In this session, 4 different speakers discussed the chronic inflammatory state that persists despite effective viral suppression with current ART regimens.

The first speaker (G Marchetti, Milan) highlighted that there is a persistent depletion of CD 4 cells in the gut despite normalisation in the peripheral blood.  There is also persistent damage to the gut tight epithelial barrier despite ART.  The altered gut tight epithelial barrier maybe a driver of inflammation.  This speaker also highlighted the fact that no matter which ART regimen is employed there is a similar reduction of T cell activation with effective viral suppression. 

The second speaker (P. Hunt, San Francisco) focussed on immune activation as a predictor of morbidity/mortality during ART.  As we know,age associated morbidities are increased in treated HIV infection.  Inflammatory markers are higher in treated HIV disease compared with HIV sero-negatives when adjusted for demographics and CV risk factors.  Chronic immune activation may also cause lymphoid tissue fibrosis.  He showed a graph which demonstrated that a single measurement of IL 6 or D-dimmer predicts morbidity or mortality over the next decade.  This indicates that some people are more susceptible to the inflammatory state of HIV than others.  However, bio markers that predict disease most strongly are not necessarily the best interventional targets.

The third speaker (N. Sander, Texas) looked at the role of interferon 1 in chronic treated HIV.  A lot of the data was based on nonhuman models.  Overal, type 1 interferons can improve protection against infection but because of immune system activation may not be suitable long term as adjuvant therapy.  This raised the question of whether there maybe a benefit of selective activation or blockade of the different pathways induced by IFN-1.

Finally, I. Pandreas (Pittsburgh) discussed approaches to reduce microbial translocation as a means of reducing immune activation.  These were with sevelamer and rifaximin.  However, in the presence of profound gut damage, these approaches are unlikely to have significant benefit.  She then examined other interfering factors on gut function such alcohol and fatty diets.  These results were based on nonhuman models.  Probiotics were shown to have benefit for gastrointestinal immunity in SIV-infected macaques.  This highlighted that lifestyle factors should be taken into consideration when designing clinical trials as they may all impact on immune system activation.  This also highlighted that therapies which target the underlying cause of immune activation and inflammation may be more effective than those aiming at reducing various bio markers increased during HIV infection.

All of these presentations highlight how complex and confusing the immune activation and inflammation process is in HIV infection!

HIV in vulnerable populations and within a public health framework. 

Monday’s Plenary included a session on co-morbidities in children and adolescents by Thanyawee Puthanakit. 

She detailed some important paediatric aspects to HIV care. Eventually these children 'graduate' to adult services thus appreciating the unique commodities in this population is important to all providers of HIV care. 

In addition to the co-morbidities seen in an adult population, children living with HIV are more likely to have delayed puberty/growth, have persistent proteinuria and tubular dysfunction, have impaired peak bone mass and low bone mineral density and suffer dyslipidaemia. 

Not surprisingly, there is a significant reduction in the risk of developing co-morbidites when commenced on HAART. This echoes the findings of START which, while it did not focus on a paediatric population, demonstrated a clear benefit to early commencement of HAART.

Of note, dyslipidaemia occurred in  approximately 22% of children and adolescents with a lack of clinical trial data that demonstrated benefits from statin use. In any case, the threshold at which to treat an adolescent remains undefined. The rates of cardiomyopathy, nephropathy, cognitive impairment and chronic lung disease are all reduced in paediatric populations that are on HAART.

Paediatric guidelines for ART are evolving somewhat like adult guidelines. The DHHS recommends integrase-based regimens with Raltegravir approved for age >2 and Dolutegravir age>12. There is no evidence yet for the use of TAF in a paediatric population. 

The barriers to optimising outcomes within the paediatric population are more evident in resource limited settings, where children and adolescents are more likely to be under-screened for HIV co-morbidities.  

The speaker alluded to 2 trials of interest 

1. ODYSSEY. Dolutergravir+2NRTIs vs standard of Care. This is an RCT of DTG based ART vs SOC in Children with HIV starting first line treatment or switching to second-line
2. IMPAACT P1093: investigating Dolutegravir use in children aged 6-12

I've just attended the presentation of the findings from the START trial (the Strategic Timing of Antiretroviral Treatment), presented by the principal investigator Dr Jens Lundgren from Denmark.

The message conveyed was that the evidence is now clear that commencing treatment at diagnosis of HIV confers definite advantages to the individual regardless of their CD4 count.

The study randomized 4685 people to go onto immediate ART or to delay treatment until CD4 was below 350.

The primary endpoint was serious AIDS and non-AIDS events or death.

It was a multi-centre trial, with 35% of participants from Europe, 25% from Latin America, 21% from Africa, 11% from North America, 8% from Asia and 2% from Australia.  Of the participants 27% were female, 30% were black, 55% acquired HIV through MSM, 38% heterosexual transmission, and 32% were smokers.  The median time since diagnosis was 1 year, the median CD4 was 650 and median viral load 12,000.

The trial was terminated early due to a clear advantage in the early treatment arm.

It was interesting to see that there was no difference in reported treatment-related adverse events in the two groups; in other words it did not appear that starting treatment earlier resulted in extra adverse events for those patients.

There was a sub analysis of the outcomes at different CD4 counts, and it showed that there was still an advantage to starting treatment early even if CD4 counts were above 800.  I would have liked to see more discussion about this, as the key question for many of our patients is about starting therapy with high CD4 counts, and the slides presenting this data were rather difficult to interpret for a non-statistician like me.

The room was abuzz with excitement when panel member Gottfried Hirnschall from WHO announced that the new guidelines being released by WHO in September will be recommending treatment for all people with HIV at all ages regardless of CD4 count.

The ensuing panel discussion was less of a discussion and more of a series of statements, mostly focusing on what the implications are for the future, and what the impediments are to global implementation of early treatment. 

Today's satellite presentation on "Injectable Options and Preventable Confusion: An update and interactive Discussion on the Pipeline on Antibodies, Long Acting ARVs and Vaccines" was certainly interactive but possibly missed the mark a little, on preventing confusion. Much heated discussion after the presentations centered around the bioethics and science of designing efficacy and effectiveness trials.

Greetings  from Vancouver where the weather ( I am sorry to make you jealous) is absolutely gorgeous.

An interesting  satellite session on Rectal Microbicides, presented today by the Microbial Trials Network (MTN). Despite the proven effectiveness of PrEP there is still enthusiasm from sectors of the community for continued development of this alternative prevention tool. Not all MSM will be able to or want to take daily Tenofovir/FTC. Anal sex is also widely practiced by heterosexual couples particularly in Africa so there is much potential for use by these couples for the same reasons  vaginal microbicides are important.

The first ever Phase II trial to assess safety and acceptability of a rectal microbicide, MTN017 has just  been completed and was discussed by protocol chair Dr  Ross Cranston of University of Pittsburgh. Subjects were MSM and transgender females in multiple global locations

There were three treatment arms –

1.daily oral TDF/FTC

2.daily rectal reduced glycerin (RG)  tenofovir 1% gel (Phase 1 studies of ordinary tenofovir 1% gel found that when applied rectally it was associated with siginificant bloating, abdominal pain and diarrhoea. A reduced glycerin preparation was made which caused less osmosis in the rectum)

 or

3. RG TFV 1% gel used only before and after sex.

 Alll participants trialled all three methods and reported back on likelihood of ongoing use and ease of use. Data will likely be published in Feb 2016.

Several interesting ethical questions about the conduct of rectal microbicide trials  were raised by  Dr Ndebele of Medical Research Council of Zimbabwe. Most importantly, now that PrEP has proven to be so effective, should it also be provided as part of the comprehensive prevention package to trial participants, along with condoms and counselling regarding safe sex ?

I tend to think it should, as did most of the rest  of the audience, given UNAIDS Guidelines on ethical standards for HIV Prevention trials state “ participants should be offered state of the art risk reduction methods as they become available.”

This obviously raises many issues such as

- impact of cost

- the ethics of providing PrEP to participants in countries where there is little chance it will be available anytime soon and then withdrawing their access at the end of study and

- if uptake of PrEP were high amongst participants it would seem unlikely that you would be able to assess the efficacy of the microbicide.So what’s the point !

Dr Ian Mc Gowan another lead investigator discussed likely future directions for the MTN. This includes attempting to find a gel which could be used as a lube rather than inserted with the unpopular applicator currently used. The possibly of developing an alternative drug dapavirine which is more potent than tenofovir was also discussed.

The session wrapped up with a panel discussion between community representatives from the trial sites in the US, Canada and South Africa.

 They discussed

- how important  the development of rectal microbicides was for them as an alternative method for HIV prevention

- the importance of getting the product right so that it was an acceptable alternative

-the need for researchers to engage and invest in the community so that community members can participate meaningfully in trials  and

-the need for a gel that could be used both vaginally and rectally, being  useful for women for both types of sex and also to avoid the stigma for MSM in many countries when buying a product that idenitfied them as being engaged in anal sex.

It will be interesting to see how the MTN  goes. There are significant challenges and probably some sectors who will be sceptical of the need for rectal microbicides. However the more choices people have the better I think !

Slides for some of these presentations available on the IAS2015 website by clicking on the session on the Programme at a Glance.

Those interested in the concept of post-treatment controllers and treatment remission, please head to Saez-Cirion's (of Visconti fame) presentation tomorrow (Monday 20 Juyl) at the 11am - persistently seeking virus. I will write a detailed post after the session as this abstract is currently under embargo.

 Greetings from Day 1 of IAS 2015,

Treatment as prevention (TasP) and the UN proposed ambitious 5-year treatment target of 90% of HIV+ve individuals being diagnosed, 90% of those diagnosed on efficacious treatments and 90% of those treated virally suppressed equating to 73% of all HIV+ve individual’s being virally supressed was the topic of discussion at the pre-conference workshop UN 90-90-90 Target Workshop: Lessons from the field.

There were four sessions spanning the day. After an opening speech by Michel Sidibé, Session One starting with RCT evidence to support immediate versus standard of care (SOC) ARV population-based roll out interventions and it’s utility to achieve the 90:90:90 target (SEARCH, HTPN071 (POPART), ANRS12249 and the Botswana Combination Prevention Protocol(BCPP). There was also some evidence reported for the utility of financial based incentives (FIs) to encourage linkage to care (HPTN065) and some discussion of acceptability of immediate ARV in sero-discordant couples (HPTN052) though 1-year follow-up results of HPTN052 will be presented Monday 2:30pm. The take home messages of session one included:

• Largely testing rates, linkage to care and viral suppression levels achieved in SEARCH, POPART, ANRS12249, and BCPP were all high, around the 80% mark, however the big question of the impact of early ARV on HIV incidence in all of these trials is yet to be determined. Results so far look promising.
• There still remain some pockets of the HIV+ve population which seem consistently hard to reach, primarily migratory young men in Africa. However while there were some gender disparities in linkage to care, once in care outcomes seemed similar for both genders. More social behavioural data from SEARCH, POPART and ANRS12249 to come.
• There was evidence to support that immediate ARV does not have detrimental impacts on adherence to treatment i.e. HIV+ve people who feel healthy still seem to be good at take their drugs
• The multi-disease approach undertaken by SEARCH, grouping testing for HIV with hypertension and diabetes was an encouraging approach
• Financial based incentives did not show significant improvements in linking known HIV+ve individuals into care in the US, however they did show some efficacy in specific sub-groups, suggesting possibly that FI should be a target rather than a broad roll out. Some discussion over the ethics of FIs and the difficulty in implemented these strategies was highlighted in the discussion

Session Two largely covered evidence from cohorts. Evidence in achieving the 90-90-90 targets was presented for HIV cohorts in rural Malawi, Swaziland, KwaZulu-Natal and Rwanda, and evidence from the new cohort AFRICOS was presented. Lessons from this session included:

• Results from rural Malawi where MSF task shifted ARV roll out from doctors to nurses which was later subsumed into the national program look very promising, 77% diagnosed, 84% on treatment and 91% of those virally suppressed. Again young men are those not linking to care.
• The Early Access to ART for All (EAA) Study in Swaziland provided evidence for scalability feasibility and acceptability of the 90-90-90 target approach. Results supported initiating ARV on the same day as testing to avoid LTFU. While this may be difficult to implement if GART for first line is part of the recommended national guidelines in most of the developing world it is not.  Further lessons from KwaZulu-Natal presented by Frank Tanser showed barriers to care were distance from treatment centres (even in non-centralised settings) and gender.
• The cascade of care in Rwanda looks close to the 90-90-90 target, with the epidemic now moving into older aged groups.

Session Three covered field implementation initiatives in China, Brazil, Thailand, and San Francisco. The ability for faith based organisations to engage people into care was also presented as well as some interesting results from a phylogenetic monitoring system that has been set up in British Colombia. Take home message from this post lunch, slightly jet-lagged session were:

• In many settings described in this session, patients still had a median CD4 at diagnosis of less than 350 so it’s not really a question of immediate or deferred ARV rather engaging people in testing and linking to care. HIV peer intervention testing and self-testing has found to have encouraging results in Brazil. While a mixed facility and community-based testing model has improved diagnosis and linkage rates in Thai MSM and Transgender populations.

• San Francisco has surpassed the 90-90-90 target and is now aiming for zero new infections. The RAPID program which enlisted individuals in immediate same-day ARV initiation looked promising. The difficulties in reaching that last 10% of the HIV+ve population in non-generalised epidemics was highlighted. How to reach specifically transgender populations was also discussed in question time, online outreach methods and linking ARV services with hormone therapy services were some of the suggestions.

• Finally a population-wide HIV resistance database in British Colombia has been used for phylogenetic monitoring of outbreaks in real time. Fascinating results but a real potential for huge legal ramifications (two Supreme Court appearances later, Art Poon and colleagues in British Colombia have managed to resist forced disclosure of individuals). What a shame we live in a world where criminalization of sex in HIV+ve individuals is still common place!

And finally the workshop ending with presentations from donors, PEPFAR and the Global fund, and agencies, CDC who highlighting the cascade in the US, and the WHO and IAPAC who discussed soon to be released guidelines. The main highlight of this session was the (unofficial) report by Gottfried Hirnschall that the new WHO ‘When to Start’ guidelines including PrEP recommendations will likely be released in September of this year. These will (unofficially) include ART initiation for all regardless of CD4 count, PrEP for individuals with substantial risk (to be defined…), Option B+ as the recommended SOC and some suggestions for dose reduction strategies.

So finally, my overall conclusions of the workshop are the 90-90-90 UN target seems a difficult target but potentially achievable in some settings. Primarily generalised epidemics where the health system can support such targets with UNAIDs strengthening the provision of ART and donors getting on board, or non-generalised epidemics where innovation methods are employ and large amounts of resources can be mobilised in support of such efforts.  It will, however, be a specific challenge in other setting where either there isn’t a national health system to support such a roll out or there isn’t the resources to achieve these target where the epidemic remains localised in particularly hard-to-reach populations. As suggested by one of the attendees, perhaps there should be a fourth 90, 90% of countries achieving the 90-90-90 UN target by the year 2020?

For details of the workshop see http://www.treatmentaspreventionworkshop.org, for a live stream of the workshop see http://flash-vs.cfenet.ubc.ca/cfestream1.html

Greetings from Vancouver IAS 2015! Reporting back after Day 1 of the 2-day IAS Cure symposium. 

Our key speakers today included:

• Dan Kuritzkes who gave a nice overview of the progress and challenges in HIV cure research
• John Mascola on neutralising antibodies including bispecific (combination) antibodies and the "ideal" antibody - cheaper, longer half life, subcutaneous delivery, more potent, greater breadth. There are two good sessions on neutralising antibodies MOBS03 on 20 July 11am and WESY06 on 22 July for those interested in this topic. Both should be terrific sessions.
• Marcus Altfeld spoke about immune recognition following latency reversal, and drew on his expertise on NK cells. They have a new nef inhibitor.
• Matthew Sharp - reminded us to keep the community engaged and also highlighted a great resource CUREiculum http://www.avac.org/cureiculum. Take a look.

We had two "roundtables" today: one on paediatric HIV cure research and the other on combination therapy. There was robust discussion about the need to advance cure research in paediatric children in parallel with adults, but at the same time being sensitive to the issues of risk and acceptability. Some of the most interesting work in HIV cure research is being done in hyper-acute/ very-very early commencement of ART in paediatrics with the aim to reduce the establishment of the latent HIV viral reservoir, +/- in combination with neutralising antibodies +/- structured treatment interruption. Did you know there is an infant monkey model? Well, there is!

Some new ideas presented today included Ingenol a Protein kinase C inhibitor (Planelles), and CD4 mimetics (Finzi), AGS004 a fully autologous DC-based immunotherapy electrophorated with autologous HIV RNA and genetic differences in the reservoir (Karn). 

David Evans from Project Inform reminded us on the need to manage the excitement about progress in cure research.

The oral abstracts are under embargo so I cannot detail those here. For those interested in HIV cure research, please follow the road mapHIV Pathogenesis (Molecular Biology - Virology - Reservoirs) found on the IAS website. 

Till next time.