Virological Failure In Patients Research Articles

Determinants of virological failure in HIV1 infected patients followed in a third-level hospital Abidjan, Cote d’Ivoire

: Côte d'Ivoire has been committed to achieving the UNAIDS 90-90-90 targets of People Living with HIV (PLHIV) follow-up since 2015. The proportion of patients on antiretroviral therapy (ART) was below the desired rates for 2020. The laboratory of the University Hospital Center (CHU) of Yopougon has been equipped with instruments capable of quantifying the plasma viral load (VL) of PLHIV on ART. This quantification allowed for early detection of virological failure in PLHIV. The objective of this study was to determine the rate of virological failure and the epidemiological, immunological and virological determinants of virological failure in patients followed at the Yopougon University Hospital in Abidjan. : This was a retrospective study covering the period from January 1, 2015 to October 31, 2019. It was carried out on data related to blood samples (plasma) of PLHIV (infected with HIV-1) under ART for at least 6 months and who had quantified their viral load.: A total of 52356 PLHIV were included in this study. The age group 40-50 years comprised the majority of the patients (46.7%) with a median age of 40 +/- 0.3 years. The female sex predominated with 72% and a sex ratio of (M/F) = 0.38. The TCD4 cell were between 500 and 350 cells/µL in 57.0% of patients at treatment initiation. The TDF+3TC+EFV treatment regimen was prescribed in the majority of patients (88.62%). The population of patients with virological failure (defined as VL ≥ 1000 copies/ml) was 12924 or a prevalence of 24.7%. The determinants of virological failure were age ≤ 15 years, male sex and CD4+ LT rate below 250 cells/µL (p <0.05).: The virological failure rate was high especially in children and male subjects at the Yopougon University Hospital. It appears therefore important to act on these determinants, by additional efforts through concrete actions such as regular and systematic measurement of CV at the time of rapid change of treatments with effective combinations for this type of PLHIV. The goal is to achieve the objectives of the UNAIDS to eradicate HIV by 2030.

Transcriptome analysis of CD4+ T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity

Some HIV-infected individuals receiving ART develop low-level viremia (LLV), with a plasma viral load of 50–1000 copies/mL. Persistent low-level viremia is associated with subsequent virologic failure. The peripheral blood CD4+ T cell pool is a source of LLV. However, the intrinsic characteristics of CD4+ T cells in LLV which may contribute to low-level viremia are largely unknown. We analyzed the transcriptome profiling of peripheral blood CD4+ T cells from healthy controls (HC) and HIV-infected patients receiving ART with either virologic suppression (VS) or LLV. To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV, KEGG pathways of differentially expressed genes (DEGs) were acquired by comparing VS with HC (VS-HC group) and LLV with VS (LLV-VS group), and overlapped pathways were analyzed. Characterization of DEGs in key overlapping pathways showed that CD4+ T cells in LLV expressed higher levels of Th1 signature transcription factors (TBX21), toll-like receptors (TLR-4, -6, -7 and -8), anti-HIV entry chemokines (CCL3 and CCL4), and anti-IL-1β factors (ILRN and IL1R2) compared to VS. Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription. Finally, we evaluated the effects of 4 and 17 transcription factors that were upregulated in the VS-HC and LLV-VS groups, respectively, on HIV-1 promoter activity. Functional studies revealed that CXXC5 significantly increased, while SOX5 markedly suppressed HIV-1 transcription. In summary, we found that CD4+ T cells in LLV displayed a distinct mRNA profiling compared to that in VS, which promoted HIV-1 replication and reactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV. CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.

Performances of Dried Blood Spots and Point-of-Care Devices to Identify Virological Failure in HIV-Infected Patients: A Systematic Review and Meta-Analysis

To broaden access to HIV viral load monitoring (VLM), the use of blood samples from dried blood spots (DBS) or point-of-care (POC) devices, could be of great help in settings where plasma is not easily accessible. The variety of assays available makes the choice complex. This systematic review and meta-analysis aims to estimate the sensitivity and specificity of DBS and POC devices to identify patients in virological failure using World Health Organization (WHO) recommendations (viral load ≥1000 copies/mL), compared with plasma, for the assays currently available. Four databases were searched for articles, and two reviewers independently identified articles reporting sensitivity and specificity of DBS and/or POC to identify patients in virological failure. We excluded articles that used other thresholds as well as articles with a total number of participants below 50 to avoid reporting bias. Heterogeneity and factors associated with assays' performances were assessed by I2 statistics and metaregression. The protocol of this review follows the PRISMA guidelines. Out of 941 articles, 47 were included: 32 DBS evaluations and 16 POC evaluations. Overall, when using DBS, the Abbott RT HIV-1, Roche CAP-CTM, NucliSENS BioMerieux and Aptima assays presented sensitivity and specificity exceeding 85%, but reported results were highly heterogeneous. Factors associated with better performances were high volume of blood and the use of the same assay for DBS and plasma VLM. Regarding the POC devices, SAMBA I, SAMBA II, and GeneXpert devices presented high sensitivity and specificity exceeding 90%, with less heterogeneity. DBS is suitable VLM, but performances can vary greatly depending on the protocols, and should be performed in trained centers. POC is suitable for VLM with less risk of heterogeneity but is more intensive in costs and logistics.

Determinants of Virological Failure in HIV Patients on Highly Active Antiretroviral Therapy (HAART): A Retrospective Cross-Sectional Study in the Upper East Region of Ghana

Background: Even though highly active antiretroviral therapy (HAART) for HIV (Human Immune Deficiency) patients has considerably improved viral load suppression, more people still struggle to reduce viral loads. The aim of the study was to determine the associated factors of virological failure in HIV patients on antiretroviral therapy (ART) in the Upper East Region of Ghana. Methods: A retrospective cross-sectional study involving 366 participants aged 15 years and above who were on HAART for six (6) months or longer with viral load results in 2020. Bivariate and multiple logistic regression analyses were conducted to identify the determinants of virological failure among HIV patients at 95% confidence interval (C.I.) with a significant level pegged at a p value less than 0.05. Results: The prevalence of viral load failure was 47.0% and adherence to antiretroviral therapy was 62.6% among patients on HAART. The significant predicators of virological failure were basic education (AOR (adjusted odds ratio) = 7.36, 95% C.I = 4.91–59.71), High school/Vocational /Technical education (AOR = 4.70, 95% C.I. = 1.90–9.69), monthly salary/income ˂ GHS 375.00 (AOR = 7.20, 95% C.I. = 1.73–29.95), duration on ART for ˂1 year (AOR = 0.27, 95% C.I. = 0.10–0.75), ART regimen (Tenofovir + Lamivudine + Efavirenz) (AOR = 3.26, 95% C.I. = 1.95–11.25), 3–5 times missed medication per month (AOR = 2.86, 95% C.I. = 1.34–6.08) and ≥6 missed medication per month (AOR = 23.87, 95% C.I. = 10.57–53.92). Conclusion: Educational status, salary/income, ART duration, ART combination regimen, and number of doses missed were statistically significantly associated with virological failure in patients on antiretroviral therapy. The majority of the respondents adhered to ART, which led to moderate viral load suppression but lower than the target for 2020. There is the need to strengthen the ongoing accelerated social behavior change communication among patients on ART to enhance adherence in order to attain the new UNAIDS target of 95% viral load suppression by 2030 in the Upper East Region of Ghana.

Incidence, survival time and associated factors of virological failure among adult HIV/AIDS patients on first line antiretroviral therapy in St. Paul's Hospital Millennium Medical College-A retrospective cohort study.

Human Immune deficiency Virus or Acquired Immune deficiency Syndrome (HIV/AIDS) is a pandemic affecting millions around the world. The 2020 the Joint United Nations Programme on HIV/AIDS report stated that the estimated number of people living with HIV (PLHIV) is 38 million globally by 2019. Ethiopia is among HIV high burden countries in Africa. By 2021, PLHIV in Ethiopia is estimated to be 754, 256. Globally out of 25.4 million PLHIV on ART, 41% reported virally non-suppressed. According to UNAIDS, the estimated viral non-suppression in Ethiopia is about 27%. A hospital based retrospective cohort study was conducted among 323 patients who were enrolled to ART from July 2016 to December 2020. The medical records of study participants were selected using simple random sampling technique & data was collected using data extraction checklist. The collected data was entered and cleaned using SPSS V.25. Kaplan-Meier is used to estimate the cumulative hazard of virological failure at different time points. During bivariate analysis variables with p<0.25 were taken for Multivariate Cox regression analysis to assess predictors of virological failure & statistically significant association was declared at p<0.05 with 95% confidence interval. The overall incidence rate of virological failure was 1.75 per 1000 months of observations. The mean survival time of virological failure was 14.80 months. Disclosure of sero-status (AHR = 0.038, 95% CI: 0.008-018), poor adherence (AHR = 4.24, 95% CI: 1.04-16), having OIs (Opportunistic infections) (AHR = 4.59, 95% CI: 1.17-18) and use of cotrimoxazole (CPT) prophylaxis (AHR = 0.13, 95% CI: 0.026-0.68) have shown statistically significant association with virological failure. The incidence of virological failure among patients on first line ART in St. Paul's hospital is low. Disclosure of sero-status, poor adherence, having OIs and use of CPT prophylaxis were associated with virological failure. Therefore, a due attention needs to be given to these factors in order to minimize virological failure in patients on ART.

Antiretroviral therapy uptake and predictors of virological failure in patients with HIV receiving first-line and second-line regimens in Johannesburg, South Africa: a retrospective cohort data analysis

ObjectiveThis study described the demographics, treatment information and identified characteristics associated with virological failure and being lost to follow-up (LTFU) for patients with HIV on first-line and second-line antiretroviral therapy...

Evidence of virological failure in patients on second-line anti-retroviral therapy in Southwestern Nigeria: An indication for HIV drug resistance testing

Background: In sub-Saharan Africa where genotypic anti-retroviral (ARV) drug resistance testing is rarely performed and poor adherence is blamed for the inability to achieve viral suppression and treatment failure, programmatic approaches to preventing and handling these are essential. This study was aimed at assessing the virological outcomes among HIV patients receiving second-line anti-retroviral therapy (ART) in Southwestern Nigeria.Methodology: This was a 5-year observational retrospective study of randomly selected people living with HIV (PLWHIV) who have been switched to second-line ART for at least six months before the commencement of the study in multiple comprehensive ART sites across the three levels of care, in Ondo and Ekiti States, Southwestern Nigeria, from January 2015 to December 2019. Quantitative viral load analysis was done using polymerase chain reaction (PCR) assay. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 24.0.Results: A total of 249 (71 males and 178 females) subjects eligible for the study were recruited using simple random sampling technique. The mean age (± SD) of the subjects was 44.21 ± 11.45 years. The mean number of years the patients have been on ART regimen was 7.92 ± 2.68 years. The mean number of years the patients were on first line ART regimen before being switched to second line was 4.27 ± 2.63 years. Patients with viral load &lt;1000 RNA copies/ml (suppressed viral load) were 216 (86.7%) out of which 113 (45.4%) had viral load &lt;20 RNA copies/ml while 33 (13.3%) had viral load &gt;1000 RNA copies/ml (unsuppressed viral load or virological failure).Conclusion: About 13% of the patients on second line ART had unsuppressed viral load of more than 1000 RNA copies/ml indicating virological failure. Thus, critical factors such as poor adherence to ART and drug resistance chiefly contributing to virological failure have to be routinely checked.&#x0D; Keywords: suppression, ART, resistance, virological, failure, Nigeria&#x0D; &#x0D; French title: Preuve d'échec virologique chez les patients sous traitement antirétroviral de deuxième intention dans le sud-ouest du Nigeria: une indication pour le test de résistance aux médicaments contre le VIH&#x0D; &#x0D; Contexte: En Afrique subsaharienne, où les tests génotypiques de résistance aux antirétroviraux (ARV) sont rarement effectués et où une mauvaise observance est imputée à l'incapacité d'obtenir la suppression virale et l'échec du traitement, des approches programmatiques pour les prévenir et les gérer sont essentielles. Cette étude visait à évaluer les résultats virologiques chez les patients VIH recevant un traitement antirétroviral (TAR) de deuxième intention dans le sud-ouest du Nigeria.&#x0D; Méthodologie: Il s'agissait d'une étude rétrospective d'observation de 5 ans portant sur des personnes vivant avec le VIH (PVVIH) sélectionnées au hasard et passées à un TAR de deuxième intention pendant au moins six mois avant le début de l'étude dans plusieurs sites de TAR complets aux trois niveaux. de soins, dans les États d'Ondo et d'Ekiti, dans le sud-ouest du Nigéria, de janvier 2015 à décembre 2019. L'analyse quantitative de la charge virale a été effectuée à l'aide d'un test de réaction en chaîne par polymérase (PCR). Les données ont été analysées à l'aide du logiciel Paquet statistique pour les sciences sociales (SPSS) version 24.0.&#x0D; Résultats: Un total de 249 (71 hommes et 178 femmes) sujets éligibles à l'étude ont été recrutés à l'aide d'une technique d'échantillonnage aléatoire simple. L'âge moyen (± ET) des sujets était de 44,21±11,45 ans. Le nombre moyen d'années pendant lesquelles les patients ont été sous traitement antirétroviral était de 7,92±2,68 ans. Le nombre moyen d'années pendant lesquelles les patients étaient sous traitement antirétroviral de première ligne avant de passer en deuxième ligne était de 4,27 ± 2,63 ans. Les patients avec une charge virale &lt;1000 copies d'ARN/ml (charge virale supprimée) étaient 216 (86,7%) dont 113 (45,4%) avaient une charge virale &lt;20 copies d'ARN/ml tandis que 33 (13,3%) avaient une charge virale &gt;1000 ARN copies/ml (charge virale non supprimée ou échec virologique).&#x0D; Conclusion: Environ 13 % des patients sous TAR de deuxième ligne avaient une charge virale non supprimée de plus de 1000 copies d'ARN/ml indiquant un échec virologique. Ainsi, les facteurs critiques tels qu'une mauvaise adhésion au TARV et la résistance aux médicaments contribuant principalement à l'échec virologique doivent être systématiquement vérifiés.&#x0D; Mots clés: suppression, TAR, résistance, virologique, échec, Nigeria&#x0D;

Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort.

The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI). This was a retrospective, observational study including patients with AEHI (Fiebig stages I-V) diagnosed between January 2008 and December 2014 at 20 Italian centres. IVR was defined by: (1) viral blip (51-1000HIV-1 RNA copies/mL after achievement of <50HIV-1 RNAcopies/mL); (2) virologic failure [>1000copies/mL after achievement of <200copies/mL, or ≥200copies/mL after 24weeks on an antiretroviral therapy (ART)]; (3) suboptimal viral response (>50copies/mL after 48weeks on ART or two consecutive HIV-1 RNA levels with ascending trend during ART). Cox regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for IVR. In all, 263 patients were studied, 227 (86%) males, with a median [interquartile range (IQR)] age of 38 (30-46) years. During a median follow-up of 13.0 (5.7-31.1) months, 38 (14.4%) had IVR. The presence of central nervous system (CNS) symptoms was linked to a higher risk of IVR (HR = 4.70, 95% CI: 1.56-14.17), while a higher CD4/CD8 cell count ratio (HR = 0.13, 95% CI: 0.03-0.51 for each point increase) and first-line ART with three-drug regimens recommended by current guidelines (HR = 0.40, 95% CI: 0.18-0.91 compared with other regimens including four or five drugs, older drugs or non-standard backbones) were protective against IVR. Patients with lower CD4/CD8 ratio and CNS symptoms could be at a higher risk of IVR after AEHI. The use of recommended ART may be relevant for improving short-term viral efficacy in this group of patients.

HIV-1 Drug Resistance, Distribution of Subtypes, and Drug Resistance-Associated Mutations in Virologic Failure Individuals in Chengdu, Southwest China, 2014-2016.

The National Free Antiretroviral Therapy (ART) Program in China has initiated to provide ART to HIV-1 patients, which has acted as an efficient method to suppress viral replication and helps prevent onward transmissions. But the problems of HIV drug resistance (HIVDR) may also come along. There is little data on the prevalence of HIVDR in Chengdu, where the number of HIV/AIDS patients ranks first among provincial capitals. Therefore, epidemiological surveillance was conducted in this area. From 2014 to 2016, HIV/AIDS patients (15 years and older) who had received first-line ART for at least six months were enrolled. Demographic, behavioral information and medical history were recorded, and blood samples were collected for viral loads and immune cell count analyses. HIV-1 pol was obtained for HIV-1 subtypes and drug resistance-associated mutations (DRMs) among virologic failure patients. A total of 13,782 individuals were enrolled, and 481 samples were sequenced for subtypes and drug resistance analysis. Six subtypes were identified, among which CRF01_AE (54.3%) and CRF07_BC (41.6%) were the dominant subtypes, and CRF55_01B (0.4%) was detected in Chengdu for the first time. The prevalence of HIVDR in treatment-experienced patients was 1.8%, with 1.2% to nucleoside reverse transcriptase inhibitors (NRTIs), 1.7% to non-NRTIs (NNRTIs), and 0.14% to protease inhibitors (PIs). The leading DRMs observed in the study were M184I/V (59.59%) against NRTIs and K103N (37.55%) against NNRTIs. This study focused on the HIVDR surveillance among patients receiving treatment in Chengdu. The overall prevalence of HIVDR was relatively low among treated patients. These findings were believed to be contributed to an understanding of HIV-1 subtypes, HIVDR prevalence, and DRMs in Chengdu and thereby optimizing clinical management, prevention, and control of HIV.

Drug resistance patterns in HIV patients with virologic failure in Iran.

We reviewed the medical charts of 1,700 patients diagnosed with HIV who referred to a central HIV clinic in Tehran between 2004 and 2017. Participants who had a viral load of > 200 copies/mL after six months or more on antiretroviral therapy (ART) were grouped as virologic failure (VF). We assessed the demographic characteristics, diagnosis date, first ART regimen, and resistance to various ART drugs. Out of 1,700 patients, 72 (4.2%) had a treatment failure. Among those with treatment failure, 51.3% were on zidovudine + lamivudine + efavirenz, 13.9% were on tenofovir + lamivudine + lopinavir/ritonavir, and 12.5% were on tenofovir + emtricitabine + efavirenz. In patients with treatment failure, the highest resistance was to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) combination (44.4%). In these patients, resistance to tenofovir (one of the NRTIs) was 29.1%. The highest treatment failure was observed among patients treated with nevirapine (NVP) and efavirenz (EFV)-based regimen. Our findings suggest that protease inhibitors should be considered as first-line drugs in ART regimens in VF patients in Iran.

HIV-1 low-level viremia affects T cell activation rather than T cell development in school-age children, adolescents, and young adults during antiretroviral therapy

ObjectivesGiven the improvements in antiretroviral therapy (ART) in recent years, more pediatric HIV patients receiving ART are reaching adolescence and adulthood. This study investigated the influence of poor virological response (low-level viremia (LLV) and virological failure (VF)) on the immune system of these patients. MethodsHIV-infected, ART-experienced pediatric patients (n=206) were enrolled in this cross-sectional study. The patients were subdivided into school-age children/early adolescents, middle adolescents, and late adolescents/young adults according to their age, and further classified into virological suppression (VS), LLV, and VF groups according to plasma viral load (pVL) measurement. Thymic output, T cells subsets, and immune activation were analyzed by flow cytometry. ResultsCompared with VS patients, VF patients displayed decreased CD4+ T cell counts, while LLV and VS patients had comparable CD4+ T cell counts regardless of age. Compared with VS patients, LLV and VF patients had higher percentages of CD8+HLA-DR+ and CD8+CD38high T cells, and the immune activation was positively correlated with pVL in VF and LLV patients. Thymic output levels (CD31+) and regulatory T cell subpopulations in LLV and VF patients were comparable to those in VS patients. LLV patients showed comparable percentages of T cell subsets (TN, TCM, TEMRA, and TEM) as VS patients in all age groups. ConclusionsLLV causes excessive immune activation although it does not impair T cell recovery or naïve-to-memory T cell conversion in pediatric patients living with HIV. Therefore, T cell immune activation should be monitored at the management of LLV during ART.

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference.

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA <50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA >50 copies/mL or one HIV-RNA >1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12–78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96–0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.

Simplifying ARV Therapy in the Setting of Resistance.

HIV treatment simplification is typically indicated for virologically suppressed patients with no baseline resistance-associated mutations (RAMs) or prior virologic failure (VF) to the simplification regimen. Simplification can occur to minimize pill burden, toxicities, drug-drug interactions, or costs. As most studies for treatment simplification excluded patients with baseline RAMs or prior VF, this review is aimed to critically analyze data regarding treatment simplification in treatment-experienced patients. Antiretroviral (ARV) regimens containing three-, two-, and one-drug(s) have been scarcely studied to assess virologic efficacy in treatment-experienced patients. Three-drug regimens with the most data and highest efficacy are with integrase strand transfer inhibitors (INSTIs). Regimens including dolutegravir (DTG) and bictegravir have been shown to maintain efficacy in patients with certain baseline RAMs. Dual therapy regimens include the use of DTG plus either lamivudine (3TC), rilpivirine (RPV), or other ARVs. None of these studies evaluated patients with baseline DTG resistance. Baseline RAMs to 3TC were not a predictor of VF in patients on DTG/3TC. Efficacy was seen with DTG/RPV; however, studies showed high rates of discontinuation. DTG plus boosted-protease inhibitors were studied in smaller but promising studies. Two small studies assessed the use of monotherapy with boosted darunavir or DTG, both showing virologic efficacy. Currently, three- and two-drug ARV regimens may be considered in this population with most studies evaluating the use of DTG and bictegravir without baseline INSTI RAMs. Future studies should include heavily treatment-experienced patients with a variety of baseline RAMs and a larger sample size.

Management of Virologic Failure in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues

Poorly controlled hepatitis B increases the risk for liver-related morbidity. Although there are now six approved nucleos(t)ide analogues (NA) for the treatment of chronic hepatitis B (CHB), drug resistance and thus virologic breakthrough still exist. This review outlines a systematic approach to the management of virologic failure in patients with CHB treated with NAs. Current NAs can be divided into older generation and newer generation agents, with newer generation agents associated with lower rates of virologic breakthrough. Both tenofovir dipovoxil fumarate (TDF) and tenofovir alafenamide (TAF) are equally as effective in addressing virologic breakthrough while on all other NAs. Entecavir is an effective treatment option for NA naive patients only, with high rates of resistance to entecavir in those exposed to older NAs. The management of virologic breakthroughs should focus on identifying risk factors for future drug resistance and escalation to appropriate newer generation drug options to avoid long-term liver-related morbidity.

Evaluation of HIV-1 reservoir levels as possible markers for virological failure during boosted darunavir monotherapy.

The gold standard for HIV-1 treatment is to administer triple antiretroviral therapy, but a shift to simplified regimens is being explored. Boosted darunavir monotherapy can be considered for patients who are for specific reasons not good candidates for dual or triple therapy. Still, a number of patients fail virologically or need to switch treatment. To identify predictive markers for those patients that are more likely to sustain virological control under monotherapy, virological and immunological markers were explored in HIV-1-positive patients that experienced virological failure on ritonavir-boosted darunavir monotherapy in the PROTEA trial. As a retrospective nested study of the PROTEA study (NCT01448707), we analysed 77 HIV-1-infected patients who were on darunavir/ritonavir 800/100 mg monotherapy up to 96 weeks. Patients were appointed to three distinct cohorts based on viral loads (VLs): (i) undetectable VL after 96 weeks; (ii) very-low-level viraemia (5-39 copies/mL); and (iii) failing treatment. Total HIV-1 DNA, integrated HIV-1 DNA and 2-long terminal repeat circular HIV-1 DNA (2LTR circles) were measured in PBMCs at baseline, week 48 and week 96. Total HIV-1 DNA and integrated HIV-1 DNA at baseline differed significantly between patients who experienced virological failure on monotherapy (P < 0.01 and P < 0.001). Although a higher level of HIV-1 DNA was measured in failures, this marker by itself does not provide enough predictive value to prospectively predict virological failure in patients on monotherapy. HIV-1 reservoir markers correlate with therapy failure in ritonavir-boosted darunavir monotherapy. However, their role as a predictive marker combined with other markers in a routine clinical setting should be further explored.

A viral genome wide association study and genotypic resistance testing in patients failing first line antiretroviral therapy in the first large countrywide Ethiopian HIV cohort

BackgroundAntiretroviral therapy (ART) was rolled-out in Ethiopia in 2005, but there are no reports on outcome of ART and human immunodeficiency virus drug resistance (HIVDR) at national level. We described acquired drug resistance mutations in pol gene and performed a viral genome wide association study in virologic treatment failure patients who started first line ART during 2009–2011 in the first large countrywide HIV cohort in Ethiopia.MethodsThe outcome of tenofovir (TDF)- and zidovudine (ZDV)-based ART was defined in 874 ART naïve patients using the on-treatment (OT) and intention-to-treat (ITT) analyses. Genotypic resistance testing was done in patients failing ART (> 1000 copies/ml) at month 6 and 12. Near full-length genome sequencing (NFLG) was used to assess amino acid changes in HIV-1 gag, pol, vif, vpr, tat, vpu, and nef genes between paired baseline and month 6 samples.ResultsHigh failure rates were found in ITT analysis at month 6 and 12 (23.3%; 33.9% respectively). Major nucleoside and non-nucleoside reverse transcriptase (NRTI/NNRTI) drug resistance mutations were detected in most failure patients at month 6 (36/47; 77%) and month 12 (20/30; 67%). A high rate of K65R was identified only in TDF treated patients (35.7%; 50.0%, respectively). No significant difference was found in failure rate or extent of HIVDR between TDF- and ZDV- treated patients. All target regions of interest for HIVDR were described by NFLG in 16 patients tested before initiation of ART and at month 6.ConclusionIn this first Ethiopian national cohort, a high degree of HIVDR was seen among ART failure patients, independent on whether TDF- or ZDV was given. However, the major reason to ART failure was lost-to-follow-up rather than virologic failure. Our NFLG assay covered all relevant target genes for antiretrovirals and is an attractive alternative for HIVDR surveillance.

Routine versus Targeted Viral Load Strategy among Patients Starting Antiretroviral in Hanoi, Vietnam.

Introduction HIV viral load (VL) testing is recommended by the WHO as the preferred method for monitoring patients on antiretroviral therapy (ART). However, evidence that routine VL (RVL) monitoring improves clinical outcomes is lacking.MethodsWe conducted a prospective, randomized controlled trial of RVL monitoring every six months versus a targeted VL (TVL) strategy (routine CD4 plus VL testing if clinical or immunological failure) in patients starting ART between April 2011 and April 2014 at Bach Mai Hospital in Hanoi. Six hundred and forty‐seven subjects were randomized to RVL (n = 305) or TVL monitoring (n = 342) and followed up for three years. Primary endpoints were death or WHO clinical Stage 4 events between six and thirty‐six months of ART and rate of virological suppression at three years.ResultsOverall, 37.1% of subjects were female, median age was 33.4 years (IQR: 29.5 to 38.6), and 47% had a CD4 count ≤100 cells/mm3 at time of ART initiation. Approximately 44% of study events (death, LTFU, withdrawal, or Stage 4 event) and 68% of deaths occurred within the first six months of ART. Among patients on ART at six months, death or Stage 4 event occurred in 3.6% of RVL and 3.9% of TVL (p = 0.823). Survival analysis showed no significant difference between the groups (p = 0.825). Viral suppression at 36 months of ART was 97.2% in RVL and 98.9% in TVL (p = 0.206) at a threshold of 400 copies/mL and was 98.0% in RVL and 98.9% in TVL (p = 0.488) at 1000 copies/mL. In ITT analysis, 20.7% in RVL and 21.9% in TVL (p = 0.693) were unsuppressed at 1000 copies/mL.ConclusionsWe found no significant difference in rates of death or Stage 4 events and virological failure in patients with RVL monitoring compared to those monitored with a TVL strategy after three years of follow‐up. Viral suppression rates were high overall and there were few study events among patients alive and on ART after six months, limiting the study's power to detect a difference among study arms. Nonetheless, these data suggest that the choice of VL monitoring strategy may have less impact on patient outcomes compared to efforts to reduce early mortality and improve ART retention.

NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir.

This study sought to clarify the factors involved in virologic failure in patients with HCV receiving retreatment with glecaprevir/pibrentasvir (GLE/PIB) in real-world practice. Forty-two patients who had previously received direct-acting antivirals (DAAs) therapies consisting of 35, 3, 3, and 1 patient(s) with genotype (GT)-1b, GT-2a, GT-2b, and GT-3b HCV, respectively, received GLE/PIB for 12weeks. Resistance-associated substitutions (RASs) at baseline were evaluated, and the dynamics of NS5A-RASs were assessed by deep sequencing in patients showing virologic failure. Baseline NS5A-RASs were found in all the patients with GT-1b HCV including 16 patients with NS3-RASs. In contrast, both NS5A-RASs and NS3-RASs were absent in 3 and 2 patients with GT-2a and GT-2b HCV, respectively. Virologic failure occurred in 3 patients with GT-1b HCV with NS5A-P32del, while a sustained virologic response (SVR) was achieved in the remaining 39 patients including those with GT-1b HCV carrying NS5A-L31V + Y93H and NS5A-A92K. Virologic failure even occurred in a patient in whom the NS5A-P32del HCV strains had become undetectable by direct sequencing, and the percentage of such strains relative to the total HCV strains was 10%, as determined by deep sequencing. In the other patient with GT-1b HCV with NS5A-P32del, NS3-A156A/V/S were found at 4weeks after GLE/PIB therapy, but had disappeared at 11weeks, as determined by direct sequencing. GLE/PIB was effective for patients with HCV who failed to achieve an SVR after prior DAA therapies except in those with GT-1b HCV carrying NS5A-P32del even when such strains became undetectable by direct sequencing.

Antiretroviral Therapy-associated Adverse Drug Reactions and their Effects on Virologic Failure- A Retrospective Cohort Study in Nigeria.

Background: Adverse drug reactions (ADRs) associated with antiretroviral therapy (ART) can rapidly reverse the gains of ART resulting in poor health outcomes. We need an improved under-standing of specific ART-related ADRs that influence virologic outcomes.Objective: To investigate the frequency of clinical ADRs and assess their effect on virologic failure in patients on ART.Method: We described the prevalence of major clinical ADRs, and the association between specific ADRs and virologic failure in a clinic cohort of HIV-1 infected Nigerians aged ≥18 years, on first-line ART between June 2004 and February 2012. Multivariable logistic regression was run to identify predictors of virologic failure at 24 and 72 weeks of ART.Results: Data of 12,115 patients with a median age of 34 (interquartile range: 29-41) years, and pre-dominantly females (67%) were evaluated. Overall, 957 (7.9%) patients experienced at least one ADR during a median follow-up period of 4 years (interquartile range: 1-7). The three most prevalent ADRs were lipodystrophy (2.6%), anemia (1.9%), and skin rash (0.7%). Virologic failure rate was 36% and 34% at 24 and 72 weeks of ART, respectively. Anemia independently predicted the odds of virologic failure at 72 weeks of ART (adjusted odds ratio, 1.74; 95% CI: 1.2-2.51); adjusted for sex, age, pre-treatment CD4+ cell count, antiretroviral regimen, and medication refill adherence.Conclusion: Antiretroviral therapy-associated anemia increases the likelihood of late virologic failure. We recommend routine monitoring of hemoglobin levels and prompt management of anemia in all pa-tients on ART as a strategy to improve virologic success rates.

Mutational pathways of resistance to inhibitors of integrase (INIs) in patients treated with first generation INIs and their impact in Dolutegravir sensitivity.

Background: First generation integrase inhibitors, Raltegravir (RAL) y Elvitegravir (EVG) have proven good efficacy and tolerability in HIV-1 patients. However, clinical studies showed that 60% of highly experienced patients in virological failure develop mutations of resistance to INIs (MARS). The most frequently used INI in Argentina is RAL and it has three major mutational pathways: Y143CHR, Q148HKR and N155H. Both INIs have widely cross resistance, preventing their sequential use while the 2nd generation INI Dolutegravir (DTG), only has cross resistance in Q148HKR together with other secondary mutations. Patients under RAL/EVG accumulate secondary mutations and switch pathways. These events can reduce sensitivity to DTG and therefore, early detection of MARS is critical. Objetives: Determine the prevalence and profile of resistance to INIs in experienced patients in virological failure to regimens including RAL or EVG. Establish the impact to DTG sensitivity for its sequential use. Methods & Materials: We analyzed the genotypic profile of the integrase gene of HIV-1 in 67 highly experienced patients: 33 subtype B, 32 subtype BF and 2 subtype C. All patients were in virological failure to treatments including RAL (66) or EVG (1). RNA was extracted from plasma samples, amplified by RT-PCR of the entire gene (corresponding to 288 amino acids), sequenced and interpreted using the Stanford Database. Results: 46 of the 67 patients showed primary mutations (69%), together with secondary ones, except for 1 case. Six patients showed one or more secondary mutations: T66A (1), L74I (1), T97A (3), G163KR (4). The remaining 15 did not demonstrate MARS. The mutational pathways observed were N155H (24), Y143R (12), Q148HKR (9), E92Q (2). All secondary mutations observed were T66A, L74IM. E92A, T97A, G118D, T121Y, A128 T, E138AD, G140AS, V151I, S153F, E157Q, G163RK. Conclusion: The high prevalence of resistance observed demonstrates that RAL has a low genetic barrier. The frequency of the pathways coincides with the literature and N155H is the most frequently selected. Since Q148H and Y143CR increase resistance and give replicative advantage, tend to replace N155H during treatment. Therefore, early detection is clinically relevant. Most of the patients (80%) that failed to RAL/EVG remain sensitive to DTG.