bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Prediction of Response to Antiretroviral Combination Therapy using the Genetic Barrier to Drug Resistance
Authors: Altmann André , Beerenwinkel Niko , Sing Tobias , Savenkov Igor , Däumer Martin , Kaiser Rolf , Rhee Soo-Yon , Fessel W Jeffrey , Shafer Robert W , Lengauer Thomas
Published: April 2022

Background

The outcome of antiretroviral combination therapy depends on many factors involving host, virus, and drugs. We investigate prediction of treatment response from the applied drug combination and the genetic constellation of the virus population at baseline. The virus's evolutionary potential for escaping from drug pressure is explored as an additional predictor.

Methods

We compare different encodings of the viral genotype and antiretroviral regimen including phenotypic and evolutionary information, namely predicted phenotypic drug resistance, activity of the regimen estimated from sequence space search, the genetic barrier to drug resistance, and the genetic progression score. These features were evaluated in the context of different statistical learning procedures applied to the binary classification task of predicting virological response. Classifier performance was evaluated using cross-validation and receiver operating characteristic curves on 6,337 observed treatment change episodes from the Stanford HIV Drug Resistance Database and a large US clinic-based patient population.

Results

We find that the choice of appropriate features affects predictive performance more profoundly than the choice of the statistical learning method. Application of the genetic barrier to drug resistance, which combines phenotypic and evolutionary information, outperformed the genetic progression score, which uses exclusively evolutionary knowledge. The benefit of phenotypic information in predicting virological response was confirmed by using predicted fold changes in drug susceptibility. Moreover, genetic barrier and predicted phenotypic drug resistance were found to be the best encodings across all datasets and statistical learning methods examined.

Availability

THEO (THErapy Optimizer), a prototypical implementation of the best performing approach, is freely available for research purposes at http://www.geno2pheno.org .
New Functional Domains of Human Cytomegalovirus pUL89 predicted by Sequence Analysis and Three-Dimensional Modelling of the Catalytic Site DEXDc
Authors: Champier Gaël , Hantz Sébastien , Couvreux Anthony , Stuppfler Stéphanie , Mazeron Marie-Christine , Bouaziz Serge , Denis François , Alain Sophie
Published: April 2022

Introduction

Benzimidazole d-ribonucleosides inhibit DNA packaging during human cytomegalovirus (HCMV) replication. Although they have been shown to target pUL56 and pUL89, the large and small subunits of the HCMV terminase respectively, their mechanism of action is not yet fully understood.

Methods and results

To better understand HCMV DNA maturation and the mechanism of action of benzimidazole derivatives, we studied the HCMV pUL89 protein by a genetic approach combined with primary structure analysis. The pUL89 sequence analysis of 25 HCMV strains and counterparts among herpesviruses allowed identification of 12 conserved regions. We also built a three-dimensional model of the pUL89 ATPasic catalytic site, including ATPase motor motifs I, II and III, that may facilitate the development of future antiviral drugs active against HCMV. Finally, we identified several putative functional domains in pUL89, such as pUL89 zinc finger (pUL89-ZF), DNA cutting sites and portal binding sites, that are probably involved in CMV DNA cleavage and packaging.
Effect of Transient Antiretroviral Treatment during acute HIV Infection: Comparison of the Quest Trial Results with CASCADE Natural History Study
Authors: Lampe Fiona C , Porter Kholoud , Kaldor John , Law Matthew , Loes Sabine Kinloch-de , Phillips Andrew N
Published: April 2022

Objective

The benefit of transient combination antiretroviral treatment (CART) during acute HIV infection is uncertain. We used the seroconverter database CASCADE to provide a historical comparison for the Quest trial, in which 79 subjects with acute HIV infection received CART for an average of 2.6 years, and 17.7% (95% confidence interval [CI]: 10.9–27.6) fulfilled the primary endpoint of VL≤1,000 copies/ml 24 weeks after CART discontinuation.

Methods

We estimated the prevalence of VL ≤1,000 copies/ml three years after seroconversion and prior to any ART among 385 sexually infected subjects in CASCADE who seroconverted between 1988 and 1996. We conducted a pre-specified comparison with the recently published Quest results, and considered potential biases.

Results and discussion

The prevalence of VL ≤1,000 copies/ml at year three in CASCADE was 10.1% (95% CI: 7.5–13.5) (absolute difference compared to 17.7% in Quest: 7.6%; 95% CI: -0.1–17.8; P=0.053). In CASCADE, VL≤1,000 copies/ml was less common among homosexual and heterosexual men compared with women (8.5%, 7.3% and 17.6% respectively) and in subjects with symptomatic infection compared with those without (6.2% and 12.6%, respectively). As Quest had a much greater proportion of symptomatic subjects than CASCADE, any true difference in VL might be underestimated. Therefore this comparison suggests that transient CART in acute infection might result in a modest increase in the probability of low VL subsequently. However, several factors mitigate this conclusion. First, this historical comparison might be subject to other unmeasured confounders. Second, a comparison of median VL at the same time point was not significant (4.02 copies/ml and 4.20 copies/ml in Quest and CASCADE, respectively; P=0.55). Finally, additional analysis suggested that the observed difference in low VL at year three would be consistent with an immediate effect of CART only - a delay of usual VL decline without additional benefit.

Conclusions

A small but significant proportion of seroconverters have low VL without ART. Transient CART in acute infection might increase the probability of low VL after treatment discontinuation, but such an effect is likely to be modest, and might represent a delay of natural history rather than a long-term therapeutic benefit.
Insulin Resistance, Glucose Intolerance and Diabetes Mellitus in HIV-Infected Patients
Authors: Florescu Diana , Kotler Donald P
Published: April 2022

An increased prevalence of insulin resistance, glucose intolerance and diabetes has been reported in HIV infection in the highly active antiretroviral therapy (HAART) era. This development might be clinically significant because of its association with cardiovascular morbidity and mortality as well as the therapeutic challenges of managing polypharmacy. The development of insulin resistance, glucose intolerance and diabetes could be related to the underlying HIV infection, the contribution of different antiretroviral agents, treatment-associated weight gain, immune restoration, as well as the non-HIV related factors. Dissecting these factors in clinical practice might be difficult. Clinical studies include short-term treatments in healthy, non-HIV-infected individuals; randomized, controlled trials; comparative studies of different HAART regimens; and randomized studies of switching regimens in patients with viral suppression and stable immune function. This article reviews the latest knowledge regarding the epidemiology, pathogenesis, prevention and treatment of insulin resistance, glucose intolerance and diabetes mellitus in HIV-infected individuals.
A Phase I/IIa Study with Succinylated Human Serum Albumin (Suc-HSA), a candidate HIV-1 Fusion Inhibitor
Authors: Vermeulen Joost N , Meijer Dirk KF , Over Jan , Lange Joep MA , Proost Johannes H , Bakker Hester I , Beljaars Leonie , Wit Ferdinand WNM , Prins Jan M
Published: April 2022

Background

Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3–loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5–5.0 μg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals.

Methods

First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined.

Results

Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 μg/ml) 12–24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase.

Conclusions

At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.
Two-year Lamivudine treatment for Hepatitis B e Antigen-Negative Chronic Hepatitis B: A Double-Blind, Placebo-Controlled Trial
Authors: Chan Henry Lik-Yuen , Wang Hao , Niu Junqi , Chim Angel Mei-Ling , Sung Joseph Jao-Yiu
Published: April 2022

Objective

We conducted a multicentre, double-blind, placebo-controlled, randomized study to investigate the efficacy of 2-year lamivudine treatment in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.

Methods

One-hundred-and-thirty-nine treatment-naive patients with HBeAg-negative chronic hepatitis B were randomized to receive either lamivudine (100 mg daily) or placebo in a 2:1 ratio for 24 months and were followed for an additional 6 months. The primary endpoint was complete response, defined as hepatitis B virus (HBV) DNA <10,000 copies/ml and normalization of alanine aminotransferase (ALT) levels at month 24.

Results

On intent-to-treat analysis at month 24, significantly more patients in the lamivudine group than in the placebo group had complete response (56% and 11%, respectively; P<0.001) or negative HBV DNA (26% and 6%, respectively; P=0.006). After adjustment of baseline HBV DNA and ALT, the odds ratio for complete response of the lamivudine group versus the placebo group was 10.8 (95% confidence interval: 3.8–30.2; P<0.001). The median log HBV DNA reduction was 3.21 copies/ml for the lamivudine group compared with 0.47 copies/ml for the placebo group ( P<0.001). Genotypic resistance was detected in 23% and 31% of patients in the lamivudine group at months 12 and 24, respectively. Negative HBV DNA at month 6 was associated with high complete response (84%) and low drug resistance (1%) at month 24. At month 30, there was no difference between lamivudine and placebo groups in the rates of complete response (26% vs 19%, respectively; P=0.38) or negative HBV DNA (10% vs 2%, respectively; P=0.09).

Conclusions

Two-year lamivudine treatment is effective in HBeAg-negative chronic hepatitis B. However, the response is not sustained after treatment cessation.
Five-Year Follow up of Once-Daily Therapy with Emtricitabine, Didanosine and Efavirenz (Montana ANRS 091 Trial)
Authors: Molina Jean-Michel , Journot Valérie , Furco André , Palmer Pierre , Castro Nathalie De , Raffi François , Morlat Philippe , May Thierry , Rancinan Corinne , Chêne Geneviève ,   for the Montana (ANRS 091) Study Group, Modaï J , Decazes J-M , Molina JM , Madeleine I , Sombardier MN , Martinie M , Séréni D , Lascoux-Combes C , Michon C , Vinceneux Ph , Delfraissy JF , Goujard C , Peretti D , Rannou MT , Galanaud P , Boue F , Colson C , Rozenbaum W , Girard PM , Adda N , Saimot AG , Coulaud JP , Landman R , Matheron S , Hoen B , Derancourt C , Drobacheff C , Salard D , Laurent R , Estavoyer JM , Beylot J , Morlat P , Lacoste D , Bonarek M , Bonnet F , Bernard N , Nouts C , Trepo C , Cotte L , Schlienger I , Rougier P , Carre C , Raffi F , Bonnet B , Allavena C , Esnault JL , Charonnat MF , Sicot M , Canton P , Burty C , Brel F , May T , Lecompte T Doco
Published: April 2022

Background

Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported.

Methods

This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability.

Results

After 5 years, 73% and 68% of patients had plasma HIV RNA levels <400 and <50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294x106 cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol.

Conclusions

A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.
Failure of Zanamivir Therapy for Pneumonia in a Bone-Marrow Transplant Recipient Infected by a Zanamivir-Sensitive Influenza a (H1N1) Virus
Authors: Medeiros Rita , Rameix-Welti Marie-Anne , Lorin Valérie , Ribaud Patricia , Manuguerra Jean-Claude , Socie Gérard , Scieux Catherine , Naffakh Nadia , Van Der Werf Sylvie
Published: April 2022

Influenza A viruses are responsible for significant morbidity and mortality after bone marrow transplantation. Here we report failure of inhaled zanamivir treatment in a bone-marrow transplant recipient with pneumonia caused by an influenza A (H1N1) virus, although the influenza viruses isolated from bronchoalveolar lavages before and after treatment were clearly found to be sensitive to zanamivir using cell-based and enzymatic assays. Subsequent oral treatment with oseltamivir allowed complete recovery. Poor bioavailability of zanamivir in the peripheral lungs might have been limiting treatment efficacy in such an immunocompromised patient.
Natural Polymorphism of the HIV-1 Integrase Gene and Mutations associated with Integrase Inhibitor Resistance
Authors: Lataillade Max , Chiarella Jennifer , Kozal Michael J
Published: April 2022

Background

Two inhibitors of the HIV-1 integrase enzyme (INIs) are in late stage clinical development. To date, approximately 42 mutations within the HIV-1 integrase (IN) gene have been associated with INI drug resistance. Naturally occurring IN gene polymorphisms may have important implications for INI development. In this study, we evaluated clinical HIV-1 strains from INI-naive patients to determine the prevalence of IN gene polymorphisms, and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance and at sites crucial for LEDGF/p75 binding and HIV-1 integration.

Methods

The IN gene from 67 INI-naive, HIV-1 clade B-infected patients were sequenced using standard population-based DNA sequencing methods. In addition, 176 unique full-length HIV-1 clade B IN gene sequences from INI-naive patients obtained from the HIV Los Alamos database were analysed.

Results

Analysis of 243 IN genes from HIV-1 clade B, INI-naive clinical strains revealed that 64% of the aa positions were polymorphic. Of the 42 aa substitutions currently associated with INI resistance, 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y/A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K. IN aa positions crucial to LEDGF/P75 binding and HIV-1 integration were well conserved.

Conclusion

Major INI mutations within the catalytic domain and extended active sites associated with high level resistance to the compounds in late stage development, especially strand transfer inhibitors (STIs), were infrequent in our study, which may help explain the excellent virological responses demonstrated in clinical trials.
DNA Polymerase Mutations in Drug-Resistant Herpes Simplex Virus Mutants Determine In Vivo Neurovirulence and Drug-Enzyme Interactions
Authors: Andrei Graciela , Fiten Pierre , Froeyen Matheus , Clercq Erik De , Opdenakker Ghislain , Snoeck Robert
Published: April 2022

Mutations in the thymidine kinase and DNA polymerase genes of herpes simplex virus (HSV) might confer resistance to antiviral drugs, particularly in immunocompromised patients who suffer from chronic and/or disseminated lesions. The patterns of cross-resistance and neurovirulence in mice of several DNA polymerase mutants selected under pressure of foscarnet (PFA) and different acyclic nucleoside phosphonates (ANPs), including ( S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), were investigated. The mutants were derived from the HSV-1 strain KOS following either single or multiple steps of selection with PFA (V714M, A719V, S724N and T821M), PMEA (S724N, L802F and R959H), PMEDAP (Q618H, S724N, S724N+D1070N), HPMPC (V573M, R700M and K960R) or HPMPA (W998L, L1007M and I1028T). These amino acid substitutions were located in different subdomains of the HSV-1 DNA polymerase, either in conserved or non-conserved regions. The sensitivity of the mutants to a new class of ANPs, the 6-(2-[phosphonomethoxy]alkoxy)pyrimidines HPMPO-DAPy and PMEO-DAPy, was investigated. Cross-resistance between the HPMP derivatives and HPMPO-DAPy, on the one hand, and between the PME derivatives and PMEO-DAPy, on the other hand, was observed. Different degrees of cross-resistance between PME derivatives, PMEO-DAPy, PFA and acyclovir were noticed. The mutants ranged from exhibiting near wild-type neurovirulence (V714M, A719V, S724N and L1007M) to significant attenuation (Q618H, S724N+D1070N, L802F, R700M, K960R, W998L and I1028T) or higher levels of attenuation (V573M). It appears that drug-resistant mutants arising under the pressure of HPMP derivatives have the lowest levels of neurovirulence.
A Novel Mutation Pattern Emerging during Lamivudine Treatment Shows Cross-Resistance to Adefovir Dipivoxil Treatment
Authors: Karatayli Ersin , Karayalçin Selim , Karaaslan Hayri , Kayhan Handan , Türkyilmaz A Resat , Sahin Fikret , Yurdaydin Cihan , Bozdayi A Mithat
Published: April 2022

Aims

This study was conducted to clarify the resistance profile of a novel mutation pattern emerging during lamivudine (3TC) therapy and showing cross-resistance to adefovir dipivoxil (ADV) in a patient with chronic hepatitis B.

Methods and results

Successful suppression of hepatitis B virus (HBV) replication by sequential therapy of 9 MU thrice weekly interferon (IFN) and 3TC was followed by genotypical resistance detected at month 28 of therapy (month 19 of lamivudine treatment). ADV was added to 3TC therapy on month 44 of antiviral treatment. Neither alanine aminotransferase normalization nor a stable decrease in HBV viral load was observed, although ADV was used for more than 40 months. The HBV pol region was amplified from serum samples obtained before and after ADV treatment. The complete genome was cloned into a TA vector. PCR products and 7–10 clones from each cloned vector were sequenced. A novel mutation, A181S, in the reverse transcriptase gene leading to a conversion of W172C in the overlapping surface antigen gene was detected along with a M204I mutation. The complete genome comprising the A181S+M204I pattern was cloned into an expression vector and its in vitro susceptibility to 3TC, ADV, tenofovir (PMPA), clevudine (l-FMAU) and emtricitabine (FTC) were determined in transiently transfected Huh7 cells. This mutation pattern displayed more than 1,000-fold resistance to the nucleoside analogues 3TC and FTC and approximately sixfold resistance to l-FMAU, while it confers 28.23- and 5.57-fold resistance for the nucleotide analogues ADV and PMPA, respectively.

Conclusion

A new mutation pattern, A181S+M204I, arising under lamivudine treatment confers cross-resistance to ADV both in vivo and in vitro.
Impact of Early Viral Kinetics on T-Cell Reactivity during Antiviral Therapy in Chronic Hepatitis B
Authors: Lau George KK , Cooksley Helen , Ribeiro Ruy M , Powers Kimberly A , Shudo Emi , Bowden Scott , Hui Chee-Kin , Anderson Jane , Sorbel Jeff , Mondou Elsa , Rousseau Franck , Lewin Sharon , Perelson Alan S , Locarnini Stephen , Naoumov Nikolai V
Published: April 2022

Background

The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined.

Methods

We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry.

Results

Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders ( P=0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients.

Conclusions

Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.
Quadruple Nucleoside Therapy with Zidovudine, Lamivudine, Abacavir and Tenofovir in the Treatment of HIV
Authors: Stürmer Martin , Staszewski Schlomo , Doerr Hans Wilhelm
Published: April 2022

Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients. However, problems such as short-term or long-term toxicity and the development of drug resistance could necessitate a change in the therapy regimen. Whereas various HAART options with low pill burden and favourable long-term tolerability profiles are available for naive patients, treatment of experienced patients tends to be more complex and remains a challenge. Treatment with class sparing nucleoside-only regimens could be an option in this context, but the combination of zidovudine (AZT), lamivudine (3TC) and abacavir (ABC) has shown to be inferior in terms of virological efficacy compared with the standard regimen. More promising data were obtained when AZT, 3TC and ABC were intensified with tenofovir (TDF), resulting in a quadruple nucleoside therapy. This regimen has demonstrated comparable potency to a standard regimen with AZT, 3TC and efavirenz in treatment-naive patients. Additionally, it has shown to be an efficient treatment option especially in moderately pretreated patients. This is accredited to the potency of the single components and the antagonistic selection pressure of AZT and TDF. The presence of L210W, or at least two of the mutations 41L, 67N, 70R, 215F/Y or 219Q/E, at or before baseline seems to be a predictor of non-response, whereas the presence of M184V does not impede virological response and might even be advantageous. This review summarizes current data on the combined use of AZT, 3TC, ABC and TDF in regard to virological and immunological outcome as well as genotypic predictors of response.
Effect of Transporter Modulation on the Emergence of Nelfinavir Resistance In Vitro
Authors: Chandler Becky , Detsika Maria , Owen Andrew , Evans Sorcha , Hartkoorn Ruben C , Cane Patricia A , Back David J , Khoo Saye H
Published: April 2022

Background

HIV drug resistance is of increasing concern and could result from inadequate drug potency, poor therapy adherence and the existence of pharmacological sanctuary sites for viral replication. One contributing factor to the generation of such sites could be drug efflux transporters, which have been shown capable of effluxing HIV protease inhibitors from cells.

Methods

In this ‘proof-of-concept’ study, the ability of the efflux transport inhibitor verapamil to modulate the intracellular accumulation of radiolabeled nelfinavir (NFV) and the antiviral effect of NFV was assessed in MT4 cells. Wild-type virus was then serially passaged with increasing concentrations of NFV with and without verapamil and resistance mutations monitored by sequencing of the viral protease gene.

Results

The cellular accumulation ratio of 3H-NFV was 116.8 ±9.7 in controls and was significantly increased to 149.8 ±24.5 following incubation with verapamil (P<0.05, n=4). The EC50 of NFV was decreased in MT4 cells in the presence of verapamil from 8.5 ±1.3 nM to 4.4 ±0.8 nM ( P<0.001, n=6). Of the 24 isolates passaged without verapamil, 21 carried the D30N mutation at detectable levels. Of the 23 passaged with verapamil, 14 carried the mutation (odds ratio=4.5; P<0.05).

Conclusions

These results suggest that ‘intracellular boosting’ of PIs is achievable through inhibition of drug efflux proteins in vitro and that such boosting has the ability to enhance suppression of viral replication, slowing the emergence of resistance mutations.
Declining Prevalence of HIV-1 Drug Resistance in Treatment-Failing Patients: A Clinical Cohort Study
Authors: Giambenedetto Simona Di , Bracciale Laura , Colatigli Manuela , Pannetti Carmen , Bacarelli Alessandra , Prosperi Mattia , Fadda Giovanni , Cauda Roberto , De Luca Andrea
Published: April 2022

Objectives

A major barrier to successful viral suppression in HIV type 1 (HIV-1)-infected individuals is the emergence of virus resistant to antiretroviral drugs. We explored the evolution of genotypic drug resistance prevalence in treatment-failing patients from 1999 to 2005 in a clinical cohort.

Patients and Methods

Prevalence of major International AIDS Society-USA HIV-1 drug resistance mutations was measured over calendar years in a population with treatment failure and undergoing resistance testing. Predictors of the presence of resistance mutations were analysed by logistic regression.

Results

Significant reductions of the prevalence of resistance to all three drug classes examined were observed. This was accompanied by a reduction in the proportion of treatment-failing patients. Independent predictors of drug resistance were the earlier calendar year, prior use of suboptimal nucleoside analogue therapy, male sex and higher CD4 levels at testing.

Conclusions

In a single clinical cohort, we observed a decrease in the prevalence of resistance to all three examined antiretroviral drug classes over time. If this finding is confirmed in multicentre cohorts it may translate into reduced transmission of drug-resistant virus from treated patients.
CD4+ T-Cell Count Increase in HIV-1-Infected Patients with Suppressed Viral Load Within 1 year after start of antiretroviral therapy
Authors: Wolbers Marcel , Battegay Manuel , Hirschel Bernard , Furrer Hansjakob , Cavassini Matthias , Hasse Barbara , Vernazza Pietro L , Bernasconi Enos , Kaufmann Gilbert , Bucher Heiner C ,   Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirsch H , Hirschel B , Hösli I H , Kahlert Ch , Kaiser L , Karrer U , Kind C , Klimkait Th , Ledergerber B , Martinetti G , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Background

CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART).

Methods

Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included ( n=1,816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4+T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes.

Results

Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/μl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/μ l at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+T-cell increases compared with stavudine.

Conclusions

In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.
Genotypic Drug Resistance and Long-Term Mortality in Patients with Triple-Class Antiretroviral Drug Failure
Authors: Lohse Nicolai , Jørgensen Louise B , Kronborg Gitte , Møller Axel , Kvinesdal Birgit , Sørensen Henrik T , Obel Niels , Gerstoft Jan ,   Danish HIV Cohort Study, Gerstat J , Obel N , Kronborg G , Pedersen C , Larsen CS , Pedersen G , Laursen AL , Kvinesdal B , Møller A
Published: April 2022

Objective

To examine the prevalence of drug-resistance-associated mutations in HIV patients with triple-drug class virological failure (TCF) and their association with long-term mortality.

Design

Population-based study from the Danish HIV Cohort Study (DHCS).

Methods

We included all patients in the DHCS who experienced TCF between January 1995 and November 2004, and we performed genotypic resistance tests for International AIDS Society (IAS)-USA primary mutations on virus from plasma samples taken around the date of TCF. We computed time to all-cause death from date of TCF. The relative risk of death according to the number of mutations and individual mutations was estimated by Cox regression analysis and adjusted for potential confounders.

Results

Resistance tests were done for 133 of the 179 patients who experienced TCF. The median number of resistance mutations was eight (interquartile range 2–10), and 81 (61%) patients had mutations conferring resistance towards all three major drug classes. In a regression model adjusted for CD4+ T-cell count, HIV RNA, year of TCF, age, gender and previous inferior antiretroviral therapy, harbouring ≥9 versus ≤8 mutations was associated with increased mortality (mortality rate ratio [MRR] 2.3 [95% confidence interval (CI) 1.1–4.8]), as were the individual mutations T215Y (MRR 3.4 [95% CI 1.6–7.0]), G190A/S (MRR 3.2 [95% CI 1.6–6.6]) and V82F/A/T/S (MRR 2.5 [95% CI 1.2–5.3]).

Conclusions

In HIV patients with TCF, the total number of genotypic resistance mutations and specific single mutations predicted mortality.
Late Presentation of HIV-Infected Individuals
Authors: Battegay Manuel , Fluckiger Ursula , Hirschel Bernard , Furrer Hansjakob
Published: April 2022

Late presentation remains a major concern despite the dramatically improved prognosis realized by ART. We define a first presentation for HIV care during the course of HIV infection as ‘late’ if an AIDS-defining opportunistic disease is apparent, or if CD4+ T-cells are <200/μl. In the Western world, approximately 10 and 30% of HIV-infected individuals still present with CD4+ T-cells <50 and <200/μl, respectively; estimates are substantially higher for developing countries. Diagnosis and treatment of opportunistic diseases and intense supportive in-hospital care take precedence over ART. Benefits of starting ART without delay, that is, when opportunistic diseases are still active, include faster resolution of opportunistic diseases and a decreased risk of recurrence. The downside of starting ART without delay could include toxicity, drug interactions and immune reconstitution inflammatory syndrome (IRIS). Among asymptomatic or oligosymptomatic individuals presenting late, where ART and primary prophylaxis are initiated, ∼10–20% will become symptomatic from drug toxicity or undiagnosed opportunistic complications, including IRIS, which require appropriate therapies. In this review we describe late presentation to HIV care, the scale of the problem, the evaluation of a late-presenting patient and challenges associated with initiation of potent anti-retroviral therapy (ART) in the setting of acute opportunistic infections and other comorbidities.
Amprenavir and Lopinavir Pharmacokinetics following Coadministration of Amprenavir or Fosamprenavir with Lopinavir/Ritonavir, with or without Efavirenz
Authors: Pham Paul A , Hendrix Craig W , Barditch-Crovo Patricia , Parsons Teresa , Khan Wasif , Parish Michelle , Radebaugh Christine , Carson Kathryn A , Pakes Gary E , Qaqish Roula , Flexner Charles
Published: April 2022

Background

Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions.

Methods

Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV ( n=7) or without EFV ( n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV ( n=10) (Study 2).

Results

In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06μg/ml, P=0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34μg•h/ml, P=0.22) or maximum concentration (Cmax; 2.61 versus 4.33 μg/ml, P=0.08); for LPV there was no difference in Cmin (median: 3.66 versus 6.18μg/ml, P=0.20), AUC (81.84 versus 93.75 μg•h/ml, P=0.37) or Cmax (10.36 versus 10.93 μg/ml, P=0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 μg/ml, P=0.0001), AUC by 76% (19.41 versus 34.24 μg•h/ml, P=0.0001), and Cmax by 75% (3.50 versus 6.14, P=0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up).

Conclusions

EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1,400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.
Intracellular Nucleoside Triphosphate Concentrations in HIV-Infected Patients on Dual Nucleoside Reverse Transcriptase Inhibitor Therapy
Authors: Moore Jeff D , Acosta Edward P , Johnson Victoria A , Bassett Roland , Eron Joseph J , Fischl Margaret A , Long Mary C , Kuritzkes Daniel R , Sommadossi Jean-Pierre
Published: April 2022

Background

Intracellular nucleoside reverse transcriptase inhibitor triphosphate (NRTI-TP) concentrations are crucial in suppressing HIV replication. Little is known about how commonly used dual-NRTI regimens affect the intracellular levels of NRTI-TPs, the active form of these drugs. This study investigates the effect of dual-NRTI therapy in intracellular NRTI-TP levels.

Methods

NRTI and NRTI-TP concentrations were evaluated in HIV-infected patients receiving either lamivudine (3TC) and stavudine (d4T) or lamivudine with zidovudine (ZDV); NRTI and NRTI-TP concentrations were determined using a validated HPLC/MS/MS method. Plasma HIV-1 RNA levels were determined at baseline and monthly to examine the relationship between NRTI-TP concentrations and plasma HIV-1 RNA.

Results

Forty-one subjects completed the study. 3TC-TP significantly increased between day 1 and week 28 from 1.48 to 5.00 pmol/106 peripheral blood mononuclear cells (PBMC; P<0.0001). NRTI-TP concentrations for d4T and ZDV did not significantly increase, with values at week 28 of 0.011 and 0.02 pmol/106 PBMC, respectively. Mean NRTI-TP/plasma ratios were 3%, 0.007% and 0.05% for 3TC, d4T and ZDV, respectively. Linear relationships were observed between ZDV- and 3TC-TP and changes in plasma HIV-1 RNA.

Conclusion

Of the three drugs studied, only 3TC-TP levels increased significantly between day 1 and week 28. ZDV-TP and 3TC-TP levels were unaffected by dual-NRTI therapy relative to monotherapy, regardless of the combination (3TC-ZDV or 3TC-d4T). Intracellular levels of d4T-TP were similar to previous reports for dual-NRTI therapy; however, in the case of d4T, these values appear lower than those achieved with d4T monotherapy.
The association of bone mineral density with HIV infection and antiretroviral treatment in women
Authors: Anastos Kathryn , Lu Dalian , Shi Qiuhu , Mulligan Kathleen , Tien Phyllis C , Freeman Ruth , Cohen Mardge H , Justman Jessica , Hessol Nancy A
Published: April 2022

Background

Low bone mineral density (BMD) has been reported in HIV-infected women and men.

Methods

We analysed cross-sectional BMD measured by regional dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN) in 152 HIV-negative and 274 HIV-positive (HIV+) women, adjusted for traditional low BMD risk factors.

Results

BMD was significantly lower in protease inhibitor (PI) users than in all other groups, and highest in HIV-negative women. In multivariate analyses the prevalence of T-score <-1.0 was significantly higher in the HIV+ women naive to antiretroviral therapy (ART; odds ratio [OR] 4.36, 95% confidence interval [CI] 1.61, 11.8) and the women receiving PI-containing HAART (OR 3.72, CI 1.43, 9.68), with a non-significant difference in non-PI HAART users (OR 2.43, CI 0.92, 6.45), compared with HIV-negative women. In pair-wise adjusted comparisons, BMD was lower in ART-naive than in HIV-negative women (1.22 versus 1.30 g/cm2 at LS; P=0.004), in PI compared with non-PI HAART users (1.00 versus 1.05 g/cm2 at FN; P=0.014) and with those ART-naive (1.00 versus 1.03 g/cm2 at FN; P=0.146). Potential confounders, including duration of ART, prior treatment regimens and traditional risk factors for low BMD did not explain these differences. Longer lopinavir use was significantly correlated with lower BMD (r2=-0.39, P=0.024 and r2=-0.46, P=0.006 at LS and FN, respectively) and longer efavirenz use with higher BMD (r2=+0.32, P=0.004 at FN).

Conclusions

HIV infection was associated with lower BMD in women, independent of the traditional risk factors for low BMD. PI-containing HAART compared with non-PI-containing HAART, and longer lopinavir use, were both associated with lower BMD, and efavirenz use was associated with higher BMD.
Risk Factors for Acute Liver Enzyme Abnormalities in HIV-Hepatitis B Virus-Coinfected Patients on Antiretroviral Therapy
Authors: Chauvel Olivia , Lacombe Karine , Bonnard Philippe , Lascoux-Combe Caroline , Molina Jean-Michel , Miailhes Patrick , Girard Pierre-Marie , Carrat Fabrice
Published: April 2022

Background

Little is known about the prognostic factors of acute liver enzyme variations in HIV-hepatitis B virus (HBV)-coinfected patients.

Objectives

To identify prognostic factors of acute liver enzyme abnormalities in HIV-HBV-coinfected patients with a focus on the putative role of antiretroviral drugs.

Design

Data from a 3-year, prospective, multicentre cohort study involving HIV-HBV patients were used.

Methods

A Markov model was used to identify prognostic factors of acute episodes of cytolysis and cholestasis in 300 HIV-HBV-coinfected patients. The effect of antiretroviral therapy was analysed according to the classes of drugs, duration of treatment and treatment modifications.

Results

The incidence rates of acute episodes of cytolysis and cholestasis were 13.4 per 100 patient-years (95% confidence interval [CI] 9.5–17.3) and 7.1 per 100 patient-years (95% CI 4.2–10.0), respectively (median follow up 34.1 months). Independent risk factors for cytolysis were a high level of HBV or HIV replication, as well as a low of CD4+ T-cell count. No antiretroviral drug was associated with cytolysis, whereas protease inhibitors seemed to be independently associated with cholestasis, along with treatment modifications and the duration of HIV infection.

Conclusion

Acute and reversible episodes of cytolysis or cholestasis were common and associated with virus- and host-related determinants. The choice of the optimal antiretroviral combination in HIV-HBV-coinfected patients must take into account the necessity of exerting an efficient control of HIV and HBV replication (associated with transient cytolysis) and the risk of inducing cholestasis (associated with the use of protease inhibitors and treatment modifications).
Lack of Rapid Virological Response Predicts Interferon-α2b/Ribavirin Therapy failure in HCV Genotype 2 Patients: A Single-Centre Study
Authors: Rumi Maria Grazia , Aghemo Alessio , D'Ambrosio Roberta , Ronchi Guido , Ninno Ersilio Del , Gallus Silvano , Colombo Massimo
Published: April 2022

Background

A minority of patients with HCV-2 chronic hepatitis does not attain a sustained virological response to interferon-based therapies. Registration trials have failed to identify the real proportion of HCV-2 non-responders, and predictors of non-response. The analysis of ‘real-life’ HCV-2 patients might help define the effectiveness of anti-HCV therapy and the role of response moderators.

Methods

A re-analysis of all treatment-naive HCV-2 patients who consecutively received weight-dosed ribavirin with either 3 MU three times a week standard interferon-α2b or 1.5 μg/kg/week pegylated interferon-α2b.

Results

The 94 interferon-treated patients and the 136 pegylated-interferon-treated patients were comparable for demography, prevalence of cirrhosis (25%) and adherence to therapy (74%). By intention-to-treat analysis, the overall sustained virological response rate was 80% (82% interferon versus 78% pegylated interferon). Overall, sustained virological rates were 83% for the 182 patients who cleared HCV RNA at week 4 (rapid virological response) and 52% for the 48 who did not ( P<0.001). The corresponding week 12 figures of HCV RNA clearance were 90% and 32%, respectively ( P<0.001). Sustained response was independent of gender, age, body mass index, modality of infection, duration and severity of liver disease, adherence to therapy and interferon type. After stratification for interferon type, the only treatment failure predictor was persistence of HCV RNA at week 4 and 12.

Conclusions

Despite the prevalence of moderators of treatment outcome, HCV-2 patients showed as high sustained virological response rates as those reported in registration trials for HCV-2 and HCV-3 pooled patients; pegylated interferon therapy failure was predicted by lack of rapid virological response.
External Quality Assessment of HLA-B*5701 Reporting: An International Multicentre Survey
Authors: Hammond Emma , Almeida Coral-Ann , Mamotte Cyril , Nolan David , Phillips Elizabeth , Schollaardt Tineke Asma , Gill M John , Angel Jonathan B , Neurath Doris , Li Jianping , Giulivi Tony , McIntyre Cathy , Koultchitski Galina , Wong Betty , Reis Marciano , Rachlis Anita , Cole David E , Chew Choo Beng , Neifer Stefan , Lalonde Richard , Roger Michel , Jeanneau Annie , Mallal Simon
Published: April 2022

Objectives

HLA-B*5701 strongly predicts abacavir hypersensitivity (HSR), but implementation of effective routine screening into clinical practice requires testing be practical and accurate. We tested the proficiency of HLA-B*5701 typing among laboratories using sequence-specific primer PCR.

Design and methods

DNA panels (1 and 2) were distributed to seven laboratories (A to G) for blinded typing of the HLA-B*5701 allele. Panel 1 ( n=10 samples; n=7 laboratories) included 3 positives and other closely related B17 subtypes (B*5702, B*5703, B*5704 and B*5801). Panel 2 ( n=96 samples; n=4 laboratories) included 36 positives among a broad spectrum of other B alleles. Two laboratories (A and B) also submitted 96 routine samples, typed by the same methodology, to the reference centre for additional analysis by sequence-based typing.

Results

All laboratories correctly typed panel 1 for HLA-B*5701 carriage. Laboratories A, B and C identified HLA-B*5701 alleles in panel 2 with 100% sensitivity and 100% specificity. Laboratory D reported one false negative, reportedly due to a sampling error. The results obtained for routine samples typed by laboratories A and B and those generated by the reference laboratory using sequencing were fully concordant.

Conclusions

Detection of HLA-B*5701 alleles among laboratories was 100% specific and 99.4% sensitive, indicating that participating HIV testing laboratories were currently offering effective primary screening to identify individuals at high risk of abacavir HSR. Accurate reporting of HLA-B*5701 status is critical for the safe administration of this drug and participation in quality assurance programmes by all sites who report HLA-B*5701 status should be promoted.