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Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Objectives: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. Methods: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12±3months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL'200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4count '750cells/μL or a 33% increase where the baseline CD4 count was ≥500 cells/μL. Poisson regression compared clinical failures (AIDS/death≥14days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. Results: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged ' 50years, 2539 (49.4%) had CD4 counts '350 cells/μL and 1891 (36.8%) had VL'100000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40–50 and '50 years), CD4 count categories (≤ 350 vs. '350 cells/μL) and VL categories at ART initiation (≤ 100000 vs. '100000copies/mL), with all investigated interactions being nonsignificant (P'0.05). Conclusions: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

Objectives To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. Methods Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL), SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVES. There is currently an urgent need to harmonize hepatitis standards of care for HIV-positive patients across Europe. The HIV epidemic in Central and Eastern Europe has often been driven by injecting drug use, therefore a higher rate of co-infection with HCV and HBV is expected in this region. We have investigated the epidemiological prevalence and treatment availability for end-stage liver disease in HIV/HCV/HBV coinfections in countries represented in the ECEE Network Group. METHODS. The Euroguidelines in Central and Eastern Europe (ECEE) Network Group was initiated in February 2016 to compare standards of care regarding HIV infection in the region. Information about HIV/HCV/HBV co-infections and the availability for end-stage liver disease treatment for HIV-positive patients were collected through on-line surveys. The respondents were ECEE members from 16 countries of the region. The information on co-infection prevalence was sourced from WHO, national HIV programmes, articles published in international journals, single clinic reports, and personal information in ten of the participating countries (62.5%). RESULTS. The HIV/HCV co-infection rate was from 3% to 99%. The range of reported of HIV/HBV coinfection percentages was 2.3% to 40%. HIV/HCV/HBV co-infection ranged from 0% to 9%. Regarding treatment for end-stage liver disease, liver transplantation was an available option for HIV-positive patients in only three countries (19%). CONCLUSION. Our findings revealed only a limited number of treatment options for the end-stage liver disease in HIV-positive patients for the vast majority of Central and Eastern European countries. There are gaps in epidemiological surveillance in this region. It appears there are many differences in the number of co-infected patients among Central and Eastern European and neighboring countries, but there is no unification of information sources.

Transition from adolescent to adult care can be challenging for youth living with HIV. We conducted a cohort study of youth born between 1985 and 1993 and infected with HIV parenterally, followed by the same medical team from age 15 years or first clinic visit until age 25 years or 30 November 2016. A longitudinal continuum-of-care was constructed, categorizing individuals' status for each month of follow-up as: engaged in care (EIC); not in care (NIC: no clinic visits within past year); lost-to-follow-up (LTFU: NIC and did not return to clinic); or died. Five hundred and forty-five individuals (52% male) were followed for 4775 person-years. At age 15, 92% were EIC, decreasing to 84% at age 20 and 74% at age 25. Of those EIC, HIV outcomes improved with age: 79% and 52% had a CD4 ≥200 cells/µl and VL400 cps/ml at age 15; increasing to 86% and 73% at age 20 and 87% and 80% at age 25. We conclude that youth infected during early childhood tended to disengage from care, even when followed by the same medical team for a lengthy period of time. For those that did engage in care, HIV-related outcomes improved from adolescence through adulthood.

WOS: 000379080900004, PubMed ID: 26492497, ObjectivesThe objective of the 1st European AIDS Clinical Society meeting on Standard of Care in Europe was to raise awareness of the European scenario and come to an agreement on actions that could be taken in the future. MethodsData-driven presentations were given on specific topics followed by interactive panel discussions. ResultsIn Eastern European countries, the epidemic is largely driven by injecting drug use, in contrast with Western Europe where the infection mainly occurs through heterosexual contact. A high proportion of people living with HIV remain unaware of their infection. Substantial differences exist in Eastern Europe and Central Asia with respect to treatment coverage, regimen availability and continuity of drug supply. In 2012, tuberculosis case notification rates were 5-10 times higher in Eastern Europe compared with Western Europe, with an alarming proportion of newly diagnosed multi-drug-resistant cases. Hepatitis C is widespread in selected geographical areas and risk groups. ConclusionsThe key conclusion from the meeting was that a high-priority group of actions could be identified, including: increasing HIV awareness and testing, improving training for health care providers, ensuring equitable patient access to treatments and diagnostics for HIV and comorbidities, and implementing best practices in infection control and treatment of HIV-infected patients coinfected with tuberculosis and hepatitis C virus, for whom direct acting antiviral treatment. should be considered., Medical Research CouncilMedical Research Council UK (MRC) [MC_UU_12023/15]

More and more highly treatment-experienced patients are achieving viral suppression. However, the durability of suppression remains unclear.Patients from Royal Free Hospital (London, UK) and JW Goethe University Hospital (Frankfurt, Germany) who had failedor = 1 antiretroviral (ARV) regimen in all three main drug classes andor = 3 previous ARV regimens and subsequently achieved viral load50 HIV-1 RNA copies/mL were included. They were followed until stopping pre-combination antiretroviral therapy, end of follow-up or viral rebound (two viral loads400 copies/mL).Two hundred and forty-seven patients contributed 723 person-years and 114 viral rebounds [rate=15.8 per 100 person-years; 95% confidence interval (CI) 12.9-18.7]. More recent calendar years of viral suppression [relative risk (RR)=0.90 per year later; 95% CI 0.81-1.00; P=0.05] and greater number of ARVs in the regimen not previously failed (RR=0.78 per 1 ARV more; 95% CI 0.65-0.95; P=0.01) were associated with lower viral rebound rates. At 0-1, 1-2, 2-3 and3 years after achieving suppression, the rebound rates were 30.9, 9.2, 4.3 and 3.5 per 100 person-years, respectively. Compared to 0-1 years, the adjusted RRs (95% CIs) after 1-2, 2-3 and3 years were 0.33 (0.18-0.58), 0.21 (0.09-0.48) and 0.14 (0.06-0.33), respectively (P0.0001).Although rebound rates are high, especially in the first year after viral suppression, this risk reduces substantially if highly treatment-experienced patients can maintain viral suppression.

OBJECTIVE: To assess and compare alternative approaches of measuring preference-based health-related quality of life (HRQoL) in treatment-experienced HIV patients and evaluate their association with health status and clinical variables. DESIGN: Cross-sectional study. SETTING: Twenty-eight Veterans Affairs hospitals in the United States, 13 hospitals in Canada, and 8 hospitals in the United Kingdom. PATIENTS: Three hundred sixty-eight treatment-experienced HIV-infected patients enrolled in the Options in Management with Antiretrovirals randomized trial. MEASUREMENTS: Baseline sociodemographic and clinical indicators and baseline HRQoL using the Medical Outcome Study HIV Health Survey (MOS-HIV), the EQ-5D, the EQ-5D visual analog scale (EQ-5D VAS), the Health Utilities Index Mark 3 (HUI3), and standard gamble (SG) and time trade-off (TTO) techniques. RESULTS: The mean (SD) baseline HRQoL scores were as follows: MOS-HIV physical health summary score 41.70 (11.16), MOS-HIV mental health summary score 44.76 (11.38), EQ-5D 0.77 (0.19), HUI3 0.59 (0.32), EQ-5D VAS 65.94 (21.71), SG 0.75 (0.29), and TTO 0.80 (0.31). Correlations between MOS-HIV summary scores and EQ-5D, EQ-5D VAS, and HUI3 ranged from 0.60 to 0.70; the correlation between EQ-5D and HUI3 was 0.73; and the correlation between SG and TTO was 0.43. Preference-based HRQoL scores were related to physical, mental, social, and overall health as measured by MOS-HIV. Concomitant medication use, CD4 cell count, and HIV viral load were related to some instruments' scores. CONCLUSIONS: On average, preference-based HRQoL for treatment-experienced HIV patients was decreased relative to national norms but also highly variable. Health status and clinical variables were related to HRQoL.

Objectives: Subcutaneous administration of interleukin-2 (IL-2) has been shown to increase CD4 counts in HIV-infected patients. It remains unclear whether this effect is associated with a clinical benefit. Patients and methods: We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm 3 received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively. Results: Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non-significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely. Conclusions: We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention.

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

A working group of the European AIDS Clinical Society (EACS) have developed these guidelines for European clinicians to help them in the treatment of adults with HIV infection. This third version of the guidelines includes, as new topics, the assessment of patients at initial and subsequent clinic visits as well as post-exposure prophylaxis. A revision of the 2005 guidelines based on current data includes changes in the sections on primary HIV infection, when to initiate therapy, which drug combinations are preferred as initial combination regimens for antiretroviral-naïve patients, how to manage virological failure and the treatment of HIV during pregnancy. In Europe, there is a wide range of clinical practices in antiretroviral therapy depending on various factors such as drug registration, national policies, local availability, reimbursement and access to treatment. These can vary greatly from one country to another, especially in Central and Eastern parts of Europe. These guidelines are intended to help clinicians achieve the best care for their patients. In some countries, particularly where the quality of and access to care are not optimal, these guidelines should help AIDS societies and physicians or patient group organizations to negotiate with their national health authorities with a view to implementing what should be the standard of care for HIV-infected patients all over Europe.

Objectives To determine prevalence and predictors of antiretroviral drug resistance in newly diagnosed individuals with HIV-1 infection, using a systematic approach to avoid selection bias. Methods Plasma samples from all persons diagnosed HIV-1 seropositive at a large London centre between April 2004 and February 2006 underwent sequencing of HIV-1 reverse transcriptase (RT) and protease genes. Subtype was assigned by phylogenetic analysis. Resistance was scored according to the IAS-USA list (2005) modified to include T215revertants and exclude isolated E44D or V118I and minor protease mutations. Recent seroconversion was identified by HIV antibody avidity testing. Results The cohort of 239 included 169 (70.7%) males, 126 (52.7%) homosexuals, 118 (49.5%) persons of white ethnicity and 144 (60.0%) persons born outside the UK. Subtypes included B 134 (56.1%), C 46 (19.2%), A 17 (7.1%), other non-B 42 (17.6%). The prevalence of resistance mutations was 17/239 (7.1%; 95% confidence interval 4.5-11.1%), comprising 10/239 (4.2%) nucleoside/nucleotide RT inhibitor (NRTI); 4/239 (1.7%) non-nucleoside RT inhibitor (NNRTI) and 4/239 (1.7%) protease inhibitor (PI) associated mutations. Dual-class (NRTI + PI) resistance mutations were detected in 1/239 (0.4%) person. The prevalence of resistance mutations was 7/85 (8.2%) and 10/154 (6.5%) in persons with recent and established infection, respectively. In multivariate analysis, having been born in the UK and high CD4 count, but not gender, age, risk group, ethnicity or subtype, were independent predictors of resistance. Conclusions In an unselected UK cohort, subtypes other than B accounted for 43.9% of new HIV-1 diagnoses. The prevalence of resistance mutations was 7.1% and highest in those born in the UK.

Nucleoside analogue reverse transcriptase inhibitors (NRTIs), used as part of highly active antiretroviral therapy for the treatment of HIV and AIDS, disrupt neuronal mitochondrial DNA synthesis, resulting in antiretroviral toxic neuropathy (ATN). Acetyl-L-carnitine (ALC) enhances neurotrophic support of sensory neurons, potentially causing symptom relief and nerve regeneration, and in addition has numerous other effects on metabolic function that might be of benefit in such patients.ALC has been given to HIV patients with symptomatic ATN in a number of clinical studies administered either twice daily intramuscularly or as oral sachets or tablets. It has been shown to significantly reduce a variety of validated pain ratings, and is generally safe and well tolerated. Using a measure of neuronal innervation in standardised skin biopsies of the affected area, cutaneous nerve density has been improved by the administration of ALC in subjects with symptomatic ATN and reduced epidermal and dermal innervation, associated with clinical improvement, which was maintained over a 4-year period. Improvements were seen in both the structure and function of small sensory fibres, which were sustained over time whilst subjects received ALC. Other open-label, non-randomised studies have shown similar benefits in patients with ATN in terms of pain reduction over the short term. Further placebo-controlled studies of both treatment and prophylaxis have been completed and are under analysis to characterise further the usefulness of this pathogenesis-based therapy for ATN.

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log 10 copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope ( Env ) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.

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.

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) used for the treatment of HIV can a cause distal symmetrical peripheral polyneuropathy by disruption of mitochondrial metabolism. Treatment with acetyl-L-carnitine (ALCAR) has shown short-term symptomatic and histological improvement. Long-term effects have not been investigated.To assess the subjective and objective degree of antiretroviral toxic neuropathy (ATN) during treatment with ALCAR.A cohort of 21 patients with ATN who commenced treatment with ALCAR between March 1999 and October 2001 was reviewed after a mean of 4.3 years using standardized questionnaires and neurological examination.Of the 21 patients, 2 had died and 3 were lost to follow-up. 16 patients were assessed. 10 were still on potentially neurotoxic drugs. 13 were still taking ALCAR. 9 were pain free. The most common symptom was numbness (mild, moderate, and severe in 12, 3, and 0 patients, respectively), followed by paraesthesia (8, 2, 2), pain (4, 3, 0), and burning (5, 2, 0). There was mildly reduced sensation in the toes of 8 patients. 13 patients reported that ALCAR had improved their symptoms very much or moderately, 2 reported no change, and 1 reported a moderate worsening.ALCAR led to long-term symptomatic improvement in most patients without the need to discontinue neurotoxic drugs. Although in this study there was no control group, this agent appears to be an effective pathogenesis-based treatment for ATN.

OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency syndrome events or death, and prove to be more cost-effective in treating human immunodeficiency virus-infected individuals previously exposed to ART drugs from the current three main classes. The aim is to randomize 1700 participants to four treatment strategy arms: (1) ARDFP + standard-ART; (2) ARDFP + mega-ART; (3) no ARDFP + standard-ART; (4) no ARDFP + mega-ART. The planned study duration is 3.5 years with 2.5 years of intake and a minimum 1 year of follow-up. The OPTIMA Trial was initiated in June 2001 at 30 U.S. Department of Veterans' Affairs hospitals, 22 hospitals in Canada, and 25 hospitals in the United Kingdom. This is the first large-scale, multicenter, randomized controlled trial to compare the relative efficacy of these different therapeutic strategies. We discuss the rationale behind the OPTIMA Trial design as well as the issues arising from the conduct of a trial that involves three national clinical trial agencies.

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.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution.

This study evaluated 1433 human immunodeficiency virus (HIV)–infected patients starting highly active antiretroviral therapy (HAART), 409 (28%) of whom had prior nucleoside experience and achieved an HIV load of !400 copies/mL by 24 weeks of therapy. Three hundred seven patients experienced virus rebound during a total of 2773.3 person-years of follow-up. There was a higher rate of virus rebound among the patients with pre-HAART nucleoside experience (relative hazard [RH], 2.86; 95% confidence interval, 2.22–3.84; ) and a P ! .0001 decreasing rate of virus rebound with increasing duration of virus suppression (i.e., time since achieving a virus load of !400 HIV RNA copies/mL) among both the nucleoside-experienced and naive patients ( ), but the difference between the groups persisted into the third P ! .0001 year of follow-up ( ). Even patients who had experienced !2 months of nucleoside P p .0007 therapy before beginning HAART had an increased risk of virus rebound (RH, 1.95; P p ). It appears that only a small period of pre-HAART nucleoside therapy is sufficient to .009 confer a disadvantage, in terms of risk of virus rebound, that persists for several years.

To determine the association between preexisting characteristics and current health and the cost of different types of advanced human immunodeficiency virus (HIV) care.Treatment-experienced patients failing highly active antiretroviral treatment (ART) in the United States, Canada, and the United Kingdom were factorial randomized to an antiretroviral-free period and ART intensification. Cost was estimated by multiplying patient-reported utilization by a unit cost.A total of 367 participants were followed for a mean of 15.3 quarters (range 1-26). Medication accounted for most (61.8%) of the $26,832 annual cost. Cost averaged $4147 per quarter for ART, $1981 for inpatient care, $580 for outpatient care, and $346 for other medications. Cost for inpatient stays, outpatient visits, and other medications was 171% higher (P.01) and cost of ART was 32% lower (P.01) when cluster of differentiation 4 (CD4) count was50 cells/μL compared with periods when CD4 count was200 cells/μL. Some baseline characteristics, including low CD4 count, high viral load, and HIV from injection drug use with hepatitis C coinfection, had a sustained effect on cost.The association between health status and cost depended on the type of care. Indicators of poor health were associated with higher inpatient and concomitant medication costs and lower cost for ART medication. Although ART has supplanted hospitalization as the most important cost in HIV care, some patients continue to incur high hospitalization costs in periods when they are using less ART. The cost of interventions to improve the use of ART might be offset by the reduction of other costs.

To investigate whether asymptomatic cytomegalovirus (CMV) viraemia impact the course of human immunodeficiency virus (HIV) infection, this study evaluated the effect of CMV replication on progression of newly-diagnosed HIV infected individuals towards AIDS events and death. In a 3-year prospective study on co-infected patients, clinical, immunological, and virological tests were performed in a national reference hospital quarterly. CMV viraemia was quantified by RoboGene® HCMV DNA Quantification Kit (Analytik Jena, Germany), on ABI Prism® 7000 Sequence Detection System (Applied Biosystems, USA). One hundred and five patients were enrolled with a balanced sex distribution and a median age of 30.7 years. Median CD4(+) cell count at enrollment was 164/mm(3) and median HIV RNA 4.6 log10 copies/ml. Detectable CMV viraemia was found in 25.7% of the patients. Kaplan-Meier analysis showed progression of HIV infection to be significantly increased in those with active CMV replication and/or low CD4(+) cell count. Cox regression indicated the risk of developing new AIDS events was 2.6 times greater in patients with detectable CMV viraemia versus those without (CI95% 1-6.6; P = 0.04). Also in multivariate analysis, the overall risk of progression to AIDS events or death was 3-fold higher in those with detectable CMV viraemia (CI95% 1.3-6.7; P = 0.008) and 2.3-fold higher if CD4(+) cell count was below 100/mm(3) (CI95% 1-5.1; P = 0.04). In these young Romanian HIV-seropositives, active CMV replication increased morbidity, even when treated with combination antiretroviral therapy. Further studies are needed to evaluate if serial quantitative CMV-DNA levels might correlate with non-infectious inflammation-related risks in patients with HIV and active CMV infection.

To compare health-related quality of life (HR-QOL) in individuals infected with HIV to general population levels and to assess the relationship between HR-QOL and markers of disease progression in the era of highly active antiretroviral therapy (HAART).This was a cross-sectional questionnaire-based study. This study included 154 individuals at least 18 years old with HIV who either were attending a London hospital or were visited by a community team in Brighton. Study participants were asked to complete two HR-QOL questionnaires. This study used HR-QOL, as measured using the Medical Outcome Study HIV Health Survey (MOS-HIV) and EuroQoL self-report (EQ-5D) questionnaires, as the main outcome measure. Responses on the EQ-5D were compared with a published general population data set. The relationships between scores on the MOS-HIV and EQ-5D questionnaires and a number of independent variables including CD4 count and viral load were also assessed.Each analysis was based on the results of at least 128 questionnaires. The mean MOS-HIV mental and physical component scores were 43.2 (SD = 12.2) and 41.8 (SD = 13.2), respectively. After adjusting for differences in age and gender, it was shown that individuals with HIV reported significantly lower EQ-5D(utility) ( p =.0001) and EQ-5D(VAS) ( p =.0001) compared with the general population. However, further analysis revealed few significant associations between markers of disease progression and HR-QOL.Individuals with HIV generally recorded significantly lower HR-QOL compared with the general population. Thus, prevention of further transmissions of the virus is still likely to prevent significant morbidity losses in addition to mortality losses, despite the availability of HAART. However, disease progression as measured is not clearly related to further reductions in HR-QOL.

The steady-state pharmacokinetics of efavirenz and nevirapine, when used in combination to treat human immunodeficiency virus type 1 (HIV-1)-infected subjects, were investigated. HIV-1-infected persons who had used efavirenz (600 mg once daily) for > or =2 weeks were eligible for study inclusion. The plasma pharmacokinetics of efavirenz were determined over 24 h. Subsequently, nevirapine (400 mg once daily) was added to the regimen. After 4 weeks, the pharmacokinetics of efavirenz and nevirapine were assessed over 24 h. The differences between the pharmacokinetic parameters of efavirenz with and without nevirapine were analyzed, and the pharmacokinetics of nevirapine were compared with those in historical control patients. The exposure to efavirenz when combined with nevirapine was significantly decreased by 22% (area under the plasma concentration vs. time curve), 36% (minimum plasma concentration), and 17% (maximum plasma concentration). Nevirapine pharmacokinetics appear to be unaffected by coadministration of efavirenz, compared with data from historical control patients.

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.

The correlation of detectable HIV-1 drug resistance mutations in plasma and PBMCs in patients extensively treated with all antiretroviral drug classes has not been fully elucidated. The detection of mutations in PBMCs may reveal resistant HIV-1 associated with past therapies. In addition, these measures in PBMCs may have a practical value when plasma virus is at low levels that are difficult to detect with current assays. The reverse transcriptase (RT) and protease (P) genes were analyzed for drug resistance, using an in-house method carried out on 36 paired samples of plasma and PBMCs from 12 treatment-experienced patients in order to investigate resistance in the two compartments. When viruses in plasma and PBMCs were analyzed by patient, the mean of the Cohen kappa values was 0.728 (substantial agreement). When viruses were analyzed by codon the mean of the Cohen kappa values was 0.715 (substantial agreement). Baseline samples were concordant at 280 of 288 (97%) codons analyzed. This study shows that a minority of mutations associated with previous therapy can be detected in PBMCs and not in plasma. Overall, mutations in plasma and PBMCs showed a substantial correlation in extensively treated patients, suggesting that either compartment is suitable for the detection of mutations as a virological guide for clinical care.

Objective To report a novel clinical presentation: a chronic erosive herpes simplex virus (HSV) infection of the penis which developed in AIDS patients following the commencement of highly active antiretroviral therapy (HAART). The lesions were unresponsive to antiviral treatments which had previously been effective, and this could not be accounted for in terms of increased antiviral resistance. Design Detailed case-note review and investigation of three cases which presented at two large HIV units in London. Methods Review of all histology with immunohistochemistry for HSV, HSV drug susceptibility assays, tissue typing and measurement of in vitro lymphocyte functional activity against HSV. Results The histology of the lesions was the same in each case, with the presence of HSV on immunohistochemistry and an unusual prominence of plasma cell and eosinophils in the inflammatory infiltrate. HSV-specific lymphoproliferative responses were normal in two cases, but subnormal in a third case. All individuals shared the HLA class I molecules B72 and Cw0202 and the class II allele DRB4. Conclusion We believe this to be a previously unreported adverse consequence of HAART, the result of partial immune restoration, reminiscent of the the recently described syndrome of immune recovery vitritis.

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open-label phase I/II dose-ranging study in protease inhibitor-naive HIV-positive men. A total of 22 patients with baseline plasma HIV RNA ≥ 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm 3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy. A capsule formulation of nelfinavir was used. The initial study period was 28 days; patients showing a virologic response of 1 log 10 reduction were eligible for enrollment in an extension phase and addition of nucleoside analogues. A maximally tolerated dose of nelfinavir was not established. A dose-response relationship was observed for four (40%) patients in the 771-mg group and six (60%) patients in the 1,026-mg group experiencing a reduction from baseline in plasma HIV RNA of at least 1 log during the 28-day study. of these patients, five sustained the reduction in plasma HIV RNA beyond day 28 (2 patients receiving 771 mg/day and 3 patients receiving 1,026 mg/day). Median increases from baseline in CD4+ counts at day 28 were 216 cell/mm 3 and 86 cell/mm 3 in the 771-mg and 1,026-mg groups, respectively. After oral administration, median nelfinavir plasma concentrations on day 28 reached a maximum at 1 hour (2,966 ng/mL) in the 771-mg group and at 3 hours (3,157 ng/mL) in the 1,026-mg group. Data for 22 patients were included in the safety analysis; 12 patients (55%) reported at least one grade 2 or worse (moderate, severe, or very severe) adverse event. The most common grade 2 or worse adverse event was diarrhea, reported by two patients (20%) receiving 771 mg/day and seven patients (70%) receiving 1,026 mg/day; followed by nausea, flatulence, asthenia, and headache (each reported in 1 patient [10%] in the 771-mg group) and dizziness (reported in 1 patient [10%] receiving 1,026 mg/day). In the small subgroup (n = 6) who continued taking nelfinavir for longer periods (between 8 and 15 months), virologic responses were sustained in the majority of patients with good tolerability. Nelfinavir is an active HIV-protease inhibitor with favorable pharmacokinetics, good tolerability, and sustained antiviral effects. Results of this early phase I/II dose-ranging study provided data for the safety and antiretroviral activity of nelfinavir and led to the selection of higher doses for phase II/III trials to further optimize virologic and immunologic responses.

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [ n = 6], 90 mg/kg twice daily [BID] [ n = 6], and 180 mg/kg QD [ n = 3]) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean ± standard deviation) 46.4 ± 10.8 μM (90 mg/kg QD), 45.7 ± 6.9 μM (90 mg/kg BID), and 64.9 ± 31.7 μM (180 mg/kg QD) on day 1 and rose to 86.2 ± 35.8, 78.7 ± 35.2, and 86.4 ± 25.0 μM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 ± 102.7 μM ( n = 13). The terminal half-life in plasma remained unchanged, averaging 5.5 ± 2.2 h on day 1 ( n = 15) and 6.6 ± 1.9 h on day 8 ( n = 13), whereas it was 5.7 ± 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% ± 2.2% (90 mg/kg QD), 9.5% ± 1.7% (90 mg/kg BID), and 7.6% ± 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 ± 1.1, 1.8 ± 0.4, and 1.7 ± 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% ± 2.6% (day 1) and 13.4% ± 6.0% (day 8), whereas it was 95.0% ± 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 ± 18 ml/min (day 1), 88 ± 13 ml/min (day 8), and 103 ± 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection with antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naïve to therapy; (ii)support of patients on treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines.

AimInvestigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months.MethodsPatients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996-2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively.ResultsAll regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens.ConclusionThe single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.

Background The organic anion transporting polypeptides (OATP)/SLCO family represents an important class of hepatic drug uptake transporters that mediate the sodium independent transport of a diverse range of amphipathic organic compounds, including the protease inhibitors. The SLCO1B1 521T>C (rs4149056) single nucleotide polymorphism (SNP) has been consistently associated with reduced transport activity in vivo, and we previously showed an association of this polymorphism with lopinavir plasma concentrations. The aim of this study was to develop a population pharmacokinetic (PK) model to quantify the impact of 521T>C. Methods A population PK analysis was performed with 594 plasma samples from 375 patients receiving lopinavir/ritonavir. Non-linear mixed effects modelling was applied to explore the effects of SLCO1B1 521T>C and patient demographics. Simulations of the lopinavir concentration profile were performed with different dosing regimens considering the different alleles. Results A one-compartment model with first-order absorption best described the data. Population clearance was 5.67 l/h with inter-patient variability of 37%. Body weight was the only demographic factor influencing clearance, which increased 0.5 l/h for every 10 kg increase. Homozygosity for the C allele was associated with a 37% lower clearance, and 14% for heterozygosity, which were statistically significant. Conclusions These data show an association between SLCO1B1 521T>C and lopinavir clearance. The association is likely to be mediated through reduced uptake by hepatocytes leading to higher plasma concentrations of lopinavir. Further studies are now required to confirm the association and to assess the influence of other polymorphisms in the SLCO family on lopinavir PK.

Background. The effect of antiretroviral therapy (ART) interruption or intensification on health-related quality of life (HRQoL) in advanced HIV patients is unknown. Objective. To assess the impact of temporary treatment interruption and intensification of ART on HRQoL. Design. A 2 x 2 factorial open label randomized controlled trial. Setting. Hospitals in the United States, Canada, and the United Kingdom. Patients. Multidrug resistant (MDR) HIV patients. Intervention. Patients were randomized to receive a 12-wk interruption or not, and ART intensification or standard ART. Measurements. The Health Utilities Index (HUI3), EQ-5D, standard gamble (SG), time tradeoff (TTO), visual analog scale (VAS), and the Medical Outcomes Study HIV Health Survey (MOS-HIV). Results. There were no significant differences in HRQoL among the four groups during follow-up; however, there was a temporary significant decline in HRQoL on some measures within the interruption group during interruption (HUI3 −0.05, P = 0.03; VAS −5.9, P = 0.002; physical health summary −2.9, P = 0.001; mental health summary −1.9, P = 0.02). Scores declined slightly overall during follow-up. Multivariate analysis showed significantly lower HRQoL associated with some clinical events. Limitations. The results may not apply to HIV patients who have not experienced multiple treatment failures or who have not developed MDR HIV. Conclusions. Temporary ART interruption and ART intensification provided neither superior nor inferior HRQoL compared with no interruption and standard ART. Among surviving patients, HRQoL scores declined only slightly over years of follow-up in this advanced HIV cohort; however, approximately one-third of patients died during the trial follow up. Lower HRQoL was associated with adverse clinical events.

BACKGROUND\ud \ud The number of people living with HIV (PLHIV) is increasing in the UK. This study estimated the annual population cost of providing HIV services in the UK, 1997-2006 and projected them 2007-2013.\ud \ud METHODS\ud \ud Annual cost of HIV treatment for PLHIV by stage of HIV infection and type of ART was calculated (UK pounds, 2006 prices). Population costs were derived by multiplying the number of PLHIV by their annual cost for 1997-2006 and projected 2007-2013.\ud \ud RESULTS\ud \ud Average annual treatment costs across all stages of HIV infection ranged from £17,034 in 1997 to £18,087 in 2006 for PLHIV on mono-therapy and from £27,649 in 1997 to £32,322 in 2006 for those on quadruple-or-more ART. The number of PLHIV using NHS services rose from 16,075 to 52,083 in 2006 and was projected to increase to 78,370 by 2013. Annual population cost rose from £104 million in 1997 to £483 million in 2006, with a projected annual cost between £721 and £758 million by 2013. When including community care costs, costs increased from £164 million in 1997, to £683 million in 2006 and between £1,019 and £1,065 million in 2013.\ud \ud CONCLUSIONS\ud \ud Increased number of PLHIV using NHS services resulted in rising UK population costs. Population costs are expected to continue to increase, partly due to PLHIV's longer survival on ART and the relative lack of success of HIV preventing programs. Where possible, the cost of HIV treatment and care needs to be reduced without reducing the quality of services, and prevention programs need to become more effective. While high income countries are struggling to meet these increasing costs, middle- and lower-income countries with larger epidemics are likely to find it even more difficult to meet these increasing demands, given that they have fewer resources.

Use of dideoxynucleoside reverse transcriptase inhibitors (dNRTIs) may lead to increased mitochondrial toxicity. We compared nucleoside reverse transcriptase inhibitor (NRTI) use as part of antiretroviral therapy (ART) in two HIV clinics: one in a low-middle income (HIV Centre Belgrade [HCB], Serbia) and one a high income (ICDC, Royal Free Hospital, London, UK) country.Antiretroviral naïve patients starting ART from 2003 to 2005 were included. Specific NRTIs were compared between centers, focusing on dNRTI use. Kaplan-Meier estimates of the percentage of patients making changes to their NRTI backbone (a) for any reason or (b) for mitochondrial toxicity (peripheral neuropathy, pancreatitis, lactic acidosis) were calculated.Of 287 HCB patients, 89 (31.0%) received didanosine (ddI)-containing, 39 (13.6%) stavudine (d4T)-containing, and 39 (13.6%) ddI+d4T-containing regimens; for 539 ICDC patients, these were 18 (3.3%), 66 (12.2%), and 0 (0.0%), respectively (p.0001). After 12 months, 57.5% and 52.6% at HCB and ICDC had switched their NRTI backbone. This was reduced to 34.5% at HCB after excluding changes due to drug supply interruption and to 11.2% and 1.3% at HCB and ICDC after changes were made for mitochondrial-related reasons. At 6 months, 73/80 (91.3%) and 385/488 (78.9%) had viral load below 50 copies/mL at HCB and ICDC, respectively.Patients treated at HCB faced higher levels of mitochondrial-related toxicity, likely due to greater dNRTI use.

R 82913, a tetrahydroimidazobenzodiazepinthione (TIBO) derivative with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro, was given to 22 patients with AIDS or AIDS-related complex in a dose-escalating pilot study. Doses of 10 to 300 mg administered daily by intravenous infusion were well tolerated for up to 50 weeks, with no haematological or biochemical evidence of toxicity. Mean OKT4 cell count rose slightly during the second month of treatment when higher steady-state plasma concentrations of the drug were achieved. Median p24 antigen concentration fell by 41% during the first month of therapy. When the rise in p24 antigen before therapy was compared to the fall during treatment, end-point analysis showed a significant difference (p less than 0.03). The combination of potent antiretroviral activity in vitro and the observed effect on HIV p24 antigen and absence of toxicity in vivo indicate that R 82913 and related TIBO derivatives merit further study in the treatment of retroviral infections.

The aim of this study was to estimate the outcome and cost-effectiveness per life-year-gained (LYG) of first-, second- and third-line non-nucleoside reverse transcriptase inhibitors (NNRTI) versus protease inhibitor (PI) containing highly active antiretroviral therapy regimens. Hospital care costs (2002 US dollars discounted 3.5% per annum) were linked to treatment failure times. Results show that the median time-to-treatment failure for first-line (nucleoside reverse transcriptase inhibitors) 2NRTIs + NNRTI was substantially longer than that for 2NRTIs + PIboosted, 2NRTIs + PI and 2NRTIs + 2PIs, whereas for second- and third-line they were similar. Comparing first-line 2NRTIs + NNRTI with 2NRTIs + PIboosted cost per LYG was US$ 12,375; US$ 12,139 per LYG when compared with 2NRTIs + PI and US$ 2948 per LYG when compared with 2NRTIs + 2PIs. For second-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PIboosted was US$ 19,501; US$ 18,364 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. For third-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PIboosted was US$ 2708; US$ 11,559 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. In conclusion, first-line 2NRTIs + NNRTI was cost-effective or cost-saving when compared with PI-containing regimens for all lines of therapy. Such information is required by clinicians and managers of HIV services to make appropriate treatment decisions based on clinical and financial grounds, and given the increasing number of people living with HIV, such information will become more important over time.

Antiretroviral drug combinations that include two nucleoside reverse transcriptase inhibitors and a protease inhibitor (PI) can suppress HIV replication to undetectable levels, improving the prognosis of HIV-infected individuals. The aim of therapy is complete virological suppression, with a current goal of

BACKGROUND We investigated the role of gender on response to efavirenz (EFV)-containing regimens in previously antiretroviral-naive patients. METHODS All previously antiretroviral-naive individuals from the Royal Free Hospital in London starting EFV from 1996 onward were included. Treatment failure was defined as the first of 2 consecutive viral load measurements >500 copies/mL more than 24 weeks after starting EFV. Standard survival methods were used to assess time to discontinuation and to treatment failure. RESULTS Ninety-six women and 337 men were included. Women were mostly of black African ethnicity (64.6%) with a heterosexual risk (94.8%), whereas men were mostly white (66.8%; P < 0.0001) with a homosexual risk (71.2%; P < 0.0001). Women had lower CD4 counts when starting EFV (median [interquartile range [IQR] = 126 [36, 220] cells/mm for women vs. 190 [109, 268] cells/mm for men; P = 0.0003). After 48 and 96 weeks, 38.8% (95% confidence interval [CI]: 28.8% to 48.7%) and 56.3% (95% CI: 45.8% to 66.9%) of women had discontinued EFV compared with 28.3% (95% CI: 23.4% to 33.2%) and 41.8% (95% CI: 36.3% to 47.3%) of men (P = 0.005). The percentage experiencing failure by 48 and 96 weeks when ignoring treatment changes but censoring at the date of discontinuing all treatment was 1.3% (0.0%, 3.9%) and 4.4% (0.0%, 9.3%) for women compared with 3.8% (1.6%, 6.0%; P = 0.49) and 5.8% (3.0%, 8.6%) for men. Median (IQR) CD4 count increases at 48 weeks were +166 (+89, +239) cells/mm for women and +176 (+93, +263) cells/mm for men. CONCLUSIONS Women seem to have comparable virologic and immunologic outcomes to first-line EFV-containing regimens compared with men, although they are more likely to discontinue the drug.

Background The success of clinical care for human immunodeficiency virus infection may vary across demographic groups, because of patient- and health care–related factors. Methods A total of 2386 patients sexually infected with the human immunodeficiency virus were seen in a London clinic from July 1, 1999, to December 31, 2004. We examined demographic variation and trends over time in the prevalence of the following: (1) a CD4 cell count of 200/μL or less; (2) a viral load of greater than 50 copies/mL among patients receiving antiretroviral therapy (ART); and (3) a viral load of greater than 50 copies/mL among patients receiving ART for 24 weeks or longer. Results Subjects were homosexual men (63.1%), white heterosexual men (4.3%) and women (5.1%), and black African or other ethnicity heterosexual men (10.2%) and women (17.3%). The CD4 cell count at the first clinic visit was highest among homosexual men and lowest among black African heterosexual men. From 1999 to 2004, ART use increased from 61.9% to 75.5%. The prevalence of a CD4 cell count of 200/μL or less decreased from 19.6% to 9.0%. The prevalence of a viral load of greater than 50 copies/mL decreased from 36.9% to 14.5% among patients receiving ART, and from 31.2% to 10.1% among patients receiving ART for 24 weeks or longer. Demographic variation in the prevalence of each outcome was apparent among men throughout the period: homosexual men had the most favorable profile, and black African heterosexual men had the least favorable profile. Differences were much greater for low CD4 cell count than for raised viral load while receiving ART. There was no consistent demographic variation among women. Favorable trends over time occurred within each demographic group, and were as strong among black African patients as among other subgroups. Conclusions The success of clinical care for human immunodeficiency virus infection increased substantially from 1999 to 2004 in this routine clinic population. All demographic subgroups benefited from improvements, despite ongoing differences in the prevalence of immunosuppression.

Recent data from clinical trials investigating the efficacy of enfuvirtide, a fusion inhibitor, in treatment-experienced patients have revealed that the addition of enfuvirtide (ENF) to an active boosted protease inhibitor regimen doubles the rate of virological response. At week 48 of the TORO studies, 55% of patients previously naive to and receiving lopinavir/ritonavir (LPV/r) with ENF achieved a viral load of400 copies/mL compared with 24% of patients treated with LPV/r alone. At week 24 of the RESIST studies, 70% of previously ENF-naive patients who took both ENF and tipranavir/ritonavir (TPV/r) achieved aor=1 log10 reduction in viral load compared with 37% of such patients treated with TPV/r alone. Similarly, concomitant use of TMC114/ritonavir (TMC114/r) with ENF, compared with TMC114/r alone, increased the number of patients with50 copies/mL from 46% to 64% in a combined 24-week analysis from the POWER trials. Data from these trials suggest that combining one agent from a new class with a new agent from a previously exposed class offers a greater chance of achieving full virological control than either type of agent alone. Undetectable viraemia should be the primary objective for treatment-experienced patients requiring a switch in therapy, and the present data support the combination of an active boosted protease inhibitor with an agent from a new class (e.g., ENF) for triple-class-experienced patients.

Background Triple-combination antiretroviral therapy (CART) for human immunodeficiency virus infection has been in use for almost a decade, but the extent to which treatment success has changed is uncertain. We examined risk of initial virological failure of CART according to the year of starting therapy. Methods We included subjects from 5 complete clinic cohorts in Europe and Canada who started CART without previous antiretroviral therapy from 1996 to 2002 with 1 or more pre-CART viral load (VL) measurement and CD4 count. Based on the first VL measurement from 6 to 12 months after CART initiation, virological failure was defined as a VL of more than 500 copies/mL. We used the following 3 inclusion strategies: (1) including all subjects, with missing VL measurement counted as virological failure (n = 3825; strategy A); (2) including all subjects with VL measurement (n = 3120; strategy B); and (3) including all subjects receiving antiretroviral therapy at VL measurement (n = 2890; strategy C). Results From 1996 to 2002, risk of virological failure fell from 38.9% to 24.8% for strategy A, 28.4% to 12.0% for strategy B, and 22.8% to 8.2% for strategy C. Estimated relative reductions in risk (95% confidence interval) over the 7-year period, adjusted for cohort, demographic factors, pre-CART VL and CD4 count, and previous AIDS, were 48% (39%-56%), 64% (53%-73%), and 79% (69%-85%) for strategies A, B, and C, respectively. Reductions in risk were greatest from 1996 to 1999, with weaker trends subsequently. Trends remained but were attenuated after further adjustment for the starting regimen. Conclusions Over a 7-year period of CART use in clinical practice, risk of initial virological failure of treatment has halved at least. These data suggest the trend is due to improvements in CART regimens and greater effectiveness of their use.

Objectives: To investigate the characteristics and clinical, immunological and virological outcomes for individuals presenting for care with low CD4 cell counts.Methods: Individuals aged > 16 years presenting for care for the first time were identified between 1 January 1996 and 31 December 2002. Late presenters were those with CD4 cell count < 50 x 10(6) cells/l. Follow-up was until last contact, death or 31 December 2002.Results: Late presenters formed 15.3% (110) of the group; they were more likely to be female (35% versus 24%), heterosexual (53% versus 38%), and of Black-African ethnicity (39% versus 27%) than other individuals. Over a median follow-up of 2.5 years, 13% of late presenters died. Ninety-nine patients started antiretroviral treatment; Of the 11 patients who did not start antiretroviral treatment, eight died within 3 months of presentation. Among those starting treatment, 87 (87.9%) achieved a viral load < 400 copies/ml and median CD4 cell counts increased from 43 x 10(6) cells/l at 0-2 months after presentation to 204 x 10(6) cells/l at 1 year. Over the first year, 71 patients attended at least one outpatient visit (median, 4.5; range, 0-39), 21 attended at least one day case visit (median, 0; range, 0-15) and 49 were admitted as an inpatient (median, 0; range, 0-4).Conclusions: Those presenting for care with very low CD4 cell counts may make large demands on clinical resources, particularly over the first few months. While some patients do have a poor outcome on highly active antiretroviral therapy, many will benefit from this therapy and will experience good immunological and virological responses. (C) 2004 Lippincott Williams Wilkins.

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitors (NRTI) disrupt neuronal mitochondrial DNA synthesis, impairing energy metabolism and resulting in a distal symmetrical polyneuropathy (DSP), an antiretroviral toxic neuropathy (ATN) that causes significant morbidity in HIV disease. Serum acetyl-l-carnitine (ALCAR) levels are decreased in neuropathy associated with NRTI therapy. ALCAR enhances neurotrophic support of sensory neurons and promotes energy metabolism, potentially causing nerve regeneration and symptom relief. OBJECTIVE: To assess the efficacy of oral ALCAR (1500 mg twice daily) for up to 33 months in an open cohort of 21 HIV-positive patients with established ATN. METHODS: Skin biopsies were excised from the leg before ALCAR treatment, at 6-12 month intervals thereafter and from HIV-negative non-neuropathic controls. Fibre types in epidermal, dermal and sweat gland innervation were quantified immunohistochemically. RESULTS: After 6 month's treatment, mean immunostaining area for small sensory fibres increased (epidermis 100%, P = 0.006; dermis 133%, P < 0.05) by more than that for all fibre types (epidermis 16%, P = 0.04; dermis 49%, P < 0.05; sweat glands 60%, P < 0.001) or for sympathetic fibres (sweat glands 41%, P < 0.0003). Compared with controls, epidermal, dermal and sweat gland innervation reached 92%, 80% and 69%, respectively, after 6 month's treatment. Innervation improvements continued (epidermis and dermis) or stabilized (sweat glands) after 24 month's treatment. Neuropathic grade improved in 76% of patients and remained unchanged in 19%. HIV RNA load, CD4 and CD8 cell counts did not alter significantly throughout the study. CONCLUSIONS: ALCAR treatment improves symptoms, causes peripheral nerve regeneration and is proposed as a pathogenesis-based treatment for DSP.

Background. Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. Methods. Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. Results. After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm 3 , respectively; 84%, 84%, and 80% of subjects had a virus load of