This will be my last blog at this Conference. I have been very privileged to have been able to attend CROI this year, my very first time (one of 25% of the first time delegates, I am told).

As the late Joop Lange had said, "Continue to do good Science"

It has been wonderful to meet up with my fellow "blogger" colleagues - Levinia Crookes, Julian Langton-Lockton, Jane Hunt, Marilyn McMurchie. We have certainly shared our experiences with one another.

There may be a few 'blogs' on this topic of PEP, but I will add my own perspective on this themed discussion.

Kenneth Meyer from Fenway Health, Boston was the Discussion leader. He talked about the challenges of PEP research (including the fact that guidelines are based on review of case series) and reminded us about the 2014 WHO guidelines on PEP to prevent HIV infections in adults, adolescents and children.

Four studies were presented :-

• Tenofovir/Emtricitabine Plus LVP/r vs MVC or Raltegravir for PEP: 2 Randomized Trials

 - The rate of discontinuation of PEP and side effects were higher in patients allocated to the Truvada and boosted lopinavir group compared to Truvada and Maraviroc or Truvada and Raltegravir

• Rilpivirine-Emtricitabine-Tenofovir for HIV Non-Occupational Postexposure Prophylaxis

- This was the Australian study which concluded that STR of FTC/RPV/TDF was well tolerated with high levels of adherence and completion

• Significant intolerability of Efavirenz in HIV Occupational Postexposure Prophylaxis

• Management of Acute HIV After Initiation of Post exposure Prophylaxis : Challenges and Lessons Learnt

- The study suggested there is lack of clinical guidance in the clinical management of Acute HIV in the setting of PEP and that in the setting of acute HIV diagnosis after PEP initiation , recommendation to continue PEP until urgent review by HIV specialist where pros and cons of continuing vs stopping ART can be discussed

The Webcasts will be available soon and I would encourage colleagues to look at them.

The 4 speakers were from Spain, Australia, Thailand and the UK.

It was interesting to be aware of what is being used for PEP in each of the countries.

The speaker from Barcelona mentioned that they used Truvada and Raltegravir.

In Bangkok, Nevaripine and Kaletra are used.

In the UK, various regimes are used including Truvada and Raltegravir, Truvada and Kaletra.

In Australia, again, various regimes are used - 2 drug to 3 drug regimes depending on the  risk according to our guidelines, as we already know. (I did not know this until today but one regime used in 1 centre is 3TC/TDF/d4T)

Several suggestions included:

1) That the full course of PEP should be given at first presentation rather than just the starter pack - ? to increase compliance.

2) 3 drugs should be used.

The issue of cost remains a consideration.

If already infected (very early infection) when initiating PEP, the question of what happens with very early treatment in this scenario remains.

Hello again.

As a follow up to this morning's plenary session, I attended this session which I believe will be of interest to some colleagues back in Australia. 

It was great to see Jenny Hoy from the Alfred Hospital moderating this session!!!!

The studies presented were

• Statin Therapy Reduces Coronary Non-calcified Plaque Volume in HV Patients: A Randomised controlled Trial
• Rosuvastatin Arrests Progression of Carotid Intima - Media Thickness in Treated HIV
• Calcified Plaque Burden is Associated with Serum Gut Microbiota -Generated TMA in HIV
• Varenicline vs Placebo for Smoking Cessation
• Body Composition Changes after initiation of Raltegravir or Protease Inhibitors
• Fracture Prediction with Modified FRAX in Older HIV+ and HIV- men
• Exposure to ARVs and development of CKD (Chronic renal disease)
• Renal and Bone Safety of TAF vs TDF

The studies were very well presented and indicate the importance of continued research into the co-morbidities that occur in our HIV positive patients

Just to summarise some of the conclusions from some the studies of interest

  1. Statin therapy prevented the progression of coronary athersclerosis and reduced overall plaque volume, especially lipid laden non calcified plaque volume .

Statin therapy reduced high risk morphology plaques

Statin therapy was safe and well-tolerated

Statin effects on arterial inflammation could not be adequately assessed but atorvastatin reduced a systemic marker of vascular inflammation

2. There appears to be a potential association of choline metabolism to subclinical atherosclerosis in HIV, assessed in relationship to plaque burden with the use of a sensitive CG angiographic technique

This relationship may be from altered gut flora or microbial translocation unique to HIV.

There is a need to assess the role of gut micro biome on CVD in HIV

3.The study on varenicline would be of interest to primary care physicians. Varenicline is safe and well-tolerated and effective as an adjunct to counselling in HIV positive patients as in general population and should be considered in HIV case management

Treatment of tobacco dependance in PLWH is a challenging priority.

4. PI/r or INSTI regimen initiation led to similar increases in limb fat with similar increases in central fat but ATV/r   containing arm tended to have higher gains in Lean Body Mass (LBM) than DRV/r but LBM gains were similar in pooled PIs vs INSTI

Higher pre-ART inflammatory markers were associated with increases in peripheral fat and LBM but not central fat

5. Studies have shown an association between the use of some ART and renal impairment as we all know. Implications from one of the studies in this oral presentation indicate cumulative increasing risk of Chronic Kidney Disease with increasing exposure to TDF, ATV/r, LPV/r in persons with an initially normal eGFR. The risk is cumulative over time.

A reminder that individual's risk of CKD can be calculated using the D:A:D CKD risk score to help determine benefits/risk  in incorporating ARVs into ongoing treatment regimen

and finally

6.  Looking at Tenofovir Alafenamide  (TAF)- the novel prodrug of Tenofovir (TDF) - we await in anticipation in Australia!!!! 

2 large RCT with detailed protocol specified renal and bone end points, confirmed favourable safety and tolerability profile of TAF  and that compared with TDF. TAF demonstrated no discontinuations due to renal Adverse effete, significantly smaller decreases in eGFR, significantly less proteinura, albuniuria and tubular proteinura, significanly less impact on spine and hip BMD and overall, greater increases in fasting lipids TC HDL same.

Most likely explanation for this = 90% lower tenofovir plasma exposure with TAF vs TDF

I would encourage colleagues to look up the webcasts which will be available later on.

Exciting work!!

The plenary session this morning on this last day of CROI on “Cardiovascular Disease in HIV Patients: An emerging Paradigm and Call to Action” was presented by Steven Grinspoon – an endocrinologist.

He reminded us of the 35000000 people living with HIV and the increased cardiovascular risk (myocardial infarction, stroke and sudden death ) in HIV positive patients.

Several important points were brought up, some of which we may already aware of

·      CVD risk in HIV infected patients is beyond that predicted by traditional risk factors

·      Excess mortality from smoking has been seen in HIV positive patients

·      Although there have been studies in the past demonstrating cART being associated with diabetes, hypertension, lipid problems, increased platelet activity etc. and various studies associating cART with myocardial infarction, Steven emphasized the importance of looking at the the newer studies showing the positive effect of cART with respect to cardiovascular risk.

·      The SMART study and the potential mechanisms for beneficial effects of viral suppression on cardiovascular diseases including decreased I 6 and increased HDL.

·      Description of persistent viral replication and microbial translocation resulting in T cell activation and monocyte activation contributing to increased inflammation and increase cardiovascular risk.

·      Steven discussed studies showing increased capacity of cholesterol efflux with cART in patients with acute HIV infection and that the duration of immune suppression and nadir CD4 related to AMI

Further points

·      HIV is a state of immune activation and suppression with implications of atherogenesis pathogenesis

·      Immune activation relates to novel atherosclerotic phenotype in HIV. In HIV patients atherosclerotic plaques are inflamed and associated with immune activation markers.

·      Markers of monocyte activation are seen in HIV postive patients with CVD. Monocytes play an important part

·      There is immune activation at surface of high risk plaque

·      Increased rates of atherosclerosis in HIV have been seen by coronary CT angiography with the presence of these plague higher in HIV patients

·      HIV positive patients have increased higher risk morphological plaques with  the associated clinical implications for these high risk morphological plagues

Importance of identification of patients with disease, optimizing time and use of ART and safe effective strategies for primary prevention

He continues to discuss the importance of interventions addressing both traditional risk modification strategies and immune response risk factors. Immune interventions mentioned included CCR5 antagonists, IL antagonists, methotrexate, statins, renin-angiotensin blockers

He concluded the need of large RCT to inform clinical pactice. It is unknown if statins prevent CVD and should be recommended for the HIV population.

Discussion of REPRIEVE study a prospective RCT

In summary, traditional and non-traditional risk factors contribute to increase CVD risk in HIV manifesting itself with inflammed non-calcified high risk plaque in association with immune activation

I would encourage colleagues to look at the webcast when available.

Our HIV population in Australia is aging and we need to be continue being informed of the comorbidities associated with HIV especially cardiovascular disease.

Following on from a symposium on "Current Issues in HIV -related Malignancies" yesterday (webcasts now available) during which HIV  associated malignancies were described as a worldwide epidemic, viral oncogenesis was discussed and a very rapid, high powered presentation on the advances and existing challenges of AIDS lymphoma to be followed immediately by the very humbling presentation on HIV malignancies in low and middle - income countries, it was of great interest to me to attend the themed discussion session on " Cancers in Young and Old and Lung Cancers in HIV"

It was useful to be reminded of the AIDS defining Cancers - Kaposi's Sarcoma, Non Hodgkin's Lymphoma and Cervical cancer and their associated etiological agents as well as the non AIDS defining cancers seen in HIV positive patients including Hodgkins Lymphoma, Anal, Lung and Liver carcinomas with their associated etiological agents.

In the US the most common AIDS defining cancer is Non- Hodgkin's Lymphoma. There have been recent decreases in Non AIDS defining cancers like Lung Ca and Hodgkin's Lymphoma but increases in liver and anal cancers. There was mention of prostate, breast and colorectal cancers although not in excess in HIV patients and with a greater association with ageing.  Aging in the HIV population needs to be considered.

5 studies were elegantly presented at this themed discussion 

• Cancer in HIV infected Children: Record Linkage Study in South Africa
• High Cancer Risk Among HIV Infected Elderly in the United States
• Smoking Outweighs HIV- related risk factors for Non-AIDS Defining Cancers
• High Frequency of Early Lung Cancer Diagnosis with Chest CT in HIV -Infected Smokers
• CD4 Measures as Predictors of Lung Cancer Risk and Prognosis in HIV infection

Key points summarised from these studies

ART was found to reduce the risk of developing cancer in HIV infected children in South Africa and the early link to care as well as the early start of ART is emphasised to further reduce the burden of cancer in these children  

Elderly patients with HIV may have a higher risk for many cancers identified as HIV-associated in younger populations. The elevation of Non-Hodgkin's Lymphoma incidence in this population was notably lower in one of the studies possibly reflecting the high frequency of NHL subtypes less strongly associated with HIV in elderly adults. The increased risk associated with ageing and HIV together, in elderly patients infected with HIV, shows a sizeable absolute risk of cancer. The need for cancer prevention and screening in this population was emphasised.

Smoking cessation programs were emphasised amongst adolescents and young adults at risk for HIVV with suggestions that this could prevent up to 46% of non AIDS defining Cancers in HIV infected adults. This emphasises the importance of primary care involvement in this population. Using ART to preserve immune status, maintain HIV viral suppression and preventing AIDs defining illnesses could prevent only up to 6% of non AIDS Defining Cancers in HIV infected adults. So, effective interventions to reduce smoking were emphasised with a continued HIV treatment focus.

Interestingly , one study showed that early lung cancer diagnosis and nodule followup with chest CT was feasible in HIV infected smokers with detection of surgically curable cancers. This study raised a lot of discussion on screening for lung cancer. I would recommend you look at the webcast when available

Finally another study found several measures of recent and cumulative exposure in immunodeficiency associated with increased risk lung cancer.

Continued vigilance of the issue of malignancy in primary care and specialist care of HIV patients needs to be emphasised.

The use of hormonal contraceptives in HIV medicine has been clouded with controversy. Do hormonal contraceptives increase HIV risk and influence a woman's susceptibility to HIV infection? From a sexual health point of view, this has been of interest to me.

This themed discussion was led by Betsy Harold from the Albert Einstein College of Medicine at the Bronx, New York and is available now on the CROI webcast. She introduced the session by pointing out that a recent meta-analysis of 18 studies including 37,124 women and 1830 HIV incident infections concluded an adjusted hazard ratio relative to no hormonal contraceptives for DMPA to be 1.50 (1.25-1.83) and for COC to be 1.03 (0.8-1.2). HIV infections appear to be be seen more often in women on DMPA and COC. She mentioned the biological plausibility of these findings including thinning epithelium, increased CCR5 expression, changes in micro biome, increased HSV and other STIs, ulcerative lesions and increased pro-inflammatory or decreased protective mediators.

It is thought that hormonal contraception may increase CCR5 expression favouring HIV infectivity and that oestrogen may modulate CCR5 expression

Four studies were presented that I will try to summarise

Oestrogen Replacement in Healthy Postmenopausal Women Reduces %CCR5+CD4+T Cells

In this study, there is a suggestion that there could be an increased risk of HIV acquisition in older postmenopausal women in that CCR5 is elevated, especially in cervical CD4+cells compared to premenopausal women. Oestrogen replacement was found to reduce %CCR5+CD4+ T cells in these postmenopausal women suggesting it could decrease HIV acquisition in this group. It is noted though that the population studied was healthy.

CCR5 Expression in HIV-Uninfected Women Receiving Hormonal contraception

This study suggested that the use of LNG-IUD and DMPA was associated with increased CCR5 expression on peripheral T cells and that comparative work in the female reproductive tract tissues and blood is needed to evaluate further increases in CCR5 expression associated with hormonal contraception. Again, the study was on uninfected women.

Progesterone Increases are Associated with HIV Susceptibility Factors in Women

Native progesterone and progestin based hormonal contraception are suspected of HIV acquisition risk in women although how these contraceptives affect HIV target cells is uncertain. The results of this study appear to suggest that the endogenous progesterone increase during the menstrual cycle luteal phase is associated with HIV target cells that have increased CCR5 expression, higher levels of activation and response to stimulation. If these progesterone effects exist in genital mucosa, this could be an important measure for identifying progestin based hormonal contraceptive risk factors.

Changes in Vaginal Microbiota and Cytokines in HIV - Seronegative women initiating DMPA

This study looked at the changes in vaginal microbiota and inflammatory milieu after DMPA initiation through which it is thought DMPA may modify HIV susceptibility. The initiation of DMPA was shown to demonstrate sustained shifts in vaginal bacterial concentrations and levels of inflammatory  mediators after adjusting for behavioural and biological confounders possibly impacting on HIV susceptibility. I am reminded of the association between bacterial vaginosis and HIV transmission.

As was pointed out by Betsy Harold, studies in this area have been retrospective studies and there is a need for prospective studies to occur

The oral presentations during this session were excellent and should be available very soon.

They  included the Proud Study from the UK, On-demand PrEP with oral TDC-FTC in MSM - results of the ANRS Ipergay Trial, The Demonstration Project of PrEP and ART, Scale-up Pre-exposure Prophylaxis in San Francisco to impact HIV incidence, the FACTS 001 Phase 3 Trial of Pericoital Tenoforvir 1% gel for HIV Prevention in Women, the Effect of oral and gel Tenofovir on Genital HSV Shedding in immunocompetent Women, Injectable Hormonal Contraception Use and Women's Risk for HSV 2 Acquisition, Medical Male Circumcision of HIV -Infected Men reducing long term penile HIV shedding.

There are some exciting results from these studies which may impact what is happening in Australia.

From a sexual health point of view, I note with interest  the study where consistent DMPA use may increase women's risk of HSV2 acquisition. Obviously as pointed out, evaluation in larger populations with more frequent follow up is needed. It was also important that they pointed out that the issue of increased HIV and HSV-2 associated with DMPA needed to be weighed against benefits, reduced risk maternal mortality and unwanted pregnancy.

I intend to report back more on the session on Hormonal Contraception and HIV in Women.

It was also very useful to revisit yet again the issue of medical male circumcision where the study concerned noted penile shedding of HIV increasing at 1-2 weeks after medical circumcision in ART naive men but then, penile HIV shedding became significantly lower after wound healing later.  They concluded that suppressive ART decreased number of HIV shedding events and quantity of HIV shedding during would healing.  There was re-enforcemnt of the long term benefits of MC in HIV positive men reducing penile HIV shedding. However the importance of prevention of HIV transmission to partners during immediate post surgical period was emphasised. Initiating ART  at time of MC reduced male to female HIV transmission risk. Implications in Australia???