Hi from Seattle. 

Very interesting plenary this morning at 8.30 presented by Jintanat Ananworanich. She spoke about the potential and possible processes for cure. It was a very good overview. She specifically discussed what can be learned from the way the immune systems of infants and children respond to HIV and how that can inform us in regard to potential for cure. Well worth watching the webcast on the CROI site when it becomes available in a few hours.

 more to come 

Greetings from Seattle. I would like to start by thanking ASHM for giving me the opportunity to attend this world-class conference and also thank the readers for taking time to read my blog.

Gilead dominated the morning session that I attended, presenting 2 novel drugs in different stages of development. I will talk about the more conventional of the novel drugs, which is now undergoing phase 3 clinical trials (4 active trials).

Bictegravir (BIC) is a novel, once daily INSTI. In-vitro studies have demonstrated it’s high level of activity against wild-type and many INSTI-resistant viruses. The drug has good oral absorption and an excellent PK profile, with a trough level well above IC95. The drug is mainly metabolised through CYP3A4 and UGT1A1 and has a favourable DDI profile. Similar to dolutegravir (DTG), there can be increased metformin levels (39%) and potentially clinically relevant interactions in the presence of potent inducers such a rifampicin. The 50mg once daily BIC dose was selected in coformulation with FTC/TAF as a single tablet regimen to progress in further studies.

Paul Sax then presented the 48 week data from a relatively small randomised double-blind active control study. 98 participants were included (from 125 screened) BIC = 65, DTG = 33. Patients with chronic hepatitis (B and C) were excluded. Overall rates of viral suppression were excellent in both groups at 24 and 48 weeks. In the BIC group, viral suppression (Defined as VL < 50 copies/ml) was 97% at 24 and 48 weeks. There were 2 discontinuations in both arms (1 lost to follow-up in each arm, 1 non-compliance in DTG, 1 AE in BIC). In terms of adverse events, diarrhoea was the most common side-effect reported in 12% of subjects in the BIC arm. Overall, AE profiles and lab abnoralities were reassuring. A minor decline in eGFR of -7.0 ml/min was observed BIC. No treatment-emergent mutations (INSTI or NRTI) were noted through week 48 in either group.

In summary, bictegravir is an exciting novel INSTI which has moved on to phase 3 clinical trials. Should it progress and eventually receive approval, it will be coformulated with FTC/TAF in a single tablet regimen, joining what is becoming a rather crowded market.

Oral session 38: Discovery of a novel potent HIV Capsid inhibitor

GS-CA1 is a first-in-class small molecule Capsid (p24) inhibitor. GS-CA1 was demonstrated to be more potent than EFV, DTG and ATV with no measurable toxicity in target and non-target primary cells. It was also highly active against major HIV mutations, with high breadth and potency of action. The inhibitor acts at multiple steps in the HIV replication cycle, impairing Capsid core assemble, core disassembly and nuclear transcription. The binding site to the Capsid is highly preserved, and while resistance has been demonstrated, the HIV mutations have reduced fitness compared to wild-type HIV.

A single subcutaneous dose in rats have shown maintained plasma concentrations out to 10 weeks. The compound shows promise as a long-acting, low-dose monthly injection in humans.

Oral session 39: Confirmation of oral dose reduction potential of nanoparticles

Solid drug nanoparticles (SDN) have shown promise as a method to reduce drug dosage while maintaining therapeutic exposure. SDN Lopinavir and SDN Efavirenz were studied using population pharmacokinetic modelling strategies. Both formulations proved well tolerated at the studied doses. With the potential of a 50% dose reduction, there is an estimated saving of USD$243 million per year

Oral session 40: Pharmacology of the HIV integrase strand inhibitor Bictegravir and Oral session 41: Randomised trial of Bictegravir or Dolutegravir with FTC-TAF

Bictegravir (BIC) is a novel integrase strand transfer inhibitor (INSTI) that is currently in Phase 3 trials. The medication has been demonstrated to have low toxicity, no effect on the QT interval and no impact on glomerular filtration. It is well absorbed (>70%) and is highly plasma protein bound (>99%). It primarily circulates as the parent drug, with clearance through oxidation (CYP3A4) and glucuronidation (UGT1A1). There is low potential for drug-drug interactions, but as with all INSTIs, they are chelated by cation-containing antacids. Therefore administration should be staggered by at least 2 hours with antacids. BIC itself does not inhibit or induce CYP3A4 or UGT1A1. Phase 2 trials developed as a single tablet regimen with FTC/TAF demonstrated that there was improved bioavailablity and a reduced food effect for the 75mg dose of BIC chosen. Therefore the dose of BIC was reduced to 50mg for Phase 3 trials, with a formulation of BIC/FTC/TAF of 50/200/25mg.

A double blind randomised control trial of BIC vs DTG with FTC/TAF demonstrated the study drug being 97% successful at achieving virologic suppression after 24 weeks and 48 weeks. There was no statistically significant difference in the outcome between the study and control drug formulations. No resistance to study medication was detected in either arm of the study. There was a rapid and robust CD4 response in both arms. Adverse events, grade 2 to 4 laboratory abnormalities and mild changes to eGFR were similar in both groups.  The trial demonstrated BIC/FTC/TAF is safe and well tolerated

Oral session 43: Prevalence and impact of pretreatment drug resistance in the ANRS 12249 TASP trial

Early initiation of ART and improved access to HIV care will lead to long-term decreased morbidity and mortality. However, there is a concern regarding an increase of pretreatment drug resistance (PDR) could lead to a delayed time to viral suppression and an increased risk of virological failure after ART initiation. New advanced technologies - Next Generation Sequencing (NGS) - have become available for low-level variant detection (at around 1% viral population), however their impact on ART outcome is still controversial.

There has been limited study of PDR in low to middle income populations or resource limited settings. The ANRS 12249 TASP trial was established to evaluate the effect of early ART, initiated irrespective of CD4 count, on HIV incidence in the general population in the same setting. The study is being conducted in the KwaZulu-Natal province of South Africa. ANRS 12249 TASP included an analysis of PDR in chronically infected and and recently infected participants. The definition of PDR used was >20% of viral population, with separate analysis using NGS of resistant virus at 2% levels. 

The prevalence of PDR detected was about 9% in both recently and chronically infected participants, with two times more low-level variants detected with NGS. NNRTI use is mostly compromised by PDR but NRTIs are still active. About 10% of PDR have multiple drug resistance (3 or more up to 7), suggesting previous exposure to ART. Interestingly, PDR did not significantly impact the cumulative probability of achieving virologic suppression at the 12 months mark, with around 95% of subjects virally suppressed at 12 months, regardless if PDR was present or not. The two consistent predictors of poor viral suppression remain high baseline viral load and poor adherence. 

Oral session 44LB: Phase III SWORD 1 & 2 SWITCH to DTG+RPV maintains virologic suppression through 48 weeks

With the high resistance barrier of DTG, SWORD 1 & 2 evaluated whether the 2-drug regimen of DTG+RPV once daily was as effective as traditional cART. The primary endpoint at 48 weeks was a snapshot of subjects with a viral load <50 copies/mL. 

The 2-drug combination demonstrated non-inferiority to cART with comparable viral suppression rates, similar rates of adverse events, a neutral effect of lipids and a statistically significant improvement in bone turnover biomarkers. There were two confirmed virologic failures in both study groups, however no integrase resistance was found.

The study supports DTG+RPV being filed as a treatment regimen and leads the way for exploration of other 2-drug regimens in the future.

Oral session 45LB: Doravirine is non-inferior to Darunavir/r in Phase 3 treatment-naive trial at week 48

Doravirine (DOR) is a novel next generation NNRTI with a unique resistance profile, low potential for drug-drug interactions and can be taken once daily without regard to food. A Phase 3, multi-centre, double-blind randomised control trial was conducted in treatment naive HIV-1 infected adults. DOR was compared to DRV/r in combination with TDF/FTC or ABC/3TC. The demographics of study participants were almost identical in both arms of the study.

There was no genotypic or phenotypic drug resistance observed in participants with protocol defined virological failure through week 48. One participant discontinued due to noncompliance at week 24 and developed DOR resistance. Approximately 80% of subjects experienced one or more adverse event, with about 30% having drug-related adverse events. Study discontinuation was 2-3% due to adverse events. Similar proportions experienced adverse events of clinical interest -  rash (7-8%) and neuropsychiatric (11-13%). DOR had a neutral effect on lipids compared to DRV/r

DOR demonstrated potency with non-inferior efficacy with a low rate of resistance (1/383 subjects). DOR is generally well tolerated and safe. 

Dr Jintanat Ananworanich presented the first plenary session on the emerging potential for an HIV cure. She disussed how information gained from adult and infant studies showed that early treatment, rapid viral suppression and sustained seronegativity results in less reservoir seeding and an extended time to viral rebound following cessation of ART. This has important implications for targeting persistent virus, particularly replication competent virus.

Early attempts at a "shock and kill" strategy have been unsuccessful at significantly  decreasing the amount of reservoir virus or killing affected cells. Fture strategies are likely to employ the use of multiple Latency Reversing Agents (LRA), the use of new classes of LRA and combination use with immune therapies. Trials in animal models using a TLR7 agonist with Ad26MVA vaccine demonstrated promise in animal models, with a reduced viral load in monkeys infected with SHIV following ART discontinuation.

Preliminary trials of VRC01, a broadly neutralising antibody (bNAb) has also shown to be ineffective. However, the more potent VRC07-523LS bNAb, combinations of bNAbs or combination with vaccines are more effective approaches being tried. A combination of VRC07+PGT121 (a vaccine) given to infant macaques 1-2 days after SHIV infection led to a complete clearance of the virus.

The final messages Dr Ananworanich presented were that new methodologies need to be considered in order to facilitate research, notably

• Consider parallel animal and human studies for combination therapies;
• Testing combinations with the same animal model;
• Streamlining the regulatory pathways for the use of agents for different indications; and
• Conducting psychosocial research concurrently with scientific studies

Day 1 CROI 2017:

An overview of CROI this year for those may not have attended previously:

Today we were reminded that The Conference on Retroviruses and Opportunistic Infections (CROI) commenced in 1993 to provide a forum for basic scientists and clinical investigators to present their latest data, and to interact. The Conference has grown in size over the past 24 years and is currently capped at about 4,000 attendees. This year the 4,200 participants are from 90 countries, and 40% of abstracts were from outside the USA. One in five attendees are new to CROI, so if you have not attended before, try to get there next year (Boston 4-7 March 2018).  The opening sessions traditionally consist of: the Bernard Fields Lecture, named in tribute to the exemplary work of esteemed microbiologist and virologist Bernard Fields, and the N’Galy-Mann Lecture, named in honour of Drs Bosenge N’Galy and Jonathan Mann for their crucial pioneering work in HIV science in Africa. It is always a sad time to reflect on the untimely deaths of these two great men working in HIV/AIDS in the very early days of the epidemic. I will always remember Dr Mann’s extraordinary speeches in those early days – he was a great orator. 

This year the Bernard Fields Lecture was delivered by Jeffrey D. Lifson, from the Frederick National Laboratory for Cancer Research and focussed on the work done in HIV prevention and pathogenesis using nonhuman primate(NHP) models. Dr Lifson made the case that, with limitations, nonhuman primate models eg in macaque and sootey mangabey monkeys with SIV models, ‘have been able to recapitulate all the key aspects of human HIV infection in research systems that could provide important experimental advantages’ but that the viruses used in in NHP were not HIV.  He also discussed the issue of gut pathogenesis in HIV/SIV infection with the sequence of events:

·       Loss of CD4+ t-cells

·       Epithelial disruption

·       Microbial translocation (microbiome shifts)

·       Local and systemic immune activation/inflammation

·       Responses to inflammation T_reg, TGF-B, LT fibrosis,

·       Not fully restored/reversed by cART.

A number of presentations at the conference will be on the changes in human gut microbiome with acute HIV infection, ARV therapy and elite controllers.

The N’Galy-Mann Lecture was delivered by James G. Hakim, University of Zimbabwe on the HIV/AIDS research in Zimbabwe which has included collaborative research with the ACTG in USA and the Kirby Institute in Australia.  The opening session concluded with a special CROI Foundation award to Oliver Mtukudzi, a wonderful musician and human rights activist from Zimbabwe.

Dr Susan Buchbinder opened CROI 2017 with a powerful statement rejecting the recently halted US Presidential edict restricting entry into the US from seven Muslim majority countries. Apart from the obvious human rights aspect of the ban, the major impact of the travel ban would be on the free exchange of scientific information. The statement was particularly meaningful given that Federal Judge James L. Robart who launched the temporary restraining order is from Seattle.

Bernard Fields Lecture

Dr Jeffrey Lifsom presented the Bernard Fields Lecture on insights into HIV prevention, pathogenesis and treatment from non-human primate (NHP) models. Dr Lifsom helped develop the highly sensitive quantitative assays for HIV and SIV that are currently used in research and management. Drawing on Dr Bernard Field's work, Dr Lifsom described how NHP models had contributed to the understanding of HIV with respect to:

• Transmission: eg. how early distal SIV RNA found in mucosal transmission correlated to tissue changes found in HIV
• Pathogenesis: eg. the discovery of the gastrointestinail system as a major site of CD4 T cell and viral replication for SIV infection, which was subsequently extended to HIV in humans. In particular, how epithelial disruptions resulted in immune activation and inflammation that was not fully reversed or restored by ART
• Vaccines: eg. the use of a CMV vectored SIV vaccine to provide a persistent immune response, demonstrating that an unconventional response appears to result in enduring protection. This may lead to the promise for novel vaccines, including for other intracellular infections such as TB and malaria.
• Treatment: eg. the use of injected TFV/PMPA in NHP models was critical in the decision to develop orally bioavailable TDF. More recent developments are the use of a highly effective long-acting triple drug regimen which will influence treatment strategies.
• Viral Reservoirs: eg. The role of immune privileged B-cell follicles and clinically expanded T-cell clones with the persistence of SIV and HIV infections

Dr Lifsom concluded by saying that thoughtful selection of NHP models matched to the question of interest can provide experimental advantages and yield important insights.

N'Galy-Mann Lecture

Dr James Hakim, prominent researcher and clinician from Zimbabwe presented a fascinating insight into how his country turned around a devastating medical and socioeconomic epidemic to be one of the leading research areas in the world for HIV today.

In 1986 Zimbabwe had an HIV prevalence of 29%, with an incidence of 4.7%. This has been turned around to a prevalence today of around 14%, with an adult incidence of 0.48%. There has been a significant collaboration with international organisation to implement a robust research agenda and build capacity in the Zimbabwean health and research workforce. The initiatives of PEPFAR and NIC have invested significantly in sub-Saharan medical schools, to empower them with an improved qualify of education, leadership and research capability.

One of the most disturbing statistics that Dr Hakim presented was that Africa has 24% of the world's disease burden with only 3% of the world's health workforce. Ongoing support and collaboration is required to continue progress towards the UNAIDS 90-90-90 targets - noting that in 2016 Zimbabwe is tracking at 74.2/86.8/86.5 against those aspirational targets - a remarkable achievement given when the country started from some three decades earlier.

Special award

The delegation was treated to a performance by Mr Oliver Mtukudzi, a musician and human rights ambassador who has championed the cause of HIV/AIDS in Zimbabwe. He was given a special award for his contribution towards raising the awareness of HIV/AIDS, and trying to reduce the stigma of the disease through his music. In his words, "Art speaks to people's conscience"

Day One  Monday  13/2/2017   program : 

1 Molecular virology: advances in  understanding of HIV-1

2 HIV  reservoirs: obstacles to an HIV cure

3 Prevention trial design in the era of PREP

4 Approaches to staging and treatment of  early stage HCV

5 Cirrhosis issues

6 Common drug  interactions with HIV/HCV coinfection

Greetings from Seattle, the Emerald City, Washington.

It’s 8pm on 11/2/17 (or 2/11/17 depending on your preference) and it’s currently a brisk 48^oF (9^oC) compared to 44^oC at home yesterday.

My initial impression on arriving in Seattle was the apparent anti-Trump sentiment in the Pacific North-West evident from the graffiti on the wall on the way from the airport announcing “STOP TRUMP”, to the Washington state legal action against the travel ban, which is currently underway.

Day 1: Today I attended the 7^th International Workshop on HIV and Women, a small workshop with a select audience of 120 registrants, 10% being men. The major focus of this meeting is to present the latest data on HIV as it affects women and most importantly to promote a dialogue and interaction between participants.

Session 1 focussed on current controversies in breastfeeding – related basic science, clinical trial evidence was presented and the session concluded with a debate on the pros and cons of breastfeeding in the context of HIV.

Infant feeding is a complex issue and related choices by an HIV infected mother should always support prevention of HIV transmission, provide greatest nutritional benefit and prevent the infant experiencing significant non-HIV morbidity and mortality eg from diarrhoeal diseases. 

There are many factors which can influence transmission of HIV via breast milk which I will not elaborate here.  Note that some studies have shown that mothers with undetectable HIV RNA in the blood can still transmit HIV in breast milk because antiretroviral drugs do not pass into breast milk with full, equal efficacy.  Studies indicate passage of NNRTIs into breast milk of 80%, PIs 20%, and there is no passage of Integrase Inhibitors (in the one paper to date).  Further sub-optimal drug levels of ARVs in breast milk may contribute to drug resistance in the infant. There is also a different viral load in breast milk between each breast. Recent trials (Mma Bana and PROMISE Study) indicated risk of MTCT from breast milk was 0.3% in the context of ARV treatment. However, we do not know what may be the best ARV regimen for breast feeding mothers.

It is very important to be aware of the latest WHO Guidelines which were updated on 01/08/2016. I draw your attention to these new guidelines as they do now have more relevance to developed world settings.  The WHO Guidelines have usually been intended for countries with high HIV prevalence, and there is not wide adoption of the WHO Guidelines in highly developed countries, and of course there are longstanding regional guidelines in operation – eg US Guidelines (last updated October 2016) where breast feeding is not recommended (AII), with guidelines from other regions - BHIVA/CHIVA, Australia, Canada (CAPG and SOGC) being similar.

In a number of developed world settings, women are starting to breast feed in the context of full virological suppression and infant post exposure ARVs (including triple therapy!) and there are some emerging case reports on outcome. In many instances women are breast feeding without their health providers knowing.

Canada is now developing a national policy document relating to the follow-up of women who have breast fed their infants.  Further, be aware that Switzerland is now starting to allow breast feeding for women with an undetectable HIV viral load and the identified cohort will be followed prospectively.

It is increasingly apparent that there is a now an emerging dilemma as to whether we can start to recommend breast feeding by mothers with HIV infection in all settings.  Are we reaching a point now in our clinical practices, where there is sufficient safety data to consider supporting breast feeding?  A recent survey of health care providers suggests that nearly 50% of health care providers would consider offering a breast-feeding option regardless of speciality.  This is in the context of a background prevailing attitude of health providers which is, quite understandably, zero tolerance for any infant HIV acquisition. There was also acknowledgement that there is an evolving professional tension in some settings, between Paediatric ID clinicians and maternal HIV clinicians and a tendency for there to be “policing of mothers” in the community and by some health providers. 

The outcome of the debate on these issues in this session, was that it is time for there to be a more open discussion between women living with HIV, in a “shared care” arrangement with their health provider, on the risks and benefits of breast feeding.  This discussion must also emphasise maintaining adherence and full virological suppression, as studies have shown a decline in adherence in the post-partum period.  The session also concluded that there needs to be a relevant dialogue between health care providers and the development of governmental or professional organisational guidelines to assist health care providers in offering a breast feeding option.