Higher Risk Of Virological Failure Research Articles

Sexual orientation, gender identity and virologic failure among people with HIV: a cohort study in all of US research program

BackgroundSexual and gender minorities (SGMs) are at higher risk of HIV incidence compared to their heterosexual cisgender counterparts. Despite the high HIV disease burden among SGMs, there was limited data on whether they are at higher risk of virologic failure, which may lead to potential disease progression and increased transmission risk. The All of Us (AoU) Research Program, a national community-engaged program aiming to improve health and facilitate health equity in the United States by partnering with one million participants, provides a promising resource for identifying a diverse and large volunteer TGD cohort. Leveraging various data sources available through AoU, the current study aims to explore the association between sexual orientation and gender identity (SOGI) and longitudinal virologic failure among adult people with HIV (PWH) in the US.MethodsThis retrospective cohort study used integrated electronic health records (EHR) and self-reported survey data from the All of Us (AoU) controlled tier data, version 7, which includes participants enrolled in the AoU research program from May 31, 2017, to July 1, 2022. Based on participants’ sexual orientation, gender identity, and sex assigned at birth, their SOGI were categorized into six groups, including cisgender heterosexual women, cisgender heterosexual men, cisgender sexual minority women, cisgender sexual minority men, gender minority people assigned female at birth of any sexual orientation, and gender minority people assigned male at birth of any sexual orientation. Yearly virologic failure was defined yearly after one’s first viral load testing, and individuals with at least one viral load test > 50 copies/mL during a year were defined as having virologic failure at that year. Generalized linear mixed-effects models were used to explore the association between SOGI and longitudinal virologic failure while adjusting for potential confounders, including age, race, ethnicity, education attainment, income, and insurance type.ResultsA total of 1,546 eligible PWH were extracted from the AoU database, among whom 1,196 (77.36%) had at least one viral failure and 773 (50.00%) belonged to SGMs. Compared to cisgender heterosexual women, cisgender sexual minority women (adjusted Odds Ratio [aOR] = 1.85, 95% CI: 1.05–3.27) were at higher risk of HIV virologic failure. Additionally, PWH who were Black vs. White (aOR = 2.15, 95% CI: 1.52–3.04) and whose insurance type was Medicaid vs. Private insurance (aOR = 2.07, 95% CI: 1.33–3.21) were more likely to experience virologic failure.ConclusionsMaintaining frequent viral load monitoring among sexual minority women with HIV is warranted because it allows early detection of virologic failure, which could provide opportunities for interventions to strengthen treatment adherence and prevent HIV transmission. To understand the specific needs of subgroups of SGMs, future research needs to examine the mechanisms for SOGI-based disparities in virologic failure and the combined effects of multi-level psychosocial and health behavior characteristics.

HIV-1 low-level viraemia predicts virological failure in first-line and second-line ART-experienced individuals in India: A retrospective longitudinal study.

To study the prevalence of low-level viraemia (LLV) and its association with virological failure (VF). We conducted a retrospective analysis of 3498 participants at YRG CARE, Chennai, India (2013-2018) on antiretroviral therapy (ART) for ≥6 months with two or more plasma viral load (pVL) measurements. Results were stratified for those with pVL <1000 copies/mL: fully suppressed (FS) (pVL <40), low-LLV (pVL 40-199), mid-LLV (pVL 200-399), and high-LLV (pVL 400-999). The study assessed the association with VF (pVL >1000 copies/mL) using Cox proportional hazard model. Among 3498 participants, 2965 (84.8%) were FS and 533 (15.2%) were LLV. During the follow-up, 348 (10%) experienced VF, with 222 (6.3%) experienced after LLV (42% of LLV) and 126 (3.6%) experienced after FS (4.3% of FS). When compared with FS, those with LLV had a greater risk of VF [adjusted hazard ratio (aHR) = 12.7; 95% confidence interval (CI): 10.2-15.9]. First-line participants had a higher VF incidence (aHR = 15.8, 95% CI: 11.4-21.9) than second-line participants (aHR = 5.6, 95% CI: 4.1-7.7). Those with high-LLV had the highest VF risk (aHR = 22.856, 95% CI: 15.204-34.359 vs. aHR = 8.186, 95% CI: 5.564-12.043, for first-line vs. second-line participants, respectively), followed by those with mid-LLV (aHR = 13.375, 95% CI: 8.327-21.483 vs. aHR = 6.261, 95% CI: 4.044-9.695) and low-LLV (aHR = 12.976, 95% CI: 7.974-21.118 vs. aHR = 4.158, 95% CI: 2.826-6.119). The prevalence of LLV was intermediate in our study population. There was a higher risk of VF among individuals with LLV, and this risk increased with the increasing levels of LLV. Close monitoring of individuals experiencing LLV could help in the early identification of VF.

Immunovirological status in people with perinatal and adult-acquired HIV-1 infection: a multi-cohort analysis from France

No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. 310P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4-25.5] and 45.9 [IQR:37.9-53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p≤0.0001. The risk of VF was particularly high among the youngest children (2-5 years), adolescents (13-17 years) and young adults (18-24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6-12 and 13-17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR=3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR=1.9 [0.9; 4.2]) respectively. P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Inserm - ANRS MIE.

Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China.

Antiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children. From January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2-4 adverse events and abnormal laboratory test results. A total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5-10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3-4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5-6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p < 0.05). The risk factors of virologic failure in ART-naïve children were clinic setting in rural hospitals (aHR = 2.251, 1.108-4.575), annual missed dose times >5 days of LPV intake (aHR = 1.889, 1.004-3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299-5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238-0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2-4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children. Our research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

The impact of the M184V resistance mutation on treatment outcomes in patients with HIV infection: a systematic review and meta-analysis.

HIV is a global deliberating infectious disease. Of note, more than 36 million people living with HIV (PLHIV) with approximately newly diagnosed 1.5 million cases annually. M184V is a single base mutation in the highly conserved YMDD domain of reverse transcriptase (RT). It is one of the most encountered resistances associated with mutations to nucleoside RT inhibitors. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in PLHIV. Therefore, the present systematic review was executed to reveal the virological failure, virological suppression, and resistance to antiretroviral therapy (ART) regimens in PLHIV with the M184V mutation. All clinical studies comparing the treatment outcomes among PLHIV harboring or not harboring M184V mutation were appropriate for systematic review and meta-analysis. The present systematic review included six articles, encompassing 4760 PLHIV. Of them, 1222 (25.67%) patients had M184V mutation, while 3538 (74.32%) PLHIV did not. The meta-analysis showed that patients with M184V mutation were 1.87 times more liable to virological failure (risk ratio [RR] 1.87; 95% 1.09, 3.20; p = 0.02). Furthermore, pooling the data from two studies revealed a significantly higher risk of viral blips (RR 2.26; 95% 1.47, 3.46; p = 0.0002). Concerning discontinuation of ART, there was no statistical difference between patients with and without M184V mutation (RR: 0.99; 95% 0.78, 1.25; p = 0.90). The present study revealed the negative impact of the M184V mutation on treatment outcomes in PLHIV. This included a higher risk of virological failure and viral blips, relative to patients without the mutation. Such patients may benefit from more aggressive and combined therapy for better disease management.

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

Impact of HIV Pretreatment Drug Resistance on Virological Failure After One-Year Antiretroviral Therapy - China, 2018-2019.

What is already known about this topic?While antiretroviral therapy (ART) has been rapidly scaled-up among the population living with human immunodeficiency virus or acquired immune deficiency syndrome (HIV/AIDS) patients since 2016, pretreatment drug resistance (PDR) has also increased.What is added by this report?PDR has an impact on ART outcomes. After one year of ART, the risk of virological failure in individuals with PDR was found to be 2.3 times higher than that of individuals without PDR. Moreover, patients with PDR to non-nucleoside reverse transcriptase inhibitors (NNRTIs) had an even higher risk of virological failure, with an odds ratio of 2.8 as compared with those without PDR.What are the implications for public health practice?PDR is associated with an increased risk of virological failure. It is recommended to regularly implement PDR monitoring in order to provide information to optimize ART regimens and to prevent HIV drug resistance.

Predictors of Virological Failure Among People Living with HIV Switching from an Effective First-Line Antiretroviral Regimen.

Aim of this study was to assess the predictors of virological failure (VF) among patients living with HIV (PLWHIV) switching from an effective first-line antiretroviral therapy (ART) regimen, and to evaluate the emergence of resistance-associated mutations. All adult patients enrolled in the Antiviral Response Cohort Analysis cohort who started ART after 2010, with at least 6 months of virological suppression (VS) before ART switch and with an available genotypic resistance test (GRT) at baseline were included. Thirty-two patients out of the 607 PLWHIV included (5.3%) experienced VF after a median of 11 months from ART switch. Younger age (adjusted Hazard Ratio [aHR] 0.96, 95% confidence interval [CI] 0.92-0.99, p = .023), being male who have sex with male (aHR 0.15, 95% CI 0.03-0.69, p = .014), and longer time from VS to ART switch (aHR 0.97, 95% CI 0.95-1.00, p = .021) resulted protective toward VF, while receiving a first-line regimen containing a backbone other than ABC/3TC or TXF/FTC (aHR 3.61, 95% CI 1.00-13.1, p = .050) and a boosted protease inhibitor as anchor drug (aHR 3.34, 95% CI 1.20-9.28, p = .021) were associated with higher risk of VF. GRT at the moment of VF was available only for 13 patients (40.6%). ART switch in patients with stable control of HIV infection is a safe practice, even if particular attention should be paid in certain cases of patients switching from regimens containing low-performance backbones or protease inhibitors.

77. Risk of Virologic Failure Among Treatment-experienced Suppressed People with HIV (PWH) Treated with Single-Tablet 2-Drug (2DR) vs 3-Drug (3DR) Regimens

BackgroundThe single-tablet regimen (STR) dolutegravir/rilpivirine (DTG/RPV) was approved in 2017 for use in virologically suppressed PWH, followed by approval in 2019 of dolutegravir/lamivudine (DTG/3TC). There is a need to evaluate outcomes of 2DR regimens in stable switch population by measuring risk of virologic failure.MethodsThis retrospective observational study of the Trio Health HIV Research Network cohort of nearly 60,000 PWH evaluated risk of virologic failure among treatment-experienced virologically suppressed PWH switching to a 2DR or 3DR STR (index = time of switch). Eligible patients (pts) were ≥ 18 yrs, treatment-experienced, suppressed at index, with post-index viral loads, ≥ 6 mo pre-index history, with dispenses for DTG/RPV, DTG/3TC or commonly used 3DR STRs initiated after Nov. 2017. Univariate comparisons were performed using Χ2 for categorical and t-test for continuous variables; Kaplan-Meier analysis was used to evaluate time to virologic failure and Cox Proportional Hazards analysis was used to evaluate risk of virologic failure accounting for age, gender, race, and baseline eGFR. Virologic failure was defined as 2 consecutive viral loads >200 cells/ml. ResultsOf 1668 pts, 132 (8%) received 2DR. Significant differences in baseline characteristics between groups are shown in Table 1. In unadjusted analysis the difference in proportion of pts with virologic failure did not reach significance: 7% (9 pts) on 2DR experienced virologic failure vs 4% (65 pts) on 3DR (p=0.166). Additionally, unadjusted risk of virologic failure and time to virologic failure were not statistically different [Figure 1, Table 2]. Based on prespecified adjusted analysis accounting for race, gender, age, and baseline eGFR, the risk of virologic failure was higher for 2DR compared to 3DR STRs (HR=2.2 CI 95% 1.1-4.5, p=0.032) [Table 2]. Adjusting for baseline CD4 was not feasible due to high proportion of missing CD4 at index.Table 1 Baseline (index) characteristics Figure 1 Unadjusted time to virologic failure Table 2 Risk of virologic failure ConclusionThis early evaluation showed higher risk of virologic failure among virologically suppressed pts who switched to 2DR vs 3DR STRs after adjusting for differences in baseline characteristics. Future analysis is warranted using a larger sample of 2DR pts with additional adjustment for prior regimen failure. Disclosures Paul Sax, MD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV (Consultant, Research Grant or Support) Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) Janna Radtchenko, MBA, Trio Health (Employee) Helena Diaz-Cuervo, PhD, Gilead Sciences (Employee) Mark Moore, PhD, Gilead Sciences (Employee) Steven Santiago, MD, Gilead Sciences (Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker's Bureau)Merck (Research Grant or Support, Speaker's Bureau)ViiV Healthcare (Consultant, Speaker's Bureau) Richard Elion, MD, Gilead Sciences (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau)Proteus (Grant/Research Support)Trio Health (Employee)ViiV (Advisor or Review Panel member)

Long-term virological suppression on first-line efavirenz + tenofovir + emtricitabine/lamivudine for HIV-1.

Objectives:Evaluate long-term rates of virological failure and treatment interruption for people living with HIV (PLWHIV) with viral suppression on first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine/lamivudine (EFV + TDF + FTC/3TC), and compare these according to patient characteristics.Methods:PLWHIV enrolled in the Collaboration of Observational HIV Epidemiological Research Europe cohort collaboration, who started first-line EFV + TDF + FTC/3TC at age at least 16 years and had viral suppression (<200 copies/ml) within 9 months were included. Rates of virological failure (≥200 copies/ml) and (complete) treatment interruption were estimated according to years since initial suppression. We used Poisson regression to examine associations of baseline characteristics with rates of virological failure or treatment interruption.Results:Among 19 527 eligible PLWHIV with median (interquartile range) follow-up 3.7 (2.0–5.6) years after initial viral suppression, the estimated rate of the combined incidence of virological failure or treatment interruption fell from 9.0/100 person-years in the first year to less than 4/100 person-years beyond 3 years from suppression; considering only those remaining on EFV + TDF + FTC/3TC, the combined rate dropped from 8.2/100 person-years in the first year to less than 3.5/100 person-years beyond 3 years. PLWHIV with injecting drug-related or heterosexual transmission were at higher risk of virological failure or treatment interruption, as were those of Black ethnicity. PLWHIV aged less than 35 years were at higher risk of virological failure and treatment interruption.Conclusion:PLWHIV starting first-line EFV + TDF + FTC/3TC had low rates of virological failure and treatment interruption up to 10 years from initial suppression. Demographic characteristics can be used to identify subpopulations with higher risks of these outcomes.

HIV-1 transmitted drug resistance in Slovenia and its impact on predicted treatment effectiveness: 2011-2016 update.

HIV-positive individuals that have a detected transmitted drug resistance (TDR) at baseline have a higher risk of virological failure with antiretroviral therapy (ART). This study offers an update on the prevalence of TDR in Slovenia, looks for onward transmission of TDR, and reassesses the need for baseline drug resistance testing. Blinded questionnaires and partial pol sequences were obtained from 54.5% (168/308) of all of the patients diagnosed with HIV-1 from 2011 to 2016. Subtype B was detected in 82.7% (139/168) of patients, followed by subtype A (8.3%), subtype C (2.4%), and CRF01_AE (1.8%). Surveillance drug resistance mutations (SDRMs) were found in four individuals (2.4%), all of them men who have sex with men (MSM) and infected with subtype B. K103N was detected in two patients and T68D and T215D in one person each, corresponding to a prevalence of 0%, 1.2%, and 1.2% of TDR to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs), respectively. The impact of mutations on drug susceptibility was found to be most pronounced for NNRTIs. No forward spread of TDR within the country was observed; however, phylogenetic analysis revealed several new introductions of HIV into Slovenia in recent years, possibly due to increased risky behavior by MSM. This was indirectly confirmed by a substantial increase in syphilis cases and HIV-1 non-B subtypes during the study period. A drug-resistant HIV variant with good transmission fitness is thus more likely to be imported into Slovenia in the near future, and so TDR should be closely monitored.

Lower pre-ART intra-participant HIV-1 pol diversity may not be associated with virologic failure in adults.

BackgroundIdentifying pre-ART factors associated with the emergence of HIV-1 drug resistance is critical for optimizing strategies to prevent virologic failure. A previous study reported that lower pre-ART HIV-1 pol diversity was associated with higher risk of virologic failure in HIV-1-infected children. To investigate this association in adults, we measured HIV-1 diversity with deep sequencing in pre-ART samples from adults with well-characterized virologic outcomes in a study (A5142) of initial ART conducted by the AIDS Clinical Trials Group (ACTG).MethodsWe identified 22 cases in ACTG A5142 who experienced virologic failure with drug resistance mutations in RT and 44 matched controls who did not experience virologic failure. cDNA was synthesized from plasma HIV-1 RNA. Each cDNA molecule was tagged with a unique primer ID and RT codons 41–103 were amplified and deep sequenced. Sequences with the same tag were aligned and a consensus was generated to reduce PCR and sequencing errors. Diversity was calculated by measuring average pairwise distance (APD) of the consensus sequences. An exact conditional logistic regression model with percent APD as the risk factor estimated the odds ratio for VF and the corresponding 95% confidence interval.ResultsConsensus single-genome sequences and diversity estimates of pol were obtained for pre-ART samples from 21 cases and 42 controls. The median (IQR) pre-ART percent APD was 0.71 (0.31–1.13) in cases and 0.58 (0.32–0.94) in controls. A possible trend was found for higher diversity being associated with greater risk of virologic failure in adults (OR = 2.2 per one percent APD increase, 95% CI = [0.8, 7.2]; p = 0.15).ConclusionsThis study in adults suggests there is a positive association between higher pre-ART pol diversity and the risk of virologic failure in adults rather than an inverse relationship reported in children.

Lamivudine monotherapy in children and adolescents: The devil is in the detail.

Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.

Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children.

BackgroundPretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children.MethodsChildren aged ≤12 years initiated first-line ART in Uganda during 2010–11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL >1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs >1000 copies/mL or death after 6 months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis.ResultsAmong 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24 months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P = 0.01).ConclusionsAlmost one-third of children experienced VF within 24 months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children ≤3 years should be initiated on a PI-based regimen as per WHO guidelines.

Patterns of Transmitted Drug Resistance and Virological Response to First-line Antiretroviral Treatment Among Human Immunodeficiency Virus-Infected People Who Use Illicit Drugs in a Canadian Setting.

Transmitted drug resistance (TDR) may compromise response to antiretroviral therapy (ART). However, there are limited data on TDR patterns and impacts among people who use illicit drugs (PWUD). Data were drawn from 2 prospective cohorts of PWUD in Vancouver, Canada. We characterized patterns of TDR among human immunodeficiency virus (HIV)-infected PWUD, and assessed its impacts on first-line ART virological outcomes. Between 1996 and 2015, among 573 ART-naive PWUD (18% with recent HIV infection), the overall TDR prevalence was 9.8% (95% confidence interval [CI], 7.3%-12.2%), with an increasing trend over time, from 8.5% in 1996-1999 to 21.1% in 2010-2015 (P = .003), mainly driven by resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). TDR-associated mutations were more common for NNRTIs (5.4%), followed by nucleoside reverse transcriptase inhibitors (3.0%) and protease inhibitors (1.9%). TDR prevalence was lower among recently infected PWUD (adjusted odds ratio, 0.39 [95% CI, .15-.87]). Participants with TDR had higher risk of virological failure than those without TDR (log-rank P = .037) in the first year of ART. Between 1996 and 2015, TDR prevalence increased significantly among PWUD in Vancouver. Higher risk of virological failure among PWUD with TDR may be explained by some inappropriate ART prescribing, as well as undetected minority resistant variants in participants with chronic HIV infection. Our findings support baseline resistance testing early in the course of HIV infection to guide ART selection among PWUD in our setting.

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.

How Much Do We Know about Drug Resistance Due to PrEP Use? Analysis of Experts' Opinion and Its Influence on the Projected Public Health Impact.

BackgroundRandomized controlled trials reported that pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine rarely selects for drug resistance. However, drug resistance due to PrEP is not completely understood. In daily practice, PrEP will not be used under the well-controlled conditions available in the trials, suggesting that widespread use of PrEP can result in increased drug resistance.MethodsWe surveyed expert virologists with questions about biological assumptions regarding drug resistance due to PrEP use. The influence of these assumptions on the prevalence of drug resistance and the fraction of HIV transmitted resistance was studied with a mathematical model. For comparability, 50% PrEP-coverage of and 90% per-act efficacy of PrEP in preventing HIV acquisition are assumed in all simulations.ResultsVirologists disagreed on the following: the time until resistance emergence (range: 20–180 days) in infected PrEP users with breakthrough HIV infections; the efficacy of PrEP against drug-resistant HIV (25%-90%); and the likelihood of resistance acquisition upon transmission (10%-75%). These differences translate into projections of 0.6%- 1% and 3.5%—6% infected individuals with detectable resistance 10 years after introducing PrEP, assuming 100% and 50% adherence, respectively. The rate of resistance emergence following breakthrough HIV infection and the rate of resistance reversion after PrEP use is discontinued, were the factors identified as most influential on the expected resistance associated with PrEP. Importantly, 17–23% infected individuals could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence.ConclusionsThere is no broad consensus on quantification of key biological processes that underpin the emergence of PrEP-associated drug resistance. Despite this, the contribution of PrEP use to the prevalence of the detectable drug resistance is expected to be small. However, individuals who become infected despite the use of PrEP should be closely monitored due to higher risk of virological failure when initiating antiretroviral treatment in the future.

Drug resistance mutations after the first 12 months on antiretroviral therapy and determinants of virological failure in Rwanda.

To evaluate HIV drug resistance (HIVDR) and determinants of virological failure in a large cohort of patients receiving first-line tenofovir-based antiretroviral therapy (ART) regimens. A nationwide retrospective cohort from 42 health facilities was assessed for virological failure and development of HIVDR mutations. Data were collected at ART initiation and at 12 months of ART on patients with available HIV-1 viral load (VL) and ART adherence measurements. HIV resistance genotyping was performed on patients with VL ≥1000 copies/ml. Multiple logistic regression was used to determine factors associated with treatment failure. Of 828 patients, 66% were women, and the median age was 37 years. Of the 597 patients from whom blood samples were collected, 86.9% were virologically suppressed, while 11.9% were not. Virological failure was strongly associated with age <25 years (adjusted odds ratio [aOR]: 6.4; 95% confidence interval [CI]: 3.2-12.9), low adherence (aOR: 2.87; 95% CI: 1.5-5.0) and baseline CD4 counts <200 cells/μl (aOR 3.4; 95% CI: 1.9-6.2). Overall, 9.1% of all patients on ART had drug resistance mutations after 1 year of ART; 27% of the patients who failed treatment had no evidence of HIVDR mutations. HIVDR mutations were not observed in patients on the recommended second-line ART regimen in Rwanda. The last step of the UNAIDS 90-90-90 target appears within grasp, with some viral failures still due to non-adherence. Nonetheless, youth and late initiators are at higher risk of virological failure. Youth-focused programmes could help prevent further drug HIVDR development.

Any impact of blips and low-level viraemia episodes among HIV-infected patients with sustained virological suppression on ART?

The objective of this study was to evaluate the prevalence of blips and risk of virological failure (VF) among HIV-infected patients with sustained virological suppression (HIV-RNA <50 copies/mL) on ART. Newly diagnosed (2004-13) HIV-infected patients with sustained virological suppression on ART (minimum follow-up of 3 months) were identified. Risk of VF was evaluated according to different plasma HIV-RNA quantification values based on the limits of quantification/detection of current commercial assays (20 copies/mL). Kaplan-Meier and Cox proportional hazards models were used to compare the cumulative incidence of VF. A total of 565 newly diagnosed HIV-infected patients were identified: 453 started ART and 354 achieved virological suppression. Prevalence of blips (isolated HIV-RNA ranging from 50 to 200 copies/mL) and VF (HIV-RNA ≥50 copies/mL) was 22.7% and 8.8%, respectively (mean follow-up of 42 months). Multivariate analysis identified differences between HIV-RNA values as an independent predictor of VF (P = 0.008); risk of VF was higher for patients with blips [HR 2.500 (95% CI 0.524-11.926)] and for those with at least three consecutive detected, but not quantified, HIV-RNA determinations (HIV-RNA <20 copies/mL) [HR 3.813 (95% CI 0.675-21.535)]. Moreover, only HIV-infected patients with at least three consecutive detected, but not quantified, HIV-RNA determinations showed a higher probability of virological rebound with >200 copies/mL [33.7% at 24 and 60 months versus <5% for other HIV-RNA values; HR 6.943 (0.728-66.261), P = 0.092]. Blips are frequent (22.7%) among HIV-infected patients with sustained virological suppression on ART. HIV patients with blips and at least three consecutive detected, but not quantified, HIV-RNA determinations (<20 copies/mL) had a higher risk of VF. These findings highlight the relevance of maintaining HIV-RNA levels below the limits of quantification of current assays (<20 copies/mL).

Increased risk of virologic failure to the first antiretroviral regimen in HIV-infected migrants compared to natives: data from the ICONA cohort

Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004–2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) >200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL >200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67–0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8–8.5) in migrants and 2.7 in natives (95% CI 2.2–3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25–2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01–1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor–based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives.