HIV & Hepatitis Nordic Conference 2019

The HIV & Hepatitis Nordic Conference have twice as high risk for cardiovascular ties. Effective treatment of modifiable was held in Stockholm in September 25 disease compared with the background risk factors – such as smoking, high cho- - 27. Almost 300 participants had come population. A study we did on peripheral lesterol and high blood pressure – can to the Swedish capital to attend. artery disease showed that PLWH have a significantly reduce an individual's risk 75 % increased risk for this disease, Prof for cardiovascular disease. Dam Poulsen continued. – The median age of PLWH has increa- – 300 is an ideal number – because it Pulmonary disease in PLWH have a sed. It is estimated that in 2030, 40 % of allows for discussions, and enables new high prevalence of airflow limitation PLWH will be 60 years old or more. This networks to be formed, Prof Magnus of 10 - 15 %, and this is associated with underlines the importance of prevention. Gisslén stated when he greeted them all death. A comparison of 598 PLWH and We should always try to get our patients welcome to the Opening session. 2,598 controls on renal impairment show to quit smoking, she said. It was for the sixth time this annual a prevalence of 3.7 % for PLWH versus Efforts to avoid late presentation may Meeting took place, focusing on the 1.7 %. also decrease co-morbidities. Collabo- Nordic region. The lecturers consisted – The overall prevalence of renal im- ration with GPs is needed in managing of – as always – an exciting mix between pairment in PLWH is 6.4 %, with some the ageing and co-morbid population of international and Scandinavian key-note geographical variation. In Northern Eu- PLWH. speakers. Prof Gisslén, Sweden, was the rope the prevalence is 4 %, Africa has the – I'm not sure GP's are updated on Chair of the Scientific and program com- highest prevalence. The decline in renal drug-drug-interactions (DDIs) and gui- mittee, who also had representatives from function in PLWH on ART is steeper delines – so we have to help them with Denmark, Finland, Iceland and Norway. than that in uninfected. that, Prof Dam Poulsen ended her lecture. Factors contributing to co-morbidi- One of the questions she was asked after Factors contributing to co-morbidities ties are traditional risk factors, ART and The first speaker in Stockholm was Prof HIV-related risk factors. Susanne Dam Poulsen from Copenhagen, – Traditionally, PLWH smoke more Denmark, who gave a lecture on co-mor- than controls and also have a higher bidities in treated HIV infection. use of recreational drugs. That has to be – Distribution of co-morbidities varies taken into account, Prof Dam Poulsen in different patients of the world, Prof underlined. Dam Poulsen said. Co-morbidities are more prevalent in Collaboration with GPs is needed people with HIV, and they occur earlier. Altered body composition and weight – A meta-analysis of 16 studies showed gain are found in PLWH and may contri- that people living with HIV (PLWH) bute to inflammation and co-morbidi- Susanne Dam Poulsen

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her talk was who should take care of co-morbidities – GPs or specialists in infectious diseases? – That is something we need to discuss in our societies. But we do need to help those GP's who do it – with DDIs and guidelines.

CSF neopterin not normalized in ART Neopterin is a marker for immune system activation. Dr Frida Rydberg, Sweden, explained that ART treatment during chronic HIV infection does not normalise cerebrospinal fluid (CSF) neopterin. She presented a study that aimed to explore to what extent does ART treatment normalize CSF immune activation mar- kers in patients with chronic HIV and high CD4 cell counts. – 176 patients were retrospectively selected from the longitudinal Gothen- burg CSF cohort study. They had lumbar punctuations at baseline (before ART), 1 year on ART and more than 3 years of creased over time – particularly in female dom comparisons from the background ART. migrants. Employment was associated population. The conclusion was that CSF neopterin with suppressive ART, high CD4 counts – Our first conclusion is that PLWH does not normalize in many patients ini- and self-reported satisfaction with have a nearly 50 % higher prevalence of tiating ART during chronic HIV. psychological and physiological health. comorbid diseases at diagnosis. We saw – This also applies to ART initiation at We also found that people with intrave- an increased incidence of ischemic heart high CD4 cell counts, Dr Rydberg said. nous drug use are an important target disease – including myocardial infarc- group for policies promoting employ- tion – chronic obstructive pulmonary Employment of PLWH increased ment, Dr Carlander summarised. disease, liver disease, moderate to severe over time renal disease and lymphoma, Dr Jespersen PLWH are less likely to be employed than Increased burden of told the audience. HIV-negative people. Rises of unemploy- non-communicable disease Congestive heart disease, cerebrovas- ment is associated with increased HIV The burden of co-morbidities in PLWH cular disease, diabetes I + II and osteo- mortality, said Dr Christina Carlander, in Denmark was the title of a study pre- porosis were not more frequent among Sweden. sented by Dr Niels Jespersen, Denmark. PLWH, but more received treatment for She presented a study with the aim to The study population was all HIV infected osteoporosis. Alcoholism-related and assess employment status in the Swedish residents, who were at least 18 years old mental disorders were more frequent HIV cohort compared to the HIV nega- at time of diagnosis, in the Central Den- among PLWH at diagnosis and during tive population, controlled for migrant mark Region during 1985 - 2017. Each follow-up. status. It was a registry-based study. HIV patient was matched by age, sex and – PLWH have an increased burden of – We found employment of PLWH in- municipality of residence with ten ran- non-communicable diseases, was his last conclusion.

CD8 T-cell exhaustion in HIV-2 In HIV type 2, natural control is more common and there is a longer asympto- matic chronic stage compared to type 1. – T-cell exhaustion can be seen in cancer and chronic infections. Its most important hallmark is loss of functional cha- racteristics, such as cytokine production, cytotoxicity, proliferative capacity and skewing of transcriptional factors, said Research assistant Lydia Scharf, Sweden. She presented a study on CD8 T-cell exhaustion, activation and differentia- tion in HIV-2 infection dependent on clinical status. A cohort in patients in Guinea- Bissau had their T-cells analysed. Frida Rydberg, Lydia Scharf, Niels Jespersen and Christina Carlander. – In our study we saw a vicious circle

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of HIV immunopathology – with T-cell activation leading to T-cell exhaustion which in turn led to disease progression and CD4 T-cell depletion, was Research assistant Sharf's conclusion.

New technologies for drug delivery British HIV Association (BHIVA) and HIV Nordic had a joint session entitled Evolving treatment and care. First speaker in this was Prof Chloe Orkin, UK, who talked about new drugs and treatment strategies. She began with an overview of drugs that are available now. – We have a lot of tolerable drugs – and are also starting with 2-drug regimens, Prof Orkin said. Then she presented the new drug pipeline, and underlined that there are also new classes of drugs. All in all there will be 9 classes. vir and rilpivirine. Non-inferiority was Do we need 3 drugs for 50 years of achieved for primary and secondary treatment? According to her, this is ques- endpoints, Prof Orkin continued. tionable. – But at present, no 2-drug regimens Advantages and disadvantages with are recommended as first line of treat- implants ment in guidelines. There are both advantages and disad- Technologies for drug delivery of ART vantages with implants. are becoming more and more important. Advantages include they are removable They include long-acting injection, mi- at end of treatment and for adverse Chloe Orkin croneedle drug patch, oral nanomedi- effects. They have a potential to provide cine and subdermal implants to name a therapy for years with a single insertion few. – and since they are palpable under skin, ARV products for HIV treatment in infants, – This is where the field is going. this indicates receipt of drug. children, adolescents, pregnant and breast- Long-acting drugs are efficacious – - pa – The disadvantages include there is a feeding women. tients stay on them – and are often pre- minor sterile medical procedure requi- – So we need more research, Prof Orkin ferred in other specialities. red for insertion and removal. Palpation stated. The ATLAS study investigated if will not determine duration of use and HIV1-infected adults with current supp- there is a complicated regulatory en- HPV vaccines are safe for PLWH ression on a regimen with 2 nucleoside vironment, Prof Orkin said. Dr Christina Carlander talked about cer- reverse transcriptase inhibitors (NRTIs) She ended her lecture by pointing vical cancer and dysplasia in HIV. plus a third agent, remain suppressed out an article in the Lancet, published – 85 % of all cases are found in low and upon switching to a two-drug intramus- in July 2019. It was on knowledge gaps middle income countries, she pointed cular long-acting regimen of cabotegra- and research priorities on long-acting out. There is a global variation in cervical human papilloma virus (HPV) incidence. There are different genotypes of HPV – genotype 6 and 11 are benign (but account for 90 % of genital warts), and genotype 16 and 18 are high-risk and account for approximately 70 % of all cervical cancers. – There is a difference in protection by vaccination, depending on if the individual is HIV infected or not. But HPV vaccines are safe for PLWH, irrespective of CD4 count. However, there are no efficacy studies in PLWH, Dr Carlander continued. HPV vaccination is recommended for girls and boys aged 11 - 26. There are no data regarding vaccination after 26 years of age.

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In her conclusions she stated that women living with HIV on ART, and who are adherent to screening, have an equal risk of invasive cervical cancer (ICC) as HIV-negative. – HPV-negative women with a normal cytology have an equal risk of ICC irrespective of HIV. But women living with HIV with HPV genotype 16 have an increased risk of ICC, compared to HIV negative, Dr Carlander said. ART is associated with less HPV/pre- cancer/ICC, and less treatment failure. Women living with HIV have less proportion of HPV 16 (causing ICC) – but they have increased proportion of high- risk HPV not covered by HPV vaccines. – Therefore, a 9-valent vaccine is a better choice for PLWH than 2/4-valent, Dr Carlander ended her lecture.

Weight gain – the topic of the year the UK and 11 % in Denmark are obese. In the Plenary session that followed, And 38 % of HIV infected pregnant wo- Prof Jan Gerstoft, Denmark, gave a lecture men in South Africa are obese. CDC re- entitled Integrase strand transfer inhibi- ports the average adult weight increase tor (INSTI) adverse events – what is the 0.6 kg per year. This has to do with culture, truth? gender, nutrition and epigenetics. He started with a list of possible ad- The NAMSAL trial was on tenofovir verse events, and began by talking about disoproxil/lamivudine+dolutegravir ver- insomnia. sus tenofovir disoproxil/lamivudine+ efa- – In the very early raltegravir days, virenz. It found that dolutegravir-based Jan Gerstoft Claudia Crowell there was one study that showed acute treatment is non-inferior to treatment onset of insomnia with the initiation of with efavirenz. But it also found a highly raltegravir. Another study five years later significant difference in weight and BMI gained more weight between 18 and 36 found it with dolutegravir-containing change between arms. weeks gestation – particularly among combination ART in real life. It was the – Clinical obesity in the tenofovir diso- those with higher pre-ART weight. top-reported adverse event. proxil/lamivudine +dolutegravir arm was Prof Gerstoft presented data on Weight gain is the topic of the year, Prof higher. long-acting injectable cabotegravir. It Gerstoft continued. A study performed in Botswana had was not associated with weight gain in – We have an obesogenic environment – found that women initiating dolutegra- HIV infected in the HPTN 077 trial. 33 % of fertile women in the US, 20 % in vir with efavirenz during pregnancy Finally, he returned to his initial questions. The first was if immune reconsti- tution inflammatory syndrome (IRIS) is a possible adverse event with INSTIs? – No, was Prof Gerstoft's short answer. Insomnia? Here he answered yes – but not with elvitegravir. And weight gain? – Yes – but it is a complex interaction with culture, gender and race. More data are needed – also on the impact of weight gain on long-term health.

Why ART is important to study in pregnancy Dr Claudia S. Crowell, USA, talked about ART in pregnancy. – There are few known teratogens – but most drugs have simply not been studied in pregnancy, she started by pointing out. HIV is associated with significant morbidity and mortality for the pregnant woman and her fetus/infant. Treatment is therefore required for both maternal health and to prevent transmission to

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the infant. However, only limited data are available on ARVs in pregnancy and lactation. – Pharmacokinetics change in pregnancy – absorption, metabolism, distribution and elimination, Dr Crowell underlined. She also presented an example on diet- hylstilbestrol (DES) – a synthetic form of estrogen prescribed to pregnant women between 1940 and 1971 to prevent mis- carriage, premature labour and pregnancy complications. – Its use declined after studies in the 1950s showed that it was not effective. In 1971, researchers linked prenatal DES exposure to cervical and vaginal clear cell adenocarcinoma in what was called "DES daughters". They were found to have a 40 % increased risk. That is why it is important to study ART in pregnancy, she explained. But there are many challenges: preg- exposed infant, 1 in non-dolutegravir or nant women are excluded from studies, efavirenz ART at conception, and 9 in birth defects are rare events and few stu- HIV-unexposed infants. The updated dies provide long-term follow up were prevalence in dolutegravir exposure was some of those Dr Crowell described. 5/1,683. The NTD prevalence was three times higher in dolutegravir at concep- Data on ARV safety in pregnancy is tion versus non-dolutegravir ART at lacking conception. It represents an excess of 2 The Tsepamo study is a birth surveillance NTDs per 1000 exposures, Dr Crowell population-based study in Botswana. It said. Sharon Walmsley is designed to compare birth outcomes This emphasize the importance of a by HIV and ART status, and to evaluate balancing act between benefit of mater- the risk of neural tube defects (NTDs) nal treatment and risk of adverse fetal rative that we study ARVs in pregnancy. with preconception efavirenz. In the effects. This is a very difficult position to Also to remember long-term follow up. study period, dolutegravir based ART be in, according to Dr Crowell. Finally, Dr Crowell quoted an article in was rolled out. Current recommendations from WHO New England Journal of Medicine: "In – In 2018, 86 NTDs were registered is dolutegravir as preferred HIV treat- this period of uncertainty regarding the in 88,755 births. In August 2019 update, ment in all populations. potential risk conferred by DTG-based there were 30,278 additional exposures, She summarised that data of ARV safety regimens, women's autonomy to make and 10 more NTDs. 1 in dolutegravir- in pregnancy is lacking, and that is impe- their own health-related decisions must remain a central tenet of public health programs". In the discussion afterwards, Dr Crowell underlined the importance of communication of risk. – If you say the risk is three times higher, you have to underline that instead of 1 in a thousand, it is 3 in a thousand!

Different views on PrEP and STIs The incidence of sexual transmitted infections (STIs) is rising in many populations world wide – syphilis is a particu- lar issue in men who have sex with men (MSM). Some centers are also seeing increased rates of congenital syphilis, said Prof Sharon Walmsley, Canada. – Data from WHO and CDC show a dramatic increase of STIs in the era of pre-exposure prophylaxis (PrEP). On top of that, we also have a problem with resistance to drugs. What is driving this? Data indicates that

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chemsex is responsible for the explosion. There are three conflicting opinions on the use of PrEP: The alarmed opinion is that PrEP causes reduced condom use, STI and antibiotic resistance and constitutes a threat for the population. The neutral view is that condom use was declining and STIs increased independently of PrEP. The optimistic view is that PrEP can be seen as diminishing the fear of HIV and engaging users in more frequent testing and treatment – that could lead to declining STIs. A meta-analysis of effect of PrEP on STIs diagnosis among MSM, found that they were – slightly – in favour of PrEP driving STIs. – But some studies included in the analysis did not show that, Prof Walmsley commented.

Multifactorial reasons for increase of STIs A French study found daily PrEP users had more sexual partners, more frequent died, Prof Walmsley said. condomless sex and higher incidence of Her conclusions were that reasons for bacterial STIs. But an Australian study the rise of STIs are likely multifactorial found that partners – not condom rates – behavioural changes, chemsex and in- – drive STI rates. creased testing. The key strategy to com- – 25 % of participants accounted for 76 bat STIs is frequent screening and con- % of all STIs! tact tracing. So we still have a lot of uncertainty. Clinical trials of PrEP mostly found no Outgrowth virus seeded a year prior evidence of increased risk behaviour or to ART Ron Swanstrom STIs – on the other hand STI incidence Next Plenary session was on reservoirs is trending upwards more sharply since and cure. Prof Ron Swanstrom started PrEP. this by talking about new insights in the Some latently infected cells could per- – What can be done to decrease the risk? formation of the HIV reservoir. sist as resting memory T-cells, while The answer is education, screening and – HIV-1 evolves either its co-receptor some latently infected cells clearly ex- enhanced partner notification. Also new phenotype or its CD4 utilization pheno- pands over time. We know there is a re- therapies – vaccines, antibiotics and type to expand its target cell choices late servoir because virus come back when mouthwash. The latter is not ready for in disease. So the virus tells us which cell therapy is stopped. prime time in praxis yet, but is being stu- it has adopted to, he said. – Resting CD4+ T-cells can be induced to produce virus – and that is another source of evidence that there is a reservoir, Prof Swanstrom continued. If the reservoir forms continuously, then outgrowth virus (OGV) should represent the entire evolutionary history of the infection. He presented data from a participant in the CAPRICA trial that had 47 OGVs sequences after starting ART. – Most of the OGVs appear just before ART. This is a very different answer, compared to the reservoir is being formed continuously. Another participant in the trial showed the same. A median of 78 % of OGVs are seeded in the year prior to ART. – And DNA too! There is more DNA – therefore it can be a source of more in- formation. There is probably always some early virus mixed with the late virus.

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Prof Swanstrom presented a new view of formation of the latent reservoir: ART doesn't just reveal the reservoir – it helps form it! – Then there is the other side of the coin – how does virus enter the reservoir in the face of ongoing replication? Or does it happen stochastically? We don't know the answer to that. He finished his lecture by stating that the virologic rules for persistent replication and even latency may be very different in the CNS compared to lymphoid tissue.

Only 2 % of CD4 T-cells in circulation Prof Jacob Estes, USA, talked about viral reservoirs in tissue. Long term persistence of HIV reservoirs remains the key obstacle to achieving an HIV cure (i.e. functional Cure" strategies. The large size of cellular cure – sustained ART-free virologic re- viral reservoirs – both active and latent mission or eradication) in HIV-infected – containing replication competent pro- individuals after ART is discontinued. viruses represents two unique potential – There are limitations of human stu- sources of viral rebound following tre- dies. Only an estimated 0.25 % - 2 % of atment interruption. Also the large re- the body's CD4 T-cell population resides pository of infectious virus trapped on at any time in the circulation. Many cell follicular dendritic cell networks within subsets and tissue resident target cells lymphoid tissues before, and persisting are not localized in the circulation, Prof during, ART highlight a unique potential Estes pointed out. source of viral rebound following treat- Jacob Estes Lucy Dorrell Nonhuman primate (NHP) research ment interruption, Prof Estes summarized. has provided many critical insights into HIV infection and disease that would Very early treatment is not enough A "shocktail" of multiple agents simply not be feasible in a clinical set- Complete cure of HIV is defined as no Broadly neutralizing antibodies (bNAbs) ting. Immune systems, anatomy and detection of HIV DNA or RNA. This is delay viral rebound. Prof Dorrell said physiology are highly similar. not achievable with antiretrovirals, and there are more than 10 trials of bNAbs – We utilized NHP models of HIV in- not achieved by natural immune responses. ongoing. fection and performed extensive tissue – So we need keep on searching, Prof Then there are host-directed antibodies. analysis to determine the key tissue loca- Lucy Dorrell, UK, said. α4β7 integrin enables T-cells to home tions and size of the total body cell reser- But what does functional cure mean? to gut lymphoid tissue. It binds to HIV voir burden before and during ART. Undetectable viral load without ART? gp120 (the viral exterior envelope gly- No transmission risk? No inflammation- coprotein). Active reservoirs in all tissues related morbidity? These were just a few – Anti- α4β7 mAb vedolizumab is re- Prof Estes explained that they had found of the examples she presented. ported to prevent viral rebound after the importance of lymphoid tissue (in – To achieve this – how much of the ART withdrawal in SIV-infected monkeys. the GI tract) to be the predominant tis- reservoir needs to be eliminated? What But other groups have been unable to re- sue sites of infected cells before and approaches are needed? There are several produce that result. during ART. questions, Prof Dorrell continued. Latency is a continuum – with multiple – "Active" reservoirs (vRNA+ cells) per- A head start is treatment during acute blocks in transcription and translation. sist in SIV-infected rhesus macaques and infection, as this has been shown to limit According to Prof Dorrell this may re- HIV-infected individuals during long- reservoir size. But it requires intensive quire a combination of latency-reversing term suppressive ART. HIV testing. agents with synergistic effects. She called B-cell follicles represent a major source – However, very early treatment is not it a "shocktail" of multiple agents. of virus before ART and continue to enough. We do need other interventions. Prof Dorrell finished with how to turn retain virus during ART. So where do But we should try to treat as early as pos- "failures" into success. The first question "active" and total (vDNA+) reservoirs sible, she underlined. was how much of the reservoir needs to predominate in the body before and Gene editing therapy can protect CD4+ be eliminated. during ART? Prof Estes stated that a key T-cells against HIV, Prof Dorrell continued. – Cases of remission provide clues – so take-home is that they found them in all – TRAILBLAZER is a randomised trial further work is needed here! tissues – in active, early chronic and late comparing modified versus unmodified What approaches are needed? chronic SIV-infected primates. CD4+ T-cells infusions in 30 patients. – Combinations with complementary – There are significant challenges to The aim is to reduce inducible reservoir, modes of action, was her answer. overcome in developing effective "HIV and results are expected in 2024. Finally, will they be safe, efficient, af-

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fordable and accessible? – This needs to be at the forefront of new drug development. Clinical trial populations should represent the wider community of PLWH, was Prof Dorrell's final statement.

Elite controllers – a heterogeneous group Dr Beatriz Mothe, Spain, talked about mechanisms of elite control. Elite controllers have lower peak viremia, less acute retroviral syndrome, and suppressed viremia without ART. They are also able to maintain low levels of reservoir, and usually do not transmit. – But they can progress or lose control (perhaps up to 35 %). They generally harbour replication competent virus and have evidence of ongoing viral replication and evolution. They have higher levels of immune activation and inflammation compared to ART-suppressed, At the end of her lecture, Dr Mothe and a higher incidence of non-AIDS re- talked about immunogenicity vaccine lated diseases, Dr Mothe pointed out. candidates. Two – AELIX-002 and In immune-mediated control of HIV, NCT03204617 – is planned to go through we know there is a temporal association Phase I - III in 2020 - 2021. of cellular responses with the initial con- – However, there are big challenges. trol of viremia. The first T-cell response Elite controllers are a heterogeneous to transmitted/founder virus contributes group of individuals. There is not a single to the decline of acute viremia to the vi- mechanism that we can reproduce being ral setpoint – and escaped variants main- just one of these. That is just one of the John Frater Anne-Geneviève Marcelin tain the viral setpoint thereafter. challenges. In the future we need that – Findings from a cohort of hyperacute immune intervention should be "perso- infection (FRESH Cohort, before peak nalized" to different study populations, tial. 25 individuals from VISCONTI are viremia) demonstrated that the onset of Dr Mothe ended her lecture. still PTC – 12 years after treatment inter- HIV viremia induces a massive HIV-spe- ruption. cific CD8+ T-cell response. A quicker Post treatment control He underlined that PTC is rare – but and stronger T-cell response was asso- – rare, but exists can serve as a model to work out what ciated with subsequent control of vire- – The time to rebound after going off our interventions should be. mia. ART varies between individuals, said – But we need new tools to understand She continued by talking about the cha- Prof John Frater, UK, who gave a lecture the reservoir. Cell sorting on a chip, de- racteristics of T-cell responses in elite on mechanisms of post treatment con- tected by laser, sorts latent infected cells controllers. trol (PTC). in a tube, Prof Frater said. – We know there is a relative Gag domi- The first suggestion of PTC came in His conclusions were that PTC is real nance, polyfunctionality of T-cells and a 2010, and was published in AIDS with – depending on where you look. It is still viral inhibition capacity of T-cells. Laurent Hocqueloux as first author. not clear how common it is. Elite controllers are a heterogeneous Then it was shown in the VISCONTI trial – PTC may relate to reservoir size, and group – with different factors likely in 2013. In the same year, SPARTAC – a "reactivate-ability". The role of the im- contributing to different controllers, Dr trial that tested whether a short period mune system is still not clear. Mothe said. of treatment with ART in the early stages There are early evidence for innate im- of HIV infection can delay the need for munity and NK/KIR interactions. ART in the longer term – had 14 % of – So there is a need for more prospec- participants undetectable 1 year off ART. tive studies! – Post treatment control in HIV is real, and shown in several studies – but not in Second generation of integrase all, Prof Frater continued. inhibitors have lower resistance risk So what predicts PTC? Prof Frater In a plenary session on virology, Prof presented a list of things he stated they Anne-Geneviève Marcelin, France, pre- think matters: Timing and duration of sented an update on resistance to integrase ART, viral blips, sex, ethnicity, and viral inhibitors. subtype were some of the items in it. – Raltegravir (RAL) has a low genetic – NK cells from PTC have enhanced viral barrier to resistance – sometimes very Beatriz Mothe capacities, and superior anti-HIV poten- rapidly and at low level of viral load (less

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Top 5 papers selected for presentation at the HIV & Hepatitis Nordic Conference

Traditionally, the Congress has a ses- viduals with homozygous CCR5-delta32 in Cell Metabolism, April 2019. sion in which the best top 5 papers in genotype have shorter life expectancy. – The take-home message is that levels basic HIV and clinical research from the of HIV infection correlates with genes past year are presented. This was also Intact proviral DNA assay involved in metabolism. Metabolic state the case in 2019. Paper number 3 was a new method for – independently of activation state – quantification of intact HIV latent reser- determines CD4+ T-cell HIV susceptibi- α4β7 therapy and CRISPR-Cas voir, published by Bruner et al in Nature, lity. CD4+ T-cells with elevated glycolysis editing of stem cells February 2019 "New methods are needed and oxidative phosphorylation are selec- Dr Marianne Jansson, Sweden, began for high throughput evaluation of intact tively HIV infected. with the top 5 from basic HIV research. reservoir, driving cure strategies". The fifth and final paper was from The first was on α4β7 integrin. – HIV DNA qPCR overestimate re- Cirelli et al in Cell, May 2019, "Slow im- – The first study, published in 2016 – servoir size, and quantitative viral out- munization enhance HIV neutralization". "Sustained virologic control in SIV ma- growth assay (QVOA = gold standard) – Until now much of the development caques after antiretroviral and α4β7 may underestimate the reservoir size. in HIV vaccine has been in the area of antibody therapy" – was promising. Full-genome long-range sequencing is immunogens and adjuvants, in addition However, four new publications coming technically demanding, and costly, Dr to passive immunization with bNAbs. out in September 2019 could not replicate Jansson explained. Less is known about dosing and kinetics the findings. Instead they show no diffe- Intact proviral DNA assay (IPDA) is of immunization, Dr Jansson said. rence to the control group of monkeys. developed by a sliding window approach The paper described a novel approach So anti-α4β7 therapy is not the antidote, for identification of optimal sites for de- – slow immunization via osmotic pumps she said. tection of deleted sequences. Two ampli- in Indian rhesus macaques. The second publication was from Xu et cons – packaging signal site and Rev- – After boost, using osmotic pump, the al, New England Journal of Medicine Sept responsive element (RRE) in Env region animals developed increased frequen- 2019 on "CRISPR-Cas editing of stem were selected. Packaging signal site is a cies of GT-TFH, elevated Env-specific cells". It is a proof of concept of engraft- deletion indicator. RRE was also selected BGC cells and BMem cells. Antibodies ment of CRISPR-Cas CCR5 gene-edited for detection of hypermutations, using recognized a wider range of Env epi- allogenic stem cells. specific probes. topes. – No clinical off-target effects were Dr Jansson ended with a tip on what to observed related to CRISPR-Cas CCR5 Genes involved in metabolism keep eyes open for in 2020: gene during follow-up (19 months), but – and osmotic pumps – TOX, a transcription factor regula- more studies are needed with higher The fourth publication was "Impact of ting CD8 T-cell exhaustion in cancer gene-targeting efficacy. There is concern metabolism on CD4+ T-cell susceptibility". and chronic infections. So – how about in regard to ablation of CCR5, since indi- It was published by Valle-Casusco et al in HIV?

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Fitness effects of the CCR5-∆32 mutation Then there were the top 5 papers in clinical HIV research. They were chosen and presented by Dr Terese Katzenstein, Denmark. The first was entitled "CCR5-∆32 is de- leterious in the homozygous state in humans", by Xinzhu Wei and Rasmus Niel- sen and published in Nature Medicine. – It is a study from UK where they used genotyping and death register informa- tion of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5-∆32 mutation. The authors estimated a 21% increase in the all-cause mortality rate in individuals who are homozygous for the ?32 allele. – Homozygosity for a deletion in a functional gene is associated with reduced fitness. It underscores that introduction – It is a huge study, with a huge underta- PrEP use and STIs of new or derived mutations in humans king. The population cohort was 52,500 "Association of HIV pre-exposure prop- using genetic engineering (CRISPR individuals. The research question was if hylaxis with incidence of sexually trans- technology or other methods) comes you scale-up test and treat – will it affect mitted infections among individuals at with a considerable risk – even if the mu- HIV incidence? high risk of HIV infection", was the title tations provided a perceived advantage. In this community-randomized trial, of the 5th and final study she presented. In this case, the cost of resistance to HIV 21 communities in Zambia and South It was published in JAMA by Michael W. may be increased to other – and perhaps Africa were randomly assigned to either: Traeger et al. more common – diseases, Dr Katzenstein Group A (combination prevention inter- – The objective was to describe STI in- summarized. vention with universal ART), group B cidence and the behavioral risk factors (the prevention intervention with ART in a cohort of predominantly gay and Combination of two monoclonal provided according to local guidelines) bisexual men on PrEP. Also to explore antibodies or group C (standard care). The preven- changes in STI incidence following PrEP The second study was published in Nature: tion intervention included home-based commencement. "Combination therapy with anti-HIV-1 HIV testing delivered by community The finding was that among 1,378 par- antibodies maintains viral suppression". workers, who also supported linkage to ticipants with pre-enrollment STI data Pilar Mendoza was the first name of au- HIV care and ART adherence. available, receipt of PrEP after study thors, and it is a Phase Ib proof-of-con- – Test and treat was found not to be enrollment was associated with an in- cept clinical trial. enough to reduce HIV incidence – it has to creased incidence of STIs compared A combination of 3BNC117 and 10- be combined with other strategies, such as with pre-enrollment. 1074, two potent monoclonal anti-HIV-1 stigma reduction, PrEP etc, Dr Katzenstein – Factors associated with STI during broadly neutralizing antibodies that tar- summarized the study's findings. follow-up were younger age, diagnoses get independent sites on the HIV-1 en- of STIs, a greater number of sex part- velope spike, was administered during Non-inferiority for a 2-drug regimen ners, participation in group sex and in- analytical treatment interruption. Par- GEMINI 1 & 2 aimed to evaluate the consistent or no condom use. The fin- ticipants received three infusions of 30 efficacy and safety of a two-drug regimen dings suggest the importance of frequent mg/kg of each antibody at 0, 3 and 6 compared with a three-drug regimen testing for STIs among gay and bisexual weeks. Infusions of the two antibodies for the treatment of HIV-1 infection in men using PrEP. Timely diagnosis and were generally well-tolerated. ART-naive adults. Patients were rando- treatment of STIs reduces the duration – The authors concluded that the com- mised to receive a once-daily two-drug of infection and transmissibility, Dr bination of the anti-HIV-1 monoclonal regimen of dolutegravir (50 mg) plus Katzenstein stated. antibodies 3BNC117 and 10-1074 can lamivudine (300 mg) or a once-daily maintain long-term suppression in the three-drug regimen of dolutegravir (50 absence of antiretroviral therapy in in- mg) plus tenofovir disoproxil fumarate dividuals with antibody-sensitive viral (300 mg) and emtricitabine (200 mg). reservoirs. Both drug regimens were administered orally. A huge study on test and treat – Non inferiority for the two drug regi- "Effect of universal testing and treat- men was met – data from week 96 show ment on HIV incidence – HPTN 071 (Po- that, said Dr Katzenstein. pART)" by Richard J. Hayes, published The study had Pedro Cahn as first in The New England Journal of Medicine author, and was published in Lancet, was Dr Katzenstein's third choice. November 2018. Per Lundblad

HIV & VIROLOGY NEWS 4· 2019 31 HIV & Hepatitis Nordic Conference 2019

Hepatitis at the HIV & Hepatitis Nordic Conference

The last of the three days in Stockholm that DAAs improve survival in patients JAMA Oncology in 2018. It was a Korean was dedicated to hepatitis. treated with HCV-related HCC that has study, by Jonggi Choi et al and it com- been successfully treated. pared the HCC risk for patients treated Prof Ola Weiland, Sweden, was the first – The improvement in survival seems with entecavir versus tenofovir. The re- speaker and he presented the top 5 to be caused by a reduction in hepatic sults are very controversial, he stated. Hepatitis papers 2018 - 2019. decompensation. DAAs did not impact – Their finding was that in a Korean on HCC recurrence. nationwide population cohort of 24,156 DAAs do not increase risk for HCC treatment-naive adult patients with The first of these was on interferon-free HCV organs can be used as grafts for chronic HBV infection, tenofovir treat- therapy and hepatocellular carcinoma transplants ment was associated with a significantly (HCC) risk. The second study was on DAA impact on lower risk of HCC and mortality, com- – In 2016, data from a study that gained HCV organ utilization during liver trans- pared with entecavir treatment. a lot of attention indicated that treatment plantation. It was published in Hepatology Given the poor prognosis of patients with direct-acting antivirals (DAAs) was 2019 by Thomas G. Cotter et al. who developed HCC, this study's fin- associated with early tumour recurrence. – The donors were HCV positive and dings may have considerable clinical In 2018, another study showed that treat- the recipients were negative. The study implications in the prevention of HCC ment of Hepatitis C (HCV) with DAAs had investigated the outcomes for these in patients with chronic Hepatitis B in- instead reduces the risk of HCV. recipients – who in all cases were suc- fection. In 2019, a study was published in Hepa- cessfully eradicated with DAAs. – I'm not sure this is true – they might tology by Lisa I. Backus et al. investiga- The summary was that the results show ting 15,059 patients infected with HCV. that with the advent of DAAs, early graft It found that those achieving sustained outcomes in both HCV-positive and virological response (SVR) had signifi- HCV-negative recipients that receive or- cant lower all-cause mortality and lower gans are excellent and similar to those of incident HCC rates than those who did HCV-negative recipients. not achieve SVR. – This increases the organ pool sub- – So DAA induced SVR in advanced stantially. It is a fantastic result, Prof HCV cirrhosis, reduced all cause morta- Weiland said. lity and HCV incidence. DAA achieves significantly clinical benefit – we can say Contradictive findings on risk for HCC that now. The third study Prof Weiland presented Highlights from this paper include was in Hepatitis B (HBV), published in Ola Weiland

HIV & VIROLOGY NEWS 4· 2019 37 HIV & Hepatitis Nordic Conference 2019

have compared pears with apples, Prof Weiland commented. Then another study came with a totally different result, published by Seung Up Kim et al in Journal of Hepatology 2019. It was a multicenter study of entecavir versus tenofovir in chronic HBV patients in South Korea. – It showed no difference in risk.

Screen for blood-borne infections in immunocompromised patients The burden of Hepatitis E (HEV) among patients with haematological malignan- cies: A retrospective European cohort study was next. It was published by Johann von Felden et al in Journal of Hepatology 2019. – The study included 50 patients with haematological malignancy, including Habiba Kamal haematopoietic stem cell transplant recipients with clinically significant HEV infection. HEV infection evolved to chronic hepatitis in 45.5 % of patients HDV viremia associated with exposed to a rituximab-containing regi- increased cancer risk men, and 47.6 % of stem cell transplant In the abstract session that followed, recipients, Prof Weiland explained. PhD student Habiba Kamal, Sweden, Highlights from the study includes that presented a long term study Hepatitis HEV is associated with liver failure and D virus (HDV) and HBV co-infected pa- mortality in haematological malignan- tients. cy. Also that blood-borne transmission – HDV is a unique RNA virus that re- contributes to the burden. quires HBsAg to infect the hepatocytes, – In Sweden we don't screen for she told the audience. blood-borne infections. Perhaps we Chronic HDV infection is recognized as Lone Wulff Madsen should do that in immunocompromised the most severe form of viral Hepatitis. patients, he commented. Early studies, mostly from tertiary care Alleviation of immunosuppressive treat- centers, reported progression to cirrhosis vious estimates from many tertiary cen- ment for HEV requires caution – it can and major liver events in 60 - 70 % of pa- ters. cause death, and ribavirin is effective tients in less than 2 - 6 years. – Poor virological response to current and should be initiated early. – We have therefore assessed the long- IFN-alpha therapy with frequent HDV term risks for HCC, liver-related com- RNA relapses was noted in both cirr- Lipophilic statins reduce HCC plications and liver-related death in 337 hotic and non-cirrhotic patients. Our incidence anti-HDV positive patients with positive results may be useful when evaluating The last study Prof Weiland presented or negative HDV RNA. the short or long-term effect of the new was on the impact of statins on HCC in- It was a retrospective cohort study. upcoming treatment regimens on the na- cidence in chronic HBV and HCV. It was – The patients were of mixed popula- tural course of the liver disease. So new published in Annals of Internal Medicine tion with origins in Asia, Europe, Africa treatment options against HDV infection by Tracey G. Simon et al. and East Mediterranean area – with the are urgently needed, was her last conclu- – The results came from a nationwide result of the study possibly generalizable sion. Swedish population, and it is an interes- to a wider population than if a selected PhD student Habiba Kamal was pre- ting paper, he said. origin. sented with the HIV & Hepatitis Nordic There are lipophilic statins (artovastatin, The study showed that HDV RNA vi- Conference 2019 Abstract Award for her simvastatin, fluvastatin and lovastatin) remia at HDV diagnosis was associated study. and hydrophilic statins (pravastatin and with a 3.8 fold increased risk for liver- rosuvastatin). The study had investi- related death or liver transplantation. 4 week treatment for HCV gated the ten-year cumulative incidence, – Presence of cirrhosis, older age and Dr Lone Wulff Madsen, Denmark, pre- absolute risk differences and hazard ra- HDV RNA viremia at baseline were in- sented a randomised controlled trial on a tios for incident HCC in a propensity dependently associated with a severe di- 4 week treatment for Hepatitis C. score-matched cohort, by statin use and sease course, Ms Kamal said. The study compared patients on gle- type in 16,668 individuals. Non-cirrhotic patients at baseline had caprevir + pibrentasvir and ribavirin ver- – The conclusion was that lipophilic a poor prognosis with development of sus glecaprevir + pibrentasvir only. statins significantly reduced HCC inci- liver-related outcome in every fifth -pa – We found that treatment with gle- dence and mortality, Prof Weiland ended tient within 15 years – but this course caprevir + pibrentasvir and ribavirin was his lecture. was nevertheless more benign than pre- well tolerated. A subpopulation with

38 HIV & VIROLOGY NEWS 4· 2019 HIV & Hepatitis Nordic Conference 2019

chronic Hepatitis C can be cured by 4 weeks of DAA treatment + ribavirin. But larger studies are needed to determine safety and efficacy, Dr Madsen reported.

HCV national elimination program in Norway HCV treatment among people who inject drugs – experiences from Norway, Den- mark and Sweden was the title of the next session. Chair Marianne Alanko pointed out that at previous Congresses experiences from Iceland and Finland have been reported. Prof Olav Dalgard, Norway was the first speaker, and talked about HCV in Nor- way. – The Norwegian government aims at elimination of Hepatitis C in Norway. A national action plan and an action plan for Oslo (capital of Norway) is in place, he said. Anna Jerkeman, Olav Dalgard and Anne Øvrehus According to data from 2017 on the approximately 10,000 individuals with – Norway aims at elimination of Hepa- sible to do, have ground level engage- HCV in Norway, 1,700 have never injected titis C within 2023. Continued political ment and great best practice examples. drugs. 1,800 have a history of previous in- leadership and commitment to the natio- Weaknesses include stable financing of jection use, 2,200 are in restrictive medi- nal elimination plans will be required – initiatives, focus on primary – not sup- cation-assisted rehabilitation (LAR) pro- but we are on track to elimination, were porting – efforts, genotyping is still re- grams – and 4,300 are actively injecting his conclusions. quired and there is a limited prescriber drugs, "pool". – People with injecting drug use (PWI- Need for a national strategy Opportunities include a national stra- DU) are a group with high prevalence of in Denmark tegy – something Dr Øvrehus stressed HCV, Prof Dalgard underlined. In Denmark, HCV treatment is centralized they really need – expanding outreach He added that the challenge they are to hospitals but treatment for PWIDU is treatment, point of care testing and test facing is to reach these individuals. This decentralized, said Dr Anne Øvrehus, and treatment outside OST. can only be done by redefining the tradi- Denmark. – Finally, threats consists of a lack of tional referral models – there is a need to 25 -50 % of PWIDU are on opioid sub- resources, lack of will and competing bring HCV care to the community. Prof stitution therapy (OST) in the country, priorities, she ended her lecture. Dalgard described how primary care and there are needle and syringe ex- works together with specialist care, and change programs in 97 municipalities, Experiences from a needle exchange according to him this works well. she continued. program in Sweden – An important model of care is scree- – These are recommended – but not Dr Anna Jerkeman, Sweden, talked ning in drug treatment clinics. Then we enforced. about HCV treatment in active injectors. have "the Hepatitis bus" – a user initiated Drug treatment centres in Denmark – Over the years there have been issues ambulant HCV clinic that visits residen- have to "repeat an offer" if a patient is re- whether we should treat PWIDU or not. tial care clinics. garded to be at risk. But I think we have come a long way He described an ongoing RCT on pa- – 87 % of people receiving OST have since then. If we are going to reach the tients in opioid agonist therapy (OAT) in been tested at least once, Dr Øvrehus, WHO goal of elimination, we have to treat the cities Bergen and Stavanger. Arm A said. PWIDU, Dr Jerkeman stated. receives integrated diagnostic and treat- Shared Addiction Care Collaboration In order to do that we have to find new ment follow-up for HCV in OAT clinics. links hospitals to addiction centres. In arenas – prisons, OST clinics, needle ex- Arm B has referral to the outpatient clinic July 2019 there were 1,915 persons in change programs and primary care, she at the local hospital with undetectable treatment. continued. HCV RNA 12 weeks after end of treat- She described a peer led test-and-treat Dr Jerkeman described the Malmö ment. The results are not ready yet program on the street level in Copenha- needle exchange program, which has exi- – Approximately 5,000 people are in- gen sted since 1987. carcerated in prisons each year, and circa – Peers act as an "extra parent" that – At the time, this and the program 25 % of them have injected drugs. GPs picks up the medicine, and have abilities in Lund were the only ones in Sweden. serve the prisons, and the Health depart- to make people stay in the program. These clinics then started to expand ment has committed resources to coor- SWOT stands for strength, weaknesses, nationally in 2010. dinate HCV care in the prisons. opportunities and threats. A SWOT-ana- In Malmö participants are registered Prof Dalgard also told about several lysis of HCV care for PWIDU in Den- under national identity numbers, and other ongoing interventions to reach mark rounded up her lecture. there is a database of participants. Offers PWIDUs in Norway. – The strengths include that it is pos- within the program include regular tes-

HIV & VIROLOGY NEWS 4· 2019 39 HIV & Hepatitis Nordic Conference 2019

ting for HIV, HBV and HCV, vaccination for HBV and HAV and general medical care. – It is estimated to be link to addiction medicine and dentistry. They also offer HCV treatment. She pointed out that 5,000 individuals have been registered in the Malmö needle exchange program since 1987. Together they constitute 70 % of the target population. In 2018, the program saw 600 individuals in a total of 8,000 visits. – It might be an ideal platform for treating HCV in active PWIDU! In 2018 they started ACTIONNE, a study on Hepatitis C infection treatment in needle exchange. Antiviral treatment is administered by the nurse at the needle exchange program weekly – assessment of adherence is made by pill count. Pa- tients receive 8 or 12 weeks of glecaprevir/pibrentasvir. – During and post treatment there are ment. Also venipuncture skills, flexibi- regular measurements of HCV RNA, as- lity in appointments and home calls and sessment of drug use and health-related reminders in the form of text-messages quality of life, Dr Jerkeman explained. and phone calls. Preliminary results from the inclusion – The next step now is microelimina- period April 2018 to May 2019 have 62 tion of HCV in Southern Sweden. There patients screened and 50 included. Their are many reasons for this being pos- median age was 46 years, and 78 % is sible to achieve, Dr Jerkeman ended her male. lecture. – There have been 3 dropouts from the In the panel discussion afterwards, the Niklas Björkström 50, 2 of those on their own initiative, and three speakers agreed on the possibility one excluded due to poor adherence. of simplifying the procedure in the future. 47/50 have reached end of treatment – Also that re-testing is important, and be discontinued after confirmed HBsAg and so far 41 of these have reached SVR presents a problem in PWIDU. loss, with or without anti-HBs sero- 12 assessment and cleared the infection. conversion. NAs can be discontinued in We have had 2 reinfections, and one pa- Combine structured NA discontinua- non-cirrhotic HBeAg-positive chronic tient died (of overdose) during follow up tion with therapeutic vaccination Hepatitis B patients who achieve stable after treatment. Next session was on Hepatitis B, and Dr HBeAg seroconversion and undetectable Factors important for success are a Niklas Björkström, Sweden, talked about HBV DNA and who complete at least 12 multiprofessional staff that is trusted stopping nuclos(t)ide analogues (NA) months of consolidation therapy. Close by the PWIDU community and a non- therapy in HBV. post-NA monitoring is warranted. judgemental, non-stigmatizing environ- EASL guidelines says that NAs should – This raises some immunological questions: Can we predict beforehand which HBV patients are most likely to remain HBV-DNA negative after stopping NAs? Or experience a viral rebound, but even- tually seroconvert and become HBsAg negative? To the first question I answer yes, maybe. To the second, I say no, Dr Björkström stated. A study he presented had the aim to characterize the NK cell response at treatment cessation and during treatment interruption. – We could see increased natural cytotoxicity responses are following NA interruption. We also studied T-cells. They are dysfunctional in chronic Hepatitis B. We found less exhausted T-cells in patients with HBsAg loss. So what are the immunological mechanisms behind viral clearance and func-

40 HIV & VIROLOGY NEWS 4· 2019 HIV & Hepatitis Nordic Conference 2019

tional cure? According to Dr Björkström early inflammatory cytokine and innate lymphocyte response is followed by a ro- bust anti-HBV T-cell response. – Therefore – combine structured NA discontinuation with therapeutic vaccination, was Dr Björkström's advice.

Myrcludex B and lonafarnib for HDV Dr Maria Buti, Spain, talked about future options for treatment of Hepatitis D. – It represents the most severe form of chronic viral Hepatitis, she underlined. HDV is underdiagnosed, and HDV screening should be performed in all HBsAg-positive patients, Dr Buti continued. – IFN for 12 months is the recommended therapy, but has limited efficacy in - pa tients with chronic Hepatitis D – and non negligible side effects. Myrcludex B (bulevirtide) has induced HDV RNA declines in the MYR201 trial. In a study presented at EASL 2018 on myrcludex B monotherapy, it was shown to induce HDV declines and improvement in ALT levels in HDV patients in the MYR202 trial (24 weeks of treatment). Lonafarnib is a small molecule, oral, prenylation inhibitor. A combo regimen with lonafarnib and ritonavir has Today, there is a gap of 82 % to that goal. showed the greatest observed decline in NAs block DNA replication, but only HDV RNA, Dr Buti pointed out. partially affect cccDNA. They rarely – New drugs are in the pipeline – with achieve viral cure, he continued. the potential to achieve a better manage- – We can decrease progression, but not ment of Hepatitis D, she stated. eliminate HBV. NUC therapy can supp- ress the virus, but not HBsAg. Barriers to HBV cure Barriers to HBV cure are the cccDNA Hepatitis B has been neglected, due to reservoir that lead to HBV persistence - the impressive evolution in HCV. But and defective CD8+ and B-cell responses Maria Buti now interest is returning, said Dr Johannes that lead to defective immune responses. Vermehren, Germany. He described ongoing research for a Worldwide approximately 257 million HBV cure, which Dr Vermehren explained people are infected with HBV. In 2015, is the new goal. – We need a HCV vaccine, he empha- HBV resulted in an estimated 887,000 – But is likely a long way down the road. sized. deaths. HCC has become the third Vaccination is still the best and most Can neutralizing antibodies (NAbs) leading cause of cancer deaths worldwide, effective therapeutic approach towards prevent chronic infection? Dr Snel- Dr Vermehren said. HBV eradication. A combination of dif- Prentø explained that NAbs co-exist – WHO elimination target for 2030 is ferent mode of actions is required to en- with the virus in chronic infection – but 90 % of infected should be diagnosed. able finite treatment duration – followed 20 - 35 % spontaneously clear acute HCV by functional cure. Whether treatment infection, and this is correlated with early induced or spontaneous HBsAg clearance, emergence of broadly reactive NAbs. there is always a risk of HBV reactiva- – So we need to define conserved epi- tion – with risk for HCC – in immuno- topes – and uncover how we target them compromised patients, Dr Vermehren in vaccine development, Dr Snel-Prentø summarized. said. He continued to describe a mouse model HVR1 protects HCV from neutrali- of the hypervariable region 1 (HVR1) of zing antibodies Hepatitis C virus that has provided new Next session was on Hepatitis C. Dr insights in HCV neutralization, interac- Jannick Snel-Prentø, Denmark, talked tions between virus and receptors, innate about lessons from antibody evasion stu- host responses and therapeutic app- Johannes Vermehren dies in HCV vaccine development. roaches.

HIV & VIROLOGY NEWS 4· 2019 41 HIV & Hepatitis Nordic Conference 2019

Jannick Snel-Prentø

His conclusions were that HVR1 protects HCV from NAbs both in vitro and in vivo. – HVR1 and glycans regulate broad NAb sensitivity by modulating global "open" or "closed" glycoprotein E1 and E2 states. Dr Snel-Prentø finished with some pers- pectives: – Removing glycans/HVR1 will not – Targets are the general population, necessarily improve NAb responses. We high prevalence groups and healthcare have to devise better E1/E2 antigens to professionals. We also need to simplify improve transmission of lessons-learned the HCV care pathway – in order to in- in full-virus studies. We also need to decrease screening and diagnosis, linkage fine NAb epitopes that are not only con- to care and increase treatment uptake. served – but available in "closed" states. Prof Dillon pointed out that today with In the discussion afterwards, he was one spot of blood, one can test for HCV. asked when we will see HCV vaccine – If the person is under 35, and has Phase I studies. no alcohol abuse, you can start treating John Dillon – We already have them – the problem right away! is that they don't work, was Dr Snel- Hence there is a need to increase the Prentø's answer. settings that can provide HCV screening interventions – drug and alcohol cli- – Egypt has treated one million people Elimination in a defined region is al- nics, primary care, prisons were some he this year. If they can do that, why can't ready possible mentioned. we? Prof John Dillon talked about the global – We also need to expand the HCV task Prof Dillon provided more examples of perspective of eradicating HCV. force within the health care system – to elimination programmes that are taking – We still have a long way to go to nurses, social workers, pharmacists, and place globally. achieve the WHO elimination targets, he peer support workers. – The first HCV micro-elimination started by stating. The Iceland elimination programme project in Asia was in the Arkhangai Initiatives are needed to identify and TRAP Hep C treated almost one half of province in Mongolia. In 18 months 100 diagnose in large pools of "hidden" pa- the diagnosed HCV population in the % of the population older than 40 years tients who need to be engaged and trea- first year – showing that elimination in a (21,599 persons) were screened. 98.5 % ted in order to eliminate HCV. defined region is feasible. of those infected (1,748 individuals) were treated with direct-acting antivirals ,and 99.7 % of them reached SVR12. He ended his talk by presenting a He- patitis C elimination programme in Tay- side, Scotland. They offered enhanced HCV testing and treatment service targeting PWIDU. – Our aim is to get 500 drug users cured. Prof Dillon finished his talk by under- lining the necessity of having a plan for elimination, also on the micro level. And with that, the third and final day of the HIV & Hepatitis Nordic Conference 2019 was over.

Per Lundblad

42 HIV & VIROLOGY NEWS 4· 2019 HIV & Hepatitis Nordic Conference 2019

Satellite symposiums at the HIV & Hepatitis Nordic Conference

A total of four satellite symposiums DRIVE-AHEAD is a study on doravirin potent in vitro activity against wild-type were held during the three days in in naive individuals that had no resis- HIV-1 and the most common NNRTI re- Stockholm. HIV & Virology News here tance at baseline. 1.9 % of participants sistance variants, he said. presents a brief report on what was on doravirin developed resistance to the Doravirine is taken once daily without said at these. drug week 48. any regard to food, and has been shown – The take-home message is that it is to have low potential for drug-drug in- The first one had the title "The role of possible to develop resistance even if it is teractions – including acid-reducing Non-nucleoside reverse transcriptase in- not there at baseline. agents. hibitors (NNRTIs) in modern ART," and Her conclusion was that barriers to There are three pivotal doravirine was sponsored by MSD. Prof Magnus resistance are more complex than we studies: DRIVE-FORWARD, a Phase Gisslén, Sweden, was the Chair and one think, and need to be proven in real-life. III, multicenter, double-blind, rando- of the lecturers. The other lecturer was mized trial (RCT) of doravirine versus Dr Emmi Andersson, Sweden. "Not all patients fit the same regimen" darunavir/raltegravir + 2 NRTIs in treat- Prof Gisslén returned to the podium to ment-naive adults with HIV-1. DRIVE- Barriers to resistance are complex talk about clinical trials on the new NNRTI. AHEAD is a Phase III RCT of doravirine/ After giving a short overview of the his- – Doravirine is a novel NNRTI with lamivudine/tenofovir disoproxil versus tory of NNRTIs, Prof Gisslén continued: – There are some problems with NN- RTIs, such as side effects in CNS (efavirenz) and hepatotoxicity and rash. They also have a low genetic barrier and resistance – and there are some drug interactions. Data on pattern of ART in Sweden 2010 - 2019 show a decline for NNRTI-based regimens, he said. Dr Andersson then described the mechanisms of NNRTI resistance, and continued with HIV-1 resistance testing. – NNRTI barriers to resistance de- pends on how many mutations are needed before failure – but also on how efficient the drug is. A fast drop in viral load is protective against resistance, she underlined. Emmi Andersson and Magnus Gisslén

HIV & VIROLOGY NEWS 4· 2019 43 HIV & Hepatitis Nordic Conference 2019

Anders Sönnerborg, Magnus Gottfredsson, Pia Kivelä and Ole Kirk

efavirenz/emtricitabine/tenofovir diso- The success of ART had caused some posium sponsored by GSK/ViiV. proxil in treatment-naive adults with not to consider it so much anymore, Prof Chair Prof Magnus Gisslén, Sweden, HIV-1. Finally, DRIVE-SHIFT is a multi- Gottfredsson said. talked about different 2-drug regimens, center, randomized, non-inferiority trial – The computer journal should have a and mentioned dolutegravir + lamivudi- to evaluate a switch from a stable ART red flag for certain patients that come up ne and dolutegravir + rilpivirine. regimen to doravirine/lamivudine/teno- automatically, Dr Kivelä suggested. – Also, there are other previous expe- fovir in virologically suppressed adults riences. The ANDES study on darunavir/ with HIV-1. More point-of-care testing is needed ritonavir + lamivudine showed that this – In DRIVE-FORWARD non-inferio- The status of presenting late and the combination seems to work. Another rity was met, and rates of adverse events estimated number of undiagnosed HIV study – NEAT-001 – on darunavir/ri- were similar to darunavir/ritonavir. In positive individuals in 4 of the 5 Nordic tonavir + raltegravir for treatment naive DRIVE-AHEAD non-inferiority was countries was presented by Prof Sönner- patients met non-inferiority to daruna- also met, and doravirine hade signifi- borg. In Iceland it is 36 %, in Finland 46 vir/ritonavir + tenofovir disoproxil/ em- cantly less drug-related adverse events %, in Sweden approximately 60 % (10 % tricitabine. compared to efavirenz. DRIVE-SHIFT undiagnosed) and in Denmark it is 39 % He continued by pointing out that if was a little more complex in design, but (also 10 % undiagnosed). one looks in the subgroups, darunavir/ in a snapshot from week 24 non-inferio- – I want to underline that the percen- ritonavir + raltegravir was inferior in rity was met, Prof Gisslén said. tage is very different in different groups, patients with high viral load and deve- He showed that doravirine now have Prof Sönnerborg added. loped resistance during virological failure. entered in some international HIV treat- Reasons for this was discussed in the Darunavir/ritonavir + maraviroc for tre- ment guidelines. panel. Prof Sönnerborg said that the im- atment naive patients was also found to – I think it is good that new drugs for pact of the disease is still limited on the be inferior. HIV still are being developed. Not all pa- population level. Prof Gottfredsson sta- – We know that not every 2 drug regi- tients fit the same regimen, Prof Gisslén ted that stigma is at the top of the list. men will work, Prof Gisslén said. commented at the end of the symposium. – And sometimes there are individuals – Future two-drug options are long-ac- especially migrants – who are not aware ting drugs including injectables – Health care staff need more training of their rights, Prof Gottfredsson added. something he stated he thinks we will Presenting late with HIV in the Nordics: – In our earlier studies we found see a lot of in the years to come. What can we do better to reduce disease doctor's delay. Patients who had symptoms and transmission burden? This was the of HIV was not tested, Prof Sönnerborg Dolutegravir/lamivudine showed title of a satellite symposium sponsored continued. durable non-inferior efficacy by Gilead. Prof Ole Kirk, Denmark, was Dr Kivelä said that we need more point- Professor Chloe Orkin, UK, talked about the Chair and Prof Anders Sönnerborg, of-care testing – in prisons, for example. why, how and when there should be treat- Sweden, Dr Pia Kivelä, Finland and Prof Prof Gottfredsson said he thinks the ment with fewer drugs. Magnus Gottfredsson, Iceland, was in emergency rooms would be good. – It is important which the 2 drugs are! the panel. – Drug users do not seek care until it We are not talking about 2 drugs versus 3 – There has been a slight decrease of is absolutely necessary. I believe rapid drugs in general. But now there are two late presenters in Europe over time. Data point-of-care testing is good in certain 2 drug regimen licensed, she underlined. are from the pre-PrEP era, so we don't settings, he explained. GEMINI-1 and -2 were identically de- know the impact of PrEP, said Prof Kirk. The symposium ended with a discus- signed RCT multicentre non-inferiority Migrants from Sub-Saharan Africa and sion on the management of late presenters. studies on dolutegravir + lamivudine versus other regions are all at high risk for late – Late presenters have a higher risk for dolutegravir + tenofovir disoproxil/ em- presentation. 27 % of late presenters had TB – so therefore we also have to test tricitabine. Snapshot week 96 showed sought health care in the preceeding 3 for that, Dr Kivelä pointed out at the that non-inferiority was met. years with AIDS- and/or HIV-associated end. – Adverse events were similar in both conditions without having a HIV-test, he arms. Renal and bone biomarkers were pointed out. Not every 2-drug regimen will work better without tenofovir disoproxil, but This caused some discussion in the panel. Why use 3 when 2 could be enough? This the lipid levels were similar. The magni- – Health care staff need more training. question was the title of a satellite sym- tude of speed of viral load decline were

46 HIV & VIROLOGY NEWS 4· 2019 HIV & Hepatitis Nordic Conference 2019

Per-Erik Klasa, Tove Lindholm and Martin Kåberg

similar, irrespective of viral load. There Treating outside the infectious clinic known to be compliant, they were sent to was no resistance in any of the two arms. The fourth and final satellite symposium the Infectious clinic close by. If not, they Her take-home messages on dolutegra- was on Hepatitis C. It was sponsored by would get their treatment at LARO. vir/lamivudine was that it should be first Gilead, and had the title HCV treatment – We can cure a HCV patient in 12 line choice of 2-drug regimens. at opioid substitution therapy clinics. weeks, Nurse Lindholm underlined. – It showed durable, non-inferior ef- Chair Dr Martin Kåberg, Sweden, began If a patient is cirrhotic, they will not ficacy versus dolutegravir + tenofovir by saying that we have stopped talking treat them. These are treated at the In- disoproxil/ emtricitabine – with no re- about if we can treat HCV – now we fection clinic. sistance at week 96. When performing a instead talk about how to get HCV pa- Today they have screened around 30 switch, dolutegravir/lamivudine shows tients in treatment. patients, and 35 - 40 % were HCV positive. non-inferior efficacy versus tenofovir – Opioid substitution treatment (OST) 8 patients are presently in treatment at alafenamide-based regimen with zero – that reduces craving and drug seeking LARO. resistance week 48, Dr Orkin ended her behaviour and reduces spread of HIV – Many things have been positive: We lecture. and hepatitis – is still not available in all have a close collaboration, provide a Professor Gisslén then presented the countries, even though it is shown to be fast track to care and have coordinated status for 2-drug regimens in the Nordic cost effective, Dr Kåberg said. appointments between the units. It is a countries guidelines. A study he presented showed that challenging and rewarding work – with a – In Norwegian guidelines dolute- among people receiving OST, treatment holistic view of the patients, who in their gravir + lamivudine can be considered completion was 97.4 % and intention to turn have given us a positive response. when other regimens are contraindi- treat SVR was 90.7 %. cated. In Denmark, the guidelines do not Nurse Tove Lindholm, Sweden, talked A designated nurse is important recommend any 2 drug regimen, except about treating Hepatitis C at LARO out- Dr Per-Erik Klaus, Sweden, is a senior in switch strategies in selected cases patient clinic – in a collaboration with consultant in psychiatry at Prima Maria of virologically suppressed PLWH. In the Infection clinic. LARO stands for addiction centre in Stockholm. Sweden, the guidelines have dolutegravir Drug Assisted Rehabilitation for Opioid – At our OST clinic we have overall 450 + generic tenofovir disoproxil/ emtrici- dependency. patients. The HCV viremia prevalence is tabine as recommended initial regimen. – We started our collaboration with the 55 %, he said. 2-drug regimens are not recommended Infection clinic by planning for our clinic All in all they have now started treat- as initial treatment. In switch strate- – had meetings and then went on with a ment in 66 patients. 60 of them have gies in virologically suppressed PLWH, pilot project, she explained. finished it, and 6 are lost to follow-up. they are however an alternative, he ex- Step 1 was screening that started in – 47 has reached SVR 12, and 2 have plained. April 2019. If a positive patient was had reinfections and the remaining 13 are waiting for SVR 12. The first key factor for success is a willingness to treat HCV at the OST clinic. Also there has to be a dedicated psychiatrist and initial hands-on tuto- ring from an infectious disease specialist, Dr Klasa stated. – It is also very important that you have a designated nurse – that has time! However, one thing that they can not do is resistance testing. Dr Kåberg therefore ended the symposium by saying that better guidelines on when to do resistance testing are needed.

Magnus Gisslén and Chloe Orkin Per Lundblad

HIV & VIROLOGY NEWS 4· 2019 47