Neal Marshall

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015

Writing Group Duncan Churchill, Chair, Royal Sussex County Hospital, Brighton, UK Laura Waters, Vice Chair, Mortimer Market Centre, London, UK Nadia Ahmed, Mortimer Market Centre, London, UK Brian Angus, University of Oxford, UK Marta Boffito, Chelsea and Westminster Hospital, London, UK Mark Bower, Chelsea and Westminster Hospital, London, UK David Dunn, University College London, UK Simon Edwards, Central and North West London NHS Foundation Trust, UK Carol Emerson, Royal Victoria Hospital, Belfast, UK Sarah Fidler, Imperial College School of Medicine at St Mary’s, London, UK †Martin Fisher, Royal Sussex County Hospital, Brighton, UK Rob Horne, University College London, UK Saye Khoo, University of Liverpool, UK Clifford Leen, Western General Hospital, Edinburgh, UK Nicola Mackie, Imperial College Healthcare NHS Trust, London, UK Neal Marshall, Royal Free Hospital NHS Trust, London, UK Fernando Monteiro, UK-CAB Mark Nelson, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

Late Ebola virus relapse causing meningoencephalitis: a case report

Summary Background There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Funding Royal Free London NHS Foundation Trust.

British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012: BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012

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

Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: A case-series of health-care workers

BACKGROUND Although a few international health-care workers who have assisted in the current Ebola outbreak in west Africa have been medically evacuated for treatment of Ebola virus disease, more commonly they were evacuated after potential accidental exposure to Ebola virus. An urgent need exists for a consensus about the risk assessment of Ebola virus transmission after accidental exposure, and to investigate the use of post-exposure prophylaxis (PEP). Experimental vaccines have occasionally been used for Ebola PEP, but newly developed experimental antiviral agents have potential advantages. Here, we describe a new method for risk assessment and management of health-care workers potentially exposed to Ebola virus and report the use of experimental antiviral therapies for Ebola PEP in people. METHODS We devised a risk assessment and management algorithm for health-care workers potentially exposed to Ebola virus and applied this to eight consecutive individuals who were medically evacuated to the UK from west Africa between January, and March, 2015. PEP with antiviral agents was given to health-care workers assessed to have had substantial risk exposures to Ebola virus. Participants were followed up for 42 days after potential exposure. FINDINGS Four of eight health-care workers were classified as having had low risk exposures and managed by watchful waiting in the community. None of these health-care workers developed Ebola virus disease. The other four health-care workers had intermediate or maximum risk exposures and were given PEP with antiviral agents. PEP was well tolerated with no serious adverse effects. None of these four health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, developed Ebola virus disease. INTERPRETATION Standardised risk assessment should be adopted and consensus guidelines developed to systematically study the efficacy and safety of PEP with experimental agents. New experimental antiviral treatments are a viable option for PEP against Ebola. FUNDING Royal Free London NHS Foundation Trust.

Kidney transplantation in HIV-positive adults: the UK experience.

HIV-positive patients are at increased risk of end-stage kidney disease (ESKD). Kidney transplantation (KT) is an established treatment modality for ESKD in the general population. Recent data have confirmed the feasibility of kidney transplantation in HIV-positive patients, and kidney transplantation is increasingly offered to ESKD patients with well-controlled HIV infection. We report clinical outcomes in a national cohort study of kidney transplantation in HIV-positive patients. In all, 35 HIV-positive KT recipients who had undergone KT up to December 2010 (66% male, 74% black ethnicity) were identified; the median CD4 cell count was 366, all had undetectable HIV RNA levels at kidney transplantation, and 44% received a kidney from a live donor. Patient survival at 1 and 3 years was 91.3%, and graft survival 91.3% and 84.7%, respectively. At one-year post-kidney transplantation, the cumulative incidence of acute rejection was 48%, and the median (IQR) eGFR was 64 (46, 78) mL/min/1.73 m2. Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. Our study corroborates the feasibility of kidney transplantation in HIV-positive patients. The high rates of acute rejection suggest that the optimal immune suppression strategy in this population remains to be refined.

Responses to Switching to Maraviroc-Based Antiretroviral Therapy in Treated Patients with Suppressed Plasma HIV-1-RNA Load

Background: Maraviroc (MVC) has shown good efficacy and tolerability in treatment-naive and treatment-experienced HIV-1-infected patients with CCR5-tropic virus. Data on patients switching to MVC while on suppressive antiretroviral therapy (ART) are limited. The aim of this study was to evaluate patients on suppressive ART switching to an MVC-containing regimen (MVC-CR), and test the hypothesis that the switch may have an impact on T cell activation. Methods: The study population comprised 20 treated adults who started MVC with a plasma HIV-1-RNA load (viral load, VL) of <50 copies/ml. Viral tropism was assessed by V3 loop sequencing using proviral DNA from peripheral blood mononuclear cells (PBMCs). Changes in clinical and laboratory parameters were evaluated at a median of 2 and 6 months of follow-up. T cell activation was determined by measuring soluble CD30 in plasma. Results: Reasons for switching to a MVC-CR were drug toxicity and tolerability, low CD4 cell count and ART simplification. Over median 7.5 months of follow-up, 3/20 patients discontinued MVC due to severe headache, fatigue and VL rebound. A significant reduction in soluble CD30 levels in MVC-treated patients was observed during follow-up at both 2 (p = 0.027) and 6 months (p = 0.001). Conclusions: Switching suppressive ART to a MVC-CR based upon genotypic tropism prediction from proviral DNA improves tolerability. The observed impact on T cell activation warrants further investigation.

Mother to child transmission (MTCT) of HIV - almost a thing of the past? A cohort study of HIV positive women starting antiretroviral drugs in pregnancy

Where available, antiretrovirals (ARVs) and antenatal HIV testing and care have significantly reduced mother to child transmission (MTCT). Higher maternal viral load (VL) is linked with higher risk of MTCT, increasing risk of MTCT for women starting ARVs during pregnancy compared to those already suppressed. A single-centre, retrospective cohort of women starting ARVs during pregnancy from 2004 till 2013. Demographic, obstetric and virological data, and neonatal outcomes were collected where available. 60 pregnancies were recorded (in 56 women) in which ARVs were started or restarted from a total of 129 recorded pregnancies. 48% (27/56) were new antenatal HIV diagnoses and in these median gestational age (GA) at diagnosis was 16.1 weeks (range 5.3-37.6). Median GA at ARV commencement was 22.4 weeks (range 8-37.7) with 63% (35/56) starting before 24 weeks and 91% (51/56) before 28 weeks. HIV diagnosis during pregnancy was associated with a later commencement of ARVs (23.9 vs 19.9 weeks, p=0.009). The ARV regimen was available for 58 pregnancies. Treatment was with two NRTIs plus NNRTI (3), or PI (54) or raltegravir (1). Raltegravir was added as a forth agent in 7 patients. 87% (52/60) had resistance genotyping before (14) or during (38) pregnancy, 81% (22/27) for new diagnoses in pregnancy. The rate of any ARV resistance was 12% (6/52): 4 patients had NNRTI and 2 NRTI resistance mutations, 4 were treatment-naive. This was not associated with treatment failure. HIV VL at delivery was available in 57 pregnancies with detectable VL in 16% (9/57). Pre-treatment VL >100,000 copies/mL during pregnancy was associated with higher risk of detectable VL at delivery (p=0.016). 69% babies were delivered by Caesarean section, 32% as an emergency. There was one late miscarriage at 17 weeks. Median GA at birth was 38 weeks (range 17-42) with 21% born at <37 weeks (10/48). There was one HIV MTCT (1.7% for those starting ARV in pregnancy, 0.8% overall) in a woman who was poorly adherent with ARVs throughout pregnancy with a VL of 216 copies/mL at delivery following a period of directly observed therapy. Over 10 years of integrated HIV and antenatal care, there was only one case of MTCT. Initiating ART for prevention of MTCT is complex, requires a multi-disciplinary approach and importantly patient engagement. Antenatal practices and guidelines have changed over the period of this dataset, allowing normalisation of pregnancy when HIV is diagnosed and treated early.

No impact of rifamycin selection on tuberculosis treatment outcome in HIV coinfected patients.

Rifabutin has been substituted for rifampicin when treating tuberculosis (TB)/HIV coinfection. However, despite reports of anti-TB treatment failure and acquired rifamycin resistance, long-term clinical outcome data are lacking. Observational analyses performed in a UK TB/HIV cohort demonstrated no difference in severe adverse events, anti-TB treatment completion, relapse frequency or subsequent rifamycin resistance when rifampicin and rifabutin were compared, using different combinations of antiretroviral therapy. Our data support the wider use of rifabutin in TB/HIV coinfection.

Real-world persistence with antiretroviral therapy for HIV in the United Kingdom: A multicentre retrospective cohort study

Summary Objectives Persistence with an antiretroviral therapy (ART) regimen for HIV can be defined as the length of time a patient remains on therapy before stopping or switching. We aimed to describe ART persistence in treatment naïve patients starting therapy in the United Kingdom, and to describe differential persistence by treatment regimen. Methods We performed a retrospective cohort study at eight UK centres of ART-naïve adults commencing ART between 2012 and 2015. Aggregate data were extracted from local treatment databases. Time to discontinuation was compared for different third agents and NRTI backbones using incidence rates. Results 1949 patients contributed data to the analysis. Rate of third agent change was 28 per 100 person-years of follow up [95% CI 26–31] and NRTI backbone change of 15 per 100 person-years of follow up [95% CI 14–17]). Rilpivirine, as co-formulated rilpivirine/tenofovir/emtricitabine had a significantly lower discontinuation rate than all other third agents and, excluding single tablet regimens, co-formulated tenofovir/emtricitabine had a significantly lower discontinuation rate than co-formulated abacavir/lamivudine. The reasons for discontinuation were not well recorded. Conclusions Treatment discontinuation is not an uncommon event. Rilpivirine had a significantly lower discontinuation rate than other third agents and tenofovir/emtricitabine a lower rate than co-formulated abacavir/lamivudine.

Important Antiretroviral Drug Interactions With Benzodiazepines Used for Sedation During Bronchoscopy

We read with interest the article by Wahidi et al 1 in CHEST (November 2011). We are concerned that the section on midazolam did not provide up-to-date information on interactions between this drug and highly active antiretroviral therapy (ART) used in HIV-infected individuals. The study that is quoted in the consensus statement suggests that higher doses of midazolam may be needed in certain HIV-infected populations. 2 We believe this refl ects the situation in IV-drug users who are HIV-positive (the main HIV study group) and are likely to have acquired a tolerance to benzodiazepines through prolonged use. There is no detail provided on ART usage; therefore, the conclusions should not be extrapolated to all patients with HIV. The majority of current ART regimens contain either potent cytochrome P450 enzyme 3A4 (CYP3A4) inhibitors, such as the HIV protease inhibitor ritonavir, or enzyme inducers, such as the non-nucleoside reverse transcriptase inhibitors efavirenz or nevirapine. Midazolam is extensively metabolized by CYP3A4 and coadministration with, for example, lopinavir/ritonavir results in a fourfold increase in midazolam bioavailability (area under the curve) after parenteral administration. 3 This may result in prolonged sedation and other adverse effects such as arrhythmias. Diazepam at reduced doses has been used in clinical practice with ritonavir (100 to 200 mg daily), although at higher ritonavir doses, it is contraindicated. 4 Alternatively, lorazepam has the least potential for interaction with ART of all the currently available benzodiazepines 5 used in bronchoscopy. It may be considered in this scenario (where available) despite its disadvantage of a longer onset of action and duration of sedation. The use of benzodiazepines for other patient groups receiving CYP3A4 inhibitors such as macrolide antibiotics, itraconazole, and the new hepatitis C virus NS3 inhibitors (boceprevir and telaprevir) should also be undertaken with caution. Conversely, the concomitant administration of CYP3A4 inducers such as efavirenz, or rifamycin antibiotics may lead to therapeutic failure of standard-dose benzodiazepines. Dose escala tion should be performed with careful clinical and physiologic monitoring. The response to sedation in patients who are HIV-positive is unpredictable. The choice of sedative and its dosage must be tailored to the individual’s history and most importantly his or her concurrent medication. Increased postprocedure monitoring is mandatory.