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Objective: Oropouche, Caraparu, Guama, Guaroa and Tacaiuma are ssRNA viruses that belong to the genus Orthobunyavirus and have been associated with human febrile illnesses and/or encephalitis. In this study, we evaluated the antiviral action of mycophenolic acid (MPA) on theseorthobunyaviruses to achieve a therapeutic agent to treat the diseases caused by these viruses. Methods: The in vitro antiviral evaluation to MPA was done by using plaque assay at different periods of treatment. Results: Results showed that MPA at a concentration of 10 μg/ml has significant antiviral activity on Tacaiuma virus when treatment was initiated either 24 h before or 2 h after viral infection. Moreover, MPA has an inhibitory effect on Guama virus replication, but only when treatment was initiated before cell infection. Addition of guanosine in the culture reverted the inhibitory effect of MPA on Tacaiuma and Guama viruses, suggesting that the antiviral activity of this substance was via depletion of the intracellular guanosine pool. Conclusion: Our results suggest that MPA would not be a good therapeutic agent to treat the diseases caused by Oropouche, Caraparu, Guama, Guaroa, and Tacaiuma viruses. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Human papilloma virus (HPV)-associated diseases are increasingly diagnosed in solid organ recipients. Cidofovir (CDV) is a broad-spectrum antiviral agent with activity against all human herpes viruses and HPV. From 2000–2004, a total of 1303 solid organ transplants (SOT) were performed at our center. Six transplant recipients were treated with topical CDV for HPV-associated lesions. One cardiac recipient responded to a single injection of CDV into his recurrent anal condylomata. In a renal recipient with recurrent penile condylomata CDV was injected into the lesions four times (2 week interval) until lesions regressed. One renal recipient developed multiple vaginal and anal intradermal neoplasias, which relapsed after laser ablation. The lesions were repeatedly injected with CDV and completely disappeared. Two renal recipients with widespread verrucae vulgares were treated with CDV gel, which resulted in regression of the lesions. One patient developed donor derived verrucae vulgares on both transplanted hands, which responded to CDV gel. Four of the six patients were switched from calcineurin inhibitors (CNIs) to Sirolimus (SIR). CDV was found effective in the treatment of HPV-associated skin lesions in SOT recipients. It needs to be determined whether switch from CNIs to SIR might have contributed to the beneficial effect of CDV. [ABSTRACT FROM AUTHOR]

Background. Incomplete adherence is the main cause of antiretroviral therapy failure during initial combination antiretroviral therapy (ART). A switch to a protease inhibitor-sparing ART may be useful when a patient does not tolerate a first protease inhibitor-containing ART regimen. Methods. To compare the biological and clinical outcomes of patients in whom a first protease inhibitor-containing ART regimen failed to control viral replication and whose treatment was switched to ART containing efavirenz, nevirapine, or abacavir, we studied 1440 patients from the French Hospital Database on HIV whose treatment was changed from a first protease inhibitor-containing ART to a 3-drug regimen with either efavirenz, nevirapine, or abacavir while their plasma viral load was detectable. Results. Kaplan-Meier 12-month probabilities of virological suppression were 73.6%, 53.9%, and 66.1% among patients whose treatment was switched to efavirenz-ART, nevirapine-ART, and abacavir-ART, respectively.Factors associated with a lower likelihood of virological suppression were antiretroviral exposure before the first ART, higher plasma viral load values at the treatment switch, a stavudine-lamivudine backbone after the switch (instead of a zidovudine-lamivudine backbone), and a switch to nevirapine (adjusted hazard ratio, 0.63 [95% CI, 0.54–0.74], compared with efavirenz) or abacavir (adjusted hazard ratio, 0.84 [95% CI, 0.68–1.04] compared with efavirenz). There was no difference among the 3 groups with regard to immunological gain (>50 CD4+ T cells/mm³) or clinical outcome. Conclusion. When virological rebound occurs from receipt of protease inhibitor-containing ART, virological suppression can be obtained after a switch to a protease inhibitor-free ART—efavirenz-ART yielding the highest rate of virological suppression. [ABSTRACT FROM AUTHOR]

This study was conducted to identify and describe the perceived morphologic changes of body fat redistribution and related distress among persons taking combination antiretroviral therapy. Six focus group interviews were conducted in four different US cities with men and women ( n =58) who reported antiretroviral-related symptoms of body fat loss and/or gain. Interview data were audiotaped, transcribed verbatim and systematically analysed using inductive techniques. Physical discomfort and impairment and psychological and social distress were reported across sex, sexual orientation and geographic subgroups. While participants acknowledged that antiretroviral drugs were keeping them alive, there was tension between the desire for life-sustaining treatment and optimal quality of life. Some participants engaged in harmful heath behaviours in an attempt to control bodily changes (e.g. non-adherence to antiretroviral regimen). Participants feared that fat loss represented disease progression and worried that visible changes would lead to unintentional disclosure of their HIV status. Although a potential source of support, healthcare providers were commonly perceived as ignoring and, in so doing, discrediting patient distress. Participants recognised the limitations of current lipodystrophy treatment options, yet a cure for the syndrome seemed less important to them in the short term than simply being listened to and the powerful, but oblique sources of distress addressed. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate a novel psycho-educational intervention intended to increase patients’ medication preparedness and treatment adherence skills before initiating highly active antiretroviral therapy (HAART). Sixty-three HIV-positive patients not currently on antiretroviral therapy participated in a randomized controlled trial of a standardized, four-session psycho-educational intervention (Supportive Therapy for Adherence to Antiretroviral Treatment; STAART). Session topics included learning techniques to increase medication adherence and learning effective strategies to cope with stress and depression. Patients completed psychological questionnaires assessing psychological readiness to initiate HAART and depressed mood. They completed both measures at study baseline and at four-weeks post-baseline. After controlling for baseline medication readiness scores, intervention patients ( n =30) reported significantly higher mean medication readiness following the STAART intervention (four-weeks post-baseline) (27.3±6.9) compared to controls ( n =33; 24.6±9.9; p [ABSTRACT FROM AUTHOR]

The Center for Adherence Support Evaluation (CASE) Adherence Index, a simple composite measure of self-reported antiretroviral therapy (ART) adherence, was compared to a standard three-day self-reported adherence measure among participants in a longitudinal, prospective cross-site evaluation of 12 adherence programs throughout the United States. The CASE Adherence Index, consisting of three unique adherence questions developed for the cross-site study, along with a three-day adherence self-report were administered by interviews every three months over a one-year period. Data from the three cross-site adherence questions (individually and in combination) were compared to three -day self-report data and HIV RNA and CD4 outcomes in cross-sectional analyses. The CASE Adherence Index correlated strongly with the three-day self-reported adherence data ( p 10 achieved a 98 cell mean increase in CD4 count over 12 months, compared to a 41 cell increase for those with scores ≤10 ( p [ABSTRACT FROM AUTHOR]

Purpose. The implications of the findings from clinical studies and pharmacokinetic analyses of the antiviral agent valganciclovir for dosing of the drug to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are reviewed. Summary. Valganciclovir, an oral pro-drug of ganciclovir, is as effective as oral ganciclovir for preventing CMV disease, although prophylaxis with either agent may delay CMV disease. Dosage reduction is required for both drugs in patients with renal impairment to prevent high plasma ganciclovir concentrations and toxicity. A valganciclovir dosage of 900 mg/day is required in patients with normal renal function, especially those at high risk for CMV disease, to provide adequate systemic ganciclovir exposure. Some studies suggest that a lower dosage might suffice for patients at a low risk for CMV disease. Conclusion. Valganciclovir dosing should be based on renal function to avoid toxicity. [ABSTRACT FROM AUTHOR]

The article explores associations between an MDR1 variant and responses to non-nucleoside reverse-transcriptase inhibitors. The relationship among MDR1, CYP2B6 and CYP3A polymorphisms and nevirapine hepatotoxicity were also examined. Reliable genetic predictors of nevirapine toxicity might allow HIV therapy that includes nevirapine to be initiated for persons with higher CD4+ counts.

Early diagnosis of human cytomegalovirus (HCMV) infection and the introduction of preemptive antiviral therapy have reduced HCMV-related mortality after allogeneic stem cell transplantation. A critical goal remains stratifying risk profiles and minimizing potential harm owing to antiviral overtreatment. We compared the commercially available standardized COBAS Amplicor CMV Monitor (CACM) to an in-house PCR assay, for the monitoring of HCMV infection. Seventy-two patients were surveyed by an in-house PCR of whole blood, quantitative viral load assessment by CACM and virus culture assays in a prospective and a retrospective study. A high concordance between CACM and PCR was documented. The viral load at onset correlated with the peak viral load (Spearman rank correlation R=0.634, P=0.0004). In patients developing HCMV disease, both viral loads were in trend higher (P=0.823, respectively P=0.053), and the viremic episodes longer (P=0.015), as compared to asymptomatically HCMV-infected patients. The serological pre-transplant status was the major risk factor for the development of HCMV disease, showing highest risk for seropositive patients receiving a seronegative graft, whereas donor type (related or unrelated) and graft type (bone marrow or peripheral blood mobilized stem cells) did not have an influence. HCMV infection proved to be a risk factor for the development of non-viral opportunistic infections (P=0.002).Bone Marrow Transplantation (2006) 38, 53–60. doi:10.1038/sj.bmt.1705408 [ABSTRACT FROM AUTHOR]

Summary: Objectives: To establish current practice in the treatment of recurrent respiratory papillomatosis (RRP) in the UK. Methods: Consultant members of the British Association of Paediatric Otorhinolaryngology (BAPO) were sent a questionnaire on current practice concerning the management of recurrent respiratory papillomatosis in the paediatric population. Results: The response rate was 39.4% perhaps reflecting the relatively small number of otolaryngologists who treat this condition. Data were analysed from 41 respondents representing 27 departments for a total of 103 patients. A total of 13 patients (12.6%) received adjuvant medical therapies with the antiviral agent cidofovir accounting for 10 patients. Distal spread of RRP has occurred in 27 (26.2%) patients. There were six reported deaths due to progressive RRP. Various lasers (CO2, KTP, and pulsed dye) are the preferred method of surgical removal of RRP in children. Spontaneous ventilation (65.3%) is the preferred method of anaesthesia. Half of the consultants do not routinely send for HPV subtyping and 75% send lesions for histological examination if there is a change in growth pattern. Two thirds of respondents do not routinely treat their patients with antireflux medication. Conclusion: There is a need for the establishment of a centralized national base to which all treating consultants can report their cases. The time has come for national multicenter controlled trials on the use of adjuvant interventions for the treatment of both severe and less severe RRP disease. Both of the above can be organized under the umbrella of BAPO. [Copyright &y& Elsevier]

Contrary to early expectations, recent studies have shown near-perfect adherence to HIV antiretrovirals in sub-Saharan Africa We conducted qualitative interviews with patients purchasing low-cost, generic antiretroviral therapy to better understand the social dynamics underlying these findings. We found that concerns for family well-being motivate adherence, yet, the financial sacrifices necessary to secure therapy may paradoxically undermine family welfare. We suggest that missed doses may be more due to a failure to access medication rather than a failure to adhere to medications, and that structural rather than behavioral interventions may be most useful to insure optimal treatment response. [ABSTRACT FROM AUTHOR]

For the synthesis of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine (8: 4′-Ed4T), a recently reported promising anti-HIV agent, a new approach was developed. Since treatment of 1-(2,5-dideoxy-β-ʟ-glyceropent-4-enofuranosyl)thymine with Pb(OBz)4 allowed the introduction of the 4′-benzoyloxy leaving group, nucleophilic substitution at the 4′-position became feasible for the first time. Thus, reaction between the 4′-benzoyloxy derivative (14) and Me3SiCCAl(Et)Cl as a nucleophile led to the isolation of the desired 4′-‘down’-ethynyl derivative (18) stereoselectively in 62% yield. As an application of this approach, other 4′-substituted nucleosides, such as the 4′-allyl (24a) and 4′-cyano (26a) derivatives, were synthesized using organosilicon reagents. In these instances, pretreatment of 14 with MeAlCl2 was necessary. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess the genotypic determinants of the virological response (VR) to didanosine (ddI) in nucleoside reverse transcriptase inhibitors (NRTI)-experienced patients. Methods: Human immunodeficiency virus type 1 (HIV-1) genotype was determined at baseline in 74 ddI-naïve-patients with baseline viral load >500copies/ml and receiving ddI as part of a new regimen. VR was defined as a plasma HIV-1 RNA <50copies/ml after three months on ddI. NRTI resistance mutations associated with higher or lower frequencies of VR with a p-value<0.25 were retained in different sets of mutations, where the mutations associated with a worse VR were added, whereas the mutations associated with a better VR were substracted. The most significant mutation scores were then studied in a multivariate analysis. Results: Changes at three codons (M41L, L210W, T215Y/F/D/C/E) were associated with a worse VR and three mutations (K70R, M184V, K219Q) with a better VR. The strongest association with the VR was obtained with the score M41L+L210W+T215Y/F/D/C/E−K70R−K219Q. The score was independently associated with the VR in the multivariate analysis. Conclusion: Taking into account the mutations associated with a better VR may improve genotypic resistance algorithms. Our results are of interest for the management of antiretroviral therapy in NRTI-experienced patients. [Copyright &y& Elsevier]

Abstract: Background: Our group has previously developed a quantitative and ultrasensitive HIV-1 p24 antigen assay that is inexpensive, easy-to-perform, and can be carried out in low-resource settings. Since antiretroviral therapies are becoming more accessible in resource-constrained countries, methods to assess HIV-1 viraemia are urgently needed to achieve a high standard of care in HIV-1 management. Objectives: To adapt our quantitative assay to dried plasma spots (DPS), in order to further simplify this test and make it more accessible to resource-constrained countries. Study design: DPS from 47 HIV-seropositive, treated or untreated adult individuals and 30 healthy individuals were examined. Results: A specificity of 100% was observed when p24 antigen was measured using DPS, and no differences of p24 concentration could be seen between DPS and venous plasma. The correlation between DPS and venous plasma p24 was excellent (R =0.93, CI95% =0.88–0.96, p <0.0001). Similarly, p24 antigen concentrations using DPS were well correlated with RNA viral load (R =0.53, CI95% =0.27–0.72, p =0.0002). Conclusions: This quantitative p24 antigen test has similar sensitivity and specificity using DPS and venous plasma, and has the potential to improve health care delivery to HIV-affected individuals in resource-constrained countries. [Copyright &y& Elsevier]

Abstract: Prolonged lamivudine therapy has been identified as the major risk for the development of resistance in HBV, with rates of 90% after 4 years of treatment. Tenofovir disoproxil fumarate showed activity against both wild type and lamivudine resistant HBV in HIV–HBV co-infected patients. In order to compare the efficacy of lamivudine/tenofovir treatment we investigated detailed HBV kinetics in 13 HIV–HBV co-infected patients with either wild type HBV or lamivudine resistant HBV. The viral strains in both patient groups showed a biphasic viral decline pattern. Only in the first phase of viral decay, which reflects the clearance rate of the free virus from plasma, there was a statistically significant response in favor of the wild type group. After the first phase we observed a similar viral decline till 24 weeks of both groups. This is reassuring for many pretreated co-infected patients harbouring mutant viruses. [Copyright &y& Elsevier]

Abstract: Background: The outcome of acute hepatitis C is determined by early host–virus interactions, particularly involving the antiviral T-cell response. Objectives: To identify early prognostic markers of spontaneous resolution of acute hepatitis C by performing a comprehensive analysis of viral and immunological factors during the natural course of acute HCV infection and reinfection. Study design: 20 patients were investigated prospectively during acute HC or confirmed reinfection and 18 of them during follow up after spontaneous or treatment-induced elimination of the virus and resolution of the disease. Multiparameter flow cytometry was used to functionally characterize virus-specific CD4+ T-cell responses relative to the virologic outcome. Results: Parallel immunologic and virologic monitoring of patients with acute HC identified distinct patterns of host–virus interaction related to HCV persistence or clearance. The highest frequency of antiviral Th1 cytokine-producing CD4+ T-cells was observed in patients with HCV reinfection, preceding rapid viral clearance within 3 weeks after disease onset. In all patients who subsequently cleared viremia, CD4+ T-cells produced Th1 cytokines following stimulation with non-structural HCV antigens (NS3 and NS4). In contrast, a chronic course of disease was associated with the absence of antiviral Th1 cytokine producing cells from the first weeks after onset of disease (acute persistent HC), or with fluctuating RNA levels (yo-yo pattern) and gradual waning of antiviral Th1 cells. Conclusions: The results highlight the variability of immune response pattern in acute hepatitis C. Most importantly, “acute persistent hepatitis C” and a lack of TH1 effector cells within the first months of acute hepatitis C represent efficacious predictors of viral persistence and could thus be used as criteria in selecting candidates for early antiviral treatment. [Copyright &y& Elsevier]

Abstract: Because of the slow kinetics of viral clearance and the spontaneous genetic variability of hepatitis B virus (HBV), antiviral therapy of chronic hepatitis B remains a clinical challenge. Despite the recent development of lamivudine, adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic HBV infection, there is still a major need for new antiviral compounds. Entecavir, a guanosine analog, has been recently approved in US for the therapy of chronic hepatitis B and its registration is expected soon in Europe. Extensive studies have been performed to characterize its antiviral activity in enzymatic and tissue culture models, as well as in animal models of HBV infection. In clinical trails, entecavir administration was associated with a significantly more potent viral suppression compared to lamivudine, and a significant advantage in terms of biochemical and histological improvement compared to lamivudine. Entecavir was tolerated as well as lamivudine in these phase III trials. No case of resistance was detected after two years of therapy in nucleoside naïve patients. Treatment of patients with lamivudine failure requires a higher dosage of entecavir and induces a significant decline in viraemia levels. However, 10% of these patients developed entecavir resistance after two years of therapy. The availability of entecavir as a new treatment option is providing clincians more choice to keep both viral replication and liver disease under control. This provides new hope for improved treatment concepts for chronic HBV infection. [Copyright &y& Elsevier]

The article looks into association of primary HIV drug resistance with poor treatment outcome of first-line highly active antiretroviral therapy (HAART) in several trials. Significantly, the study aims to assess the efficacy of first-line HAART guided by resistance training. Results have indicated that primary drug resistance was 11.2% in chronically HIV-infected patients. HAART guided by resistance testing had similar efficacy in patients with primary drug resistance as compared with patients with wild-type virus.

Summary The mortality rate in documented avian influenza A virus subtype H5N1 infection is still high, which is currently reported by WHO at about 50%. Post-mortem analyses in affected patients have revealed haemophagocytosis similar to that found in patients with haemophagocytic lymphohistiocytosis (HLH); such haemophagocytosis could be a very prominent post-mortem feature in H5N1 infection. There are also clinical similarities between H5N1 infection and HLH, such as massive hypercytokinaemia, cytopenia, and acute encephalitis. Importantly, patients with another severe viral infection that may be complicated by secondary HLH, severe Epstein-Barr-virus-associated HLH, have significantly better survival if specific HLH therapy (including the cytotoxic and pro-apoptotic drug etoposide) is initiated early, with survival reported to rise from about 50% to 90%. With this notable improvement in survival, specific HLH treatment, including cytotoxic therapy, could be considered in patients with severe avian influenza A infection complicated by secondary HLH. [ABSTRACT FROM AUTHOR]

Background. We assessed human immunodeficiency virus (HIV) antibody seroreversion among individuals initiating antiretroviral therapy (ART) during acute/early HIV infection and determined whether seroreversion was associated with loss of cytotoxic T lymphocyte responses. Methods. Subjects in a cohort with acute/early HIV infection (<12 months into infection) who initiated ART within 28 days after study entry and maintained HIV type 1 ribonucleic acid levels of ⩽500 copies/mL for >24 weeks were selected. Two clinically available second-generation enzyme immunoassays (EIAs) and a confirmatory Western blot were used to screen subjects for antibody reversion. Those with negative screening test results underwent additional antibody testing, including a third-generation EIA, and were assessed for cytotoxic T lymphocyte responses. Results. Of 87 subjects identified, 12 (14%) had negative antibody test results at the start of ART; all 12 had seroconversion, although 1 had seroconversion only on a third-generation EIA. Of the 87 subjects, 6 (7%) had seroreversion on at least 1 EIA antibody assay while receiving ART during a median follow-up of 90 weeks. The only clinical predictor of seroreversion was a low baseline ‘detuned’ (less sensitive) antibody. Cytotoxic T lymphocyte responses to HIV Gag peptides were detected in 4 of 5 subjects with seroreversion who could be tested. All 5 who had seroreversion who stopped ART experienced virologic rebound and antibody evolution. Conclusions. HIV antibody seroconversion on second-generation EIA antibody tests may fail to occur when ART is initiated early. Seroreversion was not uncommon among subjects treated early, although cytotoxic T lymphocyte responses to HIV antigens remained detectable in most subjects. Antibody seroreversion did not indicate viral eradication. A third-generation EIA was the most sensitive test for HIV antibodies. [ABSTRACT FROM AUTHOR]

Summary Introduction Avian H5N1 influenza viruses currently circulating in southeast Asia could potentially cause the next pandemic. However, currently licensed human vaccines are subtype-specific and do not protect against these H5N1 viruses. We aimed to develop an influenza vaccine and assessed its immunogenicity and efficacy to confer protection in BALB/c mice. Methods We developed an egg-independent strategy to combat the avian influenza virus, because the virus is highly lethal to chickens and the maintenance of a constant supply of embryonated eggs would be difficult in a pandemic. We used a replication-incompetent, human adenoviral-vector-based, haemagglutinin subtype 5 influenza vaccine (HAd-H5HA), which induces both humoral and cell-mediated immune responses against avian H5N1 influenza viruses isolated from people. Findings Immunisation of mice with HAd-H5HA provided effective protection from H5N1 disease, death, and primary viral replication (p<0·0001) against antigenically distinct strains of H5N1 influenza viruses. Unlike the recombinant H5HA vaccine, which is based on a traditional subunit vaccine approach, HAd-H5HA vaccine induced a three-fold to eight-fold increase in HA-518-epitope-specific interferon-γ-secreting CD8 T cells (p=0·01). Interpretation Our findings highlight the potential of an Ad-vector-based delivery system, which is both egg-independent and adjuvant-independent and offers stockpiling options for the development of a pandemic influenza vaccine. [ABSTRACT FROM AUTHOR]

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1400mg twice daily, fosamprenavir 1400mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5–2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be coadministered with caution. However, fosamprenavir can be coadministered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied. The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to coadminister fosamprenavir and fosamprenavir plus ritonavir with many other commonly coprescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents. [ABSTRACT FROM AUTHOR]

Small interfering RNAs (siRNAs) have been developed as antiviral agents for mammalian cells. The capacity of specific siRNAs to prevent virus infections has been demonstrated, and there is evidence that these new antiviral agents could have a partial therapeutic effect a few days after infection. We investigated the possibility of curing a persistent infection, several months after becoming established, using an in vitro model of persistent poliovirus (PV) infection in HEp-2 cells. Despite high virus titers and the presence of PV mutants, repeated treatment with a mixture of two siRNAs targeting both noncoding and coding regions, one of them in a highly conserved region, resulted in the complete cure of the majority of persistently infected cultures. No escape mutants emerged in treated cultures. The antiviral effect of specific siRNAs, consistent with a mechanism of RNA interference, correlated with a decrease in the amount of viral RNA, until its complete disappearance, resulting in cultures cured of virions and viral RNA.Molecular Therapy (2006) 13, 142–150; doi: 10.1016/j.ymthe.2005.07.697 [ABSTRACT FROM AUTHOR]

The issue of access to antiretrovirals (ARVs), the compounds used in combination therapies to treat AIDS, has given rise to an international debate of economic, political, and philosophical significance. This essay proposes to deconstruct the moral issues raised by the international NGOs against the economic and legal arguments of the pharmaceutical laboratories. The African continent, which, with 70% of cases, is paying the heaviest price for the AIDS pandemic, will provide the prism through which these issues will be approached. After a brief chronology of the process by which ARVs have shifted from being the commercial monopoly of the pharmaceutical companies to the “public good” advocated by the NGOs, we are led to consider the African state. In a domain in which many different dynamics are at work, the sub-Saharan countries play with international norms (or evade them) according to circumstances influenced less by epidemiology than by power relations and manifestations of political weakness in this multipolar context. Between economics and politics, morality and law, the “biopolitics” embodied in the AIDS pandemic reveals an Africa under great strain. Once described, the “moral” responsibilities of the one side, like the vigorous collective mobilisations of the other, also impel us to highlight the responsibilities of the African states in the face of the most sudden drama Africa has ever experienced in so short a space of time. [ABSTRACT FROM AUTHOR]

Studies the effect of antiretroviral therapy (ART) exposure in the first 18 months of life in uninfected children born to HIV-infected women. Efforts of the researchers to gain insight into the impact of ART on the early stages of growth among these children; Administration of prophylactic ART to reduce the risk of mother-to-child transmission; Investigation whether there were differences in growth between highly active antiretroviral therapy-exposed and unexposed premature uninfected children.

Studies the effect of a brief antiretroviral therapy (ART) adherence intervention delivered by HIV care providers in California. Efficacy of ART therapy in controlling viral load in people infected with HIV; Necessity for high levels of adherence to ART to achieve prolonged viral suppression; Significance of the study on the development of novel management and treatment approaches when treating HIV/AIDS.

Examines cost and enrollment implications of targeting different source population for an HIV treatment program by researchers from Zambia. Initiatives undertaken by the government to make antiretroviral agent accessible and available to people infected with HIV; Recommendations for an acceleration of patient enrollment; Plausibility for a rapid growth on HIV treatment programs.

Studies structured treatment interruptions in primary HIV-1 infection by researchers from France. Efficacy of primary HIV infection (PHI) with highly active antiretroviral therapy (HAART) in eradicating HIV virus; Indications showing the incapability of HAART in preventing the development of chronic infection; Advantages of using HAART during the early phase in treating PHI.

Studies measures of antiretroviral medication adherence and virologic response in AIDS in clinical trials by researchers from the U.S. Use of antiretroviral regimen adherence as a critical determinant of virologic success; Indications from HIV-infection studies showing that a very high degree of adherence is necessary for optimal suppression of HIV RNA levels in plasma; Association of poor adherence with virologic failure and the emergence of drug-resistant strains of HIV.

Studies selective drug taking during combination antiretroviral therapy in an unselected clinic population by researchers from Denver, Colorado. Significance of multidrug therapy to achieve sustained viral suppression; Plausibility for discordant adherence to individual components of a multidrug regimen to adverse outcomes; Significance of the study on the development of novel treatment approaches to HIV infections.

Despite recent progress in anti-human immunodeficiency virus (HIV) therapy, drug toxicity and emergence of drug-resistant isolates during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the process of nuclear translocation of the HIV preintegration complex. Previously we described a class of arylene bis(methylketone) compounds that inhibit HIV-1 nuclear import by targeting the nuclear localization signal (NLS) in the matrix protein (MA). Here we report a different class of MA NLS-targeting compounds that was selected using computer-assisted drug design. The leading compound from this group, ITI-367, showed potent anti-H1V activity in cultures of T lymphocytes and macrophages and also inhibited HIV-1 replication in ex viva cultured lymphoid tissue. The virus carrying inactivating mutations in MA NLS was resistant to ITI-367. Analysis by real-time PCR demonstrated that the compound specifically inhibited nuclear import of viral DNA, measured by two-long terminal repeat circle formation. Evidence of the existence of this mechanism was provided by immunofluorescent microscopy, using fluorescently labeled HIV-1, which demonstrated retention of the viral DNA in the cytoplasm of drug-treated macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for further development. [ABSTRACT FROM AUTHOR]

We assessed valganciclovir for the treatment of cytomegalovirus (CMV) in organ-transplant recipients. Virologic and clinical outcomes were compared with those in matched historical control individuals. Thirty-two patients (23 with symptomatic disease) received valganciclovir, and 32 patients received intravenous (iv) ganciclovir. The rate of virologic clearance by day 21 of therapy was similar in the valganciclovir arm (50.0%) and the ganciclovir arm (46.9%) (P value not significant). The change from baseline viral load by day 7 and day 14 of therapy was similar in both arms. Two patients treated with valganciclovir required a switch to iv ganciclovir, because of a lack of response. Valganciclovir is useful for the treatment of CMV infection and disease in selected organ-transplant recipients. [ABSTRACT FROM AUTHOR]

Background/Aims: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. Methods: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. Results: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P&#60;0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9×10−2/site/year and 1.3×10−2/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60×10−2/site/year and 0.24×10−2/site/year, P=0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n=10) than in non-responders (8.8×10−2/site/year vs. 0.38×10−2/site/year, P=0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. Conclusions: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy. [Copyright &y& Elsevier]

Lesions caused by verrucus vulgaris are commonly refractory to therapy and may become large, painful, or disfiguring in immunocompromised patients. Cidofovir is a potent nucleoside analog antiviral agent shown to have in vitro and in vivo activity against a broad spectrum of DNA viruses. We report a successful use of topical cidofovir to treat verruca vulgaris lesions in a highly immunocompromised patient, who was not considered a candidate for conventional therapy. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) has transformed HIV infection into a treatable, chronic condition. However, the need to continue treatment for decades rather than years, calls for a long-term perspective of ART. Adherence to the regimen is essential for successful treatment and sustained viral control. Studies have indicated that at least 95% adherence to ART regimens is optimal. It has been demonstrated that a 10% higher level of adherence results in a 21% reduction in disease progression. The various factors affecting success of ART are social aspects like motivation to begin therapy, ability to adhere to therapy, lifestyle pattern, financial support, family support, pros and cons of starting therapy and pharmacological aspects like tolerability of the regimen, availability of the drugs. Also, the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile compared with other regimens are to be considered before starting ART. The lack of trust between clinician and patient, active drug and alcohol use, active mental illness (e.g. depression), lack of patient education and inability of patients to identify their medications, lack of reliable access to primary medical care or medication are considered to be predictors of inadequate adherence. Interventions at various levels, viz. patient level, medication level, healthcare level and community level, boost adherence and overall outcome of ART. [ABSTRACT FROM AUTHOR]

Background. Cidofovir is a nucleotide analogue with antiviral activity against a wide range of DNA viruses, including herpes simplex virus (HSV). In vitro resistance to cidofovir has been reported with use of laboratory HSV strains; clinical failure of cidofovir therapy for HSV disease has also been reported with an isolate that was susceptible by in vitro testing. Patients and methods. Three patients with HSV disease that was unresponsive to cidofovir therapy had viral isolates obtained and stored; the isolates were analyzed for antiviral susceptibility by an antigen reduction assay (ARA). PCR cloning and automated sequencing were performed for isolates that displayed in vitro resistance. Mutations were identified by comparison with the appropriate HSV consensus sequence. Results. An HSV type 2 (HSV-2) isolate recovered from patient 2 displayed in vitro cidofovir resistance with an inhibitory concentration of 50% (IC50) of 13.06 μg/mL. HSV type 1 isolates recovered from patients 1 and 3 had elevated IC50s to cidofovir (7.32 and 8.23 μg/mL, respectively); however, these isolates did not meet the cutoff point for resistance according to the ARA. Sequencing of a cidofovir-resistant HSV-2 isolate revealed several DNA polymerase mutations that had not been previously described during in vitro resistance selection. Conclusions. To our knowledge, this is the first report of cidofovir resistance in HSV developing in vivo. The 3 sequenced clones all contained mutations truncating the poi C' end, suggesting that this region may be critical for cidofovir antiviral activity. In addition, the presence of multiple mutations suggests that the altered DNA polymerase of cidofovir-resistant virus may have introduced additional mutations into the viral genome. Introduction of the mutations identified in wild-type HSV strains is needed before the resistance phenotype can be definitively associated with any of the mutations found. Additional studies are needed to delineate the mechanisms of cidofovir resistance in HSV. [ABSTRACT FROM AUTHOR]

To examine potential changes in attitudes toward antiviral medication since the advent of highly active antiretroviral therapy (HAART), focused interviews were conducted with two samples of women living with HIV/AIDS; one in the pre-HAART era (1994–1996) and a second matched sample in the HAART era (2000–2003). Women in the pre-HAART era held highly negative attitudes toward antiviral medications, perceived them as ineffective with few benefits and viewed side effects as intolerable. In contrast, women in the HAART era were less likely to report negative attitudes, which were balanced by more frequent reports of perceived benefits and more likely to view side effects as temporary and manageable. African American women in both eras were more likely to hold negative attitudes and less likely to perceive benefits than White and Puerto Rican women. These findings suggest that views of antiviral medication have improved since the advent of HAART, but that negative attitudes and side-effect concerns remain which should be addressed in interventions to promote treatment acceptance and adherence. [ABSTRACT FROM AUTHOR]

Strict adherence to highly active antiretroviral therapy (HAART) is necessary for successful suppression of HIV replication. A large number of individuals are not adherent, however, and the reasons for non-adherence are varied and complex. We utilized cluster analyses to identify subgroups of adherers in a sample of 222 HIV positive individuals whose HAART use was electronically monitored. Five distinct subgroups were identified, with characteristic variations across the week and over the course of the 4-week study. Additional comparisons of demographic and behavioral variables found the worst adherers to have higher rates of substance use, and that a group with higher rates of cognitive impairment had a consistent drop in adherence during the weekends. In addition, the group with the best adherence had more individuals over the age of 50 years. The results of the current study indicate that distinct subgroups of adherers may exist, and suggest that interventions designed to improve adherence can be designed to accommodate this variability in behavior. [ABSTRACT FROM AUTHOR]

Background/Aims: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. Methods: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180μg/week) and ribavirin (1000–1200mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360μg/week) plus ribavirin for NUR patients. Results: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. Conclusions: An improvement in virologic efficacy was not achieved with the available individualized treatment options. [Copyright &y& Elsevier]

BACKGROUND: Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment. METHODS: We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician. RESULTS: Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment. CONCLUSIONS: The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population. (Am J Gastroenterol 2005;100:1–8) [ABSTRACT FROM AUTHOR]

Despite advances in the treatment of HIV disease, the incidence and mortality of invasive cryptococcal disease remain significant. A matched, case-control study was performed to examine the impact of highly active antiretroviral therapy (HAART) and azole use on the incidence of invasive cryptococcal disease in HIV-infected patients. The study was performed at a metropolitan hospital with a large indigent population and an incidence of seven cases of cryptococcal disease per 1000 persons with AIDS. Bivariate analysis, matched on CD4 count, revealed that both HAART use [odds ratio (OR) 0.43; 95% confidence interval (CI) 0.23–0.99] and azole use (OR 0.14; 95% CI 0.06–0.34) had a protective effect. Conditional logistic regression stratified on CD4 lymphocyte count revealed a protective role for azole use (OR 0.15; 95% CI 0.06–0.40) but not for HAART use (OR 0.47; 95% CI 0.18–1.26). Of note, the prevalence of HAART use was low in both cases and controls, with only 12% of cases and 23% of controls on HAART. The results of this study support previous evidence that azole use prevents invasive cryptococcal disease. Although current guidelines for the prophylaxis of opportunistic infections do not suggest routine prophylaxis for cryptococcal infection, this issue should be reconsidered, especially in populations that have a low prevalence of HAART use. [ABSTRACT FROM AUTHOR]

Focuses on the impact of the advent of highly active antiretroviral therapy on individuals living with HIV. Reasons behind the increase in the choice of antiviral agents; Development of new strategies to address the issues of compliance and toxicity; Moves to develop new drugs in exisitng classes to treat HIV patients.

Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/μL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/μL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts <50 cells/μL, >4 years on HAART and >6 months of complete viral suppression (<50 HIV-1 RNA copies/mL)] and 18 HIV-seronegative age- and sex-matched controls. HIV-infected patients had lower percentages of CD28-expressing CD4 lymphocytes and higher percentages of CTLA-4-expressing CD4 lymphocytes than controls. The percentage of CTLA-4-expressing CD4 lymphocytes correlated inversely with that of CD28-expressing CD4 lymphocytes. The proportion of CD4 lymphocytes expressing perforin was generally low. However, more HIV-infected patients than controls had >1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the role of three polymorphisms in the IFNAR1 (SNPs 18417 and -408) and IFNAR2 (SNP 11876) genes in multiple sclerosis (MS) susceptibility and in the IFNβ treatment response in a group of 147 patients and 210 controls undergoing interferon therapy during the last 2 years. Only the 18417 and the 11876 SNPs showed an association with disease susceptibility (p =0.001 and 0.035, respectively) although no differential genotype distribution were observed between interferon responders and non-responder MS patients. No alteration of the expression level of IFNAR-1 was observed with respect to the −408 genotypes or to interferon treatment response. These data suggest a role for the IFNAR pathway in susceptibility to MS. [Copyright &y& Elsevier]

This article focuses on the health, political, and security challenges caused by the hepatitis B (HBV) and hepatitis C (HCV) pandemics. HBV and HCV infect nearly 2 billion people worldwide. The author here reviews the distinctive patho-physiology of both HBV and HCV before addressing the public health, political, and security implications of these two pandemics. Unlike HBV, treatment for HCV is not only costly but also most unsatisfactory at any stage of the disease. The economic impact of the disease is extraordinary. Antiviral treatment for one year, reportedly, can exceed $25,000 per person in the U.S., but the actual cost is far higher due to both frequent drug side effects and co-morbidity issues. In the West, HCV infection is currently the most common reason for such transplants. The West has successfully controlled both infections with only minimal financial, political, and security concerns. In contrast, the pandemics are likely to further enfeeble the economies of those nations least equipped to cope with the huge economic toll they could exact.

Hepatitis delta virus (HDV) is encapsidated by the envelope proteins of hepatitis B virus (HBV). The major HBV lamivudine (LMV)-resistant mutations in the polymerase gene within the reverse transcriptase (rt) region at rtM204V or rtM204I are associated with changes in the overlapping envelope gene products, in particular, the gene encoding small envelope protein (s) at sI195M or sW196L/S/Stop. We have demonstrated that the LMV resistance mutations corresponding to sW196L/S inhibited secretion of HDV particles, while changes corresponding to sI195M did not affect secretion. Differential efficiencies of HBsAg proteins expressed by LMV-resistant HBV to support HDV secretion may have consequences for clinical prognosis as coinfected patients are treated with antiviral agents. [ABSTRACT FROM AUTHOR]

Examines the influence of immune activation on the evolution of CD4 T-cell counts in HIV-infected patients on highly active antiretroviral therapy. Factors contributing to the increase levels of proliferation and apoptosis; Interactions between HIV and the immune response; Improvement of the prognostic value of CD38 expression on CD8+ T cells.

Antiviral therapy has not been adequately evaluated in patients with hepatitis C virus (HCV)-related advanced liver disease due to apprehensions of adverse events and intolerance. The titrable dose of interferon (IFN)-α and ribavirin was evaluated in a flexible regimen in a pilot study.Twenty-five patients with HCV-related advanced chronic liver disease received IFN-α 1–3 MIU daily with ribavirin 200–600 mg daily for 9 months−3 years. Careful assessment of safety, tolerability and efficacy was made.Improvement in Child–Pugh score (8.4 ± 1.2 to 7.4 ± 2.0;P = 0.010) and serum albumin (3.0 ± 0.5 g/dL to 3.6 ± 0.5 g/dL;P = 0.007) occurred at follow up after antiviral therapy (median dose and duration: IFN-α 1.5 MIU/day for 12 months and ribavirin 400 mg/day for 7.5 months) as compared to baseline. Ascites regressed in 53% of patients (11/21). Thirteen patients (52%) lost HCV-RNA on therapy and eight (32%) achieved sustained virological response (SVR). Death occurred in three patients (12%) while on therapy, in two due to infection. No patient died in the responder group compared to five deaths (29%) in the non-responder group. However, there was no difference in the cumulative probability of survival in the sustained virological responder versus non-responder (P = 0.09). Adverse events were common (92%), but permanent withdrawal was required in only five patients (20%).Low and titrable dose IFN-α and ribavirin therapy in patients with HCV-related advanced chronic liver disease achieves improvement in hepatic synthetic function, Child–Pugh score and ascites. However, close monitoring for serious adverse events is warranted. [ABSTRACT FROM AUTHOR]

This article presents news related to antiviral agents. Patients receiving the fusion inhibitor enfuvirtide continue to derive clinical and immunological benefit from the drug even when viremia persists. Spanish researchers in Madrid found that, during treatment with the fusion inhibitor, changes in the HIV envelope or drug pressure may result in a shift from viruses with tropism for T cells to viruses that infect macrophages. Two pharmacokinetic studies out of Liverpool University and Chelsea and Westminster Hospital in the Great Britain reveals interactions when atazanavir, saquinavir, and ritonavir are co-administered.

Abstract: The potent antiviral potential of 5′-amino-5′-deoxy-5′-noraristeromycin (2) is limited by associated toxicity. To seek derivatives of 2 that circumvent this undesirable property, three amino substituted derivatives (acetyl, 3; formyl, 4; and methyl, 5) of 2 have been prepared in 4–7 steps from the same intermediate, (1S,4R)-4-(6-chloropurin-9-yl)cyclopent-2-en-1-ol (6). Key steps involved an improved Pd(0)-catalyzed allylic azidation and a novel Pd(0)-catalyzed allylic amidation. The three target compounds were evaluated against a large number of viruses and found to be inactive except for a very weak effect of 5 on human cytomegalovirus, varicella zoster virus, and Epstein–Barr virus. There was also no noteworthy cytotoxicity associated with the new derivatives. Thus, these results indicate variation of the cyclopentyl amine of 2 does not offer a means to improve upon its antiviral potential. [Copyright &y& Elsevier]