ILC IN VIENNA EFAVIRENZ: TOO MUCH OF A GOOD THING? THE NEW DHHS GUIDELINES

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1 HIV & VIROLOGY NEWS Issue DENMARK ILC IN VIENNA EFAVIRENZ: TOO MUCH OF A GOOD THING? THE NEW DHHS GUIDELINES. FORGETTING EVIDENCE, EMBRACING OPINION NEW DRUGS FROM NEW CLASSES OF DRUGS MONITORING THE PERSISTENT HIV RESERVOIR IN THE ERA OF HIV CURE TRIALS SYMPOSIUM ON THE SEARCH FOR A CURE

2 Beyond Ef f icacy TOLERABILITY RESISTANCE Reasons to rethink first-line treatment in HIV CONVENIENCE EFFICACY Dolutegravir-based regimens delivered SUSTAINED EFFICACY up to 96 weeks in treatment-naïve patients 1-4 In some markets, Atripla is not licensed for initial use in treatment-naïve patients. Tivicay (dolutegravir) Indikation(er): Tivicay er indiceret i kombination med andre antiretrovirale lægemidler til behandling af humant immundefektvirus (hiv)-inficerede voksne og unge over 12 år. Dosering*: Voksne: Patienter inficeret med hiv-1 uden dokumenteret eller klinisk formodet resistens over for integraseklassen: 50 mg (en tablet) oralt én gang daglig. Tivicay skal administreres 2 gange daglig i denne population, når det gives samtidigt med visse lægemidler (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller rifampicin). Patienter inficeret med hiv-1 med resistens over for integraseklassen (dokumenteret eller klinisk formodet): 50 mg (en tablet) 2 gange daglig. Samtidig administration af Tivicay med visse lægemidler skal undgås i denne population (f.eks. efavirenz, nevirapin, tipranavir/ritonavir eller rifampicin). Unge fra 12 år og derover: Hos unge (fra 12 til 17 år og med en vægt på mindst 40 kg), der er inficeret med hiv-1 uden resistens over for integraseklassen, er den anbefalede dosis af dolutegravir 50 mg én gang daglig. Kontraindikationer*: Overfølsomhed over for det aktive stof eller over for et eller flere af hjælpestofferne. Administration samtidigt med dofetilid. Forsigtighedsregler*: Beslutningen om at anvende dolutegravir ved resistens over for integraseklassen skal tage højde for at aktiviteten af dolutegravir vurderes at være kompromitteret for virale stammer, der indeholder Q sekundære mutationer fra G140A/C/S, E138A/K/T, L741. Der er rapporteret overfølsomhedsreaktioner over for dolutegravir (udslæt, konstitutionelle fund og nogle gange organdysfunktion, herunder alvorlige leverreaktioner). Dolutegravir og andre mistænkte stoffer skal omgående seponeres, hvis der udvikles tegn eller symptomer på overfølsomhedsreaktioner. Det anbefales at monitorere biokemiske leverparametre hos patienter, der er co-inficeret med hepatitis B- og/eller C-virus. Patienter i behandling med dolutegravir kan stadig udvikle opportunistiske infektioner og andre komplikationer fra hiv-infektion. Undgå samtidig administration med lægemidler, der reducerer dolutegravireksponering (f.eks. antacida indeholdende magnesium/aluminium, jernog calciumtilskud, multivitaminer og inducerende midler, tipranavir/ritonavir, rifampicin og visse antiepileptiske lægemidler). Koncentrationen af metformin kan øges af dolutegravir. Interaktioner*: Alle faktorer, der reducerer eksponering for dolutegravir skal undgås ved tilstedeværelse af resistens over for integraseklassen. Dolutegravir elimineres overvejende gennem metabolisering via UGT1A1. Dolutegravir er også substrat for UGT1A3, UGT1A9, CYP3A4, Pgp og BCRP; derfor kan lægemidler, der inducerer disse enzymer reducere plasmakoncentrationen af dolutegravir og reducere den terapeutiske effekt af dolutegravir. Samtidig administration af dolutegravir og andre lægemidler, der hæmmer disse enzymer kan øge plasmakoncentrationen af dolutegravir. Absorptionen af dolutegravir reduceres af visse syreneutraliserende lægemidler. In vitro hæmmede dolutegravir den renale transporter 2 af organiske kationer (OCT2) og multidrug og toksin ekstruderingstransporter (MATE) 1. In vivo blev et % fald i kreatininclearancen (sekretionsfraktion afhænger af OCT2 og MATE-1 transport) observeret hos patienterne. In vivo kan dolutegravir øge plasmakoncentrationerne af lægemidler, for hvilke udskillelsen afhænger af OCT2 eller MATE-1 (f.eks. dofetilid, metformin). In vitro hæmmede dolutegravir de renale optagelsestransportere, organisk anion-transporterer (OAT1) og OAT3. Baseret på manglende effekt på in vivo farmakokinetikken af OAT-substratet tenofovir, er in vivo hæmning af OAT1 usandsynlig. Hæmning af OAT3 er ikke undersøgt in vivo. Dolutegravir kan øge plasmakoncentrationen af lægemidler, hvis udskillelse er afhængig af OAT3. Graviditet og amning*: Der er utilstrækkelig mængde data fra anvendelse af dolutegravir til gravide kvinder. Det er ukendt, om dolutegravir udskilles i human mælk. Det anbefales, at hiv-inficerede kvinder under ingen omstændigheder ammer deres spædbørn, så overførsel af hiv undgås. Bivirkninger*: Meget almindelig: Hovedpine, kvalme, diarré. Almindelig: Insomni, unormale drømme, svimmelhed, opkastning, flatulens, smerter i øvre del af abdomen, abdominalsmerter, abdominalt ubehag, udslæt, pruritus, træthed, forhøjet niveau af alaninaminotransferase (ALAT) og/eller aspartataminotransferase (ASAT), forhøjet niveau af kreatinfosfokinase (CPK). Ikke almindelig: Overfølsomhed, immunrekonstitutionssyndrom, hepatitis. Overdosering*: Der er på nuværende tidspunkt begrænset erfaring med overdosering af dolutegravir. Begrænsede data med højere enkeltdoser (op til 250 mg hos raske personer) medførte ingen specifikke symptomer eller tegn ud over de tegn og symptomer, der er anført som bivirkninger. Udlevering: BEGR. Ikke tilskud. De med * mærkede afsnit er omskrevet og/eller forkortet i forhold til det af EMA godkendte produktresumé. Fuldt produktresumé kan vederlagsfrit rekvireres hos den danske repræsentant for ViiV, GlaxoSmithKline Pharma A/S, Nykær 68, 2605 Brøndby. Bivirkninger, både kendte og nyopdagede, bedes indberettet hurtigst muligt til Sundhedsstyrelsen ( eller GlaxoSmithKline (dk info@gsk.com). Dagsaktuelle priser findes på References: 1. Walmsley S et al. N Engl J Med. 2013;369(19): Tivicay Summary of Product Characteristics 3. Clotet B et al. Lancet. 2014;383: Molina J M et al. Lancet 2015; Published online March 10, DK/DLG/0012/15 maj 2015 Nykær 68 DK-2605 Brøndby T F

3 HIV & VIROLOGY NEWS HIV & Virology News is a quarterly publication with four issues per year. The magazine is distributed free of charge to all those specialists in the field of Infectious diseases in 13 European countries including the UK, the Netherlands, Belgium, Germany, France, Spain, Italy, Sweden, Norway, Denmark, Finland, Austria and Switzerland. In this issue: The magazine is in English with all content being HIV and virology related. It also include summaries of research results from the above mentioned countries as well as consensus relating from the fields of HIV and virology. Also featured are educational programmes and excerpts from seminars and conferences. Editor in Chief: Magnus Gisslén, MD, Ph.D Professor of Infectious Diseases Dpt of Infectious Diseases Sahlgrenska University Hospital, Gothenburg, Sweden magnus.gisslen@gu.se Editorial Board: Graeme J. Moyle, MD, MB BS, Dip. GUM Director of HIV Research Strategy Chelsea & Westminster Hospital London, United Kingdom gm@moyleg.demon.co.uk José Arribas, MD Associate Professor of Medicine at the Autonoma University School of Medicine in Madrid and Research Director at the HIV unit of La Paz Hospital, Madrid, Spain joser.arribas@salud.madrid.org Christine Katlama, Professor of Infectious Diseases at University Pierre and Marie Curie and Head of the AIDS Unit in the Department of Infectious Diseases at the Pitié-Salpêtrière Hospital in Paris, France christine.katlama@psl.aphp.fr Heiner Wedemeyer, Prof. Dr. Dept. of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover, Germany Wedemeyer.heiner@mh-hannover.de Advertising: Advertising space within HIV and Virology News is sold locally in each country. As a result of placing an advertisement within this magazine you will reach every specialist in the field of infectious diseases in these countries. For questions concerning advertising contact: Lars Lundblad lars@hivvirology.com Mediahuset i Göteborg AB, Sweden Marieholmsgatan 10C, SE Göteborg, Sweden Production: Mediahuset i Göteborg AB, Sweden Marieholmsgatan 10C SE Göteborg, Sweden Layout and cover picture: Eva-Lotta Emilsdotter lotta@mediahuset.se Printing: ÅkessonBerg, Emmaboda, Sweden ISSN (print) ISSN (online) Vienna 2 Letter from the Editor Magnus Gisslén 3 ILC in Vienna Per Lundblad 17 Efavirenz: too much of a good thing? Jose R Arribas 21 The new DHHS guidelines. Forgetting evidence, embracing opinion Graeme Moyle 24 Topical Conferences 25 New drugs from new classes of drugs Christine Katlama 30 Monitoring the persistent HIV reservoir in the era of HIV cure trials Ward de Spiegelaere and Linos Vanderkerckhove 34 Symposium on the search for a cure Per Lundblad 38 Banishing B - going beyond management Per Lundblad 41 Conquering C - going beyond cure Per Lundblad 42 The new landscape in management of HCV Per Lundblad 45 Notes 2015 Leo Flamholc HIV & VIROLOGY NEWS

4 Letter from the Editor New guidelines In this issue of HIV & Virology News you can read a critical review of the new US DHHS HIV treatment guidelines ( aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescenttreatment-guidelines/0) by Graeme Moyle (page 21). It is easy to agree with many of Graeme s objections to some of the new recommendations. Several recommendations are published on the same topic each year all over the world. The DHHS guidelines are one of the latest presented. Making recommendations is not an easy task. The data on which the recommendations are based are the same for all guideline groups, but the interpretations differ considerably among responsible experts. Some of the recent guidelines on recommended first line regimens for antiretroviral-naïve subjects are given in the figure below: DHHS from the US; the European guidelines (EACS); the British guidelines (BHIVA); and the Swedish guidelines. While it may be expected that certain aspects of drugs and studies are valued differently by various experts, in fact, it also gives one some perspective and humility. Most recommendations are, in fact, expert opinions (and not objective judgements) based on the strength and quality of the evidence available at present. Recommended drug regimens for ART- naïve subjects NNRTI- based regimes: EFV + ABC/3TC EFV/TDF/FTC RPV + ABC/3TC RPV/TDF/FTC DHHS 2015 EACS 2014 BHIVA 2013 Swedish 2014 PI/r- based regimens: AZV/r + ABC/3TC AZV/r + TDF/FTC DRV/r + ABC/3TC DRV/R + TDF/FTC INSTI- based regimens: EVG/c/TDF/FTC DTG/ABC/3TC DTG + TDF/FTC RAL + ABC/3TC RAL + TDF/FTC One important question is the extent to which financial considerations should be taken into account in the treatment guidelines. My personal view is that this is an important responsibility for the guideline authors. Financial resources are not unlimited in providing health care. All regimens currently in use in Western Europe and the US are well-tolerated and very effective in antiretroviral-naïve patients without resistance. Since there are only small differences between drugs, one can argue that we should use the cheapest possible combinations as the first line of treatment. The regime can be changed in the minority of subjects who experience side effects. Thus, the more expensive drugs can be saved for specific situations, such as drug resistance, significant side effects, or risk for adverse reactions due to comorbidities, etc. This will be an even more important issue as more generic drugs become available. Magnus Gisslén Editor 2 HIV & VIROLOGY NEWS

5 ILC in Vienna The annual International Liver Congress (ILC) was in 2015 held in Vienna. It is the European Association for the study of the Liver (EASL) biggest event and this year in Vienna, EASL celebrated ILC s 50th anniversary. Hepatitis C was one of the topics at the core of the Congress agenda. In his welcoming address at the Opening Ceremony, Prof Marcus Peck, The Secretary General of EASL, pointed out that the development during these 50 years had been extraordinary. At our first Meeting in Marburg, Germany in 1966 at today s date the 23:rd of April there were perhaps 50 persons present. Today we have 10,127 attendees registered in Vienna. This is very close to the 10,638 that came to ILC in London last year which was an all time high record, he said. High SVR12 rates in patients with advanced liver disease Patients with chronic HCV infection and advanced liver disease especially those with decompensated cirrhosis have a poor prognosis and limited treatments options. Liver failure and hepatocellular carcinoma related to HCV infection are the most common indications for liver transplantation in North America and Europe. This was pointed out by Prof Michael Manns in his lecture at the Opening Session. He presented a study that aimed to evaluate the safety and efficacy of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in patients with HCV genotype 1 or 4 decompensated cirrhosis and/or those with recurrent HCV post-transplantation. Ledipasvir is a once-daily, oral NS5A inhibitor, sofosbuvir is a once daily NS5B inhibitor. The two has been combined in ledipasvir/sofosbuvir fixed dose combination (FDC), a once daily single-tablet regimen for HCV. In the study 329 patients at 34 sites in 12 countries participated. They were 168 post-transplant patients with F0 - F3 fibrosis, or CPT A (= early) cirrhosis and 160 patients with decompensated cirrhosis 53 post-transplant. 1 patient was not treated, Prof Manns said. He reported that ledipasvir/sofosbuvir with ribavirin resulted in high SVR12 rates in HCV patients with advanced liver disease irrespective of transplantation status. For genotype 1 patients, the study found no difference in SVR12 rates between 12 and 24 weeks. There were too few genotype 4 patients for meaningful comparisons. Among patients with cirrhosis, virologic response was associated with improvements in MELD and CPT scores largely due to decreases in bilirubin and improvement in synthetic function (e.g. albumin), Prof Manns continued. Ledipasvir/sofosbuvir with ribavirin for weeks was generally safe and well tolerated in patients with advanced liver disease, pre- and post-liver transplantation, was Prof Manns conclusion. A pressing need to educate the public As many as half of the people infected with viral hepatitis have suffered discrimination. One quarter of them admit that family members have avoided physical contact with them after finding out they had the infection. HIV & VIROLOGY NEWS

6 ILC in Vienna This was revealed in patient survey presented at the Congress. Research conducted with the Ministry of Health in Brazil questioned 1,217 people infected with hepatitis B or C in Europe and America using an online survey tool. The aim of the research was to find out from those infected, when, and with what intensity, stigma and discrimination affect their quality of life. Few studies have evaluated the circumstances and the degree to which stigma and discrimination are present for those living with viral hepatitis. This is one of the first studies that listens to the voice of the patient in order to find out from them the context and intensity of stigma and discrimination that they experience, and how it affects their quality of life, said Dr Marcelo Naveira, Viral Hepatitis Coordination, Secretariat for Disease Surveillance Ministry of Health of Brazil, at a press conference. The survey revealed that nearly half (49.6%) of those infected have suffered some kind of discrimination. Of the 94.1% who told their family they had the infection, a quarter (24.6%) said that relatives started to avoid physical contact. Marcus Peck Marcelo Naveira Furthermore, of the 73.7% who told friends about their condition, nearly half (46.9%) said they suffered discrimination and 23.8% said they were no longer invited to social events, Dr Naveira pointed out. The stigma and discrimination faced by people living with hepatitis is all too often based on misunderstandings about the virus and its transmission. Not only is this damaging to people diagnosed with the disease, but it may also discourage others from getting tested and accessing treatment and support, Prof Peck commented on the survey s findings. There is a pressing need to educate the general public about hepatitis, in order to erode this stigma and break down barriers to timely testing, treatment and care, Prof Peck concluded. New combinations One of the many parallel sessions given at the Congress concerned HCV therapy. In one of these, Dr Xavier Forns presented interim data from the Phase II open-label SATURN study. The study investigated on-treatment virologic response and tolerability of simeprevir, daclatasvir and ribavirin in patients with recurrent HCV genotype (GT)1b infection after orthotopic liver transplantation (OLT). As you all know, simeprevir is a once daily (QD) NS3/4A protease inhibitor with antiviral activity against HCV GT 1, 2, 4, 5 and 6. It is approved in combination with peginterferon/ribavirin for chronic HCV GT 1 infection in the United States, and GT 1 and 4 infection in the European Union, Dr Forns said. Daclatasvir is a QD pangenotypic NS5A replication complex inhibitor. We found that simeprevir 150 mg + daclatasvir 60 mg QD + ribavirin achieved high rates of on-treatment response in HCV GT 1b-infected post-olt patients on immunosuppressive therapy, Dr Forns said. The combination was generally safe and well tolerated. The study is ongoing; data from the primary efficacy analysis on SVR12 will be reported later in 2015, Dr Forns stated. Dr Eric Lawitz presented a study on retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. It was an open-label study on previous failures. 71 % of patients who failed these regimens achieved SVR12 when retreated for 24 weeks, he said. The presence of baseline NS5A resistance-associated variants which was more likely to develop with longer ledipasvir/sofosbuvir treatment was associated with virologic failure. Emergence of S282T mutation was observed in 3 of 12 virologic failure patients. Retreatment with ledipasvir/sofosbuvir is feasible in patients who have failed prior ledipasvir/sofosbuvir regimens, was Dr Lawitz conclusion. Shortening therapy Grazoprevir is a HCV NS3/4A inhibitor, administered orally once-daily. Elbasvir is a HCV NS5A once-daily, oral inhibitor. Prof Fred Poordad presented a study that aimed to combine three highly potent direct-acting antivirals (grazoprevir + elbasvir + sofosbuvir), each with a different mechanism of action, in order to explore short duration therapy in the most common and difficult to cure genotypes GT 1 and 3 with and without cirrhosis. We found that this novel regimen was able to shorten treatment duration to 8 weeks or less among cirrhotic and non-cirrhotic GT 1-infected patients, he said. GT 3 patients achieved high SVR12 rates with 8-12 weeks of therapy including patients with cirrhosis, Prof Poordad added. All virologic failures were due to relapse. Patients who relapsed were most commonly infected with either wild-type virus, or with resistance-associated variants already present at baseline. Generally the regimen was safe and well tolerated, he summarized the findings. Prof Poordad s conclusions were that 4 HIV & VIROLOGY NEWS

7 ILC in Vienna this proof-of-concept study had demonstrated the concept of shortening therapy even in cirrhotic patients, and that retreatment of the virologic failures is ongoing. Significant advances with new therapy Dr Rajender Reddy presented more data on grazoprevir + elbasvir combination. It was the Phase III C-EDGE TN study in treatment naive patients. This showed that a 12-week oral regimen of once-daily single tablet grazoprevir/elbasvir is effective and well-tolerated in treatment-naive (TN) patients infected with HCV GT 1, 4 or 6, including those with compensated cirrhosis. Based on preliminary results from 316 recipients in the immediate treatment arm, 299 (95 %) achieved STR12. These initial results show that once-daily grazoprevir/elbasvir offers significant advantages over older treatments, demonstrating the ideal combination of high efficacy with good tolerability and convenience in treatment-naive patients infected with chronic HCV, Dr Reddy stated. The study is an international, randomised, blinded, placebo-controlled, parallel-group trial. Newer antiviral regimens such as this combination offer much hope to people living with HCV. They have shown great efficacy and tolerability for the treatment of this chronic infection, said EASL Vice-Secretary Dr Laurent Castera (who was elected as the new Secretary General later at the Congress). High response in CP-B patients The combination of grazoprevir and elbasvir was also studied in HCV GT 1 infected patients with Child-Pugh class B (CP-B) cirrhosis the 2 C-SALT study. It was presented by Prof Ira Jacobson. Currently, there is no approved treatment regimen for patients with CP-B cirrhosis, he started by saying. In this open-label study, 30 patients with HCV GT 1 infection and CP-B cirrhosis were given all oral 50 mg grazoprevir and 50 mg elbasvir. 10 non-cirrhotic patients with HCV GT 1 infection were enrolled for pharmacokinetic analysis. They received 100 mg grazoprevir and elbasvir. The drugs were administered as separate entities. High rates of virologic response were observed in CP-B patients. The regimen was well tolerated with no evidence of hepatotoxicity, Prof Jacobsen reported. Plasma grazoprevir exposure was slightly higher in CP-B patients receiving 50 mg, compared to non-cirrhotic patients receiving 100 mg. Elbasvir exposure was similar in both groups. This regimen was highly effective and well tolerated in a traditionally hardto-treat patient group with no currently approved treatment options, was his conclusion. DCV + SOF work across concomitant cart regimens HCV with HIV co-infection more than triples the risk of HCV-related liver disease, liver failure and liver-related death. Co-infection can also complicate the management of HIV infection. In Vienna, Phase III results of the ALLY-2 study were presented. It is a randomised, open-label study on once-daily treatment with daclatasvir + sofosbuvir, and the data showed an overall 97 % SVR12 post-treatment in patients with HCV and HIV co-infection. Importantly, due to their limited pharmacokinetic interactions with other agents, daclatasvir + sofosbuvir are able to work effectively across a broad range Fred Poordad Rajender Reddy of concomitant cart regimens without compromising HIV virologic control (98 % of patients were on cart). A total of 98 % of patients completed the study treatment. In GT 1 patients, SVR was achieved by 96 % of treatment-naive patients and 98 % of treatment-experienced patients after 12 weeks. These positive results were also seen in GT 2, 3 and 4 patients, with SVR at post-treatment week 12 reaching 100 % for all these genotypes. There were no treatment-related serious adverse events, and none of the pa- HIV & VIROLOGY NEWS

8 ILC in Vienna tients stopped treatments due to adverse events. The results show that 12 weeks of daclatasvir/sofosbuvir is a highly effective and well-tolerated treatment regimen for HCV in HIV co-infected patients, including cirrhotic patients. A ground breaking study The BOSON study demonstrate that HCV-infected GT 3 patients, with and without cirrhosis, receiving 24 weeks of sofosbuvir in combination with ribavirin and peginterferon achieved the highest sustained virological response observed in a PHASE III study to date, underlined Prof Graham Foster. Sofosbuvir in combination with ribavirin and with or without peginterferon have never been directly compared before to determine SVR12 after treatment. This study highlights that sofosbuvir with ribavirin and peginterferon should be considered for interferon-eligible GT 3 patients particularly for those with cirrhosis and/or prior treatment failure, Prof Foster continued. The study also evaluated the safety and efficacy of sofosbuvir + peginterferon/ ribavirin for 12 weeks versus sofosbuvir + ribavirin for 16 or 24 weeks in treatment-experienced GT 2 HCV-infected patients with cirrhosis. These patients had high SVR12 rates in all arms: 87 % of those receiving sofosbuvir + ribavirin for 16 weeks, 100 % of those receiving sofosbuvir + ribavirin for 16 weeks and 94 % of those receiving sofosbuvir + peginterferon/ribavirin for 12 weeks. BOSON is a ground-breaking new study that provides information about how we can ensure the best outcomes for both GT 2 and GT 3 infected HCV-infected patients. It has confirmed that 24 weeks is the optimal duration for a sofosbuvir + ribavirin combination in GT 3 patients, whilst also finding that sofosbuvir + ribavirin/peginterferon for 12 weeks resulted in the highest SVR12 rates observed to date in a Phase III study, said Prof Tom Hemming Carlsen, Scientific Committee Member of EASL. Indications for treatment One of the highlights of the Meeting is the Session in which EASL recommendations on treatment of hepatitis C are presented and discussed. It was Prof Jean-Michel Pawlotsky who did this in Vienna, and he started by defining the goals of therapy. The goal is to eradicate HIV infection to prevent cirrhosis, decompensation of cirrhosis, HCC and death, Prof Pawlotsky established. The endpoint of therapy is undetectable HCV RNA in a sensitive assay i.e. less than 15 IU/mL 12 weeks (SVR12) and 24 weeks (SVR24) after the end of treatment. He also talked about the heterogeneity of countries in Europe, and how EASL have to be aware of the differences. EASL s statement on treatment indication is: All treatment-naive and treatment-experienced patients with compensated or decompensated chronic liver disease related to HCV, who are willing to be treated and who have no contraindications to treatment, should be considered for therapy, Prof Pawlotsky continued. For HIV co-infected patients, indications for treatment are identical to those in patients with HCV monoinfection. However, potential drug-drug interactions with antiretroviral drugs should be taken into account. The drug interactions charts from the University of Liverpool, which easily can be accessed online at is the tool that EASL recommends for this purpose. Recommendation principles Three direct acting antivirals (DAAs) was approved in 2014: Sofosbuvir, a nucleotide, all genotypes, simeprevir, a NS3/4A protease inhibitor GT 1 and 4 and daclatasvir, a NS5A-inhibitor, all genotypes. DAAs approved in 2015 are sofosbuvir/ledipasvir, for GT 1, 4, 5, and 6, ombitasvir/paritaprevir/ritonavir, for GT 1 and 4 and dasabuvir for GT 1, Prof Pawlotsky said. EASL recommendations are based on evidence from existing publications and presentations or when no evidence is available the panel members experience and opinion. For each group of patients, options are provided: These options are considered equally valuable and their numbering does not indicate any prioritization. When subgroup delineation was felt difficult in clinical practice, the panel opted for the most efficacious treatment regimen in order to offer patients the best chance to achieve a cure, Prof Pawlotsky pointed out. He stated that notwithstanding the respective costs, IFN-free regimens are the best options when available because of their virological efficacy, ease of use and tolerability. But all patients with compensated or decompensated cirrhosis and patients in the post-liver transplant setting with no contra-indications to ribavirin should be treated with ribavirin, regardless of the 6 HIV & VIROLOGY NEWS

9 dolutegravir/abacavir/ lamivudine innerstrength The only once daily single-pill regimen built with DOLUTEGRAVIR Indication: Triumeq (dolutegravir/abacavir/lamivudine) is indicated for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age weighing at least 40 kg 1. Screening for HLA-B*5701 allele should be performed before prescribing Triumeq. Triumeq should not be used in patients known to carry the HLA-B*5701 allele 1. Triumeq (dolutegravir/abacavir/lamivudin) Indikation(er): Triumeq er indiceret til behandling af humant immundefektvirus (hiv)-inficerede voksne og unge over 12 år, som vejer mindst 40 kg. Før initiering af behandling med produkter, der indeholder abacavir, skal alle hivinficerede patienter, uanset raceoprindelse, screenes for om de skulle være bærer af HLA-B*5701-allelen. Abacavir bør ikke anvendes til patienter, der er bærere af HLA-B*5701-allelen. Dosering*: Voksne og unge: Den anbefalede dosis af Triumeq til voksne og unge er 1 tablet én gang daglig. Triumeq bør ikke administreres til voksne eller unge, der vejer under 40 kg, eller patienter der har brug for dosisjusteringer, da det er en fastdosis-tablet, der ikke kan dosisreduceres. I tilfælde hvor ophør med eller dosisjustering af en af de aktive substanser er indiceret, er separate præparater med dolutegravir, abacavir eller lamivudin tilgængelige. I disse tilfælde bør lægen henvise til produktinformationen for de individuelle lægemidler. Kontraindikationer: Overfølsomhed over for dolutegravir, abacavir eller lamivudin eller over for et eller flere af hjælpestofferne. Samtidig administration med dofetilid. Forsigtighedsregler*: Både abacavir og dolutegravir er forbundet med en risiko for udvikling af overfølsomhedsreaktioner (feber, udslæt, konstitutionelle fund og påvirkede organer, heriblandt alvorlige leverreaktioner). Risikoen for at udvikle en overfølsomhedsreaktion over for abacavir er signifikant større for patienter, der er testet positive for HLA-B*5701-allelen. Triumeq skal omgående seponeres, hvis der opstår tegn eller symptomer på overfølsomhedsreaktioner. Forsinket ophør af behandling med Triumeq efter indtrædelse af en overfølsomhedsreaktion, kan resultere i en livstruende reaktion.der bør udvises forsigtighed ved administration af nukleosidanaloger til patienter (specielt overvægtige kvinder) med hepatomegali, hepatitis eller andre kendte risikofaktorer for leversygdomme og fedtinfiltration på leveren (herunder visse typer medicin og alkohol), da behandlingen med Triumeq kan være forbundet med udvikling af laktacidose. Patienter co-inficeret med hepatitis C-virus, som er i behandling med interferon alfa og ribavirin, kan være særligt udsatte. Antiretroviral kombinationsbehandling er forbundet med omfordeling af legemsfedt (lipodystrofi) hos hiv-patienter. Sikkerheden og virkningen af Triumeq hos patienter med betydelige underliggende leversygdom er ikke klarlagt. Triumeq anbefales ikke til patienter med moderat til svært nedsat leverfunktion. Patienter med kronisk hepatitis B eller C, behandlet med antiretroviral kombinationsbehandling, har større risiko for alvorlige og potentielt fatale leverbivirkninger. Hos hiv-inficerede patienter med alvorlig immundefekt kan der på tidspunktet for påbegyndelse af antiretroviral kombinationsbehandling (CART) opstå en inflammatorisk reaktion på asymptomatiske eller tilbageværende opportunistiske patogener, som kan forårsage alvorlige kliniske tilstande eller forværring af symptomer. Observationsstudier har vist en forbindelse mellem myokardieinfarkt og brugen af abacavir. I disse studier omfattede patientgruppen primært patienter, der tidligere havde fået antiretroviral behandling. Patienter i behandling med Triumeq kan stadig udvikle opportunistiske infektioner og andre komplikationer fra hiv-infektion. Triumeq anbefales ikke til patienter der er i samtidig behandling med lægemidler indeholdende efavirenz, nevirapin, rifampicin, tipranavir/ritonavir og emtricitabin eller andre lægemidler indeholdende dolutegravir, abacavir eller lamivudin. Samtidig administration af Triumeq og etravirin (ETR) anbefales ikke, medmindre patienten også samtidigt behandles med atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) eller darunavir + ritonavir (DRV + RTV).Triumeq bør administreres 2 timer før eller 6 timer efter indtagelse af calcium- eller jerntilskud og bør ikke administreres med antacida. Interaktioner*: Samtidig administration af Triumeq og andre lægemidler, der hæmmer UGT1A1, UGT1A3, UGT1A9, CYP3A4 og/eller Pgp, kan øge plasmakoncentrationen af dolutegravir. Lægemidler, der inducerer disse enzymer eller transportere, kan reducere plasmakoncentrationen af dolutegravir og reducere den terapeutiske effekt af dolutegravir. Absorptionen af dolutegravir reduceres af visse syreneutraliserende lægemidler. Samtidig administration af UGT-enzym-induktorer eller -hæmmere eller af forbindelser, der elimineres via alkoholdehydrogenase, kan ændre eksponeringen for abacavir. Samtidig administration af lamivudin og OCT2- og MATE-hæmmere kan muligvis øge eksponeringen for lamivudin. Graviditet og amning*: Der er ingen data fra anvendelse af Triumeq til gravide kvinder. Det er påvist in vitro og in vivo, at nukleosid- og nukleotidanaloger i forskellig udstrækning forårsager mitokondrieskader. Der foreligger rapporter om mitokondriel dysfunktion hos hiv-negative spædbørn, som in utero og/eller efter fødslen har været eksponeret for nukleosidanaloger. Lamivudin udskilles i human mælk og på basis af data fra dyr forventes det, at dolutegravir og abacavir også udskilles i human mælk, selvom dette ikke er blevet bekræftet hos mennesker. Det anbefales, at hiv-inficerede kvinder under ingen omstændigheder ammer deres spædbørn, så overførsel af hiv undgås. Bivirkninger*: Meget almindelig: insomni, hovedpine, kvalme, diarré, træthed. Almindelig: overfølsomhed, anoreksi, abnormale drømme, depression, mareridt, søvnforstyrrelser, svimmelhed, somnolens, svær udmatning, hoste, symptomer fra næse, opkastning, flatulens, abdominalsmerter, smerter i den øvre del af abdomen, udspiling af abdomen, abdominalt ubehag, gastroøsofageal refluxsygdom, dyspepsi, udslæt, kløe, hårtab, atralgi, muskelforstyrrelser, asteni, feber, utilpashed, forhøjet niveau af CPK, forhøjet niveau af ALAT/ASAT. Ikke almindelig: neutropeni, anæmi, trombocytopeni, immunrekonstitutionssyndrom, hypertriglyceridæmi, hyperglykæmi, hepatitis. Sjælden: pancreatitis, rabdomyolyse, forhøjet niveau af amylase. Meget sjælden: ren erytrocytaplasi, perifer neuropati, paræstesi, erythema multiforme, Stevens-Johnsons syndrom, toksist epidermal nekrolyse. Overdosering*: Der ikke identificeret nogen specifikke symptomer eller tegn efter akut overdosering med dolutegravir, abacavir eller lamivudin. Udlevering: B. Ikke tilskud. De med * mærkede afsnit er omskrevet og/eller forkortet i forhold til det af EMA godkendte produktresumé. Fuldt produktresumé kan vederlagsfrit rekvireres hos den danske repræsentant for ViiV, GlaxoSmithKline Pharma A/S, Nykær 68, 2605 Brøndby. Bivirkninger, både kendte og nyopdagede, bedes indberettet hurtigst muligt til Sundhedsstyrelsen ( eller GlaxoSmithKline (dk-info@gsk.com). Dagsaktuelle priser findes på Reference: 1. TRIUMEQ Summary of Product Characteristics September DK/TRIM/0004/15 februar 2015 Nykær 68 DK-2605 Brøndby T F HIV & VIROLOGY NEWS

10 Nucleoside ILC in Vienna Free Zones PRODUKTINFORMATION RETTET TIL SUNDHEDSPERSONER Forkortet produktresumé for STRIBILD filmovertrukne tabletter for nedsat nyrefunktion, er hyppigere monitorering af nyrefunktionen nødvendig. Cobicistat hæmmer den tubulære sekretion af kreatinin og kan forårsage moderat øgning af serumkreatinin P gp, BCRP, OATP1B1 eller OATP1B3, kan føre til øgede plasmakoncentrationer af disse præparater, hvilket kunne øge eller forlænge deres terapeutiske virkning og bivirkninger. Samtidig malaci (manifesterer sig som knoglesmerter og i sjældne tilfælde medvirkende årsag til frakturer), myopati*, nyresvigt (akut og kronisk), akut tubulær nekrose, proksimal renal tubulopati, herunder Fanconis syndrom, nefritis (herunder akut Elvitegravir, cobicistat, emcitrabin, tenofovirdisoproxil interferon-free regimen used. In uden patients påvirke nyrernes glomerulære funktion. hæmmer CYP3A, kan reducere clearance af interstitiel nefritis), nefrogen diabetes insipidus. og moderat nedsættelse af kreatininclerance administration af Stribild og lægemidler, der Præsentation: with ribavirin Hver filmovertrukket contra-indications tablet indeholder Patienter or who som oplever en bekræftet øgning i cobicistat og føre til øgede plasmakoncentrationer Bivirkninger markeret med* kan forekomme som do 150 not mg tolerate elvitegravir, it 150 well mg cobicistat, treatment serumkreatinin, dura- på over 26,5 µmol/l (0,3 mg/dl) 200 tion mg emtricitabin should be og 245 doubled, mg tenofovirdisoproxil without ribavirin. fra baseline, bør overvåges tæt for renale bivirkninger. af cobicistat. Stribild må ikke administreres samtidig med adefovirdipivoxil, lamivudin eller resultat af proksimal renal tubulopati. Tilfælde af osteonekrose er rapporteret, specielt hos patienter (svarende til 300 mg tenofovirdisoproxil- fumarat To be eller continued 136 mg tenofovir) Hvis kreatininclearance på < 50 ml/min kan bekræftes eller serumphophfat falder til < didanosin og lægemidler der indeholder tenofovirdisoproxil (som fumarat). Elvitegravir er en med generelt anerkendte risikofaktorer, fremskreden hiv sygdom eller langvarig CART. Indikationer: Prof Pawlotsky Behandling af proceeded infektion med humanting immundefekt the different virus 1 (hiv treatment 1) hos voksne options Det bør også for overvejes at afbryde behandlingen with 0,32 presen- mmol/l (1,0 mg/dl) bør Stribild seponeres. i alderen They år og derover, can be som accessed er antiretroviral-behandlingsnaive homepage on eller inficerede med hiv Click nyrefunktionen, Re- når der ikke er identificeret an- from med Stribild EASL i tilfælde af progressiv forværring af moderat inducer af CYP2C9 og kan reducere plasmakoncentrationen af CYP2C9 substrater. Lægemidler, der inducerer CYP3A-aktivitet, forventes at øge clearance af elvitegravir, hvilket Hyppigheden er ukendt. Overdosering*: Såfremt der forekommer overdosering, monitoreres for tegn på toksicitet. Der skal gives støttende standardbehandling efter fører til reducerede plasmakoncentrationer behov. Da elvitegravir og cobicistat i høj grad er 1 uden search kendte in the mutationer top menu, forbundet then med resistens over for nogle af de tre antiretrovirale Clinical dre årsager. Practice Guidelines and finally Recommendavendelse med eller nylig brug af et nefrotoksisk af elvitegravir, hvilket kan forårsage svigtende bundet til plasmaproteiner, er det usandsynligt, Stribild bør undgås ved samtidig an- stoffer i Stribild. tions on treatment of Hepatitis C. lægemiddel Direct på grund af øget risiko for renale terapeutisk virkning og udvikling af resistens. at elvitegravir og cobicistat i signifikant grad vil Dosering og indgivelsesmåde*: Voksne: Én bivirkninger (med TDF-komponenten i Stribild). Samtidig administration af Stribild og nogle lægemidler, der primært metaboliseres af CYP3A, Op til 30 % af emtricitabindosen og cirka 10 % fjernes ved hæmodialyse eller peritonealdialyse. link is én gang dagligt, tages hel, oralt, med mad. Se produktresuméet for yderligere anbefalinger 2015/Summary.pdf. Børn: Sikkerhed og virkninger er ikke klarlagt mht. monitorering og seponering af behandling. kan føre til øgede plasmakoncentrationer af af tenofovirdosis kan fjernes ved hæmodialyse. hos børn The og unge recommendations <18 år. Nedsat nyrefunktion: are presented Nyresvigt, nedsat nyrefunktion, forhøjet kreatinin, hypophosphatæmi disse præparater, hvilket er forbundet med muligheden for alvorlige og/eller livstruende reak- kan fjernes ved peritonealdialyse. Det vides ikke, om emtricitabin eller tenofovir Se systematically afsnit Særlige advarsler. according to genotype, and og proksimal tubulopati Kontraindikationer: are sorted in Overfølsomhed both IFN-free over for and IFN-containing aktive stoffer regimens. eller over for et eller flere af brug af tenofovirdisoproxilfumarat i klinisk prak- Samtidig administration af Stribild og andre læ- i den originale emballage for at beskytte mod (herunder Fanconis syndrom) er rapporteret ved tioner, såsom perifer vasospasme eller iskæmi. Farmaceutiske forholdsregler*: Opbevares de hjælpestofferne. He also Samtidig discussed administration challenging med sis. patient Samtidig infektion: Hiv inficerede patienter, gemidler, der primært metaboliseres af CYP3A fugt. Hold beholderen tæt lukket. de groups, følgende lægemidler such på as grund patients af muligheden with advanced der samtidig er inficeret med HBV eller HCV i for liver alvorlige disease, og/eller livstruende with renal hændelser insufficiency eller antiretroviral and behandling har øget risiko for alvorlige er kontraindiceret. Samtidig administration af Stribild og nogle lægemidler, som inducerer CY- Pakninger och pris: Beholdere med 30 filmovertrukne tabletter. Vnr: For dags- For og the potentielt ting letale chronic hepatiske bivirknin- viral hepatitis P3A kan føre disease til signifikant sur- reducerede Review plasma- that aktuelle documents medicinpriser lack se: of informa- svigtende patients virologisk that respons need og mulig re-treatment. resistens over latter for Stribild: group, Alfa 1 adrenoreceptorantagonistersed recommendations ger. are Seponering ba- af veillance, behandling kan assessing associeres the koncentrationer burden of af disease cobicistat og elvitegravir, tion hvil- Tilskudsstatus: Ikke tilskudsberettiget. Alfuzosin. on indirect Antiarytmika: evidence Amiodaron, quini- and subject med alvorlig, to akut and eksacerbation measuring af hepatitis. the impact ket kan forårsage of interven- svigtende terapeutisk A systematic virkning Udlevering: review, BEGR presented (kun udlevering by til sygehuse) Prof din. change Antikonvulsiva: when Carbamazepin, more data phenobarbital, phenytoin. The utility Antimykobakterielle of HCV lægemidler: resistance bør testing monitoreres tæt the i mindst ILC. flere måneder efter for detaljer vedrørende lægemiddelinteraktioner rent evidence EU/1/13/830/001 base on HBV and HCV tes- become available. Patienter med samtidig tions, infektioner according af hiv/hbv to a og study udvikling presented af resistens. at Se produktresuméet Jeffrey Lazarus, Markedsføringstilladelsesnummer: concluded that the cur- Rifampicin. Ergot-derivater: Dihydroergotamin, prior to treatment is unknown. behandlingen med Stribild The ophører study for highlights symptomer på alvorlig, akut for that antiinfektiva less than og antimykotika, one ting HCV proteasehæmmere, European makrolidantibiotika, member pean inhalerede/ countries. Gilead Sciences International Ltd, Granta Park, appears Indehaver to be lacking af markedsføringstilladelsen: many Euro- ergometrin, ergotamin. Stoffer, der fremmer mave-tarm-motiliteten: Cisaprid. Naturlægemiddel: Behandlingen bør Antiviral therapy is indicated in patients awaiting liver transplantation, states third eksacerbation (27 %) af of hepatitis. WHO ikke seponeres have hos national patienter nasale strategies kortikosteroider, in place antacida, kosttilskud, The results Abington, indicate Cambridge, that CB21 some 6GT, Storbritannien. highrisk populations have been studied much Prikbladet perikum (Hypericum perforatum). med fremskreden leversygdom. Leversygdom: orale antidiabetika, narkotiske analgetika, orale Produktinformationen er forkortet. Et fuldstændigt produktresumé kan rekvireres hos because it prevents graft infection. Treatment should be initiated as soon as pos- Furthermore, only 64 % have a national more than others, but mostly in a small that contain a surveillance component. HMG Co A-reduktasehæmmere: Lovastatin, simvastatin. Neuroleptika: Pimozid. PDE on skal monitoreres. Afbrydelse eller seponering endothelin receptorantagonister, antikoagulan- indehaveren af markedsføringstilladelsen Patienter med eksisterende nedsat leverfunkti- antikonceptiva, antiarytmika, antihypertensiva, 5-hæmmere: sible in Sildenafil order til to behandling complete af pulmonal course arteriel hypertension. before transplantation. Sedativa/hypnotika: 61 % for chronic hepatitis C. pear to show high median testing uptake a full treatment system for chronic hepatitis B (HBV) and number of countries. The results also ap- af behandling skal overvejes, hvis der er tegn på tia, inhaleret beta-agonist, HMG Co A-reduktasehæmmere, PDE- 5-hæmmere, antidepressiva, den danske repræsentant: Gilead Sciences og yderligere information kan rekvireres hos forværring af leversygdom. Lipodystrofi og metabolisme: will Kombination Main af antiretroviral areas behand- in which immunosuppressiva, governments sedativa/hypnotika, levels midler in Europe. Denmark ApS, Korskildelund 6, 2670 Greve, Oralt administreret The next midazolam, available triazolam. HCV therapies Særlige be grazoprevir-elbasvir advarsler*: Stribild må ikke combination, administrerenaprevir-daclatasvir-beclabuvir sammen med andre antiretrovirale combina- patienter. Måling af the fastende study, serumlipider are development og Fertilitet, graviditet of national og amning*: show Anvendelsen methodologies Afsnit markeret that med * required er forkortet i forhold en- til det ling er blevet asu-forbundet would med lipodystrofi like WHO s hos hiv support, mod podagra. according to However, Danmark since almost Telefon: +45 all 36 of 91 the studies præparater. tion and Det sofosbuvir-gs5816 bør ikke indgives samtidig med combination. blodglucose bør plans overvejes for og lipidændringer viral hepatitis af Stribild prevention skal ledsages and af anvendelse couraged af effektiv study af EMA participants godkendte produktresumé. to undergo kontraception of the national hos kvindelige patienter testing, i den high LÆS median PRODUKTRESUMÉET testing uptake FØR levels ORDINA- andre lægemidler, So the som recommendations indeholder tenofovirdiso-arproxil bør going behandles to på control relevant måde. (39 Andre: %), estimation Lakpivoxil be (som updated, fumarat), lamivudin Prof Pawlotsky eller adefovirdi-finishetatacidose, his mitokondriel burden dysfunktion, of hepatitis immunre-(34 fertile %) alder and samt surveillan- hos mænd og kvinder. are not Stribild likely TION to ISÆR be representative MED HENSYN TIL BIVIRKNIN- of the presentation. (anvendes til behandling af virusinfektion aktiveringssyndrom, ce osteonekrose, (23 %). reduktion i bør kun anvendes under graviditeten, overall hvis den testing GER, uptake ADVARSLER in most OG KONTRAINDIKATIO- populations. med hepatitis A panel B). discussion Samtidig administration then ended af knoglemineraltæthed the Session. og didanosin frarådes, da eksponering produktresuméet need for anbefalinger for better mht. disease moko. Det surveillance må ikke anvendes and under amning. are crucial gaps Et fuldstændigt in our knowledge produktresumé on kan HBV findes In og knogleanomalier all, the study se demonstrates potentielle fordel berettiger a clear den potentielle It risi-clear NER. from our review that there Stribild for didanosin stiger betydeligt efter samtidig administration af tenofovirdisoproxilfumarat, hvilket nitorering og behandling. improvements Sjældne tilfælde in the af development Bivirkninger: Meget of almindelige national strategies undertiden fatal, to help pophosphatæmi*, prevent and svimmelhed, con- hovedpine, enough diarré, information Dato oprettelse to effective af produktinformation: public and ( 1/10): HCV Hy- testing på EMAs hjemmeside we do not yet have European countries are ill prepared pankreatitis og laktatacidose, kan øge risikoen for didanosinrelaterede bivirkninger. Selvom effektiv viral suppression med med arvelig galactoseintolerans, en særlig form nase og asteni. Almindelige ( 1/100, <1/10): Job Bag No: HIV/DK/13-07/PM/1794 er rapporteret Bør ikke anvendes til patienter kvalme, opkastning, udslæt, forhøjet Many countries in the WHO European trol the spread of viral hepatitis in the health kreatinki- responses Juli 2014 in Europe, Prof Lazarus Region are facing limitations in conduc- WHO European region. commented. antiretroviral behandling har vist sig at nedsætte af hereditær lactasemangel (Lapp Lactase Deficiency) eller glucose/galactosemalabsorption. tit, hyperglykæmi, hypertriglyceridæmi, insomni, Neutropeni, allergiske reaktioner, nedsat appe- Our research team is particularly concerned about the low numbers of publis- risikoen væsentligt for seksuel overførsel, kan residual risiko ikke udelukkes. Der skal derfor Kvinder i den fertile alder skal enten anvende hormonelle antikonceptiva, der indeholder kastning, abdominalsmerter, abdominal disten- unormale drømme, hovedpine, svimmelhed, op- Ved godkendelse af markedsføringstilladelsen, er dette lægemiddel træffes passende forholdsregler for at forebygge risikoen for at overføre hiv til andre via seksu- mindst 30 µg ethinylestradiol og norgestimat inmates and men løbende who underlagt have supplerende sex with overhed studies looking at migrants, prison sion, dyspepsi, forstoppelse, flatulens, forhøjet men vågning, som vist med den omvendte el kontakt eller kontaminering med blod. Ældre: som progestagenet eller de skal anvende en amylase herunder forhøjet pancreasamylase, all populations sorte that trekant. might Alle mistænkte benefit bivirkninger great- Stribild har begrænsede data hos patienter over anden sikker kontraceptionsmetode. Samtidig forhøjet serum lipase, forhøjet ASAT ly from og ALAT, targeted ved brug hepatitis af Stribild skal testing rapporteres interventions, ud- he continued. Gilead via til: Nordics.SafetyMail- til 65 år. Det er mere sandsynligt, at ældre patienter har nedsat nyrefunktion. Derfor skal der ud- der indeholder andre progestagener end norgeslæt, vesikulobulløst udslæt, pustuløst Prof udslæt, Tom Hemming +46 (8) 505 Carlsen og added: /eller til Sund- administration af Stribild og orale antikonceptiva, hyperbilirubinæmi, forhøjede transaminaser, box@gilead.com eller på telefon vises forsigtighed ved behandling af ældre patienter stimat er ikke undersøgt og bør derfor undgås. makulopapuløst udslæt, pruritus, urticaria, Viruses mis- that hedsstyrelsen affect the i overensstemmelse liver such med as med Stribild. Nyrefunktion: Patienter som Når patienter, som er dårlige til at metabolisere farvning af huden (øget pigmentering), HBV forhøjet and HCV det nationale can cause spontane real rapporteringssys- problems tidligere har stoppet behandling med TDF på CYP2B6, skiftes fra et behandlingsprogram, der kreatinin i blodet, smerter, asteni if og not træthed. tem. identified and treated early. We grund af nyretoksicitet bør ikke behandles med indeholder efavirenz, til Stribild, er der mulighed Ikke almindelige ( 1/1,000, <1/100): need Anæmi, to raise awareness of the threat they hypokaliæmi*, depression, selvmordstanker pose and actively encourage testing across Stribild. Patienter bør have beregnet kreatininclearance og målt glukose og protein i urinen før på grund af en langvarig CYP3A-induktion af og selvmordsforsøg (hos patienter Europe. med en This is not only vital to diagnosis for en lavere eksponering over for elvitegravir start af behandling med Stribild. Stribild behandling bør ikke startes hos patienter med kreatinin- belastning i løbet af den første måned efter be- en psykisk sygdom), pancreatitis, angioødem, efavirenz. Det anbefales at overvåge den virale eksisterende anamnese med depression and treatment, eller but also to prevention for stopping the viruses spreading through clearance under 70 ml/min. Kreatininclearance, handlingen skiftes. rabdomyolyse*, muskelsvækkelse*, nyresvigt, Panel discussion in the Session on EASL s recommendations. populations and generations to come! serumphosphat, glukose og protein i urinen bør Interaktioner*: Samtidig administration af Stribild erhvervet Fanconis syndrom, og proteinuri. monitoreres hver 4. uge i løbet af det første år og derefter hver 3. måned. Hos patienter med risiko og lægemidler, som primært metaboliseres af CYP3A eller CYP2D6, eller er substrater for Sjældne ( 1/10,000, <1/1000): Lactatacidose, steatosis hepatis, hepatitis, angioødem, osteo- HIV/DK/15-02/PM/ HIV & VIROLOGY NEWS

11 Powerful performance in HIV % achieved virologic success with STRIBILD (E/C/F/TDF) through 144 weeks in naïve patients 6,7 STRIBILD (E/C/F/TDF) is powered with Truvada because backbone matters 8-10 References: 1. SmPC Stribild. 07/2014. Available at 2. DeJesus E, et al. Lancet 2012; 379: Sax P, et al. Lancet 2012; 379: Rockstroh J, et al. J Acquir Immune Defic Syndr 2013; 62: Zolopa A, et al. J Acquir Immune Defic Syndr 2013; 63: Clumeck N, et al. J Acquir Immune Defic Syndr 2014; 65(3):e Wohl D A, et al. J Acquir Immune Defic Syndr 2014; 65(3):e United States Department of Health & Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November Available at nih.gov/guidelines. 9. Günthard HF, et al. JAMA 2014;312(4): European AIDS Clinical Society (EACS) Treatment Guidelines. November 2014 (Version 7.1). Available at elvitegravir 150 mg/cobistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil 245 mg = (E/C/F/TDF) Rethink Performance Gilead Sciences Nordic Office Hemvärnsgatan 9, SE Solna, Sweden Phone: + 46 (0) Fax: + 46 (0) HIV & VIROLOGY NEWS

12 PRODUKTINFORMATION RETTET TIL SUNDHEDSPERSONER Forkortet produktresumé for STRIBILD filmovertrukne tabletter Elvitegravir, cobicistat, emcitrabin, tenofovirdisoproxil Præsentation: Hver filmovertrukket tablet indeholder 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabin og 245 mg tenofovirdisoproxil (svarende til 300 mg tenofovirdisoproxilfumarat eller 136 mg tenofovir) Indikationer: Behandling af infektion med humant immundefekt virus 1 (hiv 1) hos voksne i alderen 18 år og derover, som er antiretroviral-behandlingsnaive eller inficerede med hiv 1 uden kendte mutationer forbundet med resistens over for nogle af de tre antiretrovirale stoffer i Stribild. Dosering og indgivelsesmåde*: Voksne: Én tablet én gang dagligt, tages hel, oralt, med mad. Børn: Sikkerhed og virkninger er ikke klarlagt hos børn og unge <18 år. Nedsat nyrefunktion: Se afsnit Særlige advarsler. Kontraindikationer: Overfølsomhed over for de aktive stoffer eller over for et eller flere af hjælpestofferne. Samtidig administration med de følgende lægemidler på grund af muligheden for alvorlige og/eller livstruende hændelser eller svigtende virologisk respons og mulig resistens over for Stribild: Alfa 1 adrenoreceptorantagonister: Alfuzosin. Antiarytmika: Amiodaron, quinidin. Antikonvulsiva: Carbamazepin, phenobarbital, phenytoin. Antimykobakterielle lægemidler: Rifampicin. Ergot-derivater: Dihydroergotamin, ergometrin, ergotamin. Stoffer, der fremmer mave-tarm-motiliteten: Cisaprid. Naturlægemiddel: Prikbladet perikum (Hypericum perforatum). HMG Co A-reduktasehæmmere: Lovastatin, simvastatin. Neuroleptika: Pimozid. PDE 5-hæmmere: Sildenafil til behandling af pulmonal arteriel hypertension. Sedativa/hypnotika: Oralt administreret midazolam, triazolam. Særlige advarsler*: Stribild må ikke administreres sammen med andre antiretrovirale præparater. Det bør ikke indgives samtidig med andre lægemidler, som indeholder tenofovirdisoproxil (som fumarat), lamivudin eller adefovirdipivoxil (anvendes til behandling af virusinfektion med hepatitis B). Samtidig administration af Stribild og didanosin frarådes, da eksponering for didanosin stiger betydeligt efter samtidig administration af tenofovirdisoproxilfumarat, hvilket kan øge risikoen for didanosinrelaterede bivirkninger. Selvom effektiv viral suppression med antiretroviral behandling har vist sig at nedsætte risikoen væsentligt for seksuel overførsel, kan residual risiko ikke udelukkes. Der skal derfor træffes passende forholdsregler for at forebygge risikoen for at overføre hiv til andre via seksuel kontakt eller kontaminering med blod. Ældre: Stribild har begrænsede data hos patienter over 65 år. Det er mere sandsynligt, at ældre patienter har nedsat nyrefunktion. Derfor skal der udvises forsigtighed ved behandling af ældre patienter med Stribild. Nyrefunktion: Patienter som tidligere har stoppet behandling med TDF på grund af nyretoksicitet bør ikke behandles med Stribild. Patienter bør have beregnet kreatininclearance og målt glukose og protein i urinen før start af behandling med Stribild. Stribild behandling bør ikke startes hos patienter med kreatininclearance under 70 ml/min. Kreatininclearance, serumphosphat, glukose og protein i urinen bør monitoreres hver 4. uge i løbet af det første år og derefter hver 3. måned. Hos patienter med risiko 10 for nedsat nyrefunktion, er hyppigere monitorering af nyrefunktionen nødvendig. Cobicistat hæmmer den tubulære sekretion af kreatinin og kan forårsage moderat øgning af serumkreatinin og moderat nedsættelse af kreatininclerance uden at påvirke nyrernes glomerulære funktion. Patienter som oplever en bekræftet øgning i serumkreatinin, på over 26,5 µmol/l (0,3 mg/dl) fra baseline, bør overvåges tæt for renale bivirkninger. Hvis kreatininclearance på < 50 ml/min kan bekræftes eller serumphophfat falder til < 0,32 mmol/l (1,0 mg/dl) bør Stribild seponeres. Det bør også overvejes at afbryde behandlingen med Stribild i tilfælde af progressiv forværring af nyrefunktionen, når der ikke er identificeret andre årsager. Stribild bør undgås ved samtidig anvendelse med eller nylig brug af et nefrotoksisk lægemiddel på grund af øget risiko for renale bivirkninger (med TDF-komponenten i Stribild). Se produktresuméet for yderligere anbefalinger mht. monitorering og seponering af behandling. Nyresvigt, nedsat nyrefunktion, forhøjet kreatinin, hypophosphatæmi og proksimal tubulopati (herunder Fanconis syndrom) er rapporteret ved brug af tenofovirdisoproxilfumarat i klinisk praksis. Samtidig infektion: Hiv inficerede patienter, der samtidig er inficeret med HBV eller HCV i antiretroviral behandling har øget risiko for alvorlige og potentielt letale hepatiske bivirkninger. Seponering af behandling kan associeres med alvorlig, akut eksacerbation af hepatitis. Patienter med samtidig infektioner af hiv/hbv bør monitoreres tæt i mindst flere måneder efter behandlingen med Stribild ophører for symptomer på alvorlig, akut eksacerbation af hepatitis. Behandlingen bør ikke seponeres hos patienter med fremskreden leversygdom. Leversygdom: Patienter med eksisterende nedsat leverfunktion skal monitoreres. Afbrydelse eller seponering af behandling skal overvejes, hvis der er tegn på forværring af leversygdom. Lipodystrofi og metabolisme: Kombination af antiretroviral behandling er blevet forbundet med lipodystrofi hos hiv patienter. Måling af fastende serumlipider og blodglucose bør overvejes og lipidændringer bør behandles på relevant måde. Andre: Laktatacidose, mitokondriel dysfunktion, immunreaktiveringssyndrom, osteonekrose, reduktion i knoglemineraltæthed og knogleanomalier se produktresuméet for anbefalinger mht. monitorering og behandling. Sjældne tilfælde af pankreatitis og laktatacidose, undertiden fatal, er rapporteret Bør ikke anvendes til patienter med arvelig galactoseintolerans, en særlig form af hereditær lactasemangel (Lapp Lactase Deficiency) eller glucose/galactosemalabsorption. Kvinder i den fertile alder skal enten anvende hormonelle antikonceptiva, der indeholder mindst 30 µg ethinylestradiol og norgestimat som progestagenet eller de skal anvende en anden sikker kontraceptionsmetode. Samtidig administration af Stribild og orale antikonceptiva, der indeholder andre progestagener end norgestimat er ikke undersøgt og bør derfor undgås. Når patienter, som er dårlige til at metabolisere CYP2B6, skiftes fra et behandlingsprogram, der indeholder efavirenz, til Stribild, er der mulighed for en lavere eksponering over for elvitegravir på grund af en langvarig CYP3A-induktion af efavirenz. Det anbefales at overvåge den virale belastning i løbet af den første måned efter behandlingen skiftes. Interaktioner*: Samtidig administration af Stribild og lægemidler, som primært metaboliseres af CYP3A eller CYP2D6, eller er substrater for P gp, BCRP, OATP1B1 eller OATP1B3, kan føre til øgede plasmakoncentrationer af disse præparater, hvilket kunne øge eller forlænge deres terapeutiske virkning og bivirkninger. Samtidig administration af Stribild og lægemidler, der hæmmer CYP3A, kan reducere clearance af cobicistat og føre til øgede plasmakoncentrationer af cobicistat. Stribild må ikke administreres samtidig med adefovirdipivoxil, lamivudin eller didanosin og lægemidler der indeholder tenofovirdisoproxil (som fumarat). Elvitegravir er en moderat inducer af CYP2C9 og kan reducere plasmakoncentrationen af CYP2C9 substrater. Lægemidler, der inducerer CYP3A-aktivitet, forventes at øge clearance af elvitegravir, hvilket fører til reducerede plasmakoncentrationer af elvitegravir, hvilket kan forårsage svigtende terapeutisk virkning og udvikling af resistens. Samtidig administration af Stribild og nogle lægemidler, der primært metaboliseres af CYP3A, kan føre til øgede plasmakoncentrationer af disse præparater, hvilket er forbundet med muligheden for alvorlige og/eller livstruende reaktioner, såsom perifer vasospasme eller iskæmi. Samtidig administration af Stribild og andre lægemidler, der primært metaboliseres af CYP3A er kontraindiceret. Samtidig administration af Stribild og nogle lægemidler, som inducerer CY- P3A kan føre til signifikant reducerede plasmakoncentrationer af cobicistat og elvitegravir, hvilket kan forårsage svigtende terapeutisk virkning og udvikling af resistens. Se produktresuméet for detaljer vedrørende lægemiddelinteraktioner for antiinfektiva og antimykotika, HCV proteasehæmmere, makrolidantibiotika, inhalerede/ nasale kortikosteroider, antacida, kosttilskud, orale antidiabetika, narkotiske analgetika, orale antikonceptiva, antiarytmika, antihypertensiva, endothelin receptorantagonister, antikoagulantia, inhaleret beta-agonist, HMG Co A-reduktasehæmmere, PDE- 5-hæmmere, antidepressiva, immunosuppressiva, sedativa/hypnotika, midler mod podagra. Fertilitet, graviditet og amning*: Anvendelsen af Stribild skal ledsages af anvendelse af effektiv kontraception hos kvindelige patienter i den fertile alder samt hos mænd og kvinder. Stribild bør kun anvendes under graviditeten, hvis den potentielle fordel berettiger den potentielle risiko. Det må ikke anvendes under amning. Bivirkninger: Meget almindelige ( 1/10): Hypophosphatæmi*, svimmelhed, hovedpine, diarré, kvalme, opkastning, udslæt, forhøjet kreatinkinase og asteni. Almindelige ( 1/100, <1/10): Neutropeni, allergiske reaktioner, nedsat appetit, hyperglykæmi, hypertriglyceridæmi, insomni, unormale drømme, hovedpine, svimmelhed, opkastning, abdominalsmerter, abdominal distension, dyspepsi, forstoppelse, flatulens, forhøjet amylase herunder forhøjet pancreasamylase, forhøjet serum lipase, forhøjet ASAT og ALAT, hyperbilirubinæmi, forhøjede transaminaser, udslæt, vesikulobulløst udslæt, pustuløst udslæt, makulopapuløst udslæt, pruritus, urticaria, misfarvning af huden (øget pigmentering), forhøjet kreatinin i blodet, smerter, asteni og træthed. Ikke almindelige ( 1/1,000, <1/100): Anæmi, hypokaliæmi*, depression, selvmordstanker og selvmordsforsøg (hos patienter med en eksisterende anamnese med depression eller en psykisk sygdom), pancreatitis, angioødem, rabdomyolyse*, muskelsvækkelse*, nyresvigt, erhvervet Fanconis syndrom, og proteinuri. Sjældne ( 1/10,000, <1/1000): Lactatacidose, steatosis hepatis, hepatitis, angioødem, osteomalaci (manifesterer sig som knoglesmerter og i sjældne tilfælde medvirkende årsag til frakturer), myopati*, nyresvigt (akut og kronisk), akut tubulær nekrose, proksimal renal tubulopati, herunder Fanconis syndrom, nefritis (herunder akut interstitiel nefritis), nefrogen diabetes insipidus. Bivirkninger markeret med* kan forekomme som resultat af proksimal renal tubulopati. Tilfælde af osteonekrose er rapporteret, specielt hos patienter med generelt anerkendte risikofaktorer, fremskreden hiv sygdom eller langvarig CART. Hyppigheden er ukendt. Overdosering*: Såfremt der forekommer overdosering, monitoreres for tegn på toksicitet. Der skal gives støttende standardbehandling efter behov. Da elvitegravir og cobicistat i høj grad er bundet til plasmaproteiner, er det usandsynligt, at elvitegravir og cobicistat i signifikant grad vil fjernes ved hæmodialyse eller peritonealdialyse. Op til 30 % af emtricitabindosen og cirka 10 % af tenofovirdosis kan fjernes ved hæmodialyse. Det vides ikke, om emtricitabin eller tenofovir kan fjernes ved peritonealdialyse. Farmaceutiske forholdsregler*: Opbevares i den originale emballage for at beskytte mod fugt. Hold beholderen tæt lukket. Pakninger och pris: Beholdere med 30 filmovertrukne tabletter. Vnr: For dagsaktuelle medicinpriser se: Tilskudsstatus: Ikke tilskudsberettiget. Udlevering: BEGR (kun udlevering til sygehuse) Markedsføringstilladelsesnummer: EU/1/13/830/001 Indehaver af markedsføringstilladelsen: Gilead Sciences International Ltd, Granta Park, Abington, Cambridge, CB21 6GT, Storbritannien. Produktinformationen er forkortet. Et fuldstændigt produktresumé kan rekvireres hos indehaveren af markedsføringstilladelsen og yderligere information kan rekvireres hos den danske repræsentant: Gilead Sciences Denmark ApS, Korskildelund 6, 2670 Greve, Danmark Telefon: Afsnit markeret med * er forkortet i forhold til det af EMA godkendte produktresumé. LÆS PRODUKTRESUMÉET FØR ORDINA- TION ISÆR MED HENSYN TIL BIVIRKNIN- GER, ADVARSLER OG KONTRAINDIKATIO- NER. Et fuldstændigt produktresumé kan findes på EMAs hjemmeside Dato for oprettelse af produktinformation: Juli 2014 Job Bag No: HIV/DK/13-07/PM/1794 Ved godkendelse af markedsføringstilladelsen, er dette lægemiddel løbende underlagt supplerende overvågning, som vist med den omvendte sorte trekant. Alle mistænkte bivirkninger ved brug af Stribild skal rapporteres til Gilead via til: Nordics.SafetyMailbox@gilead.com eller på telefon +46 (8) og /eller til Sundhedsstyrelsen i overensstemmelse med det nationale spontane rapporteringssystem. HIV/DK/15-02/PM/1120 HIV & VIROLOGY NEWS

13 ILC in Vienna Powerful performance in HIV 1 7 HBV management has advanced significantly Prof Geoffrey Dusheiko gave a talk about the current situation and definitions of a cure in chronic HBV infection. This is a dynamic field there is a regenerated interest in HBV, he started by saying. He presented primary aims achieved in antiviral therapy for HBV, and pointed out that HBV can be prevented by vaccination. In the past three decades we have seen improvement: With conventional interferon, pegylated interferon and six nucleotide analogues lamviudine, adefovir, entecavir, telbivudine, tenofovir and emtricitabine. But these are blunt instruments, even though they have been shown to delay progression of cirrhosis. Antiviral therapies also reduce but do not eliminate the risk of hepatocellular carcinoma (HCC). Existing therapy improves survival, and reduces the need for liver transplantation. But for all these achievements, a cure is still not available, Prof Dusheiko continued. He talked about the possibility to stop nucleus analogues. The benefits of this would be several cost saving, making younger patients more accepting of therapy, avoid adherence concerns and also avoiding risk of resistance and potential long term toxicities. The question is what can be considered as a defined cure. Do we mean a virological cure, a functional cure or a disease cure? At some time we have to agree on this! In his conclusions Prof Dusheiko stated that chronic hepatitis B management has advanced significantly. There are therapies that effectively suppress the virus with no risk of resistance. Current research focus on examining stopping agents and amplifying therapy. And there are new direct agents or immunological measures on the horizon to cure or control chronic infection! HCV screening essential to catch patients with advanced liver fibrosis Most individuals with HCV remain a- symptomatic, which makes the diagnosis difficult. In a study presented at the Congress, the authors used the hypothesis that individuals whose HCV is not diagnosed are less likely to have advanced fibrosis, than those who have been diagnosed. They then compared liver fibrosis between respondents of National Health 78-80% achieved virologic success with STRIBILD (E/C/F/TDF) through 144 weeks in naïve patients 6,7 STRIBILD (E/C/F/TDF) is powered with Truvada because backbone matters 8-10 Of the respondents with known HCV infection, the proportion with a high, intermediate and low probability of advanced fibrosis was 14.5 %, 40.3 % and 45.2 %, respectively. In those with undiagnosed HCV the results were 19.1 %, 30.9 % and 50.0 %, respectively. The study highlights that even if people are unaware they are infected with HCV, the virus affects their liver in the same way resulting in advanced fibrosis. These results validate the current recommendation that screening for HCV particularly among high-risk groups is vital. Combination of DAAs for patients with kidney disease Preliminary data from an ongoing study revealed at the ILC suggest that a combination of three direct-acting antivirals is well tolerated in patients with severe renal impairment or end-stage renal disease when used with or without ribavirin. In addition, the combination led to rapid HCV viral load suppression with no virological failures seen in the preliminary data. The study is called RUBY-1 and it is evaluating ombitasvir/paritaprevir/ritonavir in combination with dasabuvir in these patient categories. Treatment-naive non-cirrhotic adults with chronic HCV GT1 infection and References: 1. SmPC Stribild. 07/2014. Available at chronic 2. DeJesus kidney E, et al. Lancet disease 2012; 379: (CKD) classified 3. Sax P, et al. Lancet 2012; 379: Rockstroh J, et al. J Acquir Immune as stage Defic 4 Syndr or 5, 2013; received 62: weeks 5. Zolopa of A, et treat- al. J Acquir Immune Defic Syndr 2013; 63: Clumeck N, et al. J Acquir ment Immune with Defic Syndr this 2014; combination 65(3):e with Wohl D A, or et al. J Acquir Immune Defic Syndr 2014; 65(3):e United States Department of Health & Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults without and Adolescents. ribavirin. November There Available was at a 24-week nih.gov/guidelines. 9. Günthard HF, et al. JAMA 2014;312(4): post-treatment 10. European AIDS follow-up Clinical Society period. (EACS) Treatment As of Guidelines. November 2014 (Version 7.1). Available at February , 17 of a planned 20 patients in Cohort 1 had received treatment and Nutrition Survey in the USA, in patients with diagnosed and undiagnosed and 6 had completed it. The combination elvitegravir 150 mg/cobistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil 245 mg = (E/C/F/TDF) HCV infection. was well tolerated to date, with no treatment-related serious adverse events and no premature discontinuation of directacting antivirals. Limited data are available on the safety for treating HCV infection in this category of patients; many of them currently go untreated and are vulnerable to disease progression. Combination therapy for GT4 and 5 HCV GT4 is estimated to account for 8-13 % of all chronic HCV infections, and GT5 for about 1 %. Clinical studies evaluating the treatment outcome with new direct-acting antivirals in GT4 and especially GT5 HCV infection have been limited to date. A study was presented that demonstrated that ledipasvir in combination with sofosbuvir achieves SVR 12 of 93 % of patients with GT4, and in 95 % of patients with GT5. In the study, ledipasvir/sofosbuvir was administrated as a once-daily fixed-dose combination for 12 weeks to treatment-naive and treatment-experienced patients with and without cirrhosis. A total of 85 patients of which 44 had GT4 and 41 had GT5 were enrolled. SVR12 rates were similar across all patient types. Adds to the evidence bank Results from a retrospective study from USA show that cancer rates in patients with HCV were significantly increased, compared to a non-hcv cohort. The researchers suggested that an extrahepatic manifestation of HCV may be associated with an increased risk of cancer. Known cancer types associated with HCV are non-hodgkin s lymphoma, renal and prostate Rethink cancer Performance as well as liver cancer. Gilead Sciences Nordic Office Hemvärnsgatan 9, SE Solna, Sweden Phone: + 46 (0) Fax: + 46 (0) HIV & VIROLOGY NEWS

14 Nucleoside ILC in Vienna Free Zones The study authors recorded all cancer diagnoses in patients over 18 years of age with or without HCV during Within the timeframe of the study 145,210 patient years were included in the HCV cohort, and 13,948,826 patient years were included in the non-hcv cohort. In the HCV cohort there were 2,213 cancer diagnoses (1,524/100,000) and 1,654 cancer diagnoses when liver cancer was excluded (1,139/100,000). In the non-hcv cohort there were 84,419 cancer diagnoses (605/100,000) during the same period, and 83,795 (601/100,000) when liver cancer was excluded. When all cancers are considered the rate is 2.5 times higher in the HCV cohort when liver cancers are excluded the rate is still almost 2 times higher. The results suggest that cancer rates are increased in the cohort of HCV patients versus the non-hcv patients, both including and excluding liver cancers, said Dr Lisa Nyberg, senior author of the study. She pointed out that these findings certainly points to the suggestion that HCV may be associated with an increased risk of cancer. However, the findings must be interpreted with caution, as the study also showed confounding factors such as alcohol abuse, tobacco, obesity and diabetes modified the results, Dr Nyberg added. These data adds to the evidence bank linking HCV with an increased risk of cancer, and highlights that there is still a long way to go in order to fully understand this complex and devastating disease, Dr Laurent Castera commented. An outstanding congress At the Closing Ceremony, Prof Michael Manns summarised the Congress in Vienna. We have now seen real-world data on HCV treatment that are similar to those presented from trials a year ago in London, he said. He recapped several of the presentations that he thought will change and improve the management of patients with HCV. In the future we will be able to treat with shorter regimens. But obviously there is a barrier around week 6. Prof Manns also mentioned the new developments of hepatitis D. There are 8 genotypes and they were presented at this Congress. The new Secretary General of EASL, Dr Laurent Castera, said that the 50th anniversary of ILC had been an outstanding Meeting. I d like to thank the Scientific Committee, the Reviewers and our own EASL office who for the first time arranged the entire Congress. I also look forward to welcome all delegates next year! The 51:st International Liver Congress will take place in Barcelona April Reserve the date! Per Lundblad 12 HIV & VIROLOGY NEWS

15 Heiners article FACULTY: Annika Karlsson, Sweden Arild Maeland, Norway Pietro Lampertico, Italy Jan Gerstoft, Denmark Warner Greene, USA Soo Aleman, Sweden Philip Goulder, UK Andrew Hill, UK Steve Deeks, USA Graham Foster, UK Robert Siliciano, USA Natasha Martin, USA Helene Mens, Denmark Giovanni Guaraldi, Italy Michael Kazatchinke, Switzerland For further information, registration and abstract submission please visit HIV & VIROLOGY NEWS

16 14 HIV & VIROLOGY NEWS

17 HIV & VIROLOGY NEWS

18 Nucleoside NeuroHIV Free Zones The simplicity patients want The versatility you need New once-daily REZOLSTA (darunavir 800mg/cobicistat 150mg) is now available! Janssen is proud to introduce REZOLSTA (darunavir 800mg/cobicistat 150mg) boosted darunavir in one tablet. REZOLSTA offers the proven versatility of darunavir 1 6 with a booster for the first time in the same tablet, simplifying the regimen for many of your adult patients. 7 References: 1. Llibre JM, et al. AIDS Rev. 2013;15: Ortiz R, et al. AIDS 2009;22: Mills AM, et al. AIDS 2009;23: Orkin C, et al. HIV Med. 2013;14: Cahn P, et al. AIDS 2011;25: Nelson M, et al. J Antimicrob Chemother. 2010;65: REZOLSTA Summary of Product Characteristics. Nov 2014 REZOLSTA (darunavir/cobicistat) Lægemiddelform; Filmovertrukne tablet. Indikation: Rezolsta 800 mg/150 mg er indiceret til behandling af humant immundefektvirus 1 (hiv-1)- infektion administreret i kombination med andre antiretrovirale lægemidler hos voksne over 18 år. Dosering: Behandlingen skal påbegyndes af en læge, der har erfaring med håndtering af hiv-infektion. Efter behandling med REZOLSTA er påbegyndt, må patienten ikke ændre doseringen eller afbryde behandlingen undtagen efter aftale med lægen. ART-naive patienter En tablet en gang dagligt i forbindelse med et måltid. ART-erfarne patienter En tablet en gang dagligt i forbindelse med et måltid kan anvendes til patienter, der tidligere har været eksponeret for antiretrovirale lægemidler, men ikke har mutationer associeret med darunavirresistens (DRV-RAM s: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V )*, og som har plasma-hiv-1 RNA < kopier/ml og CD4+ celletal 100 x 10 6 celler/l. Hos alle andre ART-erfarne patienter eller i tilfælde, hvor der ikke foreligger hiv-1-genotypebestemmelse, er REZOLSTA ikke egnet. Særlige populationer Ældre REZOLSTA skal anvendes med forsigtighed til patienter over 65 år. Nedsat leverfunktion Der foreligger ingen farmakokinetiske data vedrørende anvendelse af REZOLSTA til patienter med nedsat leverfunktion. Nedsat nyrefunktion Behandling med REZOLSTA bør ikke initieres hos patienter med kreatininclearance under 70 ml/min, hvis dosisjustering på basis af kreatininclearance er nødvendig for et samtidigt administreret lægemiddel. På grund af cobicistats og darunavirs meget begrænsede renale elimination kræves der ingen særlige forholdsregler eller dosisjusteringer af REZOLSTA hos patienter med nedsat nyrefunktion. Pædiatrisk population Der foreligger ikke data om REZOLSTAs sikkerhed og virkning hos patienter i alderen 3 til 17 år. REZOLSTA bør af sikkerhedsmæssige grunde ikke anvendes til pædiatriske patienter under 3 år. Administration Oral anvendelse. Tabletten skal synkes hel inden for 30 minutter efter indtagelse af et måltid. Kontraindikationer: Overfølsomhed over for de aktive stoffer eller over for et eller flere af hjælpestofferne. Patienter med svært nedsat leverfunktion. Co-administration med følgende lægemidler er kontraindiceret på grund af risikoen for tab af terapeutisk virkning: carbamazepin, phenobarbital, phenytoin, rifampicin (antimykobakterielt lægemiddel), perikon (Hypericum perforatum). Co-administration med følgende lægemidler er kontraindiceret på grund af risikoen for alvorlige og/eller livstruende bivirkninger: alfuzosin (alfa-1-receptorantagonist), amiodaron, bepridil, dronedaron, quinidin, ranolazin, systemisk lidocain (antiarytmika/midler mod angina pectoris), astemizol, terfenadin (antihistaminer), rifampicin (antimykobakterielt lægemiddel), colchicin, ved anvendelse hos patienter med nedsat nyre- eller leverfunktion (middel mod arthritis urica), sekalealkaloider (f.eks. dihydroergotamin, ergometrin, ergotamin, methylergometrin), cisaprid (gastrointestinalt motilitetsmiddel), pimozid, quetiapin, sertindol (antipsykotika), triazolam, midazolam administreret oralt (sedativa/hypnotika) (om forsigtighed ved parenteral administration af midazolam, se produktresume), sildenafil til behandling af pulmonal arteriel hypertension, avanafil (PDE-5- hæmmere), simvastatin og lovastatin (HMG-CoA-reduktasehæmmere), ticagrelor (trombocythæmmende middel). Særlige advarsler og forsigtighedsregler vedrørende brugen. Regelmæssig kontrol af virologisk respons anbefales. Ved manglende eller tab af virologisk respons bør patienten testes for resistens. Displacering af lægemidler, der i udstrakt grad bindes til surt a1-glykoprotein, kan ikke udelukkes. REZOLSTA bør ikke anvendes til behandlingserfarne patienter med en eller flere DRV-RAM s, hiv-1 RNA kopier/ml eller CD4+ celletal < 100 x 10 6 celler/l. Der bør udvises forsigtighed ved behandling af ældre, der foreligger kun begrænsede oplysninger om brug af REZOLSTA til patienter over 65 år. Der er rapporteret alvorlige hudreaktioner hos 0,4 % af patienterne. DRESS og Stevens-Johnsons syndrom er rapporteret i sjældne tilfælde så vel som toksisk epidermal nekrolyse og akut generaliseret eksantematøs pustulose. Ved symptomer på alvorlige hudreaktioner skal REZOLSTA straks seponeres. REZOLSTA skal anvendes med forsigtighed hos patienter med kendt sulfonamid allergi. Lægemiddelinduceret hepatitis er blevet rapporteret efter anvendelse af darunavir/ritonavir. REZOLSTA anvendes med forsigtighed hos patienter med let eller moderat nedsat leverfunktion, herunder kronisk aktiv hepatitis B eller C. Monitorering for forhøjet ASAT/ALAT bør overvejes hos patienter med kronisk hepatitis eller cirrose og hos patienter med forhøjede aminotransferaser før behandlingen specielt i de første mange måneder af REZOLSTA-behandling. Ved nyopstået eller forværret leverdysfunktion hos patienter, der tager REZOLSTA, skal det omgående overvejes midlertigt at afbryde eller helt seponere behandlingen.patienter med co-eksisterende tilstande: Patienter med hæmofili skal være opmærksomme på risikoen for øget blødnings tendens. Der er rapporter om nyopstået diabetes mellitus, hyperglykæmi eller forværring af eksisterende diabetes mellitus hos patienter, der får antiretroviral behandling. Der er rapporteret tilfælde af osteonekrose, især hos patienter med fremskreden hiv-sygdom og/eller langvarig eksponering for antiretroviral kombinationsbehandling (CART). Hos hiv-inficerede patienter med svær immuninsufficiens på tidspunktet for påbegyndelse af antiretroviral kombinationsbehandling (CART) kan der opstå en inflammatorisk reaktion på asymptomatiske eller residuale opportunistiske patogener, som kan forårsage alvorlige kliniske tilstande eller forværring af symptomer. Interaktioner med lægemidler Der er indberettet livstruende og dødelige lægemiddelinteraktioner hos patienter, der blev behandlet med colchicin og potente CYP3A- og P-glykoprotein (P-gp)-hæmmere farmakokinetisk forstærkning, da der ikke er fastsat doserings anbefalinger for en sådan kombination. REZOLSTA bør ikke anvendes sammen med præparater, der indeholder ritonavir, eller regimer, der indeholder ritonavir eller cobicistat. Hvis der skiftes fra ritonavir til cobicistat som farmakokinetisk forstærker, skal der udvises forsigtighed de første to uger af REZOLSTAbehandlingen. Interaktion med andre lægemidler og andre former for interaktion Der er ikke udført interaktions studier med REZOLSTA. Da REZOLSTA indeholder darunavir og cobicistat, kan interaktioner, som er identificeret med darunavir (i kombination med lavdosis ritonavir) og med cobicistat, muligvis forekommer med REZOLSTA. Darunavir er en CYP3A-hæmmer, en svag CYP2D6-hæmmer og en P-gp-hæmmer. Cobicistat er en mekanismebaseret CYP3A-hæmmer og en svag CYP2D6-hæmmer. REZOLSTA må ikke kombineres med lægemidler, der er meget afhængige af CYP3A i forbindelse med clearance, og for hvilke øget systemisk eksponering er forbundet med alvorlige og/eller livstruende bivirkninger. En fuldstændig interaktionstabel med doseringsanbefaling kan findes i produktresuméet. Graviditet REZOLSTA bør kun anvendes under graviditet, hvis den mulige fordel opvejer den mulige risiko. Amning Mødre må under ingen omstændigheder amme, hvis de behandles med REZOLSTA. Virkning på evnen til at føre motorkøretøj og betjene maskiner Der ses ingen eller kun i ubetydelig grad påvirkning af evnen til at føre motorkøretøj og betjene maskiner. Bivirkninger Da REZOLSTA indeholder darunavir og cobicistat, kan der forventes de samme bivirkninger, der er forbundet med de enkelte stoffer. Meget almindelig bivirkninger ( 1/10) hovedpine, diarré, kvalme, udslæt. Almindelige bivirkninger ( 1/100 til < 1/10): (lægemiddel) overfølsomhed, lipodystrofi, anoreksi, diabetes mellitus, hyperkolesterolæmi, hypertriglyceridæmi, hyperlipidæmi, unormale drømme, opkastning, abdominalsmerter, abdominal distention, dyspepsi, flatulens, forhøjede pankreasenzymer, forhøjede leverenzymer, angioødem, pruritus, urticaria, myalgi, osteonekrose, træthed, forhøjet kreatinin i blodet. Ikke almindelige bivirkninger ( 1/1.000 til < 1/100): immunrekonstitutions inflammatorisk syndrom (IRIS), akut pankreatitis, hepatitis, cytolytisk hepatitis, gynækomasti, asteni. Sjældne ( 1/ til < 1/1.000): Eosinofili og systemiske symptomer som reaktion over for lægemidlet, Stevens-Johnsons syndrom Ikke kendt (hyppighed kan ikke estimeres ud fra forhåndenværende data): toksisk epidermal nekrolyse, akut generaliseret eksantematøs pustulose. Der henvises til produktresuméet for cobicistat for yderligere oplysninger. Dette lægemiddel er underlagt supplerende overvågning. Læger og sundhedspersonale anmodes om at indberette alle formodede bivirkninger via Sundhedsstyrelsen Axel Heides Gade 1 DK-2300 København S Websted: www. meldenbivirkning.dk. sst@sst.dk. Overdosering. Der findes ingen specifik antidot mod REZOLSTA. Behandling af overdosering med REZOLSTA består af generelle understøttende foranstaltninger, herunder overvågning af vitale tegn og observation af patientens kliniske tilstand. Udlv.: (BEGR) Pakninger og priser: 800 mg 30 stk (VNR ). Dagsaktuelle priser kan ses på Produktinformationerne er forkortet i forhold til produktresume godkendt af Det Europæiske Lægemiddelagentur (EMA) 19. november Produktresumeet kan vederlagsfrit rekvireres fra Janssen-Cilag A/S, Hammerbakken 19, 3460 Birkerød, Tlf , Fax , information om dette lægemiddel er tilgængelig på EMEA s hjemmeside Janssen-Cilag A/S Hammerbakken 19, DK-3460 Birkerød, Denmark, Tel , Fax , PHDEN/REZ/0315/0001 JC Janssen-Cilag A/S 16 HIV & VIROLOGY NEWS

19 Efavirenz Efavirenz: too much of a good thing? The Food and Drug Administration approved efavirenz in To the surprise of many the legendary 006 trial [1] proved that efavirenz was more efficacious than indinavir, the preferred protease inhibitor at the end of the last century. Since then, efavirenz has been part of the recommended regimens in expert guidelines for almost two decades. During these years we have joked many times efavirenz has never lost a beauty contest. New drugs came challenging efavirenz but results of the trials were stubborn: at most, new drugs achieved non-inferiority and many times they were unable to match efavirenz efficacy. This year, for the first time efavirenz is no longer a recommended regimen in the HHS guidelines (see Dr. Moyle update of the guidelines in this issue) nor in the Spanish Gesida guidelines [2,3]. Three recent clinical trials have shown inferiority of efavirenz versus other drugs. The double-blind STARTMRK trial [4] showed that after 5 years of follow up, suppression rates were significantly higher with tenofovir/emtricitabine and raltegravir than with tenofovir/emtricitabine and efavirenz. Discontinuations due to adverse events occurred in 5% of patients receiving raltegravir and in 8.9% of the patients treated with efavirenz. The open-label STAR trial [5] compared the fixed combinations tenofovir/emtri- Table 1. Baseline characteristics of patients included in ENCORE1. citabine/rilpivirine vs. tenofovir/emtricitabine/efavirenz. A statistically significant difference in efficacy favoring the rilpivirine combination was demonstrated for participants with baseline viral loads lower than 100,000 copies/ml. The main reason for this difference was a higher rate of discontinuations of efavirenz (8.7%) than of rilpivirine (2.5%). In the SINGLE study [6] dolutegravir combined with abacavir/lamivudine proved for the first time to have superior antiviral efficacy than efavirenz combined with tenofovir/emtricitabine in the primary endpoint of the trial, regardless of the baseline viral load. The main driver of this result was a significantly higher rate of discontinuations due to adverse events in the efavirenz arm (10% vs. 2%). In STARTMRK, STAR and SINGLE as expected the most common adverse events leading to discontinuation of efavirenz were related to the central nervous system. These adverse events have always been the Achilles heel of efavirenz. However in prior trials efavirenz compensated this drawback thanks to its very high antiviral efficacy. One other important aspect that has contributed to the demotion of efavirenz from the preferred category group of regimens has been the finding of an association of efavirenz with a 2-fold increased hazard of suicidality compared with a regimens not containing efavirenz. This association was observed in an AIDS Clinical Trials Group cross-protocol analysis [7]. Although other observational studies have not replicated this association [8,9] expert guidelines mention this issue as one of the reasons not to recommend efavirenz as a preferred drug. It appears that the era of efavirenz has come to an end [10]. Has it really or is there any hope for a kinder, gentler form of efavirenz? The answer to this question has big implications. The World Health Organization recommends tenofovir, lamivudine (or emtricitabine) and efavirenz as the preferred initial regimen for adults and adolescents [11]. Therefore the number of patients that could potentially receive efavirenz is enormous (more than 26 millions). HIV & VIROLOGY NEWS

20 Efavirenz The ENCORE1 study is a randomised, double blind, placebo-controlled, non-inferiority clinical trial that has compared two doses of efavirenz in antiretroviral naive patients: the usual 600 mg daily versus an experimental lower dose of 400 mg daily. Results at 96 weeks have been recently published [12]. The ENCORE1 is a very large trial. It has enrolled 636 participants from high-income, middle-income, and low-income countries, a fact that allows generalization of their findings (Table 1). Results after two years of follow up strengthen findings after 48 weeks [13] and support the durability of the 400 mg dose. Is the 400 mg dose as efficacious as the 600 mg dose? At 96 weeks, 90% of the patients in the efavirenz 400 mg group and 90.6% in the efavirenz 600 mg group had viral load below 200 copies/ml supporting non-inferiority. Results did not change using the 50 copies/ml cutoff. Baseline viral load did not impact results. Of note, one third or the patients entered the trial with baseline viral loads above 100,000 copies/ml and one quarter had CD4 cell counts lower than 200 cells/µl. Rates of virological failure and development of resistance did not differ by dosing group. Overall this data clearly support the efficacy and durability of the 400 mg dose. Is the 400 mg dose better tolerated than the 400 mg dose? Let s look at the data. Proportions of patients reporting adverse events were exactly the same: 89% in the 400 mg group and 89% in the 600 mg group (p = 0.97). When we focus in adverse events that were definitely or probably related to efavirenz there was a significant advantage in the lower dose group: proportions were 38% and 48% in the 400 mg and 600 mg groups respectively (p = 0.01) Serious adverse events rates did not differ between groups. Overall it appears that there is a modest tolerability advantage of the lower dose. What about the CNS adverse effects characteristic of efavirenz? Were they associated with the dose used? The answer is not clear-cut. The ENCORE1 trial included questionnaires about quality of life, negative emotional state, and efavirenz side-effects. There were no significant differences between treatment groups for this battery of tests, suggesting that the lower dose did not translate in a decrease in the CNS adverse events of efavirenz (dizziness, abnormal dreams) in the first (Figure 1) or second year. Neuropsychiatric adverse events were rare during the second year (5% in the 400 mg group and 4% in the 600 mg group). An unexpected and interesting finding is that recovery of CD4 cells was higher in the lower dose group. After two years the difference was 25 cells/µl in favor of the 400 mg groups. This is difference is not clinically relevant but add support to the idea that efavirenz can have some toxicity upon lymphocytes. It has been a recurrent theme than in comparative trials of efavirenz versus protease inhibitors, integrase inhibitors or maraviroc recovery of CD4 has been persistently lower with efavirenz. Recently an interesting substudy of ENCORE1 [14] looking at cerebrospinal fluid exposure of efavirenz and its major metabolites has been published. The substudy included 28 patients who consented to have a lumbar puncture. Cerebrospinal fluid concentrations were slightly lower in patients who received the 400 mg dose. Interestingly both doses of efavirenz achieved cerebrospinal fluid concentrations considered to be adequate to inhibit HIV replication. One metabolic product of efavirenz is 8-hydroxy efavirenz. This metabolite is virologically inactive but has been associated with potential central nervous system toxicities. Concentrations of this metabolite did not differ by dosing group. The substudy provides reassuring data about the ability of the 400 mg dose to suppress HIV replication in the cerebrospinal fluid. However it does not appear that lowering the dose has a positive impact in potentially toxic metabolites. In my opinion results of ENCORE1 are quite important to facilitate the access to antiretroviral therapy worldwide. A 33% reduction in the active pharmaceutical ingredient translates in very large savings in production costs. This is an impressive achievement. It is important to emphasize that the 400 mg dose is not appropriate in two scenarios: pregnancy and in patients who need to receive rifampicin for the treatment of tuberculosis. These two groups were excluded from ENCORE1 I do not think that the dose reduction solves the issues of the central nervous system adverse events of efavirenz. For this reason I consider unlikely that just by dose reduction efavirenz can regain its position as a preferred drug in expert guidelines. In contrast with ENCORE1 when raltegravir, rilpivirine and dolutegravir have compared with efavirenz it has been relatively easy to show and advantage in terms of central nervous system. DR. JOSÉ R ARRIBAS Servicio de Medicina Interna, Unidad VIH Hospital La Paz, IdiPAZ. Madrid, Spain Figure 1. Efavirenz adverse events during the first 48 weeks. References 1. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999; 341: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and 18 HIV & VIROLOGY NEWS