I tried something a little different this afternoon. The conference venue set up a simulcast of all concurrent sessions in a theatre-like venue with six screens displaying the slides from each session. Audio was provided by personal channel-selected headphones, much like the system used in some gymnasiums broadcasting TV audio to users. It was a great way to flick between sessions rather than having to run between rooms. Despite this great technology, the human limitation still applies, and you can only pay attention to one presentation at a time!

The themed discussion afternoon consisted of 4 or 5 short presentations, following by robust discussion with the audience. The session on CNS treatment strategies addressed the issue about HIV and the CNS, in particular the issue of the potential for neurocognitive deficits to persist despite apparent complete viral suppression on ART. This effect is likely due to reservoir seeding to a sequestered site, resulting in ongoing immunogenitic and inflammatory effects of HIV, as discussed at other points at the conference.

The CNS is an early target for HIV. HIV-associated Neurocognitive Disorder (HAND) encompasses the spectrum of disorders related to HIV infection and AIDS, and includes disorders of varying severities. What is known is that early identification and treatment improves HAND, and ART improves established HAND.

A study into whether delays in ART initiation would impair neurocognitive function compared initiation immediately after infection with a 24 week delay. Interestingly, early initiation led to a greater improvement in neurocognitive function over time. The observation has important implications to clinical practice and in discussions with patients about when to start treatment. Early ART initiation may prove to be an important treatment strategy to decrease the severity of HAND or lead to better improvement in HAND.  [TD-380]

The next presentation looked at the cognitive trajectories over 4 years of HIV positive women with optimal viral suppression. There was a lower baseline cognitive function in several neurocognitive domains (attention, learning, memory and global functioning) in the HIV infected group compared with demongraphically similar uninfected women. The difference observered was at least one standard deviation worse across these domains and persisted over time. In the domain of motor skills, where there was no difference at baseline, a decline was observed over the 4 year period.

In comparing women who were virally suppressed with those that were not, in some domains (eg. global function) there was no difference in the measured decline over time. Interestingly, in some domains (eg. attention and fluency) virally suppressed women actually performed worse than non-virally suppressed women.

The difference at baseline may be attributed to co-morbidities such a susbtance use, trauma and psychological risk factors. These, combined with a low cognitive reserve, are hypothesised to be contributing to accelerated CNS ageing.

The vulnerabilities in various neuropsychological domains provides a framework for further study into the pathophysiology of the CNS damage observed. Clinically it is important to understand how co-morbidities in HIV infected individuals may be contributing to the HIV specific effects.  [TD-350]

CCR5 blockade using Maraviroc intensification has been shown to improve cognitive performance in HIV infected adults on ART. CCR5 binds multiple chemokines and is a co-receptor for HIV.

Cenicriviroc (CVC) is an new oral dual CCR2 and CCR5 antagonist. CCR2 is a chemokine receptor for the monocyte chemoattractant MCP-1. Monocytes have been implicated with contributing to HIV-associated Neurocognitive Impairment (HIV NCI). In ART naive HIV infected adults, CVC has been shown to decrease viraemia and soluble CD14 levels (CD14 is a marker for monocyte activation). Additionally, in animal models CVC has been shown to have anti-inflammatory and anti-fibrotic activity.

The pilot study hypothesised that CVC will improve cognitive function in HIV NCI by reducing monocyte activation. The sample cohort was older (average age 55), ART experienced (average 16 years on ART) and had low cognitive performance at baseline. Depression was an exclusion criterion. Neuropsychological testing was conducted at entry and at 24 weeks, along with plasma markers of monocyte activation (neopterin, soluble CD14 and sCD163).

The study observed that CVC intensification improved global cognitive performance, along with specific improvements in the neurospsychological subdomains of working memory and attention. There was a positive trend seen in the domains of psychomotor speed and visuospatial. Monocyte activation was significantly decreased with all three markers measured, with a trend seen between neopterin and working memory scores.

Although only a small study (17 participants) the results are certainly promising. Even in virally suppressed, ART experienced individuals, the measured improvements in cognitive function at 24 weeks suggests that HIV NCI may be treatable. Additionally, neopterin may be a predictor of improvement in working memory. A larger randomised control trial in HIV infected people with cognitive abnormalities is required to explore these effects further.  [TD-381]

Day 3 CROI:

I am sure all the General Practitioners reading this topic are much more familiar with the management of patients with this condition than I am. 

Dr Rohit Loomba is a Gastroenterologist/Hepatologist at University of California, San Diego and he presented current work he, and colleagues, are undertaking in imaging and monitoring patients long term with NAFLD (Non- Alcoholic Fatty Liver Disease) and progression to NASH (Non-Alcoholic Steatohepatitis): Defined as >5% fatty infiltration on liver biopsy with pathognomonic ballooning of hepatocytes. NASH is now the second cause of liver transplantation in California.

NAFLD is divided into NAFL (non-progressive over many decades) and NASH (rapidly progressive over 7-8 years with a high mortality rate).

Some of the identifying clues to a patient with NAFLD are:  Metabolic Syndrome, Diabetes mellitus, older age, high AST/ALT, low platelets and low albumin. For these patients consider Hepatologist assessment for liver biopsy and appropriate imaging.

We are all aware that patients with HIV have increasing mortality due to liver disease. Dr Loomba indicated that NASH is 30-40% higher in patients with HIV infection and is independent of age, sex and BMI. He is currently looking at appropriate imaging strategies for NASH which monitor impact on pericardial fat and loss of muscle mass with progressive NASH. Sarcopenia is associated with increased mortality. His unit is also currently undertaking trials with a new medication Aramchol together with lifestyle intervention and weight loss strategies

TAKE HOME MESSAGE: We all need to be more proactive in assessing HIV infected patients with “fatty infiltration” of the liver on ultrasound especially if they have other associated clinical parameters.

           Cerebral small-vessel disease (CSVD) is a common problem with increasing age and accounts for approximately 20% of strokes and 45% of dementia. In addition to age, hypertension is a major risk factor for the development of CSVD.  CSVD is characterised by white matter hyperintensities, silent infarcts and microbleeds.

           This cross sectional study examined the prevalence of CSVD in PLHIV (who immunovirologically controlled for at least 2 months on cART), comparing them with age and sex matched controls. A 3T MRI scanner was used and the diagnosis of CSVD was made by 2 neuro-radiologists who were blinded to serostatus.

           After adjusting for known risk factors, the prevalence of CSVD was twice higher in middle aged PLHIV (aOR 2.3).

           This study adds to the continually growing list of conditions that are more common in PLHIV, even where they are immunovirologically controlled. This therefore leads us to the question of how we go about managing or mitigating this effect. I did some further reading around up-to-date guidelines on CSVD. It seems that aside from managing blood pressure, there is little evidence to support the routine use of other agents, including statins or anti-platelets. These studies however have been done primarily in HIV negative individuals. The pathophysiological mechanisms underlying (at least some of) CSVD in PLHIV may be different. Given the extensive interest in the anti-inflammatory effects of statins in HIV, one wonders whether there may be a role in managing CSVD.

Comment:

The significant rise in symptomatic and asymptomatic STIs in recent years is having a huge impact on clinical practice. Many practices struggle to manage additional presentations to test and treat those with STI symptoms and to organise treatment and followup of those with positive test results. I have also noted an increase in requests from MSM on PrEP for private Doxycycline scripts for syphilis prophylaxis.

A number of trials are underway to address the topic and it's important to acknowledge that, at present the evidence is minimal. The list of potential adverse consequences is however, a lengthy one.

The rate of HIV resistance in those who acquire HIV while taking PrEP is small..... but we're only focussing on one pathogen. There are numerous bacteria in different organ environments upon which Doxycycline prophylaxis may have an impact. While there are concerns about emerging bacterial resistance in STIs such as Gonorrhoea and Mycoplasma Genitaleum, it is essential that we explore resistance in other organisms at other sites to fully characterise the problem.

Further, intermittent antibiotic use may alter the clinical course of infection (eg Mycoplasma Genitaleum) and partially treat STIs such as syphilis, confusing interpretation of results and management issues further.

The vaginal and penile microbiome have been discussed at several sessions at CROI, and I also wonder what impact antibiotic use may have on such microbiota, and whether this could increase HIV transmission (eg BV being linked to increased transmission)?

This is an important topic and worth understanding some of the complexities so that we can educate individuals seeking prescriptions now, in the absence of evidence.

I've summarised Jean Michel Molina's presentation below:

55 ANTIBIOTIC PROPHYLAXIS FOR STIs: PROMISES OR PERILS

Jean-Michel Molina,

 Globally, more than 1 million STIs are acquired daily, and annually approximately 146 million of new infections with chlamydia, 78 million of gonorrhoea and 6 million of syphilis are diagnosed. In the US, 2015 was the second year in a row with an increase in STIs, with syphilis increasing at an alarming rate among MSM. Implementation of PrEP for HIV prevention has also highlighted the increasing incidence and prevalence of STIs in PrEP users.

 Current efforts to contain the spread of STIs are obviously not sufficient and should include:

              - promotion of condom use.

              - counselling and behavioural interventions.

- vaccinations for viral STIs (Hep A and B, HPV).

- scaling up more effective STI service.

- increased testing for STIs in high risk individuals for early diagnosis of symptomatic and asymptomatic infection.

- better notification and treatment of sex partners.

- new biomedical interventions: Antibiotic prophylaxis?

The success of PrEP for HIV has raised interest in biomedical interventions for STIs. Pending the development of vaccines against bacterial STIs, the potential role of antibiotic prophylaxis should be re-assessed.

Studies conducted by the military have shown the short-term efficacy and the limitations of post-exposure prophylaxis. More recently, periodic presumptive treatment in female sex workers with azithromycin alone or in combination have shown reduction in incidence of gonorrhoea and chlamydia but not of syphilis or HIV. Mass treatment with azithromycin for trachoma and Yaws elimination has also shown some impact on STIs prevalence.

Studies using doxycycline prophylaxis for syphilis in high risk MSM are ongoing. Should antibiotic prophylaxis be successful at reducing STIs incidence, the short-term benefits should be balanced against the potential for adverse consequences:

              Short term reduction in STI prevalence with rebound to pre-intervention rates:

              - Selection of antibiotic resistance.

              - Change in sexual behaviour/risk compensation.

              Changes in STI presentations:

              - Prolongation of the incubation period (delayed seroconversion).

              - More frequent asymptomatic carrier state with extragenital locations.

              - Emergence of new STIs resistant to chemoprophylaxis (eg Mycoplamsa Genitaleum).

              Selection of antibiotic resistance:

              - Selection and clonal dissemination of drug resistant STIs.

              - Reduction of already limited treatment options.

              - Impact on human microbiome: Drug resistance in other pathogens (eg Staph Aureus)

              Tolerability

              Cost

New strategies need to be developed to contain the spread of STIs. Antibiotic prophylaxis for bacterial STIs in high risk populations should be carefully evaluated.

Wednesday morning featured a series of oral presentations exploring the interplay of STIs and altered microbiomes might affect PrEP.

Renee Heffron presented research that explored whether bacterial vaginitis decreased the effectiveness of oral PrEP.

In the CAPRISA 004 study which demonstrated the effectiveness of intravaginal tenofovir it was observed that in women that had a vaginal biome consistent with BV there was a significantly decreased effectiveness of vaginal tenofovir gel. It is postulated that anaeobic bacteria may hasten the breakdown of tenofovir. This study explored data from the PARTNERS PrEP study .  It compared baseline vaginal swabs , graded using the nugent scale as to the number of BV related bacteria, with serum tenofovir levels and HIV seroconversion. Reassuringly BV did not seem to affect either Serum levels or PrEP effectInness.

John-Michel Molina presented an interesting IPERGAY sub study. This looked at the controversial area of STI prevention using Doxycycline PEP. Men enrolled in IPERGAY were randomised to be provided with doxycycline PEP or not provided with PEP. Those asked to take the doxycycline PEP were asked to take a stat dose of 200mg between 1 and 3 days after sex. The time to acquisition of an STI (gonorrhoea , chlamydia or syphilis) was compared. In brief , no effect on gono but significantly reduced rates of syphilis and chlamydia. The data presented didn't address the thorny issue of antibiotic resistance. They are still looking at that.

Magnet is a nurse and peer led Sexual Health service in San Francisco. It recently co-located with Strut (San Francisco AIDS Foundation) and a number of other organisations working in the sector. I was warmly welcomed by Joshua O’Neill (HIV Testing Services Manager) and Pierre Crouch (Nurse Director).

The clinic opens 6 days a week and provides the following services:

-    Free STI testing and treatment on site and in mobile units around the city. The mobile clinics occur 3-4 times/week and with a bacterial STI pick up rate of approximately 8-10%, they provide an invaluable service to those who do not access mainstream STI services. Rapid HIV and Hep C (Ab) testing are also offered. 

-  PEP is offered free of charge. 

         -   PrEP is provided to individuals through several sources. Depending on health insurance status, PrEP may be funded under an individual’s health care plan. For those with inadequate or no private health insurance, Magnet has health insurance navigators to assist the process. Like in Australia, a high proportion of individuals import PrEP via the internet. Magnet is also a part of a double blinded RCT of 5000 HIV negative MSM randomised to receive either Truvada or F/TAF as daily HIV PrEP. This trial is not being conducted in Australia. 

       - Under the Stonewall project offered by Strut, free individual or group counselling for support regarding drug or alcohol use. 

          - An art gallery and lounge aiming to promote the physical, mental and social well-being of gay men. 

          - Social events for a variety of groups including transgendered and African American MSM.

          - STI testing and access to emergency HIV medication, PrEP or PEP to those visiting from abroad (no charge for a one month supply)

 Take home messages from the visit:

 1.     Mobile STI screening units provide an excellent way to reach MSM who may not access traditional STI testing and treatment services. With an STI pick up rate 8-10%, they create an excellent opportunity not only to diagnose and treat bacterial STIs, but also to reduce the number of undiagnosed people living with HIV. The benefits to both the individual and the community are obvious. 

2.     Australian’s visiting who have misplaced their HAART or PrEP, or those who require PEP while away, are most welcome to attend the clinic and will be offered a free 4 week supply of medication. It’s worth knowing about this as many of our patients travel to San Francisco.  

3.     The staff have hosted a number of international visitors in recent years and they welcome the opportunity to show health professional services when visiting San Francisco.

Symposium 5-3 ‘Strangers in the Night; Challenges and Opportunities in STI Control: provided a fascinating insight into potential opportunities and strategies for STI control. There was so much interesting and important information in the two hours of the session that I encourage to take the time to watch the whole webcast of this session.

R. Scott McClelland presented on the ‘Vaginal Microbiome and Susceptibility to HIV’ addressing the dynamic changes in the vaginal microbiome and the conditions, eg Bacterial Vaginosis, that can lead to morbidity and increased risk for HIV entry.  Jean-Michel gave a historical overview of the outcomes and opportunities for ‘Antibiotic Prophylaxis for STIs: Promises or Perils’ – you are left feeling that the risk of antibiotic resistance (eg as has occurred with gonorrhoea) is far too great for future intervention with prophylactic antibiotics for STIs.

Matthew Golden outlined the experience in USA (and Australia) in relation to the increasing rates of STIs in ‘Syphilis in the Era of Treatment as Prevention and Pre-Exposure Prophylaxis’.  He addressed the various changes in sexual behaviour eg serosorting, rates of condom use and sex in the era of PrEP and warned that we must address the increased rate of STIs, particularly syphilis in MSM, with renewed vigilance.  Lastly, Rebecca Guy from the Kirby Institute addressed the challenges of the ‘Scale up-of Point-of Care Tests for Sexually Transmissable Infections’ addressing the sensitivity of available tests, and their appropriate use.  Rebecca outlined the Kirby Institute’s projects in antenatal clinics in PNG and with community sexual health workers in remote Australia. The implementation of POC tests with the aim of treatment on the same day, by staff in those settings was outlined.

Day 2 CROI

My colleagues have already commented on the new HIV integrase strand transfer inhibitor, Bictegravir, so onto other potential new agents/formulation:

Presented by Gilead, the HIV Capsid Inhibitor was discussed in relation to its antiviral activity and proof of concept work. The Capsid Inhibitor, GS-CA1, is a first in class. The agent acts at multiple sites in the HIV life cycle - at the assembly site of the capsid core essential for the virion and at the disassembly site of the capsid which is necessary for nuclear translocation after reverse transcriptase. The capsid inhibitor binding site is highly conserved.  The capsid inhibitor associated mutations map exclusively to the inhibitor binding site.

The EC ₅₀ = 140 picamolar. With the activity of GC-CA1 a defective virion is produced that is non-infectious. The agent is active against all HIV1 clayds (slightly less potent against HIV2). So far, PK data in rats is maintained over ten weeks, leading to a proof of concept for monthly injectable dosing and is ideal for low dose, long acting administration.

CS-CA1 is currently in a preclinical programme.

Nanoparticle antiretroviral formulation was broadly outlined in relation to two ARVs, Efavirenz and Lopinavir (the agents were chosen in 2009, so are not necessarily in line with current ARVs).  In principle, nanoparticle formulation has two benefits: it allows for lower dosing of dry nanoparticle formulations and can be used for Paediatric formulations as they can be dispersed in water. The data thus far, confirms potential for a 50% dose reduction while maintaining therapeutic exposure for a future novel combination ARV.

One final comment in this session on ARVs: Jose L Balanco et al presented on the pathways of resistance in subjects failing Dolutegravir monotherapy. It was noted that selection of genotypic resistant mutations was rapid. The Chairman noted that Dolutegravir is not approved by the regulatory body for use in monotherapy and expressed some disquiet as it appears that consent was not obtained from all patients. Refer a recent article in Antiviral Therapy (?end of 2016) on ethical issues and monotherapy.

Tuesdayy afternoon provided a session of poster presentations exploring the complicated relationship between ARV treatment , excess weight gain and hepatic steatosis.

In summary ,

Weight gain in an HIV positive male is associated with twice the diabetes risk of the same degree of weight gain in an HIV negative male

Amit Achra from Kirby Institute presented DAD data the relationship between BMI and non AIDS related adverse outcomes. The results suggested that for CV risk both very low BMI (<18) and very high BMI (>30) were associated with an increased risk , and for non AIDS related cancers , risk was significantly associated with very low BMI and very high BMI.

An exercise physiologist from Massachusetts presented a study where overweight HIV positive patients were randomised to either be enrolled in an online weight loss and health coaching program or be in a control arm with minimal weight loss suppport. The results suggested the program was both cheap to run and successful in terms of significant weight loss.

A retrospective  analysis of a study where naive patients were randomised to start either raltegravir, boosted atazanavir or boosted darunavir plus 2 nucs looked at the predictors of excess weight gain. Interestingly they were black race , higher baseline disease severity and use of Raltegravir. There was a lot of discussion about the possible explanation of Raltegravir falling out as a predictor.

Interestingly a study was presented were HIV positive women on NNRTI or PI based regimens were randomised to either stay on th regimen or swap to Raltegravir regimen. They looked a biochemical markers of hepatic steatosis , Chi3L1 and adipokine adiponectin. It was interesting that both these markers droped (suggesting decreased steatosis) in those that switched to Raltegravir.

Finally a study looking at patients swelling from a Efavirenze containing regimen to a Raltegravir regimen appeared to decrease their steatosis as measured by a CAP score, (Controlled Attenuation Parameter , an add on process done with a fibrous scan)

So Raltegravir seemed to lead to weight gain but less hepatic steatosis , a result that seems to pose more questions than it answers.

Dr Carl June presented how novel therapeutics have the potential for an HIV cure. His work in the development of Chimeric Antigen Receptor (CAR) T cells have been instrumental in the cure of lymphoid malignancies. There are similarities in CD4 cell dysfunction between cancer, which causes exhaustion of T cells, and HIV, which causes deletion of HIV specific cells.

CAR T cell therapies use synthetic biology, tools of genetic engineering and genome editing to install a competent immune system into an immunocompromised host. In cancer therapy, an individual's T cells are harvested and geneticically engineered to make the T cells stably express CAR, conferring novel antigen specificity. They are reinfused into the patient to become personal "serial killer" cells. In almost 400 patients accumlating 1500 patient years, there have been no acute T cell toxicity events (ie. no conversion to acute leukaemia). Success has been seen out to 5 years with complete cure of a paediatric patient with advanced ALL and an older adult with extensive CLL.

Unfortunately there are no CAR T cell trials in HIV currently in progress, but it is likely to be an area of future research, with work towards an HIV cure.

The issues faced with this sort of technology are based around time, cost and the need for an individual's cells to be genetically engineered for each patient. Consideration of a blood bank model or central manufacturing strategy could advance implementation. Automated genetic engineering methods could allow CAR T cell treatments to be scalable, with lower coats and increased access. A government-industry-philanthropic partnership for combined funding could be a way ahead.

Links to:
Video and slides
Audio and slides
Audio only

Comment: Abstract follows:

Doravirine seeks to address the limitations of the currently available NNRTIs: avoidance of neuropsychiatric side effects, no food requirements or concerns re co-administration with antacids/PPIs, fewer drug-drug interactions and a once daily option with a higher genetic barrier to resistance than efavirenz or rilpivirine.

83.8% (321/383) of subjects on the doravirine arm had an undetectable viral load at week 48 when compared to the darunavir/r arm  79.9% (306/383). When comparing this to the phase II F/TAF/BIC versus F/TAF/DTG data presented earlier this session (97% and 91% respectively), I wonder what role doravirine will play in the treatment naïve setting. Ideally a treatment naïve phase III trial comparing doravirine to an integrase inhibitor such as dolutegravir would help to answer this question. 

Perhaps it will find a place as a once daily salvage option?

45LB DORAVIRINE IS NON-INFERIOR TO DARUNAVIR/R IN PHASE 3 TREATMENT-NAIVE TRIAL AT WEEK 48

Jean-Michel Molina et al

Background: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily dosing and potent in vitro activity against the most common NNRTI resistant variants (K103N, Y181C, G190A). In a phase 2b study, DOR 100 mg once daily (QD) demonstrated similar efficacy to efavirenz, with favourable safety and tolerability through Week 48.

Methods: DRIVE-FORWARD is an ongoing, phase 3, multicenter, double-blind, non-inferiority trial in antiretroviral treatment-naive adults with HIV-1 infection and pre-treatment HIV-1 RNA ≥1,000 c/mL. Participants were stratified by screening HIV-1 RNA (≤ or >100,000 c/mL) and investigator-selected NRTI backbone therapy (TDF/FTC or ABC/3TC) and randomized in a 1:1 ratio to receive DOR 100 mg QD or darunavir 800 mg with ritonavir 100 mg (DRV/r) QD, in combination with the selected NRTI, for up to 96 weeks. The primary endpoint was the proportion (%) of participants achieving HIV-1 RNA <50 c/mL at Week 48 (NC=F, FDA Snapshot approach) with predefined non-inferiority margin of 10%. A secondary objective was to evaluate the effects of DOR and DRV/r on fasting serum lipids.

Results: Of 769 participants randomized, 766 (383 in each group) received study drug and were included in the efficacy and safety analyses (mean age 35.2 years, 84% male, 73% white, 87% on TDF/FTC). DOR was non-inferior to DRV/r on the primary endpoint, with 83.8% (321/383) and 79.9% (306/383), respectively, achieving HIV-1 RNA <50 c/mL at Week 48 (difference 3.9%, 95% CI [-1.6, 9.4]). In the subgroup with baseline HIV-1 RNA >100,000 c/mL, 81.0% (64/79) on DOR and 76.4% (55/72) on DRV/r achieved HIV-1 RNA <50 c/mL at Week 48 (OF approach). Adverse event rates (overall, serious, drug-related, and leading to treatment discontinuation) were similar across treatment groups. The most common drug-related AEs (>5% in one or more treatment groups) were diarrhea (5.5%, 12.8%), nausea (6.5%, 7.6%), and headache (6.0%, 2.6%) for DOR and DRV/r, respectively. Fasting LDL-C and non-HDL-C were reduced by DOR and increased by DRV/r (see table) with statistically significant treatment differences (p<0.0001).

Conclusion: At Week 48, DOR demonstrated potent efficacy and was non-inferior to DRV/r on a background of 2 NRTIs in HIV-1 treatment-naive adults. Efficacy was similar regardless of baseline HIV-1 RNA. DOR was generally safe and well-tolerated with a superior lipid profile for fasting LDL-C and non-HDL-C compared to DRV/r.

Comment: Abstract follows:

This study demonstrates non-inferiority of treatment switch to dolutegravir/rilpivirine at 48 weeks versus remaining on current antiretroviral therapy. It’s satisfying to hear in person, data presented from a trial being conducted at our site.

Since 1996, triple therapy has been standard of care in treating HIV. As the HIV population ages, we are increasingly concerned by the potential toxicities associated with either TDF or abacavir use. While the development of TAF attempts to address this important clinical issue, it’s exciting that NRTI limiting strategies are also being pursued as an alternative strategy.

 Given its’ high genetic barrier to resistance, dolutegravir is an obvious candidate to explore this strategy and in addition to this study, late-breaker data regarding dolutegravir as maintenance monotherapy (Poster 451LB) will be presented in the coming days. A study of cabotegravir/rilpivirine as oral maintenance therapy is also being presented (Poster 442). 

44LB PHASE III SWORD 1&2: SWITCH TO DTG+RPV MAINTAINS VIROLOGIC SUPPRESSION THROUGH 48 WKS

Josep M. Llibre et al

Background: The requirement for life-long antiretroviral therapy (ART) of HIV infection has highlighted interest in 2-drug regimens (2DR) to minimize cumulative drug exposure. Dolutegravir’s (DTG) potency, safety and resistance barrier make it an optimal core agent for 2DR. Rilpivirine’s (RPV) safety, tolerability and efficacy in switch regimens make it an ideal potential partner.

Methods: Two identical open-label, multicenter, global, phase III, non-inferiority studies evaluated the efficacy and safety of switching from a 3 or 4-drug current antiretroviral regimen (CAR) to DTG+RPV once daily in HIV-1-infected adults, with HIV-1 RNA<50c/mL (VL<50c/mL) for at least 12 months and no history of virologic failure. Participants (pts) were randomized 1:1 (stratified by baseline 3rd agent class; age.

Results: 1024 pts were randomized and exposed (DTG+RPV 513; CAR 511), across both studies. Switching to DTG+RPV was non-inferior to continuing CAR at Wk48 for VL<50c/mL in pooled analysis of both the ITTe population [95% vs. 95%; difference: -0.4% (95% CI: -3.1%, 2.3%)] and the per-protocol population [96% vs. 96%; difference: 0.7% (95% CI: -3.3%, 1.8%)]. Efficacy results for SWORD-1 (VL<50c/mL in ITTe [95% vs. 96%; difference: -0.6% (95% CI: -4.3%, 3.0%)]) and SWORD-2 (VL<50c/mL in ITTe [94% vs. 95%;

difference: -0.2% (95% CI: -4.2%, 3.8%)]) were comparable. Low rates of snapshot virologic failures (VFs) at Wk48 were observed for both studies (Table 1). One pt on DTG+RPV with protocol defined VF had an NNRTI RAM (K101K/E); no pts had any INI RAMs. More adverse events (AEs) were reported and led to discontinuation in the DTG+RPV arm; no unexpected AEs were identified for either drug.

Conclusion: A switch to a novel, once daily 2DR of DTG+RPV demonstrated high efficacy and was non-inferior to the continuation of CAR in virologically suppressed HIV-1-infected adults. The safety profiles of both DTG and RPV were consistent with the respective labels. A DTG+RPV 2DR offers the potential for reduction in cumulative ART exposure, without an increased risk of virologic failure.

Comment: See abstract below.

This phase II study presents non-inferior results and several bictegravir phase III trials in both naïve and switch patients are underway in Australia and abroad. It’s great to see a study comparing a new agent to DTG, essentially the gold standard integrase inhibitor at present. 

Bictegravir represents a potentially exciting addition to the integrase inhibitor family-  a once daily, un-boosted medication with a high genetic barrier to resistance. It shares the same limitations as dolutegravir in terms of interaction with polyvalent cations and metformin boosting.

If all goes well, it will be co-formulated with F/TAF as a single pill regimen. Given its’ high barrier to resistance and absence of ABC, such a regimen may become an ideal option when initiating HAART in the absence of a resistance genotype/HLA-B*5701 result (eg in acute HIV infection or resource limited settings) or in individuals with high cardiovascular risk.

41 RANDOMIZED TRIAL OF BICTEGRAVIR OR DOLUTEGRAVIR WITH FTC/TAF FOR INITIAL HIV THERAPY

Paul E. Sax et al

Background: Bictegravir (BIC, GS-9883) is a novel, unboosted, once-daily INSTI that demonstrated potent activity in a 10-day monotherapy study and has in vitro activity against most INSTI-resistant viruses.

Methods: Treatment naive, HIV-infected adults randomized 2:1 to receive blinded treatment once daily with BIC 75 mg or dolutegravir (DTG) 50 mg; both were given with open label emtricitabine 200 mg/tenofovir alafenamide 25 mg (FTC/TAF). Treatments were administered without regard for food for 48 weeks. The primary endpoint was the proportion with HIV RNA <50 copies/mL (c/mL) at Week (W) 24 using snapshot analysis. Noninferiority was assessed through 95% confidence intervals (CI) at W24 and W48. Safety

(adverse events [AEs] and laboratory results through Week 48) was a secondary endpoint.

Results: Of 98 patients enrolled, 65 were randomized to BIC+FTC/TAF and 33 to DTG+FTC/TAF. Baseline characteristics were balanced between arms. Virologic success (HIV-1 RNA <50 c/mL) at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively. One subject in the DTG arm had HIV-1 RNA >50 c/mL at W48. No viral resistance was detected in the BIC+FTC/TAF arm. Mean CD4 count increases at W48 were 258 cells/μL in the BIC arm and 192 cells/μL in the DTG arm. There were no treatment-related serious adverse events and no deaths. The most commonly reported adverse events were diarrhea (12% in each arm) and nausea (8% BIC, 12% DTG). One subject in the BIC arm discontinued due to an adverse event of urticaria following the W24 visit. Median changes in estimated glomerular filtration by Cockcroft-Gault (GFRCG) at W48 were -7.0 mL/min for BIC and -11.3 mL/min for DTG, with no discontinuations due to renal adverse events.

Conclusion: Bictegravir+FTC/TAF and DTG+FTC/TAF both demonstrated high virologic response rates at both W24 and W48. No treatment-emergent resistance was detected in the BIC+FTC/TAF arm through W48. Both treatments were well tolerated, and no significant safety signal was detected in either arm. Estimated GFR changes were consistent with known inhibition of tubular creatinine transport by BIC and DTG.

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"