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ABSTRACTBackgroundThere is little evidence to guide the perioperative management of patients on a direct oral anticoagulant (DOAC) in the absence of a last known dose. Quantitative serum titers may be ordered, but there is little evidence supporting this.AimsThis multi-center retrospective cohort study of consecutive surgical in-patients with a DOAC assay, performed over a five-year period, aimed to characterize preoperative DOAC assay orders and their impact on perioperative outcomes.Materials and methodsPatients prescribed regular DOAC (both prophylactic and therapeutic dosing) with a preoperative DOAC assay were included. The DOAC assay titer was evaluated against endpoints. Further, patients with an assay were compared against anticoagulated patients who did not receive a preoperative DOAC assay. The primary endpoint was major bleeding. Secondary endpoints included perioperative hemoglobin change, blood transfusions, idarucizumab or prothrombin complex concentrate administration, postoperative thrombosis, in-hospital mortality and reoperation. Adjusted and unadjusted linear regression models were used for continuous data. Binary logistic models were performed for dichotomous outcomesResults1065 patients were included, 232 had preoperative assays. Assays were ordered most commonly by Spinal (11.9%), Orthopedics (15.4%), and Neurosurgery (19.4%). For every 10 ng/ml increase in titer, the hemoglobin decreases by 0.5066 g/L and the odds of a preoperative reversal increases by 13%. Compared to those without an assay, patients with preoperative DOAC assays had odds 1.44× higher for major bleeding, 2.98× higher for in-hospital mortality and 16.3× higher for receiving anticoagulant reversal.ConclusionA preoperative DOAC assay order was associated with worse outcomes despite increased reversal administration. However, the DOAC assay titer can reflect the patient’s likelihood of bleeding.

Purpose: This paper examines the relationship between farm-level variables related to cash flow and premium rates on federal crop insurance coverage selection. Design/methodology/approach: Using farm-level data from the Agricultural Resource Management Survey (ARMS), the authors estimate a linear fixed effects model to evaluate the relationship between farm-level and regional variables and federal crop insurance coverage selections. Findings: The authors find evidence indicating that expected cash flow plays an important role in coverage level decisions. For example, variables directly related to cash flow, such as higher costs, are associated with significant differences in coverage level selection, though the direction of the association is dependent on the type of costs, whether fixed or variable, while higher revenue higher acreage farms insure at higher coverage levels. In addition, higher premium costs are associated with lower coverage level selections, despite subsidy incentives. Originality/value: This is the first paper that identifies a potential solution to the puzzling finding that farmers do not consistently maximize coverage level. This research points to the influence of credit constraints as playing a role in limiting coverage level selections.

We sought to examine barriers to access to, use of, and benefits from digital health services in an area of socioeconomic disadvantage of Adelaide, Australia. We conducted waiting room surveys in two hospital diabetes clinics and one hospital antenatal clinic in South Australia, and follow‐up telephone interviews with 20 patients. We examined the extent of access to, use of and benefits from digital health services, and what barriers people encountered. We undertook mixed methods, with quantitative descriptive analysis and qualitative analysis. Thirty‐seven diabetes clinic patients (54% response rate) and 99 antenatal clinic patients (33% response rate) participated. Sixty‐two percent of the patients with diabetes and 27% of antenatal clinic patients had never used digital health services. Seventeen percent of patients with diabetes and 30% of antenatal clinic patients were hesitant users, and 22% of patients with diabetes and 44% of antenatal clinic patients were confident users. Barriers included struggling to afford the technology or to stay connected and a lack of trust in online health information. Potential benefits included feeling more empowered and complementing face‐to‐face care. There are socioeconomic barriers to access, use of, and ability to benefit from digital health strategies that mean not everyone will be able to benefit from digital health services. As COVID‐19 accelerates the shift towards digital health services, people experiencing socioeconomic disadvantage may be excluded. If barriers to access and use are not addressed, they will exacerbate already increasing health inequities.

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Considerable confusion exists in the medical literature concerning postterm infants and their characteristics. In many cases, infants considered postterm (based on the expected due date) cannot be said to be postterm on the basis of ultrasonographic evidence. Some researchers maintain postterm infants grow excessively, others maintain that they show signs of weight loss. To learn more about this matter, infants were studied who were born in one medical center during an eight-year period and confirmed as postterm by ultrasonography and date of the mother's last menstrual period. The 7,005 infants were born at or after 39 weeks' gestation; those born at or after 42 weeks' gestation were designated postterm. The infants were weighed and their lengths and head circumferences recorded (these two measurements were made only for 4,020 infants). Other measurements were also made. Results showed increases in average birth weights between 39 and 42 weeks' gestation, with infants born to women with several previous births weighing more than those who were the first infant delivered. No low-birth-weight babies (less than 2,500 grams) were born after 42 weeks' gestation, but more large (more than 4,000 grams) infants were born as pregnancy continued, reaching 30 percent at 42 weeks' gestation. Severe intrauterine growth retardation (reduced birth weight) was not more common in postterm than preterm babies, nor did the ponderal index (a measure of nutritional status) indicate nutritional damage occurred after term. Placental weights also increased as gestation continued. The results do not support earlier beliefs of increased risk of distress or poor nutrition in postterm babies. Confusion has been created by different uses of the concept 'postterm' and by the notoriously unreliable method of predicting the due date from the last menstrual period. Macrosomia (a large baby) is the most important complication associated with postterm pregnancies. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ending AIDS in Asia Pacific by 2030 requires countries to give higher priority to financing community-based and key population-led service delivery. Mechanisms must be developed for civil society organisations to deliver health and HIV/AIDS services for key populations, especially men who have sex with men, and transgender people, within national health policy frameworks. Current investments in the HIV response in the Asia Pacific region reflect inadequate HIV financing for key populations, particularly for civil society and key population-led organisations that are optimally positioned to advance HIV epidemic control. These organisations are typically supported by international agencies whose investments are starting to decline. Domestic investments in key population-led organisations are often hampered by punitive laws against their communities, pervasive stigma and discrimination by policy makers, an insufficient understanding of the most effective HIV epidemic control strategies, and financing systems that limit access to funding for these organisations from the national budget. Countries in the Asia Pacific region are evolving their community-based and key population policies and programmes. We need accessible, disaggregated financial data and in-depth case studies that showcase effective key population-led programmes, to enable countries to learn from each other.

Key populations increasingly lead the design, implementation, and evaluation of HIV services, which provides an opportunity to make them more people-centred. Despite many challenges, a strong argument that these populations must have a greater role in HIV service planning, development, and delivery worldwide exists. This Viewpoint focuses on Asia, where key populations have advocated for legal reform, engaged vulnerable groups to decrease stigma, co-created innovative HIV services, and developed new key population-led health services. Further research on key populations and their roles in HIV implementation and sustainable scale-up is needed in Asia and beyond.

It never ceases to amaze how the Deluxe audience comes through when we reach out for information on old hot rods, race cars, and the folks who built and drove them. In answer to the question in the November 2019 Scrapbook section [about the hot rod at Detroit Dragway], the car was owned by Spencer Cunningham of West Dearborn, Michigan. I've been a small-time car buff since I was a kid, long before coming to work at a large Chevrolet/ Buick/GMC dealership, where I have been for nearly 20 years. He also brought the Phil Cool AMBR-winning 1932 roadster to the Historic Hot Rod Cover Cars display, which you can read more about on page 38. [Extracted from the article]

Gravity Road fed on the imagination of ordinary consumers in its campaign for Bombay Sapphire, Mark Boyd explains. Sitting down with the Bombay Sapphire brand team and the Bacardi Marketing [...]

•There exists no significant, independent relationship, as determined by a univariate meta regression, between DOAC assay concentrations and a patient's risk of bleeding or systemic embolic embolism.•Patient specific DOAC assay concentrations that may indicate adequate anticoagulation probably exist,.•Patient specific anticoagulant titres are potentially the next frontier of perioperative optimisation.

Mark Boyd believes 2011 could be the year that branded content comes of age. It's a massive challenge but 'doing and earning' has to become its mantra. Perhaps for too [...]

To determine trends in and predictors of early treatment for people newly diagnosed with human immunodeficiency virus (HIV) infection in Australia. Retrospective cohort analysis of routinely collected longitudinal data from 44 sexual health clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) program. Patients diagnosed with HIVinfections, January 2004 – June 2015. Commencement of antiretroviral therapy within 6 months of HIVdiagnosis (early treatment); demographic, clinical, and risk group characteristics of patients associated with early treatment; trends in early treatment, by CD4+cell count at diagnosis. 917 people were diagnosed with HIVinfections, their median age was 34 years (interquartile range [IQR]: 27–43 years), and 841 (92%) were men; the median CD4+cell count at diagnosis was 510 cells/μL (IQR, 350–674 cells/μL). The proportion of patients who received early treatment increased from 17% (15 patients) in 2004–06 to 20% (34 patients) in 2007–09, 34% (95 patients) in 2010–12, and 53% (197 patients) in 2013–15 (trend, P< 0.001). The probability of early treatment, which increased with time, was higher for patients with lower CD4+cell counts and higher viral loads at diagnosis. The proportion of people newly diagnosed with HIVin sexual health clinics in Australia who received treatment within 6 months of diagnosis increased from 17% to 53% during 2004–2015, reflecting changes in the CD4+cell count threshold in treatment guidelines. Nevertheless, further strategies are needed to maximise the benefits of treatment to prevent viral transmission and morbidity.

Reprints the speech by the Parliamentary Undersecretary of State for the Commonwealth of Great Britain delivered during the English Speaking Union Summer Conference on July 5, 1994, dealing with the British foreign policy. Enhancement of the security and prosperity of the United Kingdom and the Dependent Territories; Developments in Europe; Relevance of security problems outside Europe; Non-proliferation; Aid program.

TO THE EDITOR: The December 1999 issue of the Journal included a Patient-Oriented Evidence that Matters (POEMs) Review[1] of an article by Natrajan and colleagues[2] on estrogen replacement therapy (ERT) [...]

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Background To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART.Methods SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used.Results We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC.Conclusions We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Background In the era of effective antiretroviral treatment (ART) CD4:CD8 ratio is proposed as a potential marker for HIV-positive (HIV+) patients at increased risk for non-AIDS comorbidities. The current study aims to compare CD4:CD8 ratio between Asian and Caucasian HIV+ patients.Methods HIV+ patients from the Australian HIV Observational Database (AHOD) and the TREAT Asia HIV Observational Database (TAHOD) meeting specific criteria were included. In these analyses Asian and Caucasian status were defined by cohort. Factors associated with a low CD4:CD8 ratio (cutoff <0.2) prior to ART commencement, and with achieving a normal CD4:CD8 ratio (>1) at 12 and 24 months post ART commencement were assessed using logistic regression.Results There were 591 patients from AHOD and 2,620 patients from TAHOD who met the inclusion criteria. TAHOD patients had a significantly (P<0.001) lower odds of having a baseline (prior to ART initiation) CD4:CD8 ratio greater than 0.2. After 12 months of ART, AHOD patients were more than twice as likely to achieve a normal CD4:CD8 ratio compared to TAHOD patients (15% versus 6%). However, after adjustment for confounding factors there was no significant difference between cohorts in the odds of achieving a CD4:CD8 ratio >1 (P=0.475).Conclusions We found a significantly lower CD4:CD8 ratio prior to commencing ART in TAHOD compared to AHOD even after adjusting for confounders. However, after adjustment, there was no significant difference between the cohorts in odds of achieving normal ratio. Baseline CD4+and CD8+counts seem to be the main driver for this difference between these two populations.

Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir.

Some guidelines recommended two-drug antiretroviral therapies as alternative regimens to triple therapy in selected patients with the aim of reducing drug burden and toxicity and preserving future treatment options. We aimed to assess the efficacy and safety of dual-therapy versus triple therapy as first-line treatment or in treatment simplification.

A creative director shares insights on how TV and advertising can mutually learn from each other during the TV development process. The creative director believes that this process is intimidating due to lack of respect for creativity, insufficient discourse between buyers and sellers, and shortage in strategy. Suggestions on addressing these deficiencies are discussed.

Regulations in the UK broadcasting industry are prohibiting the influence of brands in shows, something that industry does not need during tough economic times. There is a crisis in funding, and the industry should be forgiven for taking in advertiser-funded projects. A personal experience on how red tape strangles programming process is also given.

Background There have been improvements in combination antiretroviral therapy (cART) over the past 15 years. The aim of this analysis was to assess whether improvements in ART have resulted in improvements in surrogates of HIV outcome.Methods Patients in the Australian HIV Observational Database who initiated treatment using mono/duo therapy prior to 1996, or using cART from 1996 onwards, were included in the analysis. Patients were stratified by era of ART initiation. Median changes in CD4+T-cell count and the proportion of patients with detectable HIV viral load (>400 copies/ml) were calculated over the first 4 years of treatment. Probabilities of treatment switch were estimated using the Kaplan-Meier method.Results A total of 2,753 patients were included in the analysis: 28% initiated treatment <1996 using mono/duo therapy and 72% initiated treatment =1996 using cART (30% 1996–1999, 12% 2000–2003, 11% 2004–2007 and 19% =2008). Overall CD4+T-cell count response improved by later era of initiation (P<0.001), although 2000–2003 CD4+T-cell count response was less than that for 1996– 1999 (P=0.007). The average proportion with detectable viral load from 2 to 4 years post-treatment commencement by era was: <1996 mono/duo 0.69 (0.67–0.71), 1996–1999 cART 0.29 (0.28–0.30), 2000–2003 cART 0.22 (0.20–0.24), 2004–2007 cART 0.09 (0.07–0.10) and =2008 cART 0.04 (0.03–0.05). Probability of treatment switch at 4 years after initiation decreased from 53% in 1996–1999 to 29% after 2008 (P<0.001).Conclusions Across the five time-periods examined, there have been incremental improvements for patients initiated on cART, as measured by overall response (viral load and CD4+T-cell count) and also increased durability of first-line ART regimens.

WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study.

The gap between advertisers and program makers should be bridged because all the programs are funded by the advertisers but they never actually meet. Only when both work together will we be able to see good budgets, proper ad support for programmes and good business.

Exposure to social risk in early life negatively impacts the health and wellbeing of children. While screening for social determinants of health is recommended, there is little evidence that identifying social risk early in life predicts longer-term poorer outcomes. The purpose of this study is to examine the extent to which assessing social risk using a standardized tool in young children up to age 6 years might predict poor health and academic performance at 10–11 years old. The social risk domains studied were housing instability, food insecurity, financial strain, transport problems, safety, lack of support and unemployment. The predictive validity of these social risk domains measured at 0–5 years was examined using data from the Longitudinal Study of Australian Children. Outcomes at 10–11 years included ongoing diseases and mental health conditions, hospitalization, injury, dental problems, overweight or obesity and academic achievement. Financial strain and inability to access support were the most sensitive measures of poor outcomes. Across all social risks, the positive predictive value was highest for academic outcomes. Across all domains, there was higher sensitivity for children with 2 or more social risks. Items in the social risk screening tool were moderate predictors of academic outcomes, but weak predictors of health outcomes at 10–11 years. This data will be useful for informing screening for social determinants of health.

To compare changes over 48 weeks in bone mineral density (BMD) between participants randomized to lopinavirritonavir (LPVr)raltegravir (RAL) or LPVr 2–3nucleosidenucleotide reverse transcriptase inhibitors (N(t)RTIs) as second line therapy.

Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV). Our study aims to project the life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments.

The unprecedented, successful collaborative international effort to provide universal access to HIV care, including effective antiretroviral therapy, has reached a crucial point. Global economic downturn, changing donor priorities, and competing priorities in the health sector threaten the target of provision of 15 million people with HIV/AIDS with treatment by 2015, as agreed by the UN General Assembly. This aspiration has received added impetus from the finding that treatment prevents transmission by reduction of infectiousness of patients. In this report we critically review success thus far and examine efforts to optimise delivery of HIV care including antiretroviral therapy in low-income and middle-income countries for four main domains: treatment strategy, drug dosing, monitoring, and service delivery.

p53, the “guardian of the genome” and the most mutated gene in cancer presents a considerable therapeutic opportunity as well as a challenge. In the past decade, several therapeutic strategies have been developed that aim to take advantage of a wealth of knowledge about p53, including insights into the biology and patho-biology of p53. Nevertheless, considerable challenges remain, not least as a result of tissue- and cancer-specific differences in p53 regulation and/or function. p53 does not act in the same manner in all tissues or in the cancers arising from them. Nor is p53 regulated in the same way in the wide variety of tissues from which cancers develop. Therefore, potential strategies for therapeutic targeting need to be tailored to each tumour/tissue type. This review summarises some of these tissue- and cancer-specific issues to suggest how different strategies are required for cancers arising from different tissues and to illustrate the complexities of therapeutic targeting of p53.

Background: The p53 gene is the most frequently mutated gene in cancer and accordingly has been the subject of intensive investigation for almost 30 years. Loss of p53 function due to mutations has been unequivocally demonstrated to promote cancer in both humans and in model systems. As a consequence, there exists an enormous body of information regarding the function of normal p53 in biology and the pathobiological consequences of p53 mutation. It has long been recognised that analysis of p53 has considerable potential as a tool for use in both diagnostic and, to a greater extent, prognostic settings and some significant progress has been made in both of these arenas. Objective: To provide an overview of the biology of p53, particularly in the context of uses of p53 as a diagnostic tool. Methods: A literature review focused upon the methods and uses of p53 analysis in the diagnosis of sporadic cancers, rare genetic disorders and in detection of residual disease. Conclusion: p53 is currently an essential diagnostic for the rare inherited cancer prone syndrome (Li-Fraumeni) and is an important diagnostic in only a limited number of settings in sporadic disease. Research in specific cancers indicates that the uses of increasingly well informed p53 mutational analysis are likely to expand to other cancers.

Background The antiretroviral enfuvirtide (ENF) is injected subcutaneously using a 27-gauge needle. Injection site reactions (ISRs) can affect long-term ENF tolerability. Alternative ENF delivery methods may ameliorate ISRs.Methods We conducted a multicentre, open-label, randomized controlled trial in which patients receiving ENF were randomized to continue receiving ENF by a 27-gauge needle, a shorter 31-gauge needle or a gas-powered, needle-free injection device (NFID). The primary study endpoint was the proportion of participants with 0.2). There was no significant between-group difference for any ISR endpoint, except for changes in the composite ISR score (that is, no ongoing pain of =grade 1 or ISR for ongoing pain =grade 1 with induration ISR

Background The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.Methods Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.Results Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).Conclusions Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.

Indinavir is one of four first-generation HIV-protease inhibitors and was the most popular amongst them in the late 1990s. It was initially licensed for use alone, given three times daily, administered away from meals and together with at least 1.5 litres of fluid per day. In clinical practice, it became common for clinicians to prescribe it with a ritonavir pharmacokinetic ‘boost to remove the food restriction, reduce the pill burden and enable a more convenient twice-daily dosing schedule. However, at a ritonavir-boosted dosing schedule of indinavir/ritonavir 800/100 mg b.i.d., the regimen proved toxic and poorly tolerable, and its use diminished as newer, better tolerated PIs became available. Recent research has suggested that ritonavir-boosted indinavir administered at lower doses, particularly indinavir/ritonavir 400/100 mg b.i.d., retains potency and is considerably less toxic. As a result, there is interest in its application in resource-constrained settings.

Objectives: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen.Methods: We measured indinavir Ctrough/C2h, serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT).Results: A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m2. At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400–800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses.Conclusions: Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term.

To investigate the association between the UGT1A16(G71R) and UGT1A128(promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with indinavir, and characterize the inhibition of human UGTs by indinavir in vitro.

Introduction The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce.Methods This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat.Results One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10HIV RNA was 4.0 (3.3–4.5) and CD4+T-cell count 166 (40–323) cells/µl. After 112-weeks of study there was no significant difference observed between arms in the mean (sd) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P=0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (sd) changes in time-weighted CD4+T-cell count from baseline were similar [88 (84) cells/week/µl three times daily arm; 70 [109] cells/week/µl twice daily arm; P=0.3).Conclusions RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.

Objective To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand.Methods This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24.Results Median baseline values for CD4 and viral load were 13 cells/mm3and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmaxand Cminwere 18.1 (15.3–23.8) mg/l•h, 4.1 (3.6–4.8) mg/l and 0.17 (0.12–0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmaxand Cminvalues found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cminbelow the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cminabove 0.10 mg/l, there was also one virological failure (6%) (P=0.30).Conclusions Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cminlevels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.