A few “Snapshots” from the Inflammation and Age-related Complications session, of interest:

1.       An update of D.A.D. data looking the association of cardiovascular disease and contemporarily used protease inhibitors, Atazanavir and Darunavir: Analysis looked at a prospective 7 years’ median follow-up (IQR 6.3 – 7.1) of 35,711 participants with 1,157 (3.2%) of participants having cardio and cerebro-vascular events (incidence rate 5.3/1000 PYFU (95% 5.0 5.6).  The analysis, with which we are now familiar, looked at crude incidence rates of CVD per 1000 PYFU stratified by cumulative use of ATV/r and DRV/r, and MI and Stroke separately. In this analysis, the cumulative use of DRV/r, but not ATV/r was independently associated with a small but increasing risk of 59% per 5 years’ exposure. The strength of the association is of a similar size for the older PIs but in contrast, does not appear to be modified by dyslipidemia.  We were reminded to exercise caution in interpretation as the study is observational only, and there are risks of unmeasured confounding. (L. Ryom et al CROI 2017 # 128LB.)

2.     Investigators in the North American AIDS Cohort Collaboration on Research and Drugs (NA ACCORD) looked at the incidence occurrence of Type 1 MI (atherothrombotic coronary event from plaque rupture) and the association with modifiable traditional risk factors by analysing the Population Attributable Factors (PAF) for MI.  They concluded that 43% of cases of MI in this cohort could have been avoided if these individuals did not have an elevated cholesterol, holding all other variables constant, 41% of MI were avoided by treating hypertension and 38% by smoking prevention. (K. Althoff et al CROI 2017 # 130.)

3.       A further analysis from the D.A.D cohort looked at cessation of cigarette smoking and the impact on cancer incidence. (N= 242 cases of lung cancer, and N=487 cases of smoking related cancers, excluding lung).  There were limitations in the study relating to the collection of cessation dates, intensity, duration or pack years unfortunately. However, the investigators concluded that smoking related cancers, excluding lung cancer, rapidly declined following cessation. Lung cancer incidence appeared to remain elevated in HIV patients several years after cessation, which is in contrast to studies in HIV negative individuals. (L. Shepherd et al CROI 2017 #131.)

Venous thromboembolism (VTE ) risk is increased in HIV patients (5.7 -11.00/1000 person years) compared to the general population (1.0/1000 person years, with all data predating 2003. C. Rokx et al aimed to look at VTE in the current era in the Dutch Athena cohort with data between 2003-2014 on 14,386 patients.202/229 first VTE occurred in proximal leg veins or pulmonary arteries and 153/202 had withdrawn anticoagulants. 32 recurrent VTE occurred (59 VTE/1000person years; 95% CI; 41-83). Kaplan-Meier recurrence rates at 1, 2 and 5 years of follow-up were 16% 19% and 28% following unprovoked first VTE. When CD4 cell count is above 500, VTE incidence approaches that of the general population. Conclusion: Patients with persistent low CD4 cell counts might benefit from longer anticoagulant therapy. C Rokx et al, CROI 2017 Abstract #620.

I have seen a number of HIV patients with VTE over the years, the last being 2 months ago with the major concern at the time being a potential drug-drug interaction.  So, what new information was available at CROI regarding that drug-drug interaction?

As you are all aware, Ritonavir (RTV) and cobicistat (COBI) are antiretroviral pharmacokinetic (PK) enhancers that can inhibit several drug transporters, including P-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 (MATE-1). Dabigatran etexilate DE (trade name Predaxa) is the prodrug form of the oral direct thrombin inhibitor, dabigatran, and is a substrate for these transporters. Kristina M. Brooks and colleagues conducted a single centre open-label fixed sequence PK study on 16 healthy volunteers to evaluate the effects of separated and simultaneous administration of RTV and COBI on dabigatran PK. Findings: No significant changes in dabigatran exposure were observed with simultaneous RTV administration, possibly due to mixed induction and inhibition of P-gp by RTV. However, COBI resulted in significant increases in dabigatran exposure that persisted despite separating administration, most likely due to intestinal P-gp inhibition. These findings suggest RTV and DE can likely be co-administered, whereas the use of DE and COBI may require reduced dosing and careful clinical monitoring. K. Brooks et al CROI 2017 # 409. My patient is continuing to do well on Dibigatran (normal dose) and Genvoya. We will see Dabigatran used more often in HIV patients with thrombo-embolic disease.

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.

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.

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.

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.