integrase inhibitors (INIs) are a potent option for HIV treatment. Limited data exist on INI resistance in West Africa, particularly in children living with HIV/AIDS. We determined the prevalence of integrase gene polymorphisms and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance. Dried blood spot (DBS) samples were obtained from one hundred and seven (107) HIV-1-infected children aged less than 15 years old in two West African countries, Benin and Mali. All children were naïve to INI treatment, 56 were naïve to anti-retroviral therapy (ART), and 51 had received ART. Genetic sequencing of HIV integrase was successful in 75 samples. The aa changes at integrase positions associated with INI resistance were examined according to the Stanford HIV Genotypic Resistance database. The median ages were 2.6 and 10 years for ART-naïve and -treated children, respectively. The most common subtypes observed were CRF02_AG (74.7%) followed by CRF06_cpx (20%). No major INI-resistance mutations at positions 66, 92, 121, 143, 147, 148, 155, and 263 were detected. The most prevalent INI accessory resistance mutations were: L74I/M (14/75, 18.6%) followed by E157Q (8/75, 10.6%), G163E/N/T/Q (5/75, 6.6%), Q95A/H/P (2/75, 2.6%), and T97A (4/75, 5.3%). Other substitutions observed were M50I/L/P, H51E/P/S/Q, I72V, T112V, V201I, and T206S. Polymorphisms at positions which may influence the genetic barrier and/or drive the selection of specific INI-resistance pathways were detected. However, no transmitted drug resistance (TDR) to INI was detected among samples of INI-naïve patients. These findings support the use of this treatment class for children with HIV-1, particularly in West Africa.

Correction for Underwood et al., "Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study".

Volume 66, no. 1, e0164321, 2022, https://doi.org/10.1128/AAC.01643-21. Page 12, “Data availability” paragraph, line 2: The reported GenBank accession numbers (MZ568467 to MZ568625) are incorrect. The GenBank accession numbers should be MZ568548 to MZ568625.

Real world use of dolutegravir two drug regimens.

Since 2015, we prescribed dolutegravir (DTG)-based two drug regimens (DTG-2DR) for 620 people [total cohort 3133 (19.8%)]. Clinic database search 1 January 15 to 31 October 21. Demographic, tolerability and HIV related data analysed. In total, 620 people identified; 561 had complete data. 446 male (79.5%); median age 54 years (interquartile range 46, 59). 343 (61.1%) MSM. Nine people who initiated naïvely achieved viral suppression (100%). 546/552 (99.0%) switched or continued and were suppressed at data censor. 460/552 (83.3%) received DTG-lamivudine (DTG/3TC), 74/552 (13.4%) received DTG-rilpivirine (DTG/RPV) and 18/552 (3.3%) received DTG-emtricitabine (DTG/FTC). 70 (12.5%) switched off DTG-2DR (55 DTG/3TC, 13 DTG/RPV, two DTG/FTC) due to side-effects. 41 episodes of blip (1 off >50 copies/ml) occurred in 30 people (5.3%). 11/41 on DTG-RPV [ n = 7 multi-tablet regimen (MTR), n = 4 single tablet regimen (STR)]. 27/41 DTG-3TC, 3/41 DTG/FTC ( n = 26 MTR, n = 4 STR). Six people (1.1%) failed (confirmed viral load >200 copies/ml or persistent low level viraemia) ( n = 4 DTG-3TC STR, n = 1 DTG-3TC MTR, n = 1 DTG-RPV MTR). Four failures due to low level viraemia, one due to non-adherence and one due to high viral load. Resistance tests performed for 5/6 - mutations detected only in latter person with high viral load failure (on DTG-3TC MTR) who developed triple class resistance. Majority of experience is in DTG/3TC stable switch. Minority of patients developed side-effects. Low number of virological failures, one developed integrase inhibitor resistance. Viral failure associated with MTR, commensurate with trial data showing no failure with resistance if DTG/3TC STR used. Overall DTG-2DR demonstrates high efficacy in real-world setting.

Long-acting PrEP: new opportunities with some drawbacks

Daily oral pre-exposure prophylaxis (PrEP) is highly effective for preventing HIV infection,1 but uptake, continuation, and adherence are low in sub-Saharan Africa.2 Long-acting injectable cabotegravir-PrEP, administered every 2 months, could enhance uptake and has superior efficacy to oral PrEP for women in sub-Saharan Africa.3 However, the use of cabotegravir-PrEP could result in integrase-inhibitor resistance if an acute HIV infection is missed when starting cabotegravir-PrEP, or if infection occurs while using cabotegravir-PrEP or after stopping cabotegravir-PrEP when residual cabotegravir is still in the system.

2060. Evaluation of the real world incidence of integrase inhibitor resistance since adoption as guideline preferred therapy

Abstract Background There are limited data reporting real-world incidence of integrase inhibitor resistance (INSTI-R) since the approval and first-line treatment recommendation of INSTIs in the US. A recent analysis of the national surveillance data estimated INSTI-R to be 6.3%. The purpose of this study was to describe real-world incidence of INSTI-R in patients who used an INSTI-based single tablet regimen (STR) in a major metropolitan area and identify risk factors for resistance. Methods This was a retrospective study of adult patients living with human immunodeficiency virus (HIV) who were prescribed an INSTI-STR between September 2017 and September 2020 and followed for &amp;gt; 12 months at the University of Illinois Chicago Community Clinic Network (UCCN). The primary endpoint was the difference in INSTI-R in UCCN patients compared to the national prevalence of 6.3%. Other outcomes included development of virologic failure (VF), defined as 2 consecutive HIV-1 viral loads (VL) &amp;gt; 200 copies/mL after week 24, and documented INSTI-R mutations. Patient specific factors associated with medication nonadherence were also collected. All endpoints were analyzed using chi-square and Fisher’s exact tests. Results Of 948 patients screened, 248 patients were included. Baseline characteristics are summarized in Table 1. VF occurred in 17 subjects (6.8%). Two of the 17 (11.8%) received subsequent INSTI-R testing and nine eventually virally suppressed without regimen changes (52.9%). Patients without VF were assumed to have no INSTI-R. No subjects developed INSTI-R, which was significantly less than the national prevalence of 6.3% (p=0.0029). Patients with a high VL at baseline were more likely to experience VF (p=0.001). The most common factors associated with nonadherence in patients with VF are summarized in Table 2. Conclusion The true rate of INSTI-R in UCCN patients is still unknown and factors associated with developing INSTI-R were unable to be assessed. Among patients at UCCN on INSTI-based STRs, INSTI-R rates were lower than the national average. Future analyses should also include patients on INSTI-based non-STR regimens as increased pill burden is a known risk factor for nonadherence leading to VF and drug resistance. Disclosures All Authors: No reported disclosures.

Genetic Subtypes and Status of Transmitted Drug Resistance of HIV/AIDS Patients in Sichuan

To investigate the distribution characteristics of the HIV genetic subtypes and the status quo of transmitted drug resistance among HIV/AIDS patients in Sichuan with no previous history of receiving antiretroviral therapy (ART). Adult HIV/AIDS patients who were hospitalized in Sichuan and who had no previous history of exposure to ART drugs exposure were enrolled. In-house sequencing of the HIV gene was done and phylogenetic tree was constructed to analyze the HIV genetic subtypes. The Stanford HIV drug resistance database was used to make online comparison of the drug resistance mutation sites and to determine the presence or absence of drug resistance, and the type and level of drug resistance. A total of 120 patients were enrolled for the study, and 120 blood samples were collected. The genetic subtypes of 87.5% (105/120) of the samples were successfully amplified. The distribution characteristics of HIV genotype were as follows, CRF01_AE accounted for 46.67% (49/105), CRF07_BC accounted for 39.05% (41/105), and the others genetic subtypes, 14.28% (15/105). There were no significant differences between the different genetic subtypes in sex, age, ethnicity, HIV transmission route, drug resistance, baseline HIV RNA and baseline CD4 ( P>0.05). Drug-resistant mutation sites were detected in 25 samples, accounting for 20.83% (25/120) of all samples, with 16.67% (20/120) being potential drug resistance and 4.17% (5/120) being transmitted drug resistance. For the 24 samples found to be resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs), the mutation frequency of V179D/E was the highest. One patient showed resistance to protease inhibitors (PI) and the mutation site was M46I. No nucleoside reverse transcriptase inhibitor (NRTI) or integrase inhibitors (INTI) resistance were found. The main genetic subtypes of HIV/AIDS patients in Sichuan with no previous history of receiving ART were CRF01_AE and CRF07_BC. The incidence of transmitted drug resistance was low. The drug resistance detected in the study was predominantly resistance to NNRTIs. Baseline HIV drug resistance testing is of great significance for formulating effective ART regimens.

Can simplified antiretroviral drug combination therapies resist resistance?

Can simplified antiretroviral drug combination therapies resist resistance?

HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.

In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration. Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay. At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants. The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.

Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia.

Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-naïve (n = 373 ART-naïve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-naïve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease- and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.

Pretreatment Human Immunodeficiency Virus (HIV) Drug Resistance Among Treatment-Naive Infants Newly Diagnosed With HIV in 2016 in Namibia: Results of a Nationally Representative Study.

BackgroundThe World Health Organization (WHO) recommends routine surveillance of pretreatment human immunodeficiency virus (HIV) drug resistance (HIVDR) in children <18 months of age diagnosed with HIV through early infant diagnosis (EID). In 2016, 262 children <18 months of age were diagnosed with HIV in Namibia through EID. Levels of HIVDR in this population are unknown.MethodsIn 2016, Namibia surveyed pretreatment HIVDR among children aged <18 months following WHO guidance. Reverse transcriptase, protease, and integrase regions of HIV-1 were genotyped from remnant dried blood spot specimens from all infants diagnosed with HIV in Namibia in 2016. HIVDR was predicted using the Stanford HIVdb algorithm.ResultsOf 262 specimens genotyped, 198 HIV-1 protease and reverse transcriptase sequences and 118 HIV-1 integrase sequences were successfully amplified and analyzed. The prevalence of efavirenz/nevirapine (EFV/NVP), abacavir (ABC), zidovudine, lamivudine/emtricitabine (3TC/FTC), and tenofovir (TDF) resistance was 62.6%, 17.7%, 5.6%, 15.7%, and 10.1%, respectively. No integrase inhibitor resistance was detected.ConclusionsThe high level of EFV/NVP resistance is unsurprising; however, levels of ABC and TDF resistance are among the highest observed to date in infants in sub-Saharan Africa. The absence of resistance to dolutegravir (DTG) is reassuring but underscores the need to further study the impact of ABC and 3TC/FTC resistance on pediatric protease inhibitor– and DTG-based regimens and accelerate access to other antiretroviral drugs. Results underscore the need for antiretroviral therapy optimization and prompt management of high viral loads in infants and pregnant and breastfeeding women.

Long-Term Efficacy, Safety, and Durability of Cabotegravir and Rilpivirine as 2-Drug Oral Maintenance Therapy After 6 Years of Study.

BackgroundIn the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine.MethodsLATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312.ResultsOf 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA ≥50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%).ConclusionsOral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1.

Resource and infrastructure challenges on the RESIST-2 Trial: an implementation study of drug resistance genotype-based algorithmic ART switches in HIV-2-infected adults in Senegal

BackgroundSecond-line treatment of HIV-2 in resource-limited settings (RLS) is complicated by a lack of controlled trial data, limited availability of HIV-2-active antiretroviral drugs, and inadequate access to drug resistance testing. We conducted an implementation trial of a dried blood spot- (DBS) based, drug resistance genotype-informed antiretroviral therapy (ART) switching algorithm for HIV-2-infected patients in Senegal.MethodsHIV-2-infected adults initiating or receiving ART through the Senegalese national AIDS program were invited to participate in this single-arm trial. DBS from participants with virologic failure (defined as viral load (VL) > 250 copies/mL after > 6 months on the current ART regimen) were shipped to Seattle for genotypic drug resistance testing. Participants with evidence of drug resistance in protease or reverse transcriptase were switched to new regimens according to a pre-specified algorithm. Participant clinical and immuno-virologic outcomes were assessed, as were implementation challenges.ResultsWe enrolled 152 participants. Ten were initiating ART. The remainder were ART-experienced, with 91.0% virologically suppressed (< 50 copies/mL). Problems with viral load testing capability resulted in obtaining VL results for only 227 of 613 (37.0%) participant-visits. Six of 115 participants (5.2%) with VL available after > 6 months on current ART regimen experienced virologic failure, with per-protocol genotypic testing attempted. One additional test was performed for a participant with a VL of 222 copies/mL. Genotypes from three participants showed no evidence of major drug resistance mutations, two showed nucleoside reverse transcriptase inhibitor (NRTI) resistance, one showed both NRTI and protease inhibitor resistance, and one test failed. No integrase inhibitor resistance was observed. Five of six successfully-tested participants switched to the correct regimen or received additional adherence counseling according to the algorithm; the sixth was lost to follow-up. Follow-up VL testing was available for two participants; both of these were virally suppressed (< 10 copies/mL). The trial was terminated early due to the COVID-19 pandemic (which prevented further VL and genotypic testing), planned rollout of dolutegravir-based 1st-line ART, and funding.ConclusionsThe RESIST-2 trial demonstrated that a DBS-based genotypic test can be used to help inform second-line ART decisions as part of a programmatic algorithm in RLS, albeit with significant implementation challenges.Trial registrationClinicalTrials.govNCT03394196. Registered on January 9, 2018.

HIV-1 drug resistance in adults and adolescents on protease inhibitor-based antiretroviral therapy in KwaZulu-Natal Province, South Africa

In low-middle-income countries, increasing levels of HIV drug resistance (HIVDR) on second-line protease inhibitor (PI)-based regimens are a cause for concern given the limited drug options for third-line antiretroviral therapy (ART). We conducted a retrospective analysis of routine HIV-1 genotyping laboratory data from KwaZulu-Natal, South Africa, to describe the frequency and patterns of HIVDR mutations and their consequent impact on standardised third-line regimens. This was a cross-sectional analysis of all HIV-1 genotypic resistance tests conducted by the National Health Laboratory Service in KwaZulu-Natal (January 2015 to December 2016) for adults and adolescents (age ≥10 years) on second-line PI-based ART with virological failure. We assigned a third-line regimen to each record based on a national treatment algorithm and calculated the genotypic susceptibility score (GSS) for that regimen. Of 348 samples analysed, 287 (82.5%) had at least one drug resistance mutation (DRM) and 114 (32.8%) had at least one major PI DRM. Major PI resistance was associated with longer duration on second-line ART (aOR per 6-months=1.11, 95% CI 1.04-1.19) and older age (aOR=1.03, 95% CI 1.01-1.05). Of 112 patients requiring third-line ART, 12 (10.7%) had a GSS of <2 for the algorithm-assigned third-line regimen. One-third of people failing second-line ART had significant PI DRMs. A subgroup of these individuals had extensive HIVDR, where the predicted activity of third-line ART was suboptimal, highlighting the need for continuous evaluation of outcomes on third-line regimens and close monitoring for emergent HIV-1 integrase inhibitor resistance.

Characterization of HIV-1 drug resistance among patients with failure of second-line combined antiretroviral therapy in central Ethiopia.

As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia. HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application. Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/µL and median (IQR) HIV-1 viral load was 30220 (7963-82598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected. We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.

No difference in HIV-1 integrase inhibitor resistance between CSF and blood compartments

Little is known about HIV-1 integrase inhibitor resistance in the CNS. This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85-5.80) and 3.59 (2.16-4.50) log10 copies/mL versus 4.79 (3.56-5.25) and 3.80 (2.68-4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.