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Objective: We aimed to see if structured treatment interruption (STI) could be supported safely with the use of two cycles of IL-2 (4.5 MIU q12h subcutaneously 5 days) before STI to prolong the time before therapy restarted.Methods: Subjects were randomly allocated to either A - continuous ART; B - continue for 9 weeks, then STI; restart with the same ART when the CD4 count falls below 200 cells; or C-two cycles of IL-2, 8 weeks apart, while still on ART; at week 9 stop ART and use a new cycle of IL-2 alone whenever the CD4 count falls

Objectives: To describe the characteristics of deaths that occur among HIV-positive individuals in the HAART era.Design: Observational database.Methods: Deaths were reviewed that occurred among HIV-positive individuals seen at the Royal Free Hospital, London between January 1998 and December 2003.Results: Over the study period, there were 121 deaths; death rates declined from approximately 2.0/100 person-years of follow-up in 1998-2000 to approximately 1.0/ 100 person-years of follow-up in 2001-2003. Approximately one half of deaths (45.5%) were from AIDS-related causes and 74 deaths (61.2%) occurred in individuals who had received HAART: patients had been exposed to a median of seven (range 214) antiretroviral drugs and two-fifths had started treatment in the pre-HAART era. Another 15 patients had received only non-HAART treatment regimens prior to death. The median pre-death CD4 cell counts were 68 and 167 cells/mu l among those who had and had not received HAART; 23 (31.1 %) and 4 (8.5%) had HIV RNA < 400 copies/ml, respectively. Of the patients exposed to HAART for at least 6 months and who experienced viral rebound, information was available on resistance for 26 (21.5% of the total deaths) and 19 of those tested had at least one resistance mutation (median 5, range, 1-16).Conclusions: While mortality rates among HIV-infected individuals at our centre have fallen since 1988, the deaths that do now occur are more diverse and are the result of a number of factors, including late presentation, delayed uptake of HAART and the previous use of treatment combinations that are now viewed as suboptimal. (C) 2006 Lippincott Williams & Wilkins.

Objectives: To study the long-term CD4 cell responses to highly active antiretroviral therapy (HAART) in treatment-naive patients whose viral loads remained below 500 copies/ml for prolonged periods. Design: A total of 237 patients whose viral loads remained below 500 copies/ml for one year or more. Median follow-up was 1.9 years. Methods: CD4 cell counts were analysed to investigate long-term immunological response using mixed-effects models with the slope allowed to change after 1, 12 and 24 months of HAART. Results: The median baseline CD4 cell count was 175 cells/mm 3 . After an initial rapid increase in the first month after HAART (97.2 cells/mm 3 a month), increases in CD4 cell counts continued less rapidly (11.6 cells/mm 3 a month). This increase slowed by 2.4 cells/mm 3 a month after one year. CD4 cell counts continued increasing after 2 years, but the rate of increase again slowed (estimated slope at 2 years 5.4 cells/mm 3 a month; decrease in slope from year 2 compared with years 1-2 3.7 cell/mm 3 a month). A total of 198 out of 211 patients (94%) with measurements at baseline and one year experienced an increase in CD4 cell counts in this interval; 81 and 67% had an increasing slope between 1 and 2 and 2 and 3 years, respectively. By the end of follow-up, CD4 cell counts had increased by 319 cells/mm 3 , and were more than 500 cells/mm 3 in 40% of patients. Conclusion: Although the rate of immune recovery slowed after 2 years, CD4 cell counts rose in most and began to return to levels seen in HIV-negative individuals.

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. (C) 2003 Lippincott Williams Wilkins.

To describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic.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).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, P0.0001), 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; P0.0001) were more likely to modify HAART.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 log(10) 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/mm(3) in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm(3) 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 (C) 2000 Lippincott Williams & Wilkins.

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 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 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 day c 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 In = 8, group A); 2 weeks-2 months, median 6.4 weeks In = 7, group B) and 2 months-6 months, median 12.9 weeks In = 10, group C). Of primary mutations (protease: 30N, 461/L, 82A, 90M; reverse transcriptase: 70R, 1841/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 To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment. METHODS The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged > or = 14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described. RESULTS A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P 30% before 1990 to < 5% during 1997 (P = 0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission. CONCLUSIONS Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.

The occurrence of viral breakthrough on treatment was examined in 233 previously antiretroviral-naive HIV-infected patients who started highly active antiretroviral therapy (HAART) and who achieved initial viral suppression to less than 50 copies/ml. The rate of viral breakthrough despite the continuation of therapy was 3.6 per 100 person-years (12 cases occurred during 332.8 person-years of follow-up). Viral suppression on HAART is proving extremely durable in those who can tolerate these regimens over long periods.

Objective: To determine the efficacy of high-dose oral acyclovir in preventing cytomegalovirus (CMV) and other herpesvirus disease in patients with advanced HIV disease and to evaluate its effect on patient survival.Design: Double-blind, placebo-controlled randomized trial of up to 1 year's therapy.Setting: Outpatient clinics in 16 hospitals in Europe and Australia.Participants: A total of 302 patients with Centers for Disease Control and Prevention stage IV HIV disease, seropositive for CMV and with CD4+ lymphocyte counts less than or equal to 50x10(6)/l.Interventions: Oral acyclovir (800 mg, four times daily) or matching placebo for 48 weeks.Main outcome measures: Time to development of CMV and other herpesvirus disease. Following the resuIts of another study, the protocol was amended to make survival a second major endpoint.Results: Acyclovir fai led to reduce the incidence of CMV disease: the probability of developing CMV disease at 1 year was 0.24 and 0.23 in the placebo and acyclovir groups, respectively (P=0.53). However, acyclovir significantly reduced the probability of dying at 1 year of follow-up (from 0.39 to 0.23; P=0.018). As expected, acyclovir significantly reduced the incidence and frequency of herpes simplex virus disease. There were no notable differences between treatment groups in clinically adverse experiences and no changes in haematological parameters to indicate clinically significant drug-induced toxicity.Conclusions: High-dose acyclovir failed to reduce the incidence of CMV disease, but significantly reduced the probability of dying at 1 year of follow-up.

We prospectively followed 166 individuals on antiretroviral therapy with viral loads less than 50 copies/ml and CD4 cell counts greater than 500 cells/mm 3 to ascertain CD4 cell count changes while the viral load remained below 50 copies/ ml. On average, CD4 cell counts remained stable and high. Only five patients experienced a decline to below 350 cells/mm 3 , and these were typically isolated low values with CD4 cell percentages remaining high. Our findings suggest that it may be possible to reduce the frequency of CD4 cell count monitoring in individuals with a value greater than 500 cells/mm 3 so long as regular viral load monitoring indicates a value less than 50 copies/ml.

Addition of varying concentrations of HIV-1-seropositive plasma to purified virus particles and soluble viral antigen preparation inhibited the detection of HIV-1-antigen by ELISA. The degree of inhibition on p24 antigen ELISA depended on the relative concentrations of viral antigen and anti-p24 antibodies in the mixtures. The relevance of these observations to clinical specimens was demonstrated when serial plasma samples from nine AIDS-related complex (ARC) patients in a clinical trial of foscarnet therapy were assayed for p24 antigen. Six (66.6%) out of nine patients were negative on screening. However, when their plasma was centrifuged through a sucrose solution, virus particles were pelleted that were depleted of anti-p24 and virus-specific p24 antigen was detected in resuspended pellets obtained from samples from all six patients. Eight serial samples collected from a male homosexual over 50 weeks following seroconversion were also subjected to the separation procedure. HIV-1-antigen was detected in all eight samples. In the light of these observations, the application of the separation technique in monitoring the efficacy of zidovudine or other anti-retroviral therapy should reveal more precise antigen levels in patients who otherwise appear to be antigen-negative in HIV-antigen assays. We propose that the natural history of HIV infections follows a pattern of chronic viral infection with continuous shedding of virus particles circulating as immune complexes.