Chloe Orkin

Comparison of Changes in Bone Density and Turnover with Abacavir-Lamivudine versus Tenofovir-Emtricitabine in HIV-Infected Adults: 48-Week Results from the ASSERT Study

BACKGROUNDnAbacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles.nnnMETHODSnIn this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis.nnnRESULTSnA total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001).nnnCONCLUSIONSnThis study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study

BACKGROUNDnDolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.nnnMETHODSnSPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824.nnnFINDINGSn411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.nnnINTERPRETATIONnThe non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.nnnFUNDINGnViiV Healthcare.

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

Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

BACKGROUNDnHepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection.nnnMETHODSnIn this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662.nnnFINDINGSnBetween June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia.nnnINTERPRETATIONnThis HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.nnnFUNDINGnMerck Sharp & Dohme Corp.

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011.

1.u2002Levels of evidence 1.1u2002Reference 2.u2002Introduction 3.u2002Auditable targets 4.u2002Table summaries 4.1u2002Initial diagnosis 4.2u2002Assessment of ART‐naïve individuals 4.3u2002ART initiation 4.4u2002Initial assessment following commencement of ART 4.5u2002Routine monitoring on ART 4.6u2002References 5.u2002Newly diagnosed and transferring HIV‐positive individuals 5.1u2002Initial HIV‐1 diagnosis 5.2u2002Tests to determine whether acquisition of HIV infection is recent 5.3u2002Individuals transferring care from a different HIV healthcare setting 5.4u2002Communication with general practitioners and shared care 5.5u2002Recommendations 5.6u2002References 6.u2002Patient history 6.1u2002Initial HIV‐1 diagnosis 6.2u2002Monitoring of ART‐naïve patients 6.3u2002Pre‐ART initiation assessment 6.4u2002Monitoring individuals established on ART 6.5u2002Assessment of adherence 6.6u2002Recommendations 6.7u2002References 7.u2002Examination 7.1u2002Recommendations 8.u2002Identifying the need for psychological support 8.1u2002References 9.u2002Assessment of immune status 9.1u2002CD4 T cell counts 9.2u2002CD4 T cell percentage 9.3u2002References 10.u2002HIV viral load 10.1u2002Initial diagnosis/ART naïve 10.2u2002Post ART initiation 10.3u2002Individuals established on ART 10.4u2002Recommendations 10.5u2002References 11.u2002Technical aspects of viral load testing 11.1u2002References 12.u2002Viral load kinetics during ART and viral load ‘blips’ 12.1u2002References 13.u2002Proviral DNA load 13.1u2002References 14.u2002Resistance testing 14.1u2002Initial HIV‐1 diagnosis 14.2u2002ART‐naïve 14.3u2002Post treatment initiation 14.4u2002ART‐experienced 14.5u2002References 15.u2002Subtype determination 15.1u2002Disease progression 15.2u2002Transmission 15.3u2002Performance of molecular diagnostic assays 15.4u2002Response to therapy 15.5u2002Development of drug resistance 15.6u2002References 16.u2002Other tests to guide use of specific antiretroviral agents 16.1u2002Tropism testing 16.2u2002HLA B*5701 testing 16.3u2002References 17.u2002Therapeutic drug monitoring 17.1u2002Recommendations 17.2u2002References 18.u2002Biochemistry testing 18.1u2002Introduction 18.2u2002Liver function 18.3u2002Renal function 18.4u2002Dyslipidaemia in HIV‐infected individuals 18.5u2002Other biomarkers 18.6u2002Bone disease in HIV‐infected patients 18.7u2002References 19.u2002Haematology 19.1u2002Haematological assessment and monitoring 19.2u2002Recommendations 19.3u2002References 20.u2002Serology 20.1u2002Overview 20.2u2002Hepatitis viruses 20.3u2002Herpes viruses 20.4u2002Measles and rubella 20.5u2002Cytomegalovirus (CMV) 20.6u2002References 21.u2002Other microbiological screening 21.1u2002Tuberculosis screening 21.2u2002Toxoplasma serology 21.3u2002Tropical screening 21.4u2002References 22.u2002Sexual health screening including anal and cervical cytology 22.1u2002Sexual history taking, counselling and sexually transmitted infection (STI) screening 22.2u2002Cervical and anal cytology 22.3u2002Recommendations 22.4u2002References 23.u2002Routine monitoring recommended for specific patient groups 23.1u2002Women 23.2u2002Older age 23.3u2002Injecting drug users 23.4u2002Individuals coinfected with HBV and HCV 23.5u2002Late presenters 23.6u2002References Appendix

Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count.

Objective:To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART. Design:Analysis of data from an ongoing HIV cohort study. Methods:The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts ≥ 350 cells/μl among patients in the UK CHIC Study. Results:In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350–499, 500–649 and > 650 cells/μl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500–649 cells/μl compared with those with CD4 cell count ≥ 650 cells/μl was 1.55 [95% confidence interval (CI), 1.11–2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count ≥ 350 cells/μl, there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76–0.93; P = 0.001), independent of viral load and age. Conclusions:The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count ≥ 350 cells/μl range in ART-naive people.

Simeprevir (TMC435) With Pegylated Interferon/Ribavirin in Patients Coinfected With HCV Genotype 1 and HIV-1: A Phase 3 Study

BACKGROUNDnSimeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection.nnnMETHODSnPatients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received response-guided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12).nnnRESULTSnOne hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-four of 61 eligible patients (88.5%) met RGT criteria for 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0-F2 and F3-F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal.nnnCONCLUSIONSnSimeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection.nnnCLINICAL TRIALS REGISTRATIONnNCT01479868.

Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial

Summary Background Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. Methods In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patients virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074. Findings Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events. Interpretation Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection. Funding National Institute for Health Research.

Sofosbuvir and Ribavirin for Treatment of Chronic Hepatitis C in Patients Coinfected With Hepatitis C Virus and HIV: The Impact on Patient-Reported Outcomes

BACKGROUNDnSofosbuvir-containing regimens have been approved for treatment of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients. We assessed the effect of treatment with sofosbuvir and ribavirin on patient-reported outcomes (PROs) in individuals with HIV/HCV coinfection.nnnMETHODSnHIV/HCV-coinfected patients were treated for 12 or 24 weeks with sofosbuvir and ribavirin. Matched HCV-monoinfected controls were also evaluated. All subjects completed standard PRO questionnaires before, during, and after treatment.nnnRESULTSnIncluded were 497 participants from the PHOTON-1 and PHOTON-2 clinical trials. At baseline, more impairment in PRO scores was noted in HIV/HCV-coinfected patients, compared with HCV-monoinfected patients. During treatment, moderate decrements in PRO scores (change, up to -6.8% on a 0%-100% scale; P = .0053) were experienced regardless of treatment duration and were similar to those for HCV-monoinfected patients (all P > .05). In 413 HIV/HCV-coinfected patients with a virologic response sustained for 12 weeks after treatment cessation, most PRO scores improved (change, up to +7.6%; P < .0001), similar to findings for HCV-monoinfected patients. In multivariate analysis, in addition to clinico-demographic predictors, coinfection with HIV was associated with PRO impairment at baseline (beta, up to -7.6%; P < .002) but not with treatment-emergent changes in PRO scores (all P > .05).nnnCONCLUSIONSnPatients with HIV/HCV coinfection tolerate interferon-free sofosbuvir-based anti-HCV regimens well and, despite the presence of some baseline impairment, have treatment-emergent changes in PRO scores that are similar to those of patients with HCV monoinfection.nnnCLINICAL TRIALS REGISTRATIONnNCT01667731 (PHOTON-1), NCT01783678 (PHOTON-2), NCT01604850 (FUSION), and NCT01682720 (VALENCE).

Potential health risks of complementary alternative medicines in HIV patients

To determine the prevalence and purpose of complementary alternative medicines (CAMs) use in people receiving treatment for HIV infection. To identify and quantify potential health risks of CAM use in this population and to explore options for improved pharmacovigilance.