Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study.

OBJECTIVES: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. METHODS: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. RESULTS: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-naïve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). CONCLUSIONS: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.

Estimated glomerular filtration rate slopes on tenofovir alafenamide.

OBJECTIVES: The aim of the study was to analyse and compare estimated glomerular filtration rate (eGFR) slopes during exposure to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) in individuals who initiated TAF, regardless of prior regimen, before October 2016. METHODS: An observational cohort study was conducted at 11 clinics in the UK and Ireland. Mixed effects models with random intercept and time terms fitted were used to generate and compare eGFR slopes while participants were exposed to TDF and TAF, with adjustment for age, eGFR at TDF/TAF initiation, gender, ethnicity, and time-updated CD4 cell count and HIV RNA measurements. RESULTS: Data were available for 357 subjects (median age 50 years; 80% male; 82% white/other ethnicity; 51% men who have sex with men; median nadir CD4 count 216 cells/µL). The median duration of exposure to TAF was 2.0 (interquartile range 1.6, 2.3) years. At TAF initiation, the median CD4 count was 557 cells/µL, the median eGFR was 80 mL/min/1.73 m2, and 86% had suppressed HIV infection. The mean adjusted eGFR slope during TDF and TAF exposure was -2.08 [95% confidence interval (CI) -2.24, -1.92] and 1.18 (95% CI 0.20, 1.52) mL/min/1.73 m2/year, respectively (P < 0.001). Individuals who experienced rapid eGFR decline (> 3 or 5 mL/min/1.73 m2/year) while receiving TDF experienced significant eGFR recovery while on TAF (P < 0.001). CONCLUSIONS: Significant improvement in eGFR slope was observed in patients who switched from TDF- to TAF-containing antiretroviral regimens. These data provide further support for the renal safety of TAF, and for switching those who experience progressive worsening of renal function from TDF to TAF.

Dual therapy with renally adjusted lamivudine and dolutegravir: a switch strategy to manage comorbidity and toxicity in older, suppressed patients?

OBJECTIVES: The aim of the study was to evaluate the efficacy of dual therapy with lamivudine (3TC), with dose adjustment for renal function, and dolutegravir (DTG) in a subgroup of patients fully suppressed on treatment who were switched because of concerns about comorbidity and toxicity on their current triple drug regimen. METHODS: A retrospective evaluation of clinical and pathological parameters from an electronic patient record from a single centre was carried out. RESULTS: There were no virological failures in 52 patients with a median age of 60.5 years. The median duration of follow-on dual therapy was 2.29 years (28 months; range 1.10-3.34 years). In 25 of 52 (48%) cases, the dose of 3TC was adjusted taking into account reduced renal function, and none of these patients experienced virological failure. Four additional patients discontinued early, because of side effects of the switch, with no failure. CONCLUSIONS: This retrospective review suggests that 3TC and DTG may be effective in controlling viral load in older patients with comorbidities. This regimen appears to be a useful option in the context of comorbidities (including renal impairment) and polypharmacy in older patients. However, this review has been conducted in one centre and in a small population of patients. Therefore, further multicentre trials involving larger populations of patients are needed.

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

The use of funnel plots with regression as a tool to visually compare HIV treatment outcomes between centres adjusting for patient characteristics and size: a UK Collaborative HIV Cohort study.

OBJECTIVES: A measure used for assessing the effectiveness of HIV care and comparing clinical centres is the proportion of people starting antiretroviral therapy (ART) with viral suppression (VS) after 1 year. We propose a method that adjusts for patients' demographic characteristics, and visually compares this measure between different sites accounting for centre size. METHODS: We analysed viral load measurements for UK Collaborative HIV Cohort (UK CHIC) patients starting ART between 2006 and 2013. We used logistic regression to estimate the proportion with VS after 1 year of ART adjusted for patient mix (in terms of age and a combined gender/ethnicity/acquisition mode variable) and calendar year. We compared outcomes between centres using funnel plots which account for centre size. RESULTS: The overall proportion of the cohort with VS 1 year after starting ART was 90% and increased from 83% to 93% between 2006 and 2013. VS was lower in younger individuals. White men who have sex with men (MSM) had the highest (94%), and black African (81%) and white (82%) heterosexual women the lowest proportions achieving VS. Comparing the unadjusted funnel plot with the adjusted, there were movements of some centres from outside to inside the 95% contour limits, which was largely explained by the patient mix of these centres. CONCLUSIONS: VS 1 year after ART start was associated with demographic characteristics and centre size; therefore, to compare the performances of centres, adjustment for these factors is required. Adjusted funnel plot is an effective tool which accounts for both the demographic characteristics and the centre size. Social factors, rather than treatment decisions within the control of the centres, may drive differences in outcomes.

A novel strategy to reduce very late HIV diagnosis in high-prevalence areas in South-West England: serious incident audit.

Background: Very late diagnosis of HIV is a serious public health issue. We used serious incident reporting (SIR) to identify and address reasons for late diagnoses across the patient pathway. Methods: Cases of very late HIV diagnosis were reported via SIR in two 6-month batches between 2011 and 2012 in Bournemouth, Poole and Bristol. Case notes were reviewed for missed opportunities for earlier diagnosis using a root-cause analysis tool. Results: A total of 33 patients (aged 30-67 years, 66% male) were diagnosed very late. Although the majority were white British (n = 17), Black African (n = 9) and Eastern European (n = 4) ethnicities were over-represented. Twenty-four (73%) patients had clinical indicator conditions for HIV, 30 (91%) had a risk factor for HIV acquisition, with 13 (39%) having 2 or more (men-who-have-sex-with-men (n = 11), partner HIV positive (n = 11), from high-prevalence area (n = 12)). Actions resulting from SIR included increasing awareness of indicator conditions, HIV education days within primary care, and initiatives to increase testing within hospital specialities. Conclusions: SIR allowed identification of reasons for very late HIV diagnosis and provided an impetus for initiatives to address them. SIR may be part of an effective strategy to prevent late diagnosis of HIV which would have important benefits for individual and population health.

C1 inhibitor deficiency: 2014 United Kingdom consensus document.

C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.

The effects of age on associations between markers of HIV progression and markers of metabolic function including albumin, haemoglobin and lipid concentrations.

OBJECTIVES: We investigated whether age modified associations between markers of HIV progression, CD4 T lymphocyte count and HIV RNA viral load (VL), and the following markers of metabolic function: albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). METHODS: A retrospective analysis of data from the United Kingdom Collaborative HIV Cohort was carried out. Analyses were limited to antiretroviral-naïve subjects to focus on the impact of HIV disease itself. A total of 16670 subjects were included in the analysis. Multilevel linear regression models assessed associations between CD4 count/VL and each of the outcomes. Statistical tests for interactions assessed whether associations differed among age groups. RESULTS: After adjustment for gender and ethnicity, there was evidence that lower CD4 count and higher VL were associated with lower TC, LDL-C, haemoglobin and albumin concentrations but higher triglyceride concentrations. Age modified associations between CD4 count and albumin (P < 0.001) and haemoglobin (P = 0.001), but not between CD4 count and HDL-C, LDL-C and TC, or VL and any outcome. Among participants aged < 30, 30-50 and > 50 years, a 50 cells/µL lower CD4 count correlated with a 2.4 [95% confidence interval (CI) 1.7-3.0], 3.6 (95% CI 3.2-4.0) and 5.1 (95% CI 4.0-6.1) g/L lower haemoglobin concentration and a 0.09 (95% CI 0.07-0.11), 0.12 (95% CI 0.11-0.13) and 0.16 (95% CI 0.13-0.19) g/L lower albumin concentration, respectively. CONCLUSIONS: We present evidence that age modifies associations between CD4 count and plasma albumin and haemoglobin levels. A given reduction in CD4 count was associated with a greater reduction in haemoglobin and albumin concentrations among older people living with HIV. These findings increase our understanding of how the metabolic impact of HIV is influenced by age.

Non-uptake of highly active antiretroviral therapy among patients with a CD4 count < 350 cells/µL in the UK.

OBJECTIVES: Current British HIV Association (BHIVA) guidelines recommend that all patients with a CD4 count <350 cells/µL are offered highly active antiretroviral therapy (HAART). We identified risk factors for delayed initiation of HAART following a CD4 count <350 cells/µL. METHODS: All adults under follow-up in 2008 who had a first confirmed CD4 count <350 cells/µL from 2004 to 2008, who had not initiated treatment and who had >6 months of follow-up were included in the study. Characteristics at the time of the low CD4 cell count and over follow-up were compared to identify factors associated with delayed HAART uptake. Analyses used proportional hazards regression with fixed (sex/risk group, age, ethnicity, AIDS, baseline CD4 cell count and calendar year) and time-updated (frequency of CD4 cell count measurement, proportion of CD4 counts <350 cells/µL, latest CD4 cell count, CD4 percentage and viral load) covariates. RESULTS: Of 4871 patients with a confirmed low CD4 cell count, 436 (8.9%) remained untreated. In multivariable analyses, those starting HAART were older [adjusted relative hazard (aRH)/10 years 1.15], were more likely to be female heterosexual (aRH 1.13), were more likely to have had AIDS (aRH 1.14), had a greater number of CD4 measurements < 350 cells/µL (aRH/additional count 1.18), had a lower CD4 count over follow-up (aRH/50 cells/µL higher 0.57), had a lower CD4 percentage (aRH/5% higher 0.90) and had a higher viral load (aRH/log(10) HIV-1 RNA copies/ml higher 1.06). Injecting drug users (aRH 0.53), women infected with HIV via nonsexual or injecting drug use routes (aRH 0.75) and those of unknown ethnicity (aRH 0.69) were less likely to commence HAART. CONCLUSION: A substantial minority of patients with a CD4 count < 350 cells/µL remain untreated despite its indication.

Hepatitis E virus coinfection in patients with HIV infection.

OBJECTIVES: Hepatitis E virus (HEV) infection is an emerging infection in developed countries and is thought to be a porcine zoonosis. HEV can cause chronic infection and cirrhosis in the immunosuppressed, including patients with HIV infection. Little is known about HEV and HIV coinfection. The aim of the study was to document the incidence of chronic HEV coinfection in patients with HIV infection and to determine the anti-HEV seroprevalence and compare it with that of a control population. METHODS: A cohort/case-control study was carried out in two teaching hospitals in southwest England. A total of 138 patients with HIV infection were tested for HEV using an immunoassay for anti-HEV immunoglobulin M (IgM) and IgG and reverse transcriptase-polymerase chain reaction (RT-PCR), and 464 control subjects were tested for anti-HEV IgG. Demographic, lifestyle and laboratory data were prospectively collected on each patient with HIV infection. The anti-HEV IgG seroprevalence in patients with HIV infection was compared with that in controls and demographic risk factors for HEV exposure were explored using logistic regression models. RESULTS: There was no difference in anti-HEV IgG seroprevalence between the HIV-infected patients and controls. The only risk factor predictive of anti-HEV seropositivity was the consumption of raw/undercooked pork; sexual risk factors were unrelated. No patient with HIV infection had evidence of chronic coinfection with HEV CONCLUSIONS: Anti-HEV seroprevalence is similar in controls and patients with HIV infection. Risk factor analysis suggests that HEV is unlikely to be transmitted sexually. Chronic coinfection with HEV was absent, indicating that chronic HEV/HIV coinfection is not a common problem in this cohort.

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study.

OBJECTIVE: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends. METHODS: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated. FINDINGS: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load. CONCLUSIONS: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.

Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease.

OBJECTIVE: The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. METHODS: Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. RESULTS: The median (interquartile range) CPE score for initial cART regimen increased from 7 (5-8) in 1996-1997 to 9 (8-10) in 2000-2001 and subsequently declined to 6 (7-8) in 2006-2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤ 4, and less frequently in those with scores ≥ 10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤ 4 were independently associated with increased risk of death. CONCLUSION: Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses.

Responses to highly active antiretroviral therapy and clinical events in patients with a low CD4 cell count: late presenters vs. late starters.

OBJECTIVE: We investigated whether adverse responses to highly active antiretroviral therapy (HAART) associated with late HIV presentation are secondary to low CD4 cell count per se or other confounding factors. METHODS: A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study of individuals starting HAART in 1998-2007 was carried out, comparing late presenters (presenting/starting HAART at a CD4 count <200 cells/µL) with late starters (presenting at a CD4 count>350 cells/µL; starting HAART at a CD4 count<200 cells/µL), using 'ideal starters' (presenting at a CD4 count>350 cells/µL; starting HAART at a CD4 count of 200-350 cells/µL) as a comparator. Virological, immunological and clinical (new AIDS event/death) outcomes at 48 and 96 weeks were analysed, with the analysis being limited to those remaining on HAART for>3 months. RESULTS: A total of 4978 of 9095 individuals starting first-line HAART with HIV RNA>500 HIV-1 RNA copies/mL were included in the analysis: 2741 late presenters, 947 late starters and 1290 ideal starters. Late presenters were more commonly female, heterosexual and Black African. Most started nonnucleoside reverse transcriptase inhibitors (NNRTIs); 48-week virological suppression was similar in late presenters and starters (and marginally lower than in ideal starters); by week 96 differences were reduced and nonsignificant. The median CD4 cell count increase in late presenters was significantly lower than that in late starters (weeks 48 and 96). During year 1, new clinical events were more frequent for late presenters [odds ratio (OR) 2.04; 95% confidence interval (CI) 1.19-3.51; P=0.01]; by year 2, event rates were similar in all groups. CONCLUSION: Amongst patients who initiate, and remain on, HAART, late presentation is associated with lower rates of virological suppression, blunted CD4 cell count increases and more clinical events compared with late starters in year 1, but similar clinical and immunological outcomes by year 2 to those of both late and ideal starters. Differences between late presenters and late starters suggest that factors other than CD4 cell count alone may be driving adverse treatment outcomes in late-presenting individuals.

Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations.

OBJECTIVE: Effective antiretroviral therapy (ART) has transformed the care of people with HIV, but it is important to monitor time trends in indicators of treatment success and antic future changes. METHODS: We assessed time trends from 2000 to 2007 in several indicators of treatment success in the UK Collaborative HIV Cohort (CHIC) Study, and using national HIV data from the Health Protection Agency (HPA) we developed a model to project future trends. RESULTS: The proportion of patients on ART with a viral load <50 HIV-1 RNA copies/mL increased from 62% in 2000 to 84% in 2007, and the proportion of all patients with a CD4 count <200 cells/microL decreased from 21% to 10%. During this period, the number of patients who experienced extensive triple class failure (ETCF) rose from 147 (0.9%) to 1771 (3.9%). The number who experienced such ETCF and had a current viral load >50 copies/mL rose fromz 118 (0.7%) to 857 (1.9%). Projections to 2012 suggest sustained high levels of success, with a continued increase in the number of patients who have failed multiple drugs but a relatively stable number of such patients experiencing viral loads >50 copies/mL. Numbers of deaths are projected to remain low. CONCLUSIONS: There have been continued improvements in key indicators of success in patients with HIV from 2000 to 2007. Although the number of patients who have ETCF is projected to rise in the future, the number of such patients with viral loads >50 copies/mL is not projected to increase up to 2012. New drugs may be needed in future to sustain these positive trends.

CYP2B6 G516T genotyping in a UK cohort of HIV-positive patients: polymorphism frequency and influence on efavirenz discontinuation.

OBJECTIVES: The nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz undergoes phase I metabolism by the cytochrome P450 enzyme, CYP2B6. Previous studies outside of the United Kingdom have shown associations between the CYP2B6 polymorphism G516T and increased toxicity. This study aimed to develop a CYP2B6 G516T genotyping assay to identify individuals at risk of efavirenz toxicity. The frequency of this polymorphism in a UK HIV-infected population and its prevalence in individuals who had discontinued efavirenz were also to be assessed. METHODS: Genomic DNA from HIV-positive patients (n = 206) attending clinic at Southmead Hospital, North Bristol NHS Trust was extracted from spare blood taken for CD4 monitoring. An allele-specific polymerase chain reaction (PCR) method for the CYP2B6 G516T polymorphism was used to assign patients' genotypes. Patients' age, sex, ethnicity and drug history were also recorded. RESULTS: The G516T polymorphism was more prevalent in Blacks (16%; n = 10/63) than Caucasians (6%; n = 9/143). No significant difference in the distribution of genotypes between individuals who had discontinued efavirenz (n = 31) and individuals who had continued efavirenz (n = 74) was observed (chi(2); P = 0.63). CONCLUSIONS: A genotyping method for the CYP2B6 G516T method was used to assess the polymorphism frequency in a UK cohort of HIV-infected patients. The polymorphism was not more prevalent in individuals who had discontinued efavirenz. Reasons for drug discontinuation are likely to be multifactorial and as this study showed cannot be explained by this genetic difference alone. For this reason we do not advocate testing for this polymorphism in routine clinical practice at present.

Treatment outcome and cost-effectiveness of different highly active antiretroviral therapy regimens in the UK (1996-2002).

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 + PI(boosted), 2NRTIs + PI and 2NRTIs + 2PIs, whereas for second- and third-line they were similar. Comparing first-line 2NRTIs + NNRTI with 2NRTIs + PI(boosted) 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 + PI(boosted) 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 + PI(boosted) 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.

C1-inhibitor deficiencies (hereditary angioedema): where are we with therapies?

Hereditary angioedema, an autosomal dominant disorder, presents clinically as recurrent episodes of swelling. It results from either deficient production or function of C1 inhibitor. Acquired angioedema is associated with lymphoproliferative or autoimmune disease. Conventionally attenuated androgens and antifibrinolytics have been used for prophylaxis, both for the long term and presurgically. Fresh frozen plasma and plasma-derived C1 inhibitor concentrate have been used primarily for treatment of acute attacks. All have drawbacks in side effects or potential for infection transmission. New treatments (recombinant C1 inhibitor, icatibant, DX-88, and for acquired angioedema, rituximab) so far show good safety profiles. Early data suggest these may be effective treatment alternatives. The efficacy of current treatment and the potential held by newer agents that target specific elements in complement or kinin pathways are examined. Some agents are likely to have a wider role in treatment of other, more common, forms of angioedema.