bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobile phones and the experience of time: New perspectives from a deprivation study of teenagers
Authors: Rosenberg Hananel , Blondheim Menahem , Sabag-Ben Porat Chen
Published: April 2022

A number of studies have sought to understand how mobile phones affect time practices, and beyond them, the experience of time in users’ daily lives. This article is a further effort in that direction, employing the deprivation study method. We conducted a field study of 80 adolescents, or “cellular natives,” separating them from their cellphones for 1 week. The findings indicate that the cellphone’s absence indeed had a dominant impact on a variety of adolescents’ time-related practices and experience, that yielded in turn both negative and positive feelings. We propose three main axes for understanding the cellphone’s implications for the time experience: The mobile’s flexible time v. Rigid time, its ritual time v. Linear time, and its fragmented time v. Continuous time. In all these dimensions, we point to distinct features of the time experience associated with the mobile phone, and also try to relate it to the emotional state and state of mind of today’s teens. In conclusion, we propose that a broad understanding of the cellphone’s role need to include the aspect of time, at least as it is experienced by adolescents in our current media climate.
Chronic Deciduitis With Plasma Cells: A Quantitative and Clinicopathological Analysis Concerning Different Trimesters
Authors: Feist Henning , Schaumann Nora , Bajwa Simin , Hager Thomas , von Kaisenberg Constantin , Pecks Ulrich
Published: April 2022

Background: Chronic deciduitis is a chronic inflammatory placental disease. It is associated with severe perinatal complications, especially recurrent miscarriage, preterm birth, preterm labor, and preterm prelabor rupture of membranes.

Methods: This study presents a detailed quantification of plasma cells and lymphocytes, and regards clinicopathological associations concerning different trimesters in 99 cases displaying chronic deciduitis with plasma cells (CD), 23 cases from the second trimester and 76 cases from the third trimester, respectively. The control group without CD consisted of matched placentas concerning the gestational weeks.

Results: In every instance lymphocytes were more numerous than plasma cells. The mean value/highest score in ten high power fields were 50/321 for plasma cells, and 460/995 for lymphocytes, respectively. In the second trimester the scores for plasma cells were significantly higher than in the third trimester. In the third trimester preterm labor occurred significantly more often in cases with chronic deciduitis related to the control group ( P < .05).

Conclusion: In chronic deciduitis the plasma cell count is usually higher in the second compared to the third trimester. A brisk infiltration of the decidua with plasma cells could probably point to a more severe clinical manifestation and a higher risk for preterm labor and preterm birth.
Artificial Emotions and Love and Sex Doll Service Workers
Authors: Belk Russell
Published: April 2022

Realistic looking humanoid love and sex dolls have been available on a somewhat secretive basis for at least three decades. But today the industry has gone mainstream with North American, European, and Asian producers using mass customization and competing on the bases of features, realism, price, and depth of product lines. As a result, realistic life size artificial companions are becoming more affordable to purchase and more feasible to patronize on a service basis. Sexual relations may be without equal when it comes to emotional intimacy. Yet, the increasingly vocal and interactive robotic versions of these dolls, feel nothing. They may nevertheless induce emotions in users that potentially surpass the pleasure of human-human sexual experiences. The most technologically advanced love and sex robots are forecast to sense human emotions and gear their performances of empathy, conversation, and sexual activity accordingly. I offer a model of how this might be done to provide a better service experience. I compare the nature of resulting “artificial emotions” by robots to natural emotions by humans. I explore the ethical issues entailed in offering love and sex robot services with artificial emotions and offer a conclusion and recommendations for service management and for further research.
Persisting Long-Term Benefit of Genotype-Guided Treatment for HIV-Infected Patients Failing Haart. The Viradapt Study: Week 48 Follow-Up
Authors: Clevenbergh P , Durant J , Halfon P , del Giudice P , Mondain V , Montagne N , Schapiro JM , Boucher CAB , Dellamonica P
Published: April 2022

Objective

We report the 12 months follow-up of the patients who participated in the Viradapt study.

Methods

A total of 108 HIV-infected patients failing antiretroviral (ARV) therapy (HIV RNA >10000 copies/ml, therapy >6 months with nucleoside reverse transcriptase inhibitors, >3 months with protease inhibitors (PIs) were randomized into two arms: standard of care in the control arm, and treatment according to the resistance mutations in the protease and reverse transcriptase genes in the study arm. After the first 6 months of the randomized study, open-label, genotype-guided treatment was offered in both arms. A multivariate analysis was performed to assess the predictive factors of treatment success (HIV RNA <200 copies/ml).

Results

The two arms were comparable in terms of risk factors, age, sex, previous treatments, CD4 cell count and log10 HIV-1 RNA at baseline. At week 24, an interim combined analysis showed a statistically significant difference in the drop in viral load at months 3 and 6 ( P=0.015, repeated measures analysis of variance) in favour of the genotype group. Patients in both arms were then offered open-label genotyping. Genotype analysis was performed every 3 months, and treatment changes could accordingly be made. As some of the patients in the control arm had already progressed to months 9 or 12, only 69% (30/43) of these patients received genotype-guided treatment changes. In the genotype arm, the mean drop in HIV RNA of 1.15 log10 copies/ml, obtained at month 6, persisted at months 9 and 12 (1.15 log10 copies/ml ±0.17). In the control arm, an additional drop in HIV RNA to 0.98 log10 ±0.22 copies/ml was observed by month 12. In control patients receiving open-label genotype, the percentage of patients with HIV-1 RNA levels below detection limit (200 copies/ml) rose from 14% at month 6 to 30.5% at month 12. This percentage in the study arm remained stable at 31.3% and 30% at months 9 and 12, respectively. Genotype-guided therapy, primary protease mutations and PI plasma concentrations were significantly correlated with virological success.

Conclusions

In this heavily pretreated patient population, genotype-guided therapy resulted in a sustained reduction in HIV RNA of greater than one log10 throughout a 1 year follow-up period. Performance of genotype-guided therapy may have contributed to the additional viral load reduction seen in patients in the control group who received open-label genotyping after the 6 month point. Multivariate analysis showed that the presence of primary protease mutations, performance of genotype-guided treatment changes and PI plasma concentrations independently affected virological response.
Hepatitis C Virus Kinetics
Authors: Herrmann Eva , Neumann Avidan U , Schmidt Jürgen M , Zeuzem Stefan
Published: April 2022

The balance of virus production and clearance for untreated patients with chronic hepatitis C virus (HCV) results in a decline of viraemia when initiating active antiviral treatment. During the first phase of interferon-α therapy, after a delay of about 8–9 h, the kinetics of the viral load is characterized by a rapid dose-dependent decline. This early response can be observed for almost all patients treated with interferon-α. After about 24–48 h, the viral decline enters a second phase of relatively slow exponential decay during the following weeks of therapy. Non-responding patients, however, show constant viraemia or even a rebound during this second phase. The rate of the exponential decline of the viral load in responding patients in this second phase is less sensitive to the dose of interferon-α and varies considerably among patients. Furthermore, combination therapy with interferon-α plus ribavirin does not significantly improve the initial viral decay, although it may prevent more patients from rebounding. Mathematical modelling of viral dynamics reveals high turnover rates of pre-treatment viral production and clearance, and permits the estimation of in vivo half-lives of a few hours for free HCV virions and of 1–70 days for productively infected cells. Infected cell death rate, which determines the second phase decline slope, is predictive of response to treatment. Current models indicate that the early biphasic viral decline is explained if interferon-α partially blocks virion production from infected cells, yet they do not rule out additional antiviral or immunological effects. Therapeutic implications are the advisability of use of frequent (daily) and comparatively high initial doses. In conclusion, kinetic analysis of the viral decay during the first weeks of treatment permits the prediction of response at the end-of-therapy and might help to evaluate new drugs and to optimize therapy.
Enhanced Antiviral Benefit of Combination Therapy with Lamivudine and Alpha Interferon against WHV Replication in Chronic Carrier Woodchucks
Authors: Korba Brent E , Cote Paul , Hornbuckle William , Schinazi Raymond , Gangemi J David , Tennant Bud C , Gerin John L
Published: April 2022

Cell culture studies in our laboratory previously demonstrated synergistic antiviral activity for the combinations of lamivudine and a novel recombinant hybrid human alpha B/D interferon (rHuαB/D IFN) against hepatitis B virus (HBV) replication. Based on these results, a study was designed to determine if an enhanced antiviral effect with this drug combination could be demonstrated in vivo using the woodchuck hepatitis virus (WHV)/woodchuck experimental model of chronic HBV infection. Both antiviral agents have been shown to be effective against WHV replication in WHV chronic carriers during previous studies by our laboratories. Two combination treatment regimens were compared to matched monotherapies in a placebo-controlled trial. The first used simultaneous administration of rHuαB/D IFN and lamivudine for 24 weeks. The other combination treatment regimen used a staggered dosing schedule of 12 weeks of administration of lamivudine alone, followed by 12 weeks of simultaneous dosing with both drugs, followed by 12 weeks of therapy with rHuαB/D IFN alone. Both treatment regimens with combinations of lamivudine and rHuαB/D IFN were more effective at reducing WHV replication in chronically infected wood-chucks than the corresponding monotherapies. Both combination treatments produced antiviral effects that were at least equal to that expected for additive activity based on estimations generated by Bliss Independence calculations. The staggered treatment regimen reduced viraemia and intrahepatic WHV replication significantly more than that expected for additive interactions, indicating synergistic antiviral effects. These studies demonstrate that combination therapy of chronic WHV infection has enhanced antiviral benefit over corresponding monotherapies and indicate that combination treatment of chronic HBV infection can be superior to therapies using a single antiviral agent.
Virological Failure among Patients on Haart from across Europe: Results from the Eurosida Study
Authors: Mocroft A , Miller V , Chiesi A , Blaxhult A , Katlama C , Clotet B , Barton S , Lundgren Jens D
Published: April 2022

Objectives

To monitor the response to highly active anti-retroviral therapy (HAART) over time and the proportions of patients with poor virological control in order to help provide some insight into drug resistance.

Design

Analysis of data from the EuroSIDA study; an observational study initiated in 1994 of almost 8500 patients with HIV from across Europe.

Methods

Patients who initiated HAART, and had both a CD4 lymphocyte count and viral load measured in the 3 months prior to starting HAART, were included in analyses. The proportion of patients with a poor virological response (defined as a viral load of >10 000 copies/ml, using either a single measure or two consecutive measures) at 16 and 48 weeks was determined. Multivariate logistical regression was used to determine the factors associated with a poor virological response at both time points.

Results

Median CD4 cell count at starting HAART was 218 cells/mm3 [interquartile range (IQR), 113–327 cells/mm3] and median viral load was 4.36 log10 copies/ml (IQR, 3.57–5.04 log10 copies/ml). At 16 weeks, 16% had a viral load of >10 000 copies/ml based on a single viral load measure and 10% if the more stringent definition of two consecutive viral loads above this level was used. At 48 weeks these proportions were 19% and 13%, respectively. Compared with patients from Southern Europe, patients from both Central and Northern Europe had approximately half the chance of a poor virological response at 16 weeks (odds ratios 0.53 and 0.47, P=0.0015 and P<0.0001, respectively), while at 48 weeks both regions still had approximately a 25% reduced chance of a poor virological response, but this was no longer statistically significant (odds ratio 0.77 and 0.75, P=0.17 and P=0.13, respectively).

Conclusions

There were marked differences in virological response to HAART across regions of Europe, which may be partly explained by regional differences in access to HAART and utilisation. If drug resistance is closely related to virological failure, these results may help to provide an early insight into the potential problem of drug resistance across Europe. Continued follow-up is essential to monitor patients with poor virological control.
Cellular Factors for Resistance against Antiretroviral Agents
Authors: Fridland Arnold , Connelly Michele C , Robbins Brian L
Published: April 2022

Substantial advancements have been made in our understanding of the complex replication cycle of, and immunopathology associated with HIV infection as well as the drugs used to treat the disease. The nucleoside reverse transcriptase inhibitors remain the cornerstones of current antiviral treatment modalities. Unfortunately, their long-term use often leads to adverse reactions and the emergence of virus mutants with decreased susceptibility to therapeutic agents. In addition to viral resistance, prolonged antiviral treatment may affect metabolic changes in the host cells that can diminish the efficacy of the treatment. Thus, both viral and cellular resistance mechanisms must be considered in the context of failing antiviral chemotherapy. This review article concerns the intracellular pharmacology of antiviral nucleoside analogues in human lymphoid cells and the possible impact of a newly identified nucleotide transporter on drug resistance.
Effectiveness and Pitfalls of Initial Highly Active Antiretroviral Therapy in HIV-Infected Patients in Routine Clinical Practice
Authors: Moreno Ana , Perez-Elías María J , Casado Jose L , Muñoz Vicente , Antela Antonio , Dronda Fernando , Navas Enrique , Fortún Jesús , Quereda Carmen , Moreno Santiago
Published: April 2022

Objective

To assess the long-term effectiveness of and factors associated with response to protease inhibitors (PIs) in a cohort of treatment-naive HIV-infected patients.

Design and setting

Prospective study in a tertiary care centre.

Subjects

A total of 207 treatment-naive patients starting PIs from March 1996 to May 1998. Main outcome measures: Clinical, virological and immunological outcomes, and adherence to therapy after 12 months.

Results

Baseline median CD4 cell count and viral load were 160 cells/mm3 and 5 log10 copies/ml, respectively. After 48 weeks, 168 patients (81%) reached plasma HIV-RNA levels below 400 copies/ml, and the mean increase in CD4 cell count was 196 cells/mm3. Clinical events were observed in 29 patients (14%) after a median time of 100 days on therapy, yet mortality was extremely low (0.9%). By multivariate analysis, adherence over 90% [relative risk (RR), 16.66; 95% confidence interval (CI), 5.26–50; P=0.00001] and AIDS diagnosis at baseline (RR 0.35; 95% CI, 0.14–0.90; P=0.02) were the strongest predictors for virological suppression. An immunological recovery over 100 cells/mm3 was significantly associated with an initial virological response (RR 2.94; 95% CI, 1.31–6.66; P=0.009) and adherence over 90% (RR 3.44; 95% CI, 1.61–7.69; P=0.005). There were high rates of change with the first PI (40%), mostly due to adverse events (51%), but it did not compromise long-term effectiveness. Conclusions: Initial PI treatment in the clinical setting is able to reach equally good outcomes as those found in controlled trials. Changes in therapy due to toxicity do not compromise a successful outcome, which clearly depends on an adequate adherence to therapy.
Predictors of Virological Response in HIV-Infected Patients to Salvage Antiretroviral Therapy that Includes Nelfinavir
Authors: Walmsley Sharon L , Becker Mark I , Zhang Min , Humar Atul , Harrigan P Richard
Published: April 2022

Different salvage strategies have been used to regain control in patients with HIV who have virological failure on combination antiretroviral therapy. We conducted a cohort study of 63 extensively antiretroviral pretreated patients who initiated nelfinavir as part of salvage therapy, to determine predictors of virological response. The maximum HIV RNA response was >0.5 log10 copies/ml reduction in 43 patients (68%), including 21 patients (33%) who had suppression to <500 copies/ml. Corresponding response rates at 24 weeks were 41 and 19%, respectively. Responders and non-responders could not be distinguished by mean baseline HIV RNA or CD4 cell count, duration of prior protease inhibitor (PI) use, introduction of an initial non-nucleoside reverse transcriptase inhibitor or the number of antiretroviral agents changed when nelfinavir was added, likely reflecting the homogeneity of the population studied. The only parameter predictive of response was virus genotype. Response rates were lower in patients with increasing numbers of primary ( P=0.045) or secondary ( P=0.001) PI mutations. The addition of increasing numbers of reverse transcriptase mutations further impaired response rates ( P=0.004).
Durable HIV-1 Suppression with Indinavir after Failing Lamivudine-Containing Double Nucleoside Therapy: A Randomized Controlled Trial
Authors: Foudraine Norbert A , Jurriaans Suzanne , Weverling Gerrit Jan , Burger David M , Hoetelmans Richard MW , Roos Marijke TL , Maas Jaap , Miedema Frank , Reiss Peter , Portegies Peter , de Wolf Frank , Lange Joep MA
Published: April 2022

Objective

To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48.

Design

In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count ≥200 cells/μl and a plasma HIV-1 RNA level ≥10000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml).

Results

Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/μl, with 150 cells/μl in the zidovudine/lamivudine arm, and from 290 cells/μl, with 310 cells/μl in the stavudine/lamivudine arm ( P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level <50 copies/ml at week 12 and 48, respectively. The CSF indinavir concentration ranged from 50 to 170 ng/ml.

Conclusion

The long-term HIV-1 suppression observed in this study is remarkable, as adding a single antiretroviral agent to a failing regimen goes against current notions of adequate therapy.
Resistance Profiles to Antiretroviral Drugs in HIV-1 Drug-Naive Patients in Argentina
Authors: Kijak Gustavo H , Pampuro Sandra E , Avila María M , Zala Carlos , Cahn Pedro , Wainberg Mark A , Salomón Horacio
Published: April 2022

The drug resistance profile of treatment-naive HIV-infected individuals living in Buenos Aires, Argentina, was studied. Samples taken from 94 drug-naive individuals with established HIV infection and 13 patients with primary HIV infection were assessed by nucleotide sequencing and LiPA. The prevalence of drug-associated primary mutations in individuals with established infection was very low. In the viral protease region, 1/86 (1.2%) individuals carried the D30N mutation, whereas 1/85 (1.2%) had the M41L mutation in the reverse transcriptase (RT) region. Secondary mutations in both the protease and RT regions were found in almost 90% of the individuals. In individuals with primary infection, primary mutations were detected in 2/13 (15.4%) patients, one of them carrying M46I mutation in the protease while the other patient had a mutation at codon 184 of the RT. In accordance with current drug resistance testing guidelines, the results of this study suggest that susceptibility tests need not be performed at this time prior to initiation of antiretroviral therapy in HIV-1-infected people in Argentina. However, the public health implications of this subject warrant follow-up studies that will examine a larger number of drug-naive patients, not only in Buenos Aires but also in other major Argentinian cities and in rural areas.
Increased Drug Susceptibility of HIV-1 Reverse Transcriptase Mutants Containing M184V and Zidovudine-Associated Mutations: Analysis of Enzyme Processivity, Chain-Terminator Removal and Viral Replication
Authors: Naeger Lisa K , Margot Nicolas A , Miller Michael D
Published: April 2022

The presence of the HIV reverse transcriptase (RT) resistance mutation, M184V, induced by lamivudine and abacavir treatment results in increased tenofovir, adefovir and zidovudine susceptibility for HIV-1 with zidovudine-associated RT mutations in vitro. Treatment with oral prodrugs of tenofovir and adefovir has resulted in substantial HIV-1 RNA reductions in antiretroviral-experienced patient populations who have lamivudine-and zidovudine-resistant HIV-1. An enzymatic analysis was undertaken to elucidate the mechanisms of altered drug susceptibilities of HIV-1 containing zidovudine-associated mutations in the presence or absence of M184V. The inhibition constants (Ki) for the active metabolites of tenofovir, adefovir and zidovudine did not vary significantly between recombinant mutant and wild-type RT enzymes. Although increased removal of chain-terminating inhibitors by pyrophosphorolysis and ATP-dependent unblocking correlated with reduced susceptibility of viruses with zidovudine-associated mutations, a reduction in the removal of chain-terminators was not observed, which would explain the increased drug susceptibility of mutants containing M184V plus zidovudine-associated mutations. However, analyses of single-cycle processivity of the mutant RT enzymes on heteropolymeric RNA templates showed that all M184V-containing mutant RT enzymes were less processive than wild-type RT, most notably for mutants expressing both zidovudine-associated mutations and M184V. Similarly, the in vitro replication capacity of a mutant virus expressing a zidovudine-associated mutation and M184V was significantly reduced compared with wild-type virus. The observed decrease in enzymatic processivity of the M184V-expressing RT enzymes might result in decreased viral replication, which then might contribute to the increased drug susceptibility of HIV-1 expressing these RT mutations.
HIV-1 Reverse Transcriptase Mutations Found in a Drug-Experienced Patient Confer Reduced Susceptibility to Multiple Nucleoside Reverse Transcriptase Inhibitors
Authors: Fitzgibbon Joseph E , DiCola May B , Arnold Edward , Das Kalyan , Sha Beverly E , Pottage John C , Nahass Ronald , Gaur Sunanda , John Joseph F
Published: April 2022

HIV-1 reverse transcriptase (RT) genotypes were obtained from 13 patients treated with stavudine. No previously-reported mutations indicative of stavudine resistance were found in these patients and no novel mutations occurred in more than two patients. One patient, treated with stavudine for 1 month and treated previously with zidovudine, zalcitabine and lamivudine, carried a mutation at codon 75 of the RT (V75M). A chimeric virus, including the patient's RT sequence from codon 25 to codon 220, which carried the resistance mutations M41L, D67N, T69D, K70R, L210W and T215Y in addition to V75M, displayed reduced susceptibility to multiple nucleoside RT inhibitors (NRTIs). Removal of V75M from this RT background resulted in a return of susceptibility to didanosine and lamivudine. Our data are in agreement with previous studies demonstrating the rarity of stavudine resistance mutations in stavudine-treated patients. However, we describe a new set of mutations, found in the RT of a heavily-treated patient, that can confer reduced susceptibility to multiple NRTIs. These results underscore the importance of increased vigilance for possible multiple-drug resistance in patients who have been heavily treated with NRTIs.
Observations of HIV-1 Genotypic Drug Resistance in a Trial of Four Reverse Transcriptase Inhibitors (Quattro Trial)
Authors:   QUATTRO Steering Committee, Kaye S , Dunn DT , Babiker AG , Darbyshire JH , Hooker MH , Nesarantnam S , Newberry A , Weber J , Breckenridge A , Babiker A , Back D , Blatchford N , Darbyshire JH , Gazzard B , Gartland M , Hooker M , Jeffries D , Johnson M , Plummer K , Wills B , Kitchen V , Loveday C , Tedder R , Weber J , Weller IVD , Withnall R
Published: April 2022

The Quattro Trial compared the use of four HIV-1 reverse transcriptase (RT) inhibitors (zidovudine, lamivudine, loviride and zalcitabine), given either as four-drug combination therapy or monotherapy, with 8-week cycles of each drug, with zidovudine/lamivudine dual therapy. Observations of resistance associated and other mutations in the RT gene were made to determine whether therapy failure could be explained by acquisition of these mutations and whether novel mutation patterns developed. As in the intent-to-treat analysis, the use of cyclical monotherapy gave a smaller reduction in plasma virus load at 64 weeks (0.4 log10 copies/ml below baseline) than the quadruple or dual therapy arms (1.3 and 0.8 log10 copies/ml below baseline). Cyclical therapy appeared to generate less genotypic resistance to zidovudine, loviride or zalcitabine than the other arms. Resistance to lamivudine (mutation M184V) developed rapidly in all three arms. Resistance to zidovudine was acquired by a larger proportion of subjects on dual therapy than on quadruple therapy. Resistance to loviride or zalcitabine was rarely observed. During lamivudine monotherapy the M184V mutation was rapidly acquired and viral load rebounded. Zalcitabine monotherapy initially selected M184V mutants, but these were lost as therapy continued. Novel mutations that may have been associated with combination or cyclical quadruple therapy were observed infrequently. There was no clear correlation between changes in response to therapy and the development of previously described resistance mutations or with novel mutations in the RT gene.
Selection of a T-Cell Line Resistant to Stavudine and Zidovudine by Prolonged Treatment with Stavudine
Authors: Turriziani Ombretta , Scagnolari Carolina , Bambacioni Federica , Bellomi Francesca , Focher Federico , Gentile Massimo , Antonelli Guido
Published: April 2022

It has been demonstrated that prolonged treatment with nucleoside analogues, such as 3′-azido-3′-deoxythymi-dine (zidovudine), 2’,3′-dideoxycytidine (zalcitabine) and 9-(2-phosphonylmethoxyethyl) adenine (PMEA), may cause selection of cells that are resistant to their anti-HIV activity. A human T-lymphoblastoid cell line that is resistant to the antiviral and cytotoxic activity of 2’,3′-didehydro-3′-deoxythymidine (stavudine) has developed as a result of prolonged treatment. These cells, called CEMstavudine, are also less sensitive to zidovudine. The cellular/pharmacological resistance acquired by the CEMstavudine cells is relatively low and appears to correlate with a reduction in thymidine kinase (TK) activity, rather than with a decreased expression of TK mRNA.
Evaluation of the Risk Factors Associated with Lipodystrophy Development in a Cohort of HIV-Positive Patients
Authors: Seminari Elena , Tinelli Carmine , Minoli Lorenzo , Sacchi Paolo , Filice Gaetano , Zocchetti Cristina , Meneghetti Grazia , Bruno Raffaele , Maserati Renato
Published: April 2022

The prevalence of lipodystrophy in an HIV-infected population and the risk factors associated with body shape changes were analysed in this study. Five hundred and four subjects were included. Among these, 201 (39.9%) had features of lipodystrophy syndrome (cases); 303 (60.1%) constituted the control group. Compared with the control group, the lipodystrophy subjects were different in age ( P=0.01); duration of antiretroviral therapy ( P<0.001); length of exposure to nucleoside reverse transcriptase inhibitors (NRTIs) ( P<0.001) and to protease inhibitors ( P<0.001); nadir of CD4 cell count ( P<0.001); and value of plasma HIV-RNA before anti-retroviral therapy ( P=0.008). In a multivariate analysis, length of therapy and a nadir CD4 cell count below 250 cell/μl were associated with an increased risk of lipodystrophy. Among patients with lipodystrophy, isolated fat loss was observed in 46 (23%); isolated fat accumulation in 40 (20%); mixed (loss and accumulation) syndrome in 50 (25%); and isolated metabolic changes in 65 (32%). Subjects with morphological alterations displayed a greater cumulative time of exposure to NRTIs and to protease inhibitors than patients with isolated metabolic alterations. Patients with lipoatrophy had had a greater exposure to stavudine.
Genotypic and Phenotypic Resistance Patterns in Early-Stage HIV-1-Infected Patients Failing Initial Therapy with Stavudine, Didanosine and Nevirapine
Authors: Vidal Carme , Arnedo Mireia , Garcia Felipe , Mestre Gabriel , Plana Montserrat , Cruceta Anna , Capon Alicia , Gallart Teresa , Miro José M , Pumarola Tomas , Gatell José M
Published: April 2022

The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine, stavudine and nevirapine. These patterns of resistance were determined at baseline and at time of virological failure in 89 antiretroviral-naive patients with CD4 cells >500 cells/ml and viral load >5000 copies/ml who received initial antiretroviral therapy with didanosine plus stavudine and nevirapine as part of the SCAN study, and who failed after having reached undetectable plasma levels (<200 copies/ml). Of the 89 patients recruited in the SCAN study, 14 (16%) developed a virological failure after reaching a viral load below 200 copies/ml after a median of 20 months of follow-up. At baseline, none of these 14 patients had genotypic resistance. At time of failure, six out of 14 (43%) failing patients had wild-type genotype and no phenotypic resistance. Suboptimal compliance could be documented in four of these six patients. Seven patients (50%) had nevirapine resistance mutations (mainly K103N [4/7], Y181C/I [2/7], G190A/S [2/7] and V108I [1/7]) associated with phenotypic high-level resistance to nevirapine, delavirdine and efavirenz (nevirapine >47.4-to 58.1-fold, delavirdine >74.4- to 168.9-fold and efavirenz >56.0- to 347.2-fold). Four of these seven patients also had thymidine analogue-associated mutations (TAM) (T215Y/F [2/4], M41L [1/4], D67N [2/4] and K70R [1/4]). Finally, one patient (7%) had exclusively TAM mutations (M41L). None of the patients developed mutations associated with didanosine resistance or phenotypic resistance to didanosine or stavudine. Suboptimal compliance or selection of nevirapine resistance often with TAM mutations was frequently associated with virological failure in a cohort of early-stage chronic HIV-1-infected patients treated with a protease inhibitor-sparing regimen.
Using a Database of HIV Patients Undergoing Genotypic Resistance Test after Haart Failure to Understand the Dynamics of M184V Mutation
Authors: Zaccarelli Mauro , Perno Carlo Federico , Forbici Federica , Cingolani Antonella , Liuzzi Guiseppina , Bertoli Ada , Trotta Maria Paola , Bellocchi Maria Concetta , Di Giambenedetto Simona , Tozzi Valerio , Gori Caterina , D'Arrigo Roberta , De Longis Patrizio , Noto Pasquale , Girardi Enrico , De Luca Andrea , Antinori Andrea
Published: April 2022

Objective

M184V/I mutation is associated with high-level phenotypic resistance to lamivudine (3TC). The aim of the present analysis was to correlate the time of appearance/disappearance of M184V/I with duration of 3TC treatment.

Methods

Overall, 211 patients were selected from a database of HIV patients undergoing genotypic resistance test after virological failure of HAART regimens in two major reference centres in Rome between 1999 and 2001. At the time of genotyping, 120 of them (56.9%) were failing a 3TC-including HAART, while 91 (43.1%) received 3TC only in previous HAART. Duration of the current 3TC-containing regimen and the time from the end of last 3TC treatment to genotypic resistance test (GRT) were analysed.

Results

Among patients currently undergoing 3TC-containing HAART, the prevalence of M184V/I was 82.5% (78.3/4.2%, respectively) and significantly associated to current 3TC use at GRT. Prevalence of M184V/I was associated to longer history of 3TC (from 47.1% in patients treated with 3TC for <6 months, to 84.0% among those treated for 7–12 months; 100.0% of patients with >42 months of current 3TC carried M184V. At logistic regression analysis, the rate of increase of M184V/I in 3TC-failing patients was statistically significant (OR: 1.066 per month of current 3TC therapy, 95% CI: 1.020–1.114, P<0.01), suggesting a 6.6% monthly increase of probability of M184V/I. Among patients who interrupted 3TC, overall prevalence of M184V/I was 23.1%: proportion of patients carrying the M184V/I dropped from 83.3% among those who interrupted 3TC from ≤3 months, to 56.3, 20, 10.5 and 0% for those interrupting 3TC from 6, 12, 24 and ≥24 months, respectively. At logistic regression, the rate of disappearance of M184V/I was also statistically significant (OR: 0.883 per month, 95% CI: 0.804–0.970, P=0.01), indicating a 11.7% monthly decrease of probability of M184V/I after 3TC interruption.

Conclusions

Dynamics of appearance/disappearance of M184V/I mutation is rapid after 3TC failure/interruption, suggesting ease of development of such a mutation, but also suggesting a remarkable growth disadvantage for HIV. From the clinical perspective, recycling of drugs whose antiviral activity is affected by M184V mutation can be successful after appropriate drug wash-out, also in heavily pretreated patients.
Predictive Factors and Selection of Thymidine Analogue Mutations by Nucleoside Reverse Transcriptase Inhibitors According to Initial Regimen Received
Authors: Flandre Philippe , Descamps Diane , Joly Véronique , Meiffrédy Vincent , Tamalet Catherine , Izopet Jacques , Aboulker Jean-Pierre , Brun-Vézinet Françoise
Published: April 2022

Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219.
ISDR Pattern and Evolution in Patients with Chronic Hepatitis C Treated with Standard Or Peg-Ifn plus Ribavirin
Authors: Cappiello Giuseppina , Abbate Isabella , Iacono Oreste Lo , Longo Roberta , Solmone Mariacarmela , Ferraro Donatella , Antonucci Giorgio , Di Marco Vito , Di Stefano Rosa , Craxì Antonio , Ippolito Giuseppe , Capobianchi Maria Rosaria
Published: April 2022

The aim of the study was to characterize the interferon sensitivity determining region (ISDR) mutation pattern and its changes at 4 weeks of treatment in a population of patients infected with hepatitis C virus (HCV) genotype 1b receiving standard or PEG-IFN plus ribavirin (RBV), to find possible early correlates of therapy outcome.

Forty-five patients with chronic hepatitis due to HCV 1b were treated by PEG-IFN-α2b (n=23) or IFN-α2b (n=22) plus RBV 1000–1200 mg/day. They were classified 24 weeks after stopping therapy as sustained responders (SR), relapsers (REL) or non-responders (NR). Sixteen patients were SR, 12 REL and 17 NR. ISDR mutations were evaluated by direct sequencing at baseline in all and after 4 weeks in patients with detectable viraemia (n=30).

The frequency of the three ISDR types was 26.7% wild-type, 64.4% intermediate-type and 8.9% mutant-type, without significant difference in their frequency in SR, REL and NR, independent of IFN formulation. Average numbers of mutations in SR, REL and NR were 1.88 ±0.54, 1.33 ±0.33 and 0.94 ±0.25, respectively, P>0.05. The baseline number of ISDR mutations was not related to the extent of viral load decline in the first month of therapy. Sequence analysis of ISDR region performed 4 weeks after starting therapy revealed qualitative or quantitative changes of ISDR sequence in only seven patients, without correlation with response.

Thus, in our patients the baseline pattern of ISDR was unrelated to treatment outcome. Selection towards a dominant IFN-resistant strain did not occur under standard or PEG-IFN plus RBV.
Salvage Therapy with Abacavir in HIV-1-Infected Patients with Previously Documented M184V Mutation: A Possibility of Nrti Recycling
Authors: Maggiolo Franco , Callegaro Annapaola , Arici Claudio , Quinzan Giampaolo , Gregis Giampietro , Ripamonti Diego , Tebaldi Alessandra , Goglio Antonio , Suter Fredy
Published: April 2022

We evaluated in an open-label, randomized, controlled, pilot trial if the re-emergence of previously selected resistant strains, harbouring M184V mutation, could be modulated by the use of different drug associations as components of the new antiretroviral regimens. In addition, we assessed the clinical relevance of this mutation on the management of heavily pretreated HIV-infected patients. The primary end-point of the study was the re-selection of M184V mutation. Secondary end-points were the variation over time of HIV RNA plasma levels and CD4 cell counts and the progression of HIV disease. The primary population for efficacy analysis was the intention-to-treat exposed population. After a run-in phase consisting in a new treatment regimen excluding either lamivudine (3TC) or abacavir (ABC) so as to clear the previously documented M184V mutation, 18 patients with an HIV RNA plasma level greater than 10 000 copies/ml were randomized to receive an antiretroviral drug regimen (at least three drugs) including either ABC or the association of ABC+3TC. All patients were naive to ABC. The M184V mutation reappeared in 1/9 patients in the ABC group and in 8/9 patients in the ABC+3TC group (P<0.003, 95% CI: 0.5–1). In the ABC group we observed a rapid decrement of viral load that was maintained throughout all the study period (P<0.05). On the contrary, in the ABC+3TC group, after a transient decrement at 2 months, a progressive increment towards baseline values was observed. The proportion of patients with a viral load reduction of at least 0.5 logs at 12 months was significantly higher in the ABC group: 8/9 patients vs 3/9 (P=0.05, 95% CI: 0.2–0.92). Similarly, from an immunological point-of-view, the increase at all time points (since randomization) in CD4 cell count was statistically significant in the ABC group (P<0.01), while no difference was observed in the ABC+3TC group. The possibility of a successful use of ABC in salvage regimens opens alternative therapeutic options for heavily pretreated patients with previously documented M184V mutation. Further studies should clarify whether this is true for other drugs of the nucleoside analogues class.
Rosiglitazone in the Treatment of Haart-Associated Lipodystrophy – a Randomized Double-Blind Placebo-Controlled Study
Authors: Sutinen Jussi , Häkkinen Anna-Maija , Westerbacka Jukka , Seppälä-Lindroos Anneli , Vehkavaara Satu , Halavaara Juha , Järvinen Asko , Ristola Matti , Yki-Järvinen Hannele
Published: April 2022

Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as insulin resistance and lipodystrophy, that is, atrophy of subcutaneous fat and accumulation of intra-abdominal fat. Currently, there is no pharmacological treatment for lipoatrophy. Glitazones, a novel class of insulin-sensitizing anti-diabetic agents, increase subcutaneous fat in patients with type 2 diabetes. There are no controlled studies of glitazones in patients with HAART-associated lipodystrophy (HAL). In this randomized, double-blind, placebo-controlled study, 30 patients with HAL received either rosiglitazone (8 mg daily) or placebo for 24 weeks. Baseline characteristics were compared to a group of 30 age-, sex- and weight-matched HIV-negative controls. At baseline, patients with HAL had 1.8-fold (P<0.001) more intra-abdominal and 2.4-fold (P<0.05) more liver fat than HIV-negative controls, who had 1.8-fold (P<0.001) more subcutaneous fat than the patients. After 24 weeks of treatment, rosiglitazone had no effect on body weight, subcutaneous or intra-abdominal fat (magnetic resonance imaging), total body fat (bioimpedance analysis), anthropometric measurements or serum leptin concentrations (a circulating marker of adipose tissue mass). However, rosiglitazone decreased % liver fat (spectroscopy) and serum insulin concentrations, and normalized liver function tests. During the first 12 weeks of rosiglitazone treatment, serum triglycerides increased from 3.5 ±0.5 to 6.5 ±2.0 mmol/l (from 310 ±44 to 575 ±177 mg/dl) (P<0.05) and serum cholestrol from 6.0 ±0.4 to 7.8 ±0.7 mmol/l (from 232 ±15 to 301 ±27 mg/dl) (P<0.01). Contrary to data in other patient groups, rosiglitazone did not increase subcutaneous fat in patients with HAL after 24 weeks of treatment. Rosiglitazone seemed to ameliorate insulin resistance judged by the decreased serum insulin concentrations and % liver fat. Rosiglitazone unexpectedly caused significant increases in serum triglyceride and cholesterol concentrations, which must be carefully monitored if glitazones are used in these patients.
Advances in the Development of Ribozymes and Antisense Oligodeoxynucleotides as Antiviral Agents for Human Papillomaviruses
Authors: Alvarez-Salas Luis Maret , Benítez-Hess Maria Luisa , DiPaolo Joseph A
Published: April 2022

Urogenital human papillomavirus (HPV) infections are the most common viral sexually transmitted disease in women. On a worldwide basis cervical cancer is the second most prevalent cancer of women. Although HPV infection is not sufficient to induce cancer, the causal relation between high-risk HPV infection and cervical cancer is well established. Over 99% of cervical cancers are positive for high-risk HPV. Therefore, there is a need for newer approaches to treat HPV infection. Two novel approaches for inactivating gene expression involve ribozymes and oligonucleotides. Methods for identification of target genes involved in neoplastic transformation and tumour growth have been established, and these will lead to therapeutic approaches without any damage to normal cellular RNA molecules, which is often associated with conventional therapeutics. Ribozymes and oligonucleotides represent rational antiviral approaches for inhibiting the growth of cervical lesions and carcinomas by interfering with E6/E7 RNA production. The E6 and E7 genes of high-risk HPVs cooperate to immortalize primary epithelial cells and because they are found in cervical cancer are considered the hallmark of cervical cancer. The use and modification of ribozymes and antisense oligodeoxynucleotides can inhibit the growth of HPV-16 and HPV-18 immortalized cells, and tumour cells by eliminating E6/E7 transcript. Hammerhead and hairpin ribozymes have been widely studied because of their potential use for gene therapy and their place as therapeutic tools for cervical cancer is being evaluated. Although antiviral ribozymes and anti-sense molecules have been effective as in vitro or in vivo inhibitors of high-risk HPV-positive cells, none is currently in clinical trial. There are, however, a number of other antisense therapies in Phase I–III clinical trial for several oncogenes.
Drug Resistance Genotypes Predict Response to Amprenavir-Containing Regimens in Highly Drug-Experienced HIV-1-Infected Patients
Authors: Sabin Caroline A , Wilkins Ed , Murphy Maurice , Fisher Martin , de Ruiter Annemiek , Easterbrook Philippa J , Leen Clifford , Vlahakis Emmanuel , Cane Patricia A , Li Xu , Pillay Deenan
Published: April 2022

We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.