Search

Pleasurability of individual chords, known as sensory consonance, is widely regarded as physiologically determined and has been shown to be associated with differential activity in the auditory cortex and in several other regions. Here, we present results obtained contrasting isolated four-note chords classified as consonant or dissonant in tonal music. Using event-related functional MRI, consonant chords were found to elicit a larger haemodynamic response in the inferior and middle frontal gyri, premotor cortex and inferior parietal lobule. The effect was right lateralized for nonmusicians and less asymmetric for musicians. Using event-related potentials, the degree of sensory consonance was found to modulate the amplitude of the P1 in both groups and of the N2 in musicians only.

To date, the neural correlates of musical syntax processing have been investigated mainly by means of paradigms in which isolated chords are made incongruent with the harmonic context. Here, we present results obtained contrasting unfamiliar one-part piano melodies with unstructured note sequences, comparable in pitch and rhythm but devoid of any syntactic structure. This paradigm indexes a superset of the cognitive functions involved in processing of harmonic rules. Using functional magnetic resonance imaging, differential activation of a bilateral cortical network comprising the inferior frontal gyrus, superior temporal gyrus and premotor cortex was found. Using event-related potentials, the N2 evoked by each note in melodies was found to have longer latency and a more frontal distribution than that evoked in unstructured sequences.

Objective: To compare virological outcome and genotypic resistance profiles in HIV-1-infected patients starting non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens., Methods: NNRTI-naive patients were included who started treatment with nevirapine (NVP) or efavirenz (EFV) with genotypic resistance test results available at time of initiation (baseline). Virological failure was defined as two consecutive values > 500 copies/ml after starting the regimen. Cox models were used to investigate time to virological failure (the first of two values)., Results: A total of 759 patients were included (13% antiretroviral-naive): 389 initiated NVP and 370 initiated EFV. Baseline IAS-USA NNRTI resistance mutations were detected in 3%. Using the Rega algorithm (version 7.1) to interpret resistance, 460 (64%) patients had resistance (full or intermediate) to at least one drug they were starting (69% NVP, 60% EFV, P = 0.011); 287 (74%) NVP and 168 (45%) EFV patients experienced virological failure after treatment initiation, P < 0.001. After adjustment for previous antiretroviral use, previous AIDS, year started NNRTI, CD4 cell count (baseline, nadir), viral load (baseline, maximum), and baseline drug resistance (measured by Rega), the relative hazards (EFV versus NVP) of virological failure was 0.50, 95% confidence interval: 0.39-0.65, P < 0.001. At time of virological failure, comparable levels of NNRTI resistance were detected. The K103N mutation emerged more in patients failing EFV and Y181C in patients failing NVP., Conclusions: NVP may be associated with an inferior virological outcome compared to EFV in NNRTI-naive patients with extensive resistance to other drug classes. The profile of NNRTI resistance mutations when virologically failing an NNRTI-containing regimen appears to depend on the NNRTI the patients fail.

Objective: To estimate the extent of drug resistance accumulation in patients kept on a virologically failing regimen and its determinants in the clinical setting., Design: The study focused on 110 patients of EuroSIDA on an unchanged regimen who had two genotypic tests performed at two time points (t0 and t1) when viral load was > 400 copies/ml., Methods: Accumulation of resistance between t0 and t1 was measured using genotypic susceptibility scores (GSS) obtained by counting the total number of active drugs (according to the Rega system v6.4.1) among all licensed antiretrovirals as of 1 January 2006. Patients were grouped according to the number of active drugs in the failing regimen at t0 (GSS&#95;f-t0)., Results: At t0, patients had been on the failing combination antiretroviral therapy (cART) for a median of 11 months (range, 6-50 months). Even patients with extensive resistance to the failing regimen were still receiving benefit from treatment. An overall 6-monthly increase of 1.96 (SD, 2.23) International Aids Society-mutations and an average loss of 1.25 (SD, 1.81) active drugs were estimated. In comparison with patients with GSS&#95;f-t0 = 0, the number of active drugs lost was -1.08 [95% confidence interval (CI), -2.13 to -0.03; P = 0.04] in those with GSS&#95;f-t0 of 0.5-1.5 and -1.24 (95% CI, -2.44 to -0.04; P = 0.04) in those with GSS&#95;f-t0 >or= 2., Conclusions: In patients kept on the same virologically failing cART regimen for a median of 6 months, there was considerable accumulation of drug resistance mutations, particularly in patients with initial low level of resistance to the failing regimen. Randomized comparisons of maintenance treatment strategies while awaiting a new suppressive therapy to become available are warranted.

Background: Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice., Methods: We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI)., Results: 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008)., Conclusion: In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Background: Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus., Methods: We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily., Results: The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken., Conclusion: These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential 'resistance-proof' strategy for achieving significant viral load suppression.

Objective: To assess the occurrence of viral load greater than 50 copies/ml in patients on highly active antiretroviral therapy (HAART) having achieved less than 50 copies/ml and the chance of whether a viral load greater than 50 copies/ml would lead to a sustained and increasing viral load., Design: A cohort of 553 patients on HAART with viral loads of less than 50 copies/ml were followed., Results: Over a median of 56 weeks 35% of patients experienced a transient increase and 8% virological failure (two consecutive viral loads of > 400 copies/ml). Transient increases and virological failure were more common in those with greater drug experience, and those with initial raised viral load values of more than 400 copies/ml were more likely to have a sustained increase and become virological failures., Conclusion: Transient increases in viral load are common, mainly in the 50-400 copies/ml range, and the majority of subsequent viral load estimations show a return to less than 50 copies/ml. A single raised viral load should lead to adherence support and intensified monitoring. Subsequent treatment decisions can then be based on evidence of true virological rebound and failure.

Objective: To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns., Methods: We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells., Results: Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence., Conclusions: This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.

Objective: To describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic., Subjects: A total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC)., Results: The median CD4 count at starting HAART was 171 x 10(6) cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years; P = 0.0008], as were previously treatment-naive patients (RH, 0.65; P = 0.0050), those in a clinical trial (RH, 0.64; P = 0.027) and those who started nelfinavir (RH, 0.57; P = 0.035). Patients who started with four or more drugs (RH, 2.21, P < 0.0001), who included ritonavir in the initial regimen (RH, 1.41; P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51; P < 0.0001) were more likely to modify HAART., Conclusions: There was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

Objective: To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed., Methods: We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen., Results: Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002)., Conclusion: Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption.

Background: Highly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses., Objectives: To describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre., Methods: Kaplan-Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London., Results: The median CD4 cell count at starting HAART was 186 x 10(6) cells/l [interquartile range (IQR) 76-310] and viral load was 5.13 log10 copies/ml (IQR 4.66-5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 x 10(6) cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2-4.4). At 6 months after the first viral load was < 400 copies/ml, 16.4% of patients were estimated to have failed on the basis of a single viral load > 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%)., Conclusion: A good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

Objective: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth., Methods: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery., Results: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery., Conclusions: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Objectives: Many haemophilic individuals infected with HIV died before receiving antiretroviral therapy (ART). Most who remain alive are chronically infected with hepatitis C virus (HCV), which has implications for their prognosis and choice of ART. The clinical status of a cohort of HIV-positive haemophilic men is reported together with their response to highly active antiretroviral therapy (HAART)., Design: Longitudinal cohort study., Setting: A comprehensive care haemophilia centre., Patients: A group of 111 haemophilic men who seroconverted to HIV in the period 1979 to 1985., Results: The cohort has been followed since 1979. By 30 April 1999, 57 of the 111 men had developed AIDS and 65 had died: Kaplan-Meier rates of 57.0% [95% confidence interval (CI) 46.9-67.0) and 65.1% (95% CI 52.7-77.4) by 19.5 years, respectively. AIDS rates have declined since 1997 but death rates have remained high, largely owing to deaths from non-HIV-related causes. Thirty-five patients remain alive and under follow-up at the clinic. The 28 men who had received ART had lower CD4 cell counts than the seven patients who had not received ART, but the two groups were otherwise similar. In total, 21 patients are known to have started HAART while under care at the centre. By 10-12 months after starting HAART, viral loads dropped by 2.06 log10 copies/ml and CD4 cell counts increased by 60 x 10(6) cells/l. In 10 out of 18 patients with viral loads initially > 400 copies/ml, a viral load below this level was attained; four had changed therapy at the time., Conclusions: While the decision to initiate HAART in haemophilic men should be made carefully because of the possible adverse events, our results suggest that a good response rate was achieved in this group of men.

Objective: To investigate the rate of decline of drug resistant viruses after stopping therapy., Design: Twenty-five patients receiving multiple combination therapies (mean five; range three to nine drugs) for more than 3 months were tested for HIV-1 resistance on therapy and off therapy. The sample off therapy was tested 6-175 days after stopping therapy., Methods: Patients were tested for genotypic changes associated with drug resistance using an in-house automated DNA sequencing assay to detect resistance in the protease and reverse transcriptase genes., Results: All samples tested when patients were on therapy showed evidence of drug resistance (range 1-9 mutations). The patients were divided into three groups: <2 weeks after stopping therapy, median 1.1 weeks (n = 8, group A); 2 weeks-2 months, median 6.4 weeks (n = 7, group B) and 2 months-6 months, median 12.9 weeks (n = 10, group C). Of primary mutations (protease: 30N, 461/L, 82A, 90M; reverse transcriptase: 70R, 184I/V, 215 Y/F) detected on therapy 100% remained after stopping therapy in group A; 68% remained in group B and 15% remained in group C. For secondary mutations 98% remained in group A; 99% remained in group B and 57% in group C., Conclusions: This study showed a rapid decline in detectability of the majority of primary mutations within 13 weeks of stopping combination therapy. From this data, HIV-1 resistance testing to direct patients' therapy should only be carried out when on existing therapy, or < 2 weeks off therapy, if reliable decisions are to be made relating to future combinations.

Objective: Previous studies on patients treated with potent antiretroviral therapy have shown that viral clearance rates do not tend to change between early and advanced HIV-1 infection. Our objective was to investigate whether the other major aspect of virus dynamics, viral replicative capacity, does change. In vitro work has indicated that the viral replicative, capacity increases but in vivo evidence has been lacking., Methods: As an in vivo measure of the viral replicative capacity, we studied the rate of rebound of plasma HIV RNA level during a 1-week therapy interruption in previously untreated patients who had received 2 weeks of antiretroviral therapy., Results: Such therapy in five previously drug-naive patients with high CD4 lymphocyte counts (mean, 611 x 10(6)/l) and five patients with low counts (mean, 49 x 10(6)/l) led to a mean 2.2 log10 copies/ml decrease in plasma HIV-1 levels (from 5-6 log10 copies/ml) in 2 weeks. This was similar in the two groups. Interruption of therapy for the ensuing week resulted in a stable HIV-1 level for approximately 2 days followed by a rebound towards pretherapy level, which was much more marked in the patients with low CD4 cell counts (estimated mean rise 2.22 log10 versus 1.06 log10 copies/ml; P < 0.02). After restarting therapy, HIV RNA levels returned to pre-interruption levels., Conclusions: These findings need confirmation, but the ability of HIV-1 to replicate in vivo appears to increase during HIV-1 infection. This increased replicative capacity, for which there are several potential explanations, may be the cause of gradual CD4 lymphocyte depletion.

Objective: To assess the prognostic value of HIV RNA levels measured shortly after HIV seroconversion and whether markers of immune response (CD4+ and CD8+ T-cell counts, IgA and IgG) measured at the same time, continue to provide prognostic information once the HIV RNA level is known., Design and Methods: HIV RNA levels were measured approximately 2.5 years after seroconversion in 97 haemophilic men followed for up to 17 years. Levels of CD4+ and CD8+ T cells, IgA and IgG were measured within 1 year of the HIV RNA level. The relationships between these markers and progression to AIDS and death were studied using Kaplan-Meier plots and proportional hazards regression models., Results: High HIV RNA levels were associated with faster progression to AIDS and shorter survival in univariate Cox regression models. High IgA and IgG levels were also associated with faster disease progression. In multivariate models, high HIV RNA levels remained independently associated with faster disease progression [relative hazard (RH), 1.86; P = 0.01 for AIDS; RH, 1.66; P = 0.05 for death). However, high IgA and IgG levels provided strong independent prognostic information for AIDS and death (IgA: RH, 1.38; P = 0.006 for AIDS; RH, 1.33; P = 0.07 for death; IgG: RH, 1.10; P = 0.02 for AIDS; RH, 1.12; P = 0.01 for death)., Conclusions: Our results confirm the importance of the HIV RNA level in assessing the long-term prognosis in individuals infected with HIV. However, our results suggest that immune activation markers, rather than merely reflecting high HIV RNA levels are important in assessing prognosis in their own right. These findings may improve our understanding of HIV pathogenesis and may aid clinical management of patients.

Objective: To evaluate the efficacy of 3TC (lamivudine), a synthetic nucleoside analogue that inhibits HIV reverse transcriptase in vitro, as treatment for HIV-positive, asymptomatic or mild AIDS-related complex patients., Design: Open-label, multinational and multicentre, non-comparative, escalating dose study., Methods: Patients who meet the selection criteria (n = 104) were enrolled in three European countries. Ten to 15 patients were included at each of the six dose levels of 3TC (0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 20.0 mg/kg daily in two divided doses every 12 h). Virological parameters--immune-complex dissociation (ICD) assay for HIV p24 antigenaemia, plasma HIV RNA load, whole blood assay and cellular viraemia--were evaluated at weeks 0, 4, 12 and 24., Results: Sustained reductions in HIV RNA load and in ICD p24 antigen levels were observed and maintained over the 12-week assessment period. Greater reductions were noted at higher doses but this trend did not reach statistical significance. In 38 patients, reductions of cell viraemia were significantly greater at 4 weeks for patients treated at higher doses of 3TC., Conclusion: These virological data show that 3TC is a potent inhibitor of HIV replication in HIV-positive, asymptomatic or mild ARC patients as assessed by ICD p24 antigenaemia, plasma HIV RNA load and cell viraemia.

Objective: To derive reliable estimates of the sensitivity of HIV-1 DNA polymerase chain reaction (PCR) in the neonatal period and to quantify the relative contributions of intra-uterine and intra-partum transmission., Methods: After reviewing studies on the early diagnosis of HIV-1 infection, investigators were asked to provide published and unpublished PCR test results on prospectively followed, non-breastfed, vertically infected children. Age-specific estimates of the sensitivity of PCR were derived using distribution-free methods for interval-censored data., Results: Data on 271 infected children were combined for analysis. PCR detected HIV-1 DNA in an estimated 38% [90% confidence interval (CI), 29-46] of HIV-infected children tested on the day of, or day after, birth. Sensitivity was observed to rise rapidly in the second week of life, reaching 93% (90% CI, 76-97) by 14 days of age., Conclusion: The sensitivity of PCR in the neonatal period is higher than previously reported. This affects the clinical interpretation of an early negative test result and encourages the use of PCR as an endpoint for trials to evaluate interventions to reduce vertical transmission in non-breastfed populations. Approximately one-third of vertically acquired HIV-1 infection could be attributable to intra-uterine transmission.

In an open study of the treatment of patients with AIDS-related complex (ARC) and AIDS with zidovudine, we evaluated the response of serum p24 antigen (p24Ag) and antibody to p24Ag (anti-p24) levels. Before treatment, serum from 49 out of 73 (67%) patients was p24Ag-positive, and of these patients 42 received zidovudine 800-1200 mg daily for greater than 4 weeks and had a baseline mean serum level of p24Ag of 119 pg/ml (s.e. 15.7). On zidovudine there was a reduction of p24Ag to 21.12% (s.e. 4.76) of pretreatment values at 3 months; however, there was a subsequent trend for levels after 6 months to increase to greater than 50% of pretreatment levels at 12 months. Serum levels of anti-p24 were measured in 26 patients. Of 16 patients whose serum contained p24Ag and 10 whose serum did not, four and nine, respectively, had detectable levels of anti-p24. There was no significant change in the serum anti-p24 with zidovudine therapy.