Tristan Barber

Cerebrospinal Fluid Exposure of Efavirenz and Its Major Metabolites When Dosed at 400 mg and 600 mg Once Daily: A Randomized Controlled Trial

BACKGROUNDnThe optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities.nnnMETHODSnCerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily.nnnRESULTSnOf 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all. Geometric mean CSF efavirenz, 7OH-, and 8OH-efavirenz concentrations (with 90% confidence intervals [CIs]) for the 400-mg and 600-mg dosing groups were 16.5 (13-21) and 19.5 (15-25) ng/mL; 0.6 (.4-.9) and 0.6 (.4-1) ng/mL; and 5.1 (4.0-6.4) and 3.1 (2.1-4.4) ng/mL, respectively. Efavirenz concentration in CSF was >0.51 ng/mL (proposed CSF 50% maximal inhibitory concentration for wild-type virus) in all subjects, and 8OH-efavirenz concentration in CSF was >3.3 ng/mL (a proposed toxicity threshold) in 11 of 14 and 7 of 14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whereas CSF efavirenz concentration was significantly associated with plasma concentration (P < .001) and cytochrome P450 2B6 genotype (CSF efavirenz GG to GT/TT geometric mean ratio, 0.56 [90% CI, .42-.74]), CSF 8OH-efavirenz concentration was not (P = .242 for association and CSF 8OH-efavirenz GG to GT/TT geometric mean ratio, 1.52 [90% CI, .97-2.36]).nnnCONCLUSIONSnWith both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication, although concentrations of 8OH-efavirenz were greater than those reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and, as we postulate, may be subject to saturable pharmacokinetic effects.nnnCLINICAL TRIALS REGISTRATIONnNCT01011413.

The pharmacokinetic profile of raltegravir-containing antiretroviral therapy in HIV-infected individuals over 60 years of age

Abstract Background: Antiretroviral safety and efficacy and may differ in older versus younger HIV-infected patients. The objective of this study was to assess the pharmacokinetic (PK) profile in older HIV-infected subjects (>60u200ayears) switching combination antiretroviral therapy (cART) to a raltegravir (RAL) containing regimen. Methods: Nineteen HIV-infected patients over 60u200ayears of age on effective cART (HIV-RNA <u200950 copies/ml) were enrolled in this prospective 24-week study. On day 1, patients switched to tenofovir/emtricitabine (245/200u200amg once daily) and RAL (400u200amg twice daily). On day 28, intensive PK sampling was undertaken in a fasted state and RAL plasma concentrations determined. Neurocognitive function was assessed at baseline and week 24 using a neuropsychological battery. RAL PK parameters were compared to those of two younger historical HIV-infected control groups that received twice-daily RAL co-administered with darunavir/ritonavir (DRV/r) 800/100 once daily by nonlinear mixed effects modelling. Results: In HIV-infected subjects over the age of 60 (meanu2009±u2009SD age: 66u2009±u20093.4u200ayears, nu2009=u200919) switching to a RAL containing regimen, we observed no safety concerns, no plasma virological rebounds, and no differences in RAL apparent oral clearance when compared to younger HIV-infected populations (meanu2009±u2009SD age: 41u2009±u20099.2u200ayears, nu2009=u200938) based on population pharmacokinetic analysis. After 24u200aweeks of study therapy a decline in cognitive function was observed [change in (SD) global score of (0.91 (1.3), Pu2009=u20090.018]. Conclusions: No significant changes in RAL exposure associated with age were observed.

Impact of NRTI backbone on renal, bone and cardiovascular markers in HIV-infected individuals receiving a boosted protease inhibitor

We have previously shown in the SSAT 044 study that unconjugated hyperbilirubinaemia in subjects receiving a boosted protease inhibitor (PI/r) has limited impact on renal, cardiovascular (CV) and bone biomarkers, as well as on neurocognitive performance, relative to those receiving PI/r with a normal bilirubin. We present here a secondary analysis comparing markers in those receiving abacavir‐ vs tenofovir‐ based antiretroviral therapy (ART).

Effect of hyperbilirubinaemia on neurocognitive, renal, bone and cardiovascular markers in HIV infection treated with boosted protease inhibitors

Use of some protease inhibitors (PI) is associated with unconjugated hyperbilirubinaemia (HBR), due to inhibition of UGT1A1. As observed in Gilberts syndrome, HBR may have antioxidant and anti‐inflammatory effects. Inflammation may be relevant to neurocognitive (NC) impairment, cardiovascular, renal and bone co‐morbidities in HIV infection. This study aimed to analyse correlations between antiretroviral associated HBR and NC impairment as well as renal, bone and cardiovascular parameters.

Electronic learning and specialty training in genitourinary medicine

The UK Department of Health have commissioned the Electronic Learning for Healthcare programme,1 from which the sexual health and HIV (eHIV–STI) project has been developed by the British Association for Sexual Health and HIV (BASHH) and the Federation of Royal Colleges of Physicians. Professional bodies within the UK are increasingly looking to such packages for the delivery of training to healthcare professionals.2nneHIV–STI provides a web-based learning programme for both the sexually transmitted infections foundation course3 and will also, when completed, cover all the knowledge components of the genitourinary medicine (GUM) specialty curriculum.4 A survey of specialist/specialty registrars in GUM before eHIV–STI was available found that 70% believed web-based delivery of the knowledge component of their curriculum to be either a better approach or as effective. …

Person-centred care and HIV: challenges and solutions

Person-centred consultations (PCCs) are fundamental to effective healthcare communication, and its use is embedded within key clinical guidance. There are three aspects to PCC: use of the best available research evidence, clinical expertise of the clinician and the patient’s circumstances, goals, values and wishes. Balancing theses three aspects in the context of HIV prevention and management can be challenging, and we use three case examples to highlight these.

P132 An audit of the use of suppressive aciclovir in patients on stable art with suppressed HIV viraemia in plasma

Introduction BASHH guidelines state suppressive therapy for HSV in HIV+ individuals as aciclovir 400mg BD. Anecdotally some HIV+ patients report better control of genital HSV on different antiretroviral (ART) regimens. Previous studies have shown HIV protease inhibitors (PI) may induce antiviral effects against HSV. We audited our suppressive aciclovir (sACV) use in undetectable HIV patients on stable ART against BASHH standards. We noted frequency of genital HSV outbreaks in those on PI vs non-boosted ART regimens to see any signal that PIs may confer protection against HSV reactivation. Methods Patients were eligible if they were receiving prophylactic aciclovir, male, 18–50 years of age, with HIV viral load below 50 copies/ml on current ART. The dose of aciclovir was recorded. We also collected information on: HSV outbreaks 1/10/16-31/1/17, ART regime, CD4 count, age/ethnicity, and duration of HIV infection. Results 60 patients were identified. 47/60 patients were taking aciclovir 400mg BD. 13/60 were prescribed ACV 400mg OD only. For those on BD:Abstract P132 Table 1 HSV suppression by ART Outbreak No outbreak PI/boosted 1 11 Non boosted 6 29 This gave a relative risk of HSV outbreak on a PI of 0.49 over the time studied. Discussion Of eligible patients 78.3% of prescriptions met BASHH standards. Patients on sACV dosed at 400mg BD had a lower risk (RR 0.49) of symptomatic HSV recurrence if they were on PI based ART. This is important in the therapeutic management of co-infected patients and warrants further studies to better define the relationship.

A cross-sectional study to evaluate the association of hyperbilirubinaemia on markers of cardiovascular disease, neurocognitive function, bone mineral density and renal markers in HIV-1 infected subjects on protease inhibitors

Background: Ongoing inflammation in controlled HIV infection contributes to non-AIDS comorbidities. High bilirubin appears to exhibit an anti-inflammatory effect in vivo. We therefore examined whether increased bilirubin in persons with HIV was associated with differences in markers of inflammation and cardiovascular, bone, renal disease, and neurocognitive (NC) impairment. Methods: This cross-sectional study examined inflammatory markers in individuals with stable HIV infection treated with two nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Individuals recruited were those with a normal bilirubin (NBR; 0–17 μmol/L) or high bilirubin (>2.5 × upper limit of normal). Demographic and anthropological data were recorded. Blood and urine samples were taken for analyses. Pulse wave velocity (PWV) measurement, carotid intimal thickness (CIT), and calcaneal stiffness (CSI) were measured. Males were asked to answer a questionnaire about sexual function; NC testing was performed using CogState. Results: 101 patients were screened, 78 enrolled (43 NBR and 35 HBR). Atazanavir use was significantly higher in HBR. Whilst a trend for lower CIT was seen in those with HBR, no significant differences were seen in PWV, bone markers, calculated cardiovascular risk (Framingham), or erectile dysfunction score. VCAM-1 levels were significantly lower in the HBR group. HBR was associated with lower LDL and triglyceride levels. NBR was associated with a calculated FRAX significantly lower than HBR although no associations were found after adjusting for tenofovir use. No difference in renal markers was observed. Component tests of NC testing revealed differences favouring HBR but overall composite scores were similar. Discussion: High bilirubin in the context of boosted PI therapy was found not to be associated with differences in with the markers examined in this study. Some trends were noted and, on the basis of these, a larger, clinical end point study is warranted.

P214 Are we missing something? extra-genital CT/GC naat testing in female patients attending a young persons clinic

Background/introduction Our service has a dedicated Young Persons Clinic (YPC) for women age ≤25. Current policy is to only offer routine vulvo-vaginal (VVS) or cervical CT/GC NAAT swabs for female patients but we are aware that STIs in non-genital sites may therefore be missed. From 15/04/14 we offered female patients attending our YPC VVS/cervical and extragenital (throat and rectum) swabs, regardless of exposure stated. Aim(s)/objectives To quantify the number and result of CT/GC extragenital samples from YPC female patients. Methods NAAT results for all women attending YPC between 15/04/14–16/09/14 were extracted retrospectively from an electronic database held within the clinic. Results Number of patients % STI Screens 193 Acute STI diagnosed at that visit (including TV and PID) 29/193 15 Positive CT/GC NAAT at that visit 24/193 12 More than one site sampled 34/193 18 with positive extragenital CT/GC NAAT *and negative VVS/cervical CT/GC NAAT 4/34 12 * GC throat × 2, CT throat × 1, CT throat + GC rectal × 1 42 patients were documented to have been offered extragenital swabs. Of those, 34 (81%) accepted. Discussion/conclusion Uptake of extragenital site testing was low. This is likely to reflect low rates of offering extragenital swabs, as there was a high rate (81%) of acceptance where an offer was documented. Five infections were solely identified from extragenital testing. It is recognised that a positive result does not necessarily imply infection and extragenital tests are currently unlicensed. Therefore this data suggests that further review would be useful.

P238 Hepatitis C testing in msm – are we asking the right questions?

Background Concern regarding high rates of hepatitis C infection in sub-groups of MSM may warrant targeted testing. Aim We examine whether we routinely collect the necessary information from MSM to identify those at risk and target hepatitis C testing, and assess whether our concerns about emerging risk factors for hepatitis C are implicated in new diagnoses in our cohort. Methods Notes audit of all MSM GUM attendances during November 2013 assessed documentation of fisting, rectal bleeding with sex, group sex, and drug use, as well as hepatitis testing. Notes of all patients coded for hepatitis C infection during 2011–2013 were examined to assess risk factors for hepatitis C infection. Results 147 MSM attendances were reviewed. The proportion of men asked about specific risk factors was: drug use (18%), rectal bleeding (1%), group sex (1%), fisting (1%). 8% MSM had hepatitis C screens, none with traditional risk factors. Over 3 years, 46 patients were coded for hepatitis C. 34% of these were new infections. 33% were HIV positive, 48% had injected drugs (41% no documentation), 22% had hepatitis C positive partners, 11% were sex workers. Discussion/conclusion Drug use and high risk sexual practices were not always fully recorded in our sample. Testing rates were low and did not seem to relate to identifiable risks. We identified few cases of new infection, largely limited to patients with traditional risk factors. It is not clear if better recording of risk factors would lead to increased Hepatitis C testing or diagnosis.