Mapping sources of noise in an intensive care unit.

Excessive noise in hospitals adversely affects patients' sleep and recovery, causes stress and fatigue in staff and hampers communication. The World Health Organization suggests sound levels should be limited to 35 decibels. This is probably unachievable in intensive care units, but some reduction from current levels should be possible. A preliminary step would be to identify principal sources of noise. As part of a larger project investigating techniques to reduce environmental noise, we installed a microphone array system in one with four beds in an adult general intensive care unit. This continuously measured locations and sound pressure levels of noise sources. This report summarises results recorded over one year. Data were collected between 7 April 2017 and 16 April 2018 inclusive. Data for a whole day were available for 248 days. The sound location system revealed that the majority of loud sounds originated from extremely limited areas, very close to patients' ears. This proximity maximises the adverse effects of high environmental noise levels for patients. Some of this was likely to be appropriate communication between the patient, their caring staff and visitors. However, a significant proportion of loud sounds may originate from equipment alarms which are sited at the bedside. A redesign of the intensive care unit environment to move alarm sounds away from the bed-side might significantly reduce the environmental noise burden to patients.

Go/no-go decision in anaesthesia: wide variation in risk tolerance amongst anaesthetists.

BACKGROUND: The variability in risk tolerance in medicine is not well understood. Parallels are often drawn between aviation and anaesthesia. The aviation industry is perceived as culturally risk averse, and part of preflight checks involves a decision on whether the flight can operate. This is sometimes termed a go/no-go decision. This questionnaire study was undertaken to explore the equivalent go/no-go decision in anaesthesia. We presented anaesthetists with a range of situations in which additional risk might be expected and asked them to decide whether they would proceed with the case. METHODS: An electronic questionnaire was distributed to anaesthetic colleagues of all grades in one National Health Service Trust. Eleven scenarios, all drawn from critical incident data, were presented. Participants were invited to consider whether they would proceed, how they would modify their anaesthetic technique, and to predict whether a colleague with similar experience would make the same decision. Textual responses were analysed qualitatively. RESULTS: The scenario response rate was 28%. Consultants were significantly more likely to proceed than trainees. In no scenario was there absolute agreement over whether to proceed, even in scenarios where national guidelines would suggest a case should be cancelled. Thematic analysis suggested a wide variability in what anaesthetists consider acceptable or professional behaviour. CONCLUSIONS: It is clear that safety decisions cannot be made in isolation and that clinicians must consider operational requirements, such as throughput, when making a go/no-go decision. The level of variability in decision-making was surprising, particularly for scenarios that appeared to go against guidelines.

Research-intensive cancer care in the NHS in the UK.

In the late 1990 s, in response to poor national cancer survival figures, government monies were invested to enhance recruitment to clinical cancer research. Commencing with England in 2001 and then rolling out across all four countries, a network of clinical cancer research infrastructure was created, the new staff being linked to existing clinical care structures including multi-disciplinary teams. In parallel, a UK-wide co-ordination of cancer research funders driven by the 'virtual' National Cancer Research Institute, combined to create a 'whole-system approach' linking research funders, researchers and NHS clinicians all working to the same ends. Over the next 10 years, recruitment to clinical trials and other well-designed studies, increased 4-fold, reaching 17% of the incident cancer population, the highest national rate world-wide. The additional resources led to more studies opened, and more patients recruited across the country, for all types of cancers and irrespective of additional clinical research staff in some hospitals. In 2006, a co-ordinated decision was made to increasingly focus on randomized trials, leading to increased recruitment, without any fall-off in accrual to non-randomized and observational studies. The National Cancer Research Network has supported large successful trials which are changing clinical practice in many cancers.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Patient and public involvement.

The involvement of patients and the public in the development of clinical research initiatives in the UK has been central and is increasing. Whilst initially developed in relation to cancer research and cancer care, this activity has now generalized to all of healthcare research particularly through organizations such as INVOLVE (www.invo.org.uk). Patients and Public Involvement (PPI) has been evaluated and shown to be established across the NHS in the UK. The National Institute for Health Research in England has made PPI central in its development. More recently evidence is accumulating that PPI has significant impact on the quality and delivery of clinical research in healthcare but more work on the evaluation of its impact is required.

PRION-1 scales analysis supports use of functional outcome measures in prion disease.

OBJECTIVES: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives. METHODS: To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1. RESULTS: Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size. CONCLUSIONS: Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.

Strengthening clinical cancer research in the United Kingdom.

BACKGROUND: In 1999, 270,000 cases of cancer were registered in the United Kingdom, placing a large burden on the NHS. Cancer outcome data in 1999 suggested that UK survival rates were poorer than most other European countries. In the same year, a Department of Health review noted that clinical trials accrual was poor (<3.5% of incident cases) and hypothesised that increasing research activity might improve outcomes and reduce the variability of outcomes across England. Thus, the National Cancer Research Network (NCRN) was established to increase participation in cancer clinical research. METHODS: The NCRN was established in 2001 to provide a robust infrastructure for cancer clinical research and improvements in patient care. Remit of NCRN is to coordinate, support and deliver cancer clinical research through the provision of research support staff across England. The NCRN works closely with similar networks in Scotland, Wales and the Northern Ireland. A key aim of NCRN is to improve the speed of research and this was also assessed by comparing the speed of study delivery of a subset of cancer studies opening before and after NCRN was established. RESULTS: Patient recruitment increased through NCRN, with almost 32,000 (12% of annual incident cases) cancer patients being recruited each year. Study delivery has improved, with more studies meeting the recruitment target - 74% compared with 39% before NCRN was established. CONCLUSION: The coordinated approach to cancer clinical research has demonstrated increased accrual, wide participation and successful trial delivery, which should lead to improved outcomes and care.

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

BACKGROUND: Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults. METHODS: Participants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779. FINDINGS: 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on ART was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or BMI (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. INTERPRETATION: Our results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

BACKGROUND: Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. METHODS: A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat. RESULTS: The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001). CONCLUSIONS: The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Interleukin-2 therapy in patients with HIV infection.

BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.

BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN: Randomized, controlled trial. SETTING: Sites in 33 countries. PATIENTS: 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS: Opportunistic disease or death was the primary outcome. RESULTS: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. CONCLUSION: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK.

UNLABELLED: BACKGROUND, PURPOSE AND METHODS: This observational study assessed the effect of continuous intraventricular infusion of pentosan polysulphate (PPS) in seven patients at different clinical centres in the UK. RESULTS: Complications of intraventricular catheterization were frequent. PPS was well-tolerated over a wide dose range (11-110 microg/kg/day) during the 6-month study. Four patients were assessed for the entire study period: one remained stable, two showed minimal deterioration and one progressed significantly. CONCLUSION: Mean survival of all patients was longer than reported values for natural history of specific prion disorders. Possible reasons for these findings are explored.

The UK Diabetes Research Network--an opportunity and a challenge.

The Department of Health has funded a national diabetes network to support clinical research. The network will facilitate recruitment into clinical trials and has been widely welcomed by clinicians. However, if the network is to reach its full potential, all those involved will need to advocate a change in attitude towards clinical trials and research, encouraging participation and contribution of data. Clinicians need to be willing to take a proactive view about research studies, and to encourage patients to adopt a positive and altruistic attitude towards trial participation. The future of trials and other important clinical research in the UK may depend on it.

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

A prospective study of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in adults with human immunodeficiency virus-1.

Antibody titres against Kaposi's sarcoma associated herpesvirus (KSHV or human herpesvirus 8 (HHV-8)) and Epstein-Barr virus (EBV) were examined in people who subsequently developed Kaposi's sarcoma and non-Hodgkin's lymphoma, within randomised controlled trials of antiretroviral therapy in adults infected with the human immunodeficiency virus-1 (HIV). For each case of Kaposi's sarcoma (n=189) and each case of non-Hodgkin's lymphoma (n=67), which developed after randomisation, one control was randomly selected from other trial participants, after matching for age, sex, ethnicity, mode of HIV transmission, type of treatment received and period of follow-up. Using sera taken an average of two and a half years before the diagnosis of cancer, titres of antibodies against KSHV latent (LANA) and lytic (K8.1) antigens and against EBV (VCA) antigens were investigated in relation to subsequent risks of cancer by calculating odds ratios (OR) using conditional logistic regression. Latent antibodies against KSHV were detectable among 38% (72 out of 189) of Kaposi's sarcoma cases and 12% (23 out of 189) of their controls (OR=4.4, 95% confidence intervals (CI) 2.3-8.3, P<0.001). The OR for Kaposi's sarcoma increased with increasing antilatent KSHV antibody titre (chi(2)(1) for trend=32.2, P<0.001). Lytic antibodies against KSHV were detectable among 33% (61 out of 187) of Kaposi's sarcoma cases and 19% (36 out of 187) of their controls (OR=2.0, 95% CI 1.2-3.4, P=0.003) and the OR for Kaposi's sarcoma increased with increasing antilytic KSHV antibody titre (chi(2)(1) for trend=6.2, P=0.02). Virtually, all cases and controls had anti-EBV antibodies detected and the OR for non-Hodgkin's lymphoma associated with a doubling of the anti-EBV antibody titre was estimated to increase by a multiplicative factor of 1.3 (95% CI 0.9-1.7, P=0.1). Kaposi's sarcoma was not associated with antibody levels against EBV (P=0.4) and non-Hodgkin's lymphoma was not associated with antibodies against KSHV (latent P=0.3; lytic P=0.5). Adjustment for CD4 count at the time of sample collection made no material difference to any of the results. In conclusion, among human immunodeficiency virus infected people, high levels of antibodies against KSHV latent and lytic antigens are strongly associated with subsequent risk of Kaposi's sarcoma but not non-Hodgkin's lymphoma. Antibody titre to EBV does not appear to be strongly associated with subsequent risk of Kaposi's sarcoma or non-Hodgkin's lymphoma in HIV infected people.

A randomized controlled trial of the value of phenotypic testing in addition to genotypic testing for HIV drug resistance: evaluation of resistance assays (ERA) trial investigators.

OBJECTIVES: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options. DESIGN: Multicenter randomized trial. METHODS: Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months. RESULTS: Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%). CONCLUSION: The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.