Drug-resistant Virus Research Articles

Virological Failure, HIV-1 Drug Resistance and Early Mortality in Adults Admitted to Hospital in Malawi: A Nested Observational Cohort Study

Background: Antiretroviral therapy (ART) scale-up in sub-Saharan Africa (SSA) combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance and early mortality among hospital inpatients in Malawi. Methods: An observational cohort study nested in a trial of urine-based TB screening in unselected HIV-positive adults followed up for 2 months. Patients taking ART for ≥6 months at hospital admission had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA ≥1000 copies/ml had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR Algorithm Findings: Of 1316 patients recruited in the Malawi trial site between October 2015 and September 2017, 786 had taken ART for ≥6 months of whom 252/786 (32.1%) patients had viral load ≥1000 copies/ml (virological failure). Mean age was 38 years, 61.5% were female and median CD4 count was 60 cells/µL. Of 237 (94.0%) patients with HIV drug resistance results available, 195 (82.3%) had resistance to lamivudine, 128 (54.0%) to tenofovir and 219 (92.4%) to efavirenz. Resistance to at least 2 drugs was common (196/237, 82.7%) and this was associated with increased 2-month mortality (adjusted hazard ratio 1.7, 95% CI 1.2-2.4, p=0.004). Interpretation: HIV virological failure and HIV multidrug resistance were common in HIV-positive inpatients, and associated with increased early mortality. Targeted interventions including adherence support, rapid viral load testing and routine access to drug resistance testing are urgently needed. Enabling prompt diagnosis and switching to alternative ART could reduce early mortality among HIV-positive inpatients. Funding Statement: The Screening for TB to Reduce AIDS Related Mortality in Hospitalised Patients (STAMP) trial was funded by the Joint Global Health Trials Scheme of the UK Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council and Wellcome Trust (MR/M007375/1). AGW has received a Royal College of Physicians London James Maxwell Grant Prophit Fellowship, and ELC has received a Wellcome Trust Fellowship (WT200901/Z/16/Z). Declaration of Interests: The authors declare no conflicts of interest exist. Ethics Approval Statement: All patients provided informed written consent for participation and sample storage. Retrospective HIV viral load and drug resistance testing was approved by the research ethics committee of the London School of Hygiene and Tropical Medicine, and the University of Malawi College of Medicine Research and Ethics Committee (COMREC).

Influenza a viruses: Future challenges and opportunities in relation to therapeutics

Influenza viruses are of major concern for respiratory infection in humans and animals. They are significantly important on account of the possible cause for pandemics in human and animal populations. Major strategy directed for control and prevention of disease is vaccination, however, continuous viral mutations make the vaccines redundant over a period of time and require continuous harmonization. Another approach to mitigate influenza is treatment with antiinfluenza drugs treatment, which again have limited options due to emergence of drug resistant viruses and less success in developing the novel antiviral drugs resulting from subsequent failure of lead drug molecules in clinical trials. The re-emergence of influenza posed continuous potential pandemic threat for human and animal population. Therefore, there is a great demand to work on antiviral therapeutics by exploiting modern technologies for repurposing available drugs and screening of novel antiviral molecules and phytochemicals with different combinations and doses. Hence, the present review portrays the epidemiology of the disease along with its therapeutics (available and possible in future).

HIV-related Peer Support in Dar es Salaam: A Pilot Questionnaire Inquiry

Abstract HIV drug resistance (HIVDR) in Tanzania is a complex problem with many interconnected causes. Some important factors contributing to the selection of drug resistant viruses in people infected with HIV are stigma, poverty, poor health, illiteracy, and insufficient adherence to antiretroviral therapy. Several studies have suggested the implementation of peer support groups as a way to shift the workload associated with adherence support, antiretroviral therapy (ART) distribution, and HIV education away from the doctors to the people living with HIV (PLHIV) themselves. We conducted interviews with local PLHIV to investigate the desirability and feasibility of a peer support group in the Pasada and Kisarawe hospitals in Dar es Salaam, Tanzania. A standardized questionnaire was completed by 27 PLHIV in July and August 2017 at the time of a follow-up visit. In this cohort, major causes for missing a dose of ART are lack of support from family and friends and forgetfulness. Reasons for wanting to join <target target-type="page-num" id="p-2"/>a peer support group include psychological support, fighting stigma, and increasing education about their disease. Interestingly, several respondents linked HIV peer support to business support groups such as village community banks (VICOBA). These are informal microfinance groups meant to offer economic stability to individuals. As this link was made by PLHIV themselves, we suggest that it may be worthwhile to explore mixed financial and HIV peer support groups in which HIV education is provided for both HIV positive and negative members. Such groups may reduce the risk of infection and stigma and provide combined psychological, financial, and logistic support to PLHIV.

The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation.

The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.

Favorable outcome of retreatment by direct-acting antivirals for hepatitisC patients with daclatasvir plus asunaprevir combination therapy failure.

In patients with hepatitisC virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed. Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.

Baloxavir Marboxil Treatment of Nude Mice Infected With Influenza A Virus.

Immunocompromised patients infected with influenza virus require prolonged treatment with neuraminidase inhibitors, because these patients are not able to eradicate the virus from the respiratory tract, leading to the emergence of drug-resistant mutant viruses. In this study, we examined the efficacy of baloxavir marboxil in nude mice that were immunologically deficient. Daily treatment with a suboptimal dose of baloxavir marboxil increased the survival time of the virus-infected nude mice but did not clear the virus from their respiratory organs, resulting in gradual body weight loss after termination of treatment. Despite the prolonged baloxavir marboxil treatment, few resistant mutants were detected.

Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition.

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil

Baloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October 2018, drug resistant viruses have already been detected from clinical trials owing to an I38 mutation of CEN. To investigate the reduction of drug sensitivity by the I38 mutant variants, we performed a molecular dynamics (MD) simulation on the CEN-BXM complex structure to analyze variations in the mode of interaction. Our simulation results suggest that the side chain methyl group of I38 in CEN engages in a CH-pi interaction with the aromatic ring of BXM. This interaction is abolished in various I38 mutant variants. Moreover, MD simulation on various mutation models and binding free energy prediction by MM/GBSA method suggest that the I38 mutation precludes any interaction with the aromatic ring of BXA and thereby reduces BXA sensitivity.

Synthesis and Characterization of Long-Acting Darunavir Prodrugs.

Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.

Diverse Human Immunodeficiency Virus-1 Drug Resistance Profiles at Screening for ACTG A5288: A Study of People Experiencing Virologic Failure on Second-line Antiretroviral Therapy in Resource-limited Settings.

Human immunodeficiency virus (HIV) drug resistance profiles are needed to optimize individual patient management and to develop treatment guidelines. Resistance profiles are not well defined among individuals on failing second-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). Resistance genotypes were performed during screening for enrollment into a trial of third-line ART (AIDS Clinical Trials Group protocol 5288). Prior exposure to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs and confirmed virologic failure on a protease inhibitor-containing regimen were required. Associations of drug resistance with sex, age, treatment history, plasma HIV RNA, nadir CD4+T-cell count, HIV subtype, and country were investigated. Plasma HIV genotypes were analyzed for 653 screened candidates; most had resistance (508 of 653; 78%) to 1 or more drugs. Genotypes from 133 (20%) showed resistance to at least 1 drug in a drug class, from 206 (32%) showed resistance to at least 1 drug in 2 drug classes, and from 169 (26%) showed resistance to at least 1 drug in all 3 commonly available drug classes. Susceptibility to at least 1 second-line regimen was preserved in 59%, as were susceptibility to etravirine (78%) and darunavir/ritonavir (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+ T-cell counts, and those who had received lopinavir/ritonavir, but was lower among prior nevirapine recipients. Highly divergent HIV drug resistance profiles were observed among candidates screened for third-line ART in LMIC, ranging from no resistance to resistance to 3 drug classes. These findings underscore the need for access to resistance testing and newer antiretrovirals for the optimal management of third-line ART in LMIC.

2505. Incidence of Transmitted Drug Resistance and Its Clinical Implications Between 1999 and 2018 in a Regional HIV Population

BackgroundBaseline genotype antiretroviral resistance testing (GART) were introduced to allow better selection of antiretroviral therapy (ART), minimizing the use of less effective drugs and risk for ongoing transmission of drug-resistant virus. However, the value of baseline GART has recently been questioned due to declining incidence of TDR in the setting of improved drug tolerability profiles and effectiveness. We aimed to evaluate the long-term clinical and economic impact of TDR using a well characterized, geographically defined cohort between 1999–2018.MethodsIn the Southern Alberta Cohort (SAC) database we identified all (ART naïve) HIV patients, ≥16 years of age, with a baseline GART. They were classified by presence or absence of TDR. Clinical and sociodemographic data were obtained from database and chart review. All statistical analysis was performed with Stata.ResultsDuring the study 745 GART tests were done on ART naïve patients. Baseline ART resistance was documented in 78 /745 patients. TDR was to the NNRTI class in 59 (75.6%), to NRTI in 12 (15.4%) and to the PI class in 7 (8.9%) patients. Two patients had two class resistance and none had INSTI resistance. There was a significant difference in cost per year of therapy comparing the TDR and control ($17,152/year vs. $15,362/year, P ≤ 0.001). Patients with TDR had greater pill burden with 20% being on BID/TID ART regimens compared with the controls of 13% (P = 0.003). No differences in incident ART adverse events (12.8% TDR vs. 13.3% no TDR), drug interactions (1.6% vs. 1.0%) or reasons to stop or change ARVs were seen between study groups. The duration of ART on any given drug class was similar between the two populations (P = 0.6694) as was status of viral suppression at one year 73% vs. 65%.ConclusionPresence of TDR at baseline had little immediate impact on ART initiation or tolerance, but by limiting choices negatively impacted pill burden and dosing as well as drug costs. Disclosures All authors: No reported disclosures.

Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape.

The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.

Deep Knockoffs

This article introduces a machine for sampling approximate model-X knockoffs for arbitrary and unspecified data distributions using deep generative models. The main idea is to iteratively refine a knockoff sampling mechanism until a criterion measuring the validity of the produced knockoffs is optimized; this criterion is inspired by the popular maximum mean discrepancy in machine learning and can be thought of as measuring the distance to pairwise exchangeability between original and knockoff features. By building upon the existing model-X framework, we thus obtain a flexible and model-free statistical tool to perform controlled variable selection. Extensive numerical experiments and quantitative tests confirm the generality, effectiveness, and power of our deep knockoff machines. Finally, we apply this new method to a real study of mutations linked to changes in drug resistance in the human immunodeficiency virus. Supplementary materials for this article are available online.

Antiviral Activities of Hibiscus sabdariffa L. Tea Extract Against Human Influenza A Virus Rely Largely on Acidic pH but Partially on a Low-pH-Independent Mechanism.

Influenza A virus (IAV) infection is perennially one of the leading causes of death worldwide. Effective therapy and vaccination are needed to control viral expansion. However, current anti-IAV drugs risk inducing drug-resistant virus emergence. Although intranasal administration of whole inactivated virus vaccine can induce efficient protective immunity, formalin and β-propiolactone are the currently used and harmful inactivating agents. Here, we analyzed the antiviral activity of hibiscus (Hibiscus sabdariffa L.) tea extract against human IAV and evaluated its potential as a novel anti-IAV drug and a safe inactivating agent for whole inactivated vaccine. The in vitro study revealed that the pH of hibiscus tea extract is acidic, and its rapid and potent antiviral activity relied largely on the acidic pH. Furthermore, the mouse study showed that the acidic extract was not effective for either therapeutic or vaccination purposes. However, hibiscus tea extract and protocatechuic acid, one of the major components of the extract, showed not only potent acid-dependent antiviral activity but also weak low-pH-independent activity. The low-pH-independent activity did not affect the conformation of immunodominant hemagglutinin protein. Although this low-pH-independent activity is very limited, it may be suitable for the application to medication and vaccination because this activity is not affected by the neutral blood environment and does not lose antigenicity of hemagglutinin. Further study of the low-pH-independent antiviral mechanism and attempts to enhance the antiviral activity may establish a novel anti-IAV therapy and vaccination strategy.

Impact of NRTI resistance mutations on virological effectiveness of antiretroviral regimens containing elvitegravir: a multi-cohort study.

Antiretroviral drug resistance mutations remain a major cause of treatment failure. To evaluate the impact of NRTI resistance mutations on virological effectiveness of elvitegravir-containing regimens. We selected treatment-experienced HIV-1-infected patients starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), with at least one protease/reverse transcriptase genotype available before switching and at least one HIV-1 RNA viral load (VL) measurement during follow-up. The primary endpoint was virological failure (VF), defined as one VL value of ≥1000 copies/mL or two consecutive VL values of >50 copies/mL. We included 264 ART regimens: 75.6% male, median (IQR) age 47 years (39-53), 7 years (3-16) of HIV infection, nadir CD4+ 247 cells/mm3 (105-361), 81.5% with VL ≤50 copies/mL and 11.7% with at least one NRTI mutation at baseline. Eleven (5.2%) VFs occurred in virologically suppressed patients versus eight (15.1%) in viraemic patients. The estimated probability of VF at 48 weeks with versus without any NRTI mutation was 7.4% (95% CI 2.3-12.5) versus 3.8% (2.1-5.5) in virologically suppressed patients and 66.7% (39.5-93.9) versus 11.2% (6.5-15.9) (P<0.001) in viraemic patients. The only predictor of VF was time on therapy (per 1 year more, adjusted HR 1.14, 95% CI 1.02-1.27, P=0.024) in viraemic patients. A switch to E/C/F/TDF or E/C/F/TAF is safe for virologically suppressed patients without documented NRTI resistance, but not recommended in viraemic patients with a history of NRTI resistance. Although we did not detect a detrimental effect of past NRTI resistance in virologically suppressed patients, a fully active regimen remains preferred in this setting due to possible rebound of drug-resistant virus in the long term.

Molecular docking, design, synthesis and biological evaluation of novel 2,3-aryl-thiazolidin-4-ones as potent NNRTIs

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.

Italian Registry of HIV-1 Infected Patients With Drug-RESistant Virus to Reverse Transcriptase Inhibitors, InteGrasE and Viral Protease.

Italian Registry of HIV-1 Infected Patients With Drug-RESistant Virus to Reverse Transcriptase Inhibitors, InteGrasE and Viral Protease.

Prevalence and Correlates of Pre-Treatment HIV Drug Resistance among HIV-Infected Children in Ethiopia.

Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, in part because the administration of combination antiretroviral therapies (cART) is inherently complex in this population and because viral load and drug resistance genotyping are not routinely available in these settings. Children may also be at elevated risk of transmission of drug-resistant HIV as a result of suboptimal antiretroviral administration for prevention of mother-to-child transmission. We investigated the prevalence and the correlates of pretreatment HIV drug resistance (PDR) among HIV-infected, cART-naive children in Ethiopia. We observed an overall PDR rate of 14%, where all cases featured resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs): ~9% of participants harbored resistance solely to NNRTIs while ~5% harbored resistance to both NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs). No resistance to protease inhibitors was observed. No sociodemographic or clinical parameters were significantly associated with PDR, though limited statistical power is noted. The relatively high (14%) rate of NNRTI resistance in cART-naive children supports the use of non-NNRTI-based regimens in first-line pediatric treatment in Ethiopia and underscores the urgent need for access to additional antiretroviral classes in resource-limited settings.

Artesunate derivative TF27 inhibits replication and pathogenesis of an oncogenic avian alphaherpesvirus

Nucleoside analogues have been the cornerstone of clinical treatment of herpesvirus infections since the 1970s. However, severe side effects and emergence of drug resistant viruses raise the need for alternative treatment options. We recently investigated the broad and strong antiherpesviral activity of the optimized artesunate derivative TF27 in vitro. TF27 efficiently inhibited replication of the highly oncogenic Marek's disease virus (MDV), a virus that infects chickens, causes deadly lymphomas and threatens poultry populations worldwide. In this study, we used this natural virus-host model for herpesvirus-induced cancer by infecting chickens with MDV, and evaluated the protective efficacy of TF27 and the nucleoside analogue valganciclovir (VGCV) on virus replication and tumorigenesis. We could demonstrate that both drugs reduced viral load in the blood and prevented tumor development in a large portion of the animals. Antiviral treatment also had a positive impact on body weight gain, while no negative compound-associated side effects were observed. This research provides the first evidence that the artesunate derivative TF27 and VGCV can be used in avian species and that they inhibit MDV replication and tumorigenesis. In addition, our study paves the way for promising approaches in future antiherpesviral drug development.

National survey of pre-treatment HIV drug resistance in Cuban patients.

BackgroundThe World Health Organization (WHO) recommends a method to estimate nationally representative pretreatment HIV drug resistance (PDR) in order to evaluate the effectiveness of first -line treatments. The objective of the present study was to determine the prevalence of PDR in Cuban adults infected with HIV-1.Materials and methodsA cross-sectional study in Cuban adults infected with HIV-1 over 18 years was conducted. The probability proportional to size method for the selection of municipalities and patients without a prior history of antiretroviral treatment during the period from January 2017 to June 2017 was used. The plasma from 141 patients from 15 municipalities for the determination of viral subtype and HIV drug resistance was collected. Some clinical and epidemiological variables were evaluated.Results80. 9% of the patients corresponded to the male sex and 76.3% were men who have sex with other men (MSM). The median CD4 count was 371 cells / mm3 and the median viral load was 68000 copies / mL. The predominant genetic variants were subtype B (26.9%), CRF19_cpx (24.1%), CRF 20, 23, 24_BG (23.4%) and CRF18_cpx (12%). Overall, the prevalence of PDR was 29.8% (95%, CI 22.3–38.1). The prevalence was 12.8% (95%, CI 6.07–16.9) for any nucleoside reverse transcriptase inhibitor (NRTI), 23.4% (95%, CI 16.7–31.3) for any non-reverse transcriptase inhibitor (NNRTI) and 1.4% (95%, CI 0.17–5.03) for any protease inhibitor (PI). The most frequent mutations detected were K103N (12.9%), G190A (6.4%) and Y181C (4.8%).ConclusionsThe NNRTI prevalence above 10% in our study indicates that the first-line antiretroviral therapy in Cuba may be less effective and supports the need to look for new treatment options that contribute to therapeutic success and help the country achieve the global goals 90-90-90 set forth by UNAIDS.