ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

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Greetings

 

My apologies for not getting this blog out earlier (time travel and jet lag)

 

What a great conference.  It has been great pleasure to meet many of the 2015 CROI ASHM bloggers.

 

There has been a lot of research and data looking at HIV infection and chronic systemic inflammation measured by an array of inflammatory biomarkers to predict HIV morbidity from cardiovascular disease, Neuro cognitive disease and cancers to name a few.  This research has highlighted the importance of HIV infection and the risk of HIV morbidities especially in older age groups and that predictive value of traditional markers in HIV infection such as CD4 and VL must be further evaluated.

 

To continue on this theme of HIV morbidity; Steven Grindspoon of Massachusetts General Hospital.

Presented cardiovascular disease in HIV patients – An emerging Paradigm and call to action

This plenary session presented that the understanding of current CVD risk in HIV is limited as are treatment preventions. Chronic inflammatory biomarkers can be used as predictive markers. HIV individuals at risk of CVD risk are not identified through traditional screening pathways. We should not forget the HIV drug combination and other factors such as smoking, body fat composition, type 2 diabetes, platelet dysfunction, endothelial, renal function that contribute to CVD.

 

HIV immune activation relates to novel atherosclerotic phenotype in HIV. It is therefore vital to identify these individuals who may be at risk of CVD. With the current CVD risk stratification many individuals would not receive recommendation for statin treatment under current guidelines.

 

It is known that statins decrease CVD events in non HIV patients with low LDL and raised CRP (LDL lowering and dampening immune activation)

 

Newer statins do not effect glucose and less likely to have drug interactions with ARVs. Pitavastatin is primarily metabolised by glucoronidation. Minimally metabolised by CYP3A which have very little drug interaction with ARVs and no dose reduction needed

REPRIEVE a RCT, looking at Pitavastatin versus placebo in asymptomatic HIV participants with a cardiac risk score of less than 7.5

 

Conclusion – Traditional and non tradition risk factors contribute to CVD, modulation of these factors needed. Atherosclerotic plaque formation in HIV positive individuals has unique pathophysiology and characteristics.  Significant challenges remain to identify at risk individuals and prevention strategies.

 

Cynthia Firnhaber presented a one year follow up cervical screening in HIV positive women in South Africa, this is significantly poignant as Cervical cancer is the highest cancer in women in Africa and responsible for 23% of all cancers. The risk of cervical cancer in HIV positive women is 3-6% higher than the general population.

 

In this cohort of 671 women 392, 92% were on ARVs, 80% were fully suppressed, average CD4.

 

Cynthia Furnhaber, University of Witswatersrand, Johannesburg, South Africa

One year follow up of HIV positive women, screen with VIA (visual inspection with
acetic acid), HPV and cytology

Cervical cancer is the leading cause of death in South Africa, with the risk of developing cervical cancer in HIV cancer 3-6 times the general population. In the WHO Africa region AFRO in 2012, 250,317 died of cancer (23% cervical cancer).

 

Screening for cervical cancer has proven preventable measure

1202 HIV positive women screen from a Johannesburg Clinic. All positive PAP smears and VIA had a colposcopy. Abnormal cervical areas got cryotherapy with CO2 or NO2.

837 women enrolled at baseline and 677 reviewed at one year. Characteristics such as age, CD4, VL, HPV were analysed separately.

Baseline 33% HSIL, 40%LSIL, 27% Normal a

One year follow up HSIL 7%, LSIL 70%, and Normal 23%

Average CD4 387, 87% VL< 1000, 93% ARVs

16% New HPV infection, 48% cleared HPV infection,

22% Progressed, 63% regressed via VIA

 

This study concluded that even HIV positive women who are on treatment have a significant risk of CIN progression and that cervical screening and access to healthcare is imperative to ensure gains in health for HIV positive women.

 

 

A eye opening plenary by Frances M Cowan, University College London, London, United Kingdom

The Price of Selling Sex: HIV Among Female Sex Workers—The Context and the Public Health Response

 

Globally female sex workers (FSW) are more 15% more likely to have HIV than general population. Meta-Analysis of the Burden of HIV in FSW –Asia 29% (countries not defined), Latin America 12%, Sub Saharan Africa 12% and modes of HIV transmission probably underestimate the effect of FSW in HIV transmission globally.

 

This talk then looked at prevention framework, legislation against violence against sex worker could reduce HIV transmission by 17-20% 0ver next decade, decrimalising sex work reduce HIV transmissions by 33-46% over the next decade.

 

Prevention framework should be through (individual, peers, community, public policy, and environment)

1)      Structural. Social justice and human rights.

2)      Behavioural

3)      Biomedical ART and Non ART

 

Implementation through social cohesion and safe space, collective power and sex worker participation.  (lubrication and condoms, STI treatment, HIV treatment, contraception, drug education, peer review, violence reduction and community empowerment.

Systemic review and met analysis of 22 studies and 33,000 FSW, showed a significant reduction in HIV, STIs (Gonorrhea, Chlamydia, Syphilis) and an increase in consistent condom usage with new and regular clients. Also discussed were newer biomedical interventions such as PrEP, PEP and HIV treatment to prevent MTCT.

 

WHO Guidelines - HIV diagnosis, treatment and care for key populations 2014

This talk focused on Sisters with a Voice  started in 2012 HIV and STI programme for FSW based at 5 sites in Zimbabwe –  Clinical services, health education, peer educators, community empowerment

24,000 women seen, 20,000 STI treatments, 7500 HIV tests, 3,200 HIV diagnoses and referred fro treatment. 1.4 million Condoms distributed (M) 96 000 (W) in 2014. 10 new HIV infections per 100 yrs follow up.

HIV prevalence in FSW in Zimbabwe 50-70%, minority are

SAPPIRE (Sisters Anti retroviral Programme for Prevention of HIV-an Integrated Response)

14 outreach sites in Zimbabwe, 200 FSW per site, 2800 in total

Random allocation of usual care sites to intervention sites

Usual care – (condoms, health education and HIV referral, Syndromic STI treatment, contraception, cervical screening and legal advice)

Intervention sites – (all usual care plus –HIV negative  HTC and PrEP, HIV positive – POC CD4 and onsite ART, community mobilisation – SMS and adherence support,  Adherence sisters programme.

 

Conclusions

Global epidemiology FSW 13.5 times higher risk of HIV than general population, effective HIV prevention and treatment programmes, novel biomedical approaches.

 Proper inclusion of sex workers and other key populations is essential to reach 90:90:90

 

The Thursday Afternoon Themed discussion  PEP- Remember me?

Kenneth H. Mayer

Fenway Health, Boston, MA, United States

 

Overview – Changes with PEP is transmission risk is one off event which needs prompt response with treatment, mostly conducted with animal studies and occupational studies, HIV transmission is relatively inefficient <1%. Guidelines are based on peer review studies. PEP guidelines vary with country to country even centre to centre.

Other options such as Behavioural/exposure/adherence, decrease host susceptibility, decrease source HIV infection

 

2014 WHO HIV PEP guidelines FOR Adults, adolescents and children 2014

PEP drugs 3> 2 is better

In adults and adolescents

-      2 ARVs is effective but evidence strength is low

-      TDF/3TC as preferred backbone evidence low- moderate

-      LPV/r or ATV/r as 3rd drug Evidence very low (where available RAL, DRV/r, EFR considered as alternate options)

-      28 days good strength but evidence low

-      Adherence support conditional but evidence

Children

-      AZT/3TC preferred evidence low (ABC/3TC or TDF/FTC if available)

-      LPV/r (ATV/r/RAL/EFR/NVP) alternatives evidence low

-       

This looked at data from Tenofovir/Emtricitabine Plus LPV/r vs. MVC or Raltegravir for PEP: 2 Randomized Trials

Lorna Leal, Hospital Clinic Barcelona, Barcelona, Spain

 

Rilpivirine-Emtricitabine-Tenofovir for HIV No occupational Post exposure Prophylaxis

Rosalind Foster

Sydney Sexual Health Centre, Sydney, Australia

Significant Intolerability of Efavirenz in HIV Occupational Post exposure Prophylaxis

Surasak Wiboonchutikul

Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand

Management of Acute HIV After Initiation of Postexposure Prophylaxis: Challenges and Lessons Learnt

Goli Haidari

St Mary's Hospital–Imperial College Healthcare NHS Trust, London, United Kingdom

 

There were many good questions directed at the panel.

Drug tolerability and good adherence

Cost effectiveness and cost 2 drugs vs 3 drugs

No clear guidelines on HIV seroconversion during PEP

POC HIV tests  vs  4th generation tests at baseline

Time to treatment similar to Occupational PEP

Genital tissue drug levels in men versus women - PrEP studies and long acting agents

This session concluded that there is very little evidence behind PEP especially with the newer drugs, WHO recommends 3 drugs  in PEP 2014 guidelines

Tolerability of drugs ( side effects and pill burden) impact on completion and adherence

More work is needed in this field

Tagged in: croi2015

HCV: new frontiers and controversies was the final session I attended, abstracts 179 to 181.  It built on the earlier workshop, HCV in the interferon-free era, blogged by Jane.  In the pathogenesis of acute infection, Ashwin Balagopal described a doubling time of 7.5 hours with 21 days to reach a viraemia of over 6 logs. HCV infects a minority of hepatocytes at 20-45% with about 100 copies of HCV RNA per hepatocytes. 1-3 trillion copies of RNA are made daily and rapidly cleared to maintain set point. 20-25% of people clear infection, usually within the first six months, and prior clearance of an earlier infection makes this more likely (as does being female, non-African and HIV negative).  In reminding us of ELITE controllers, he raised the vaccine option. 

IL28B is now known as interferon lambda 3 which can mutate to IFN L4 to which HCV binds differently. Evidence of immune response is also seen in that neutralising antibodies from people who have cleared HCV previously have an effect in a further clearance of infection.  

Greg Dore first defined terminology in his HCV treatment as prevention talk.  There are three approaches: eradication as in small pox, elimination in which the incidence is zero but on-going work is required (measles and polio) and epidemic control where incidence decreases over time. 

The dilemma in HCV treatment is whether to focus on the liver disease burden in older people (defined as over 35) or on HCV infection prevention in younger people. He presented data which indicated that 75% of people aged 15 to 19 years had ever injected, this rate falling to 25% over the age of 35. 

In discussing treatment as prevention in Australia in the 10% co-infected with HIV and HCV, he reported on the CEASE study: approximately 80% of co-infected people have been diagnosed, around 80% of those are linked to / retained in care but only about two thirds are / have received treatment.  Of the treated fraction, HIV RNA is suppressed in over 60%. 

He spoke of the harm reduction approach for PWID, noting that only 41% of countries have NSP programs and only 30% have opiate substitution programs.  HCV incidence in Australia was around 25% per annum in the 1990s falling to about 5% per annum in the 2000s.  The target groups for treatment as prevention are PWID, prisoners (12% of injectors are jailed annually with an incident HCV infection rate of 10% per annum), HIV positive MSM and pregnant women.  

He outlined the STOP C study of early and deferred treatment with sofosbuvir and GS5816 for 12 weeks planned for two medium to maximum security prisons in New South Wales. 

In abstract 181, HCV therapeutics: It's the virus stupid, Mark Sulkowski described the HCV life cycle and where the directly acting molecules fit.  He also spoke of the class cross resistance seen (in the low number of people who fail treatment) to date with telapravir and daclatatasvir and of the benefit in preventing failure in adding ribaviron. 

He define Perfectovir, introduced by Greg Dore in the preceding talk, as achieving SVR in > 90%, working for all genotypes, administered as a once daily pill and with no side effects.  He also thanked all the people who were in clinical trials which did not show benefit.  

Marion Peters had given a superb talk in the HCV workshop on HCV cirrhosis with early decompensation in which she demonstrated the usefulness of the Childs Pugh score as well as the MELD during treatment for assessing decompensation.  She had reminded us that the natural history of ESLD is that 5-7% of people decompensate annually.   In this the last talk of the conference, she was given the title of HCV therapeutics: big sticks with big stickers. In noting that SVR produced a 70% reduction in HCC and a 50% reduction in all cause mortality (renal and bone disease, cryoglobulinaemia, lymphoproliferative disease, CVD and cognitive impairment) as well as reducing portal hypertension. 

Cost effectiveness of staging determined treatment as opposed to treating all patients yielded a best result for immediate treatment of anyone with a Fibroscan score of > F1. The cost of treating T2DM, HIV, HER2 positive breast cancer and HCV with IFN RBV and a PI were about the same but the difference is that the costs with HCV treatment are all up front, not spread out over time.  A time delay in treatment (until people reached Medicaid age in the USA) meant two thirds had at least one other chronic disease which could complicate treatment.  

91 countries across the world to date have made deals of various sorts with pharma to access treatments for their populations.  The obvious inequities were discussed in question time.  

Marion Peters ended her talk saying that the problem is the patient load of HCV infection worldwide and that in its management of HCV, Australia could be considered the greatest country in the world. 

Tagged in: croi2015

It seems to be the ultimate irony that a cure has been found to treat Hepatitis C ( HCV) and we can't afford it. That the world's 180 million people infected with HCV now have access to daily tablets with tolerable side effects and could be free of the virus in up to 12 weeks is remarkable.

However, the estimated cost of achieving this at today's prices would be $US 15.1 Trillion, close to the US GDP of $US 16.7 Trillion. Add to this dilemma the nature of HCV transmission and high rates of re-infection in some settings, and the subsequent recurring costs, and this makes the task of eliminating - let alone eradicating - HCV seem unachievable. It also lends support for the need to implement other strategies which reduce transmission of infection and for the obvious need to develop a vaccine.

Professor Greg Dore from St Vincent's Hospital and the University of NSW, in Sydney Australia, provided an eloquent account of the priorities and strategies he proposes for tackling treatment as prevention. (The prevalence of chronic HCV in Australia is 280,000.)

He proposes a strategy which provides for:

  • Programs to increase testing/screening (in Australia this has already been well covered with 85-95% of cases detected).
  • Programs which enhance harm reduction for people who inject drugs (PWID) through needle syringe programs (NSP) and opiate substitution therapy (OST).
  • Prioritised treatment so that "the transmitters", those most likely to transmit HCV - particularly the under 25yr old PWID who are more likely to share needles more often - prisoners, MSM (and pregnant women) are treated early.
  • Increase treatment rates in those with more advanced liver disease who have a more imminent risk of severe morbidity and mortality.

Professor Dore modelled a scenario where 8% per year of PWID in Melbourne are treated. Using this projection he predicted elimination of HCV in Melbourne by 2027. His proposal that a rapid scale-up of treatment be implemented in the PWID group, so that high transmitters are treated contemporaneously and removed as sources of reinfection for each other, seems to provide a possible solution to this problem.

Currently there are no interferon-free HCV treatment regimes subsidised in Australia. Hopefully this will change in the near future with clinicians, stakeholders, patients, government and Pharmas negotiating prices that are more affordable, as have some of the developing countries who have used their huge economies of scale to negotiate relatively low cost supplies of HCV antiviral drugs.

We all look forward to a world free of the suffering and stigmatisation associated with HCV infection.

 

Tagged in: croi2015

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.

Tagged in: croi2015

Cindy Zahnd reported on data modeled from the Swiss HIV and hepatitis C Cohort. Specifically the considered the impact of deferring treatment initiation in HIV-HCV co-infected patients. There was not difference starting in a month or 12 months. But treatment outcomes were heavily impacted by fibrosis score at treatment commencement. Delaying till F3 doubled the risk of disease progression and delaying till F4 saw a five fold increase.

Interestingly patients with F4 were more likely to have a serious or fatal liver event even after having had an SVR on treatment. This is probably because even though the virus was cleared irreversible damage was sustained. A salient message for clinicians and patients who might be waiting for the next best drug to come along.

You can view this and other coinfection oral presentations from the http://www.croiwebcasts.org/ it was session O-12 Curing hepatitis C: Mission accomplished

 

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!!

Tagged in: croi2015

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.

Tagged in: croi2015

 

Greetings from CROI

 

High rate of HSIL on HRA in HIV positive women not meeting criteria for anal screening

 

Anal dysplasia in HIV positive women

 

Anal cancer is an uncommon cancer affecting 1.8 per 100000, although this figure is increasing in resource rich countries by 2% per year, the risk of developing anal cancer can be 10 times higher in HIV.

 

 

 

New York guidelines recommended that anal cytology should be taken at baseline and then annually in the following HIV-infected populations:

 

•Men who have sex with men

 

•Any patient with a history of anogenital condylomas

 

•Women with abnormal cervical/vulvar histology

 

Fanny Ita-Nagy presented a study from Icahn School of Medicine at Mount Sinai, New York

 

In this study from 2009 to 2014 they screened all HIV positive women who received care at the centre

 

Total number of women who had anal screening was 877. Out of this group 290 women were referred for high resolution anoscopy (HRA) due to high grade cytological changes.

 

Following HRA and anal biopsy 79 women had a histological diagnosis of HSIL and 1 woman had invasive anal squamous cell carcinoma.

 

In this study they also measured specific parameters, which included

 

Age, cervical intraepithelial neoplasia, genital warts, anal sex, smoking, HIV viral load, CD4 count.

 

This study concluded that 26% of the anal HSIL would have been missed if local anal screening guidelines had been followed.

 

Smoking was the only measured parameter that had a positive correlation with HSIL

 

This study recommended that the anal screening programme should be extended to all people living with HIV

 

HPV related high grade cervical and anal neoplasia have many parallels.

 

Take home message in Australia it is recommended that all HIV positive women should have an annual cervical PAP, although figures show that less than > 10% of HIV positive women who attended STI clinics actually underwent the recommended annual cervical PAP smear.

 

Tagged in: croi2015

This symposium provided a great analysis of some of the issues confronting prevention efforts. Julie Overbaugh gave a great overview of HIV biology, particularly that period of time known variously as HIV stage 0, pre-seroconversion and/or early infection. She emphasised that this was the period before viral-load peaks and a time where it is very difficult to study what is happening in humans as they are not aware they are infected. Macaques provide the study model, but given the complexity of this period even slight differences between the hosts and the viruses might introduce great variation. So with that caveat she explained that there is considerable dissemination of virus int he first 1 - 3 days and by days 3 - 7 the reservoir is establishing in gut and lymph nodes. The impact of prevention diminishes as the reservoir is established.

She also suggested that there is selective pressure not just from the dominant virus but that CCR5 is more common in transmission that CXCR4 virus, making R5 inhibitors logical for PrEP. CCR5 virus is also more resistant to interferon, which is produced in a storm during infection. She lastly she compared cell to cell infection and cell free virus, and suggested that infection may be facilitated to hindered depending on whether cell to cell or cell free viruses are the target. Meaning that what drives transmission in breast feeding for example may be very different from what is important in vaginal transmission.

Christophe Fraser discussed phylogenetics and gave a detailed analysis of comprehensive sequencing of virus in the Netherlands. He suggested that about 69% of new infections were originating from the undiagnosed and ~24% from diagnosed but not on treatment and only 7% from people on ART. Immediate treatment could be expected to result in a reduction of between 25-30% of transmissions. PrEP and treatment might result in a reduction of 50-60% of infections, summarising that there is a lot to do to push prevention beyond where we are now.

Richard Elion building on the this reviewed optimising ART and looked at Treatment as Prevention. He made the statement that "we can't just treat our way out." He suggested that we need to better know where infections are occurring in populations and compared the treatment cascade between a number of countries. But to illustrate this point he then dissected the 19% of people with HIV in the USA who are estimated to have suppressed virus a number of ways: 6% of people under 30 and 28% over thirty; 16% black MSM and 34% Caucasian. He also questioned some of the definitions within the cascade. and challenged what was meant by "in care" when 74% are in continuous care while 26% are in only sporadic care.  He ended his talk by looking at how to engage the unengaged and identified: stigma, delivery methods, integration of bio-medical approaches and resourcing as the critical issues. This led seamlessly into the last talk.

Jeffrey Crowley looked at HIV criminalisation and suggested that laws are not protective, even though law makers might want them to be. And in places with a high prevalence it is unrealistic to expect the assumption of negativity. He pointed out the important role of health care workers in educating about HIV and pointed out that provisions such as anti-discrimination legislation are not sufficient alone to remove stigma.

Australia was referred to in the questions. A country which has excelled in the response but which is still seeing sustained incidence. The strong take-home message from this session was the importance of biomedical prevention to interrupt the the establishment of infection. This will challenge many attitudes but it may, in combination with treatment and testing, be the only way to significantly reduce new infections, particularly in settings, such as ours, where retention in care, treatment and viral suppression are approaching their maximum potential. 

The session was symposium S-5 4.00 pm - 6.00 pm Wednesday Advancing HIV prevention. You can view it from the webcast http://www.croiwebcasts.org/

A new term  "condomless anal intercourse"  (CLAI) replaces " unprotected anal intercourse" due to the acknowledgement that different strategies are used by MSM to reduce their risk of or " protect" themselves from contracting HIV when having sex without a condom. Some of the strategies include:

- Serosorting, such that HIV negative men only having CLAI with other HIV negative men

- Negotiating a regular ongoing relationship where both men are tested and if both are HIV negative they make an agreement not to have CLAI outside the relationship.

- Withdrawal method (of the penis prior to ejaculation)

- Strategic positioning during sex so that the HIV negative man takes the insertive role and the HIV positive man only takes the receptive role

- Viral load sorting, so that CLAI takes place only when the HIV positive partner's viral load is undetectable

- Pre- exposure prophylaxis (PrEP) used and the HIV negative person only engages in CLAI once he is taking ART on a regular basis

There were four presentations on this topic, the details of which can be seen in poster presentations at CROI. Some of their important observations include:

- The Centre for Disease control observed that  in the U.S. CLAI has increased between 2005 and 2014 in both HIV concordant and discordant sexual encounters. This trend was not different for men on or not on ART. It was not possible to conclude whether reliance on treatment explained the difference.

- in a Seattle seroconversion cohort of newly diagnosed MSM there was evidence of large and sustained serosorting behaviour changes which would have potential for reducing HIV transmission to HIV negative men.

- in a review of Philadelphian Local National Behavioural Surveillance data serosorting was common amongst African- American MSM but of limited safety because of the low level of testing, with 60% not having been tested in the last year

- in a Nigerian study looking at the use by MSM of sexual positioning and serosorting, undiagnosed HIV was present in 20% of those engaged in serosorting.

In the interesting question and discussion time some of the issues raised were:

- the need for collection of data which provides more detailed information about seroadaptive behaviours

- the need for clinicians to have conversations with patients about reducing risk of acquiring or transmitting HIV. There was acknowledgement that the most effective recent developments coming out of recent studies and presented at this conference support the impact of treatment as prevention and the goal of achieving and maintaining an undetectable viral load using cART in order to make HIV Transmission unlikely.

- regular/ frequent testing is essential for enabling early treatment and to reduce transmission but also to improve the effectiveness of serosorting behaviours. Clearly, serosorting in a context of low testing and high rates of undiagnosed HIV is a perilous strategy. 

- the acknowledgement that there is a problem with increasing STIs in HIV positive men, and also the problem that HIV avoidance behaviours are not the same thing as STI avoidance and hence don't mitigate that risk.

Some important findings pertaining to seroadaptive behaviours pertaining to viral load sorting and also to treatment as prevention can be seen in the interim results of the Opposites Attract Study, an Australian study lead by Andrew Grullich and Ben Bavington ( Poster 1019). The study aims to establish whether HIV transmission in homosexual HIV serodiscordant couples is greatly reduced when the HIV- positive partner is receiving combination ART and has an undetectable viral load, as has previously been seen in studies of heterosexual couples. To date the study reports that there have been no linked HIV transmissions in 150 couples over the 2 years follow up. This finding is extremely important and will offer considerable reassurance to gay serodiscordant couples having CLAI.

 

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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.

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 Greetings from CROI

 

 Clinical pharmacology of HIV prevention- Marta Boffito (Chelsea and Westminster NHS Trust / Imperial College, London)

 

Marta Boffito presented a fascinating look at the pharmacology data of current drugs used in PrEP, the potential use of alternative drugs such as integrase inhibitors and CCR5 inhibitors and also data on the long acting nano technology of the future injectable drugs such as long acting Rilpiverine and Cabotegravir.

 

So what makes an ideal drug for PrEP?

  • It needs to have good tissue distribution to achieve tissue drug levels
  • It needs drug persistence (a long half-life)
  • Protein binding affects penetration
  • Affinity for transporter membranes

Tenofovir/FTC

 The data from large PrEP studies such as iPREX shows that Tenofovir/FTC achieved these targets when good adherence levels were achieved, however there was marked differences in drug levels in rectal samples compared to vaginal samples even with lower rates of adherence to the drugs in male group. This opens up some interesting questions on the optimal adherence needed for women to achieve adequate protective  vaginal drug levels.

 

CCR5 inhibitor

Maraviroc was looked at in men and women looking at serum samples, vaginal tissue and rectal tissue.  After only 2 hrs post standard dose of Maraviroc, protective drug levels were achieved in rectal and vaginal tissue samples. Rectal and vaginal drug levels were higher than serum levels( with x 30 times higher in rectal tissue than plasma).

 

Integrase inhibitors

Raltegravir - blood, vaginal and rectal samples. In vaginal fluid the half-life of standard dose of Raltegravir (400mg twice daily) was 17hrs compared to 7 hrs in blood sample. Both vaginal fluid and rectal samples had higher drug levels than found in blood samples. Drug levels  in rectal samples was higher than levels found in vaginal samples.

 

 Dolutegravir at standard dose, the drug levels in both vaginal and rectal samples were 10% and 17% higher than blood samples.

 

Long acting injectable drugs

 The SSAT040 study looked at drug levels in both vaginal and rectal tissue and fluid samples after a dose Rilpivirine (1200mg) from male and female participants. This study found that drug levels in the rectal samples were significantly higher than found plasma levels.

 Protective drug levels were found in both rectal and vaginal tissue at 1 month post treatment. It was also noted that lower drug levels were found in participants with a higher BMI.

 

In this study there was one case of drug failure and HIV transmission in a female participant at the lower Rilpivirine dose of 300mg. (the HIV transmission is thought to have occurred 4 days post dose).

 

After an initial dose of 1200mg Rilpivirine, drug levels in rectal tissue was found to be at  protective at four months.

 

Finally the long acting GSK 744 Cabotegravir at an 800mg dose found good serum drug levels at 4/12 months.

 

In an animal study, Macaques who received Cabotegravir as treatment sustained a viral suppression for up to 20 weeks post dose.

 

Conclusions

  • Drug resistance to PrEP is rare.
  • The debate of which drug is best is still out there.
  • More work is required in this field to standardise intracellular drug concentrations.
  • Ongoing debate on regular vs episodic PrE.

Take home message for current and future clinical practice.

Good clinical data on alternative and emerging drugs to be considered for PrEP. This interesting data also has valuable implications that may be applied for clinical use in non-occupational PEP use for CCR5 inhibitor and integrase inhibitors, where HIV transmission risk is significantly increased in the presence of multiple concurrent STIs.

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Ebola - not a retrovirus but an international emergency

Ebola did in months what HIV took years to do. There were over 23,000 cases and more than 9,000 deaths as of last week.  The emergency medical coordinator for Ebola in Liberia, Dr Gilles Van Cutsem, of Medecins Sans Frontieres (MSF), described the response to the challenge.  

Ebola is a RNA virus in the same family as Marberg and Lassa fever. The incubation period is 2-21 days with an early febrile stage, then overwhelming GI symptoms, shock and death or recovery.  

The case fatality rate is 30-90%, severity is related to a high viral load at presentation. Transmission is from human to human, via contact with infected fluids. It is not airborne. The animal host is thought to be bats.  

This epidemic is different from previous Ebola epidemics with more cases than all other epidemics combined; previous epidemics have been confined to rural or remote areas and gradually burned out. Now there are massive outbreaks in cities. 

The index patient was a three-year-old child probably infected by a bat in Guinea in December 2013. All family members died rapidly then it spread to distant family and other villages. The first epidemic spread through 500 km.

In March 2014 the second outbreak occurred with rapid spread through neighbouring countries of Liberia and Sierra Leone.  Then there was a third wave of epidemic involving the cities of Monrovia and Freetown and further spread. The hIghest risk of transmission is thought to be later in disease progression; a small infectious viral load only is needed. Five hundred health care workers in Liberia have died. 

The Lagos outbreak was well handled by the Nigerian Ministry of Health. The interventions were based on community education/mobilisation with distribution of protective kits, case/outbreak investigation and contact tracing (which must be rapid), home disinfection, safe transport of patients (for isolation and treatment) and safe burial (it takes six people many hours to ensure decontamination).  One hundred percent of cases on contact lists were traced in Liberia but this is much less in the surrounding countries; in Guinea, 16% of contacts are traced and there the incidence is not falling. 

Current case fatality has been estimated at 51% but the death rate is declining over time in most centres.  A decreased VL on presentation for care has become more common.  The reason for this is unclear; perhaps decreased viral fitness or perhaps a lower infective inoculum in cases because of behaviour change.  

A pregnant woman about to deliver presented to a MSF care station. She was otherwise  asymptomatic and was accepted into the unit only because delivery was very close. She was checked for Ebola because it was routine and found to have a high viral load.  She remained asymptomatic for 3 days.  

Health system closures mean that people are dying from other disease. MSF isolation capacity has been close to full and people died waiting outside the centres. WHO declared a public health emergency only in August 2014 despite several earlier calls for MSF for a response.  MSF had actually called for civil and military biohazard response - unusual for MSF, and the response is still slow and not coordinated. There is a real difficulty balancing patient care and outbreak control.  WHO called for coordination and community organisation on 18 February 2015.   

There is no functional global response to epidemics in countries with fragile health systems. The decreasing incidence in Liberia is largely due to the quality of the response.  The national case manager from Liberia spoke of the country's response - they trained all their HCW and provide training to those who come to help. If there is any next time, the situation should not repeat. 

There was a standing ovation.  

Prevention and Treatment

Prevention and treatment were discussed by H. Clifford Lane from the National Institute of Health.  The NIH was involved following a direct government to government invitation.  

Ebola represents HIV compressed into a couple of months.  Ebola is different from HIV in that  survival means immunity but there is no clear correlate of protective immunity.  There are two current vaccine candidates: recombinant VSV and recombinant chimpanzee adenovirus.  There are the usual vaccine side effects including transient reactive arthritis.  Antibody induction post vaccination has been demonstrated.  

He proposed a trial of a vaccine candidate with probable 50% efficacy and assuming a 1% incidence in Liberia, initially focussing on people at higher risk such as contacts, HCWs and burial teams.  A clinical endpoint study is feasible because of the relatively high mortality and short clinical course. 

Potential therapeutic approaches are neutralising antibodies, nucleoside or nucleotide analogues and agents related to cellular cytotoxicity. Currently there is a monoclonal antibody focused on glycoprotein, a drug called brincidovir, convalescent plasma and an antisense compound. 

An adaptive trial of an investigational intervention would be added to supportive/standard of care. If the experimental arm is effective, then it becomes SOC.  The fatality rate means only 

small sample numbers. Historical controls may not be effective because of changes in the virus over time (74% morality in mid 2014, now at 25%).  The FDA have agreed to easing their licensing  process in this situation.       

Dr Lane emphasised "doing things the right way" and not just "doing something"; compassionate studies muddy the water and complicate subsequent decision making.  Rigorous research programs by extension enhance the local healthcare systems and may improve coordination of the various countries and organisations working in Ebola affected areas. 

 

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Three unintended pregnancies were reported in women using levonorgestrel implants while on an efavirenz based regimen.

Late breaker 86 reported that in only one woman was the level of efavirenz below the recommended therapeutic level.

The authors suggest that, if a depot gestagenic contraceptive is used, women should be informed of the small risk of pregnancy and advised that nevirapine or ritonavir boosted lopinavir may be safer choices in this setting.   

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Clinical pharmacology of drugs used in PrEP was discussed by Marta Boffito from the Chelsea and Westminster Hospital London.  They measured drug concentrations in cervicovaginal fluid, rectal lavage fluid and in tissue from both sites.  

All data was not presented today. In cervicovaginal fluid, CCR5 is high and maraviroc is less protein bound than in plasma.  Raltegravir concentrates in cervicovaginal fluid, reaching steady state by 4 days; the half life is 17 hours in cervicovaginal fluid compared with seven hours in blood.

Both maraviroc and raltegravir had high concentrations when measured in rectal tissue in woman.  There is data in men but little was presented.  Dolutegravir was detected three hours after a single dose and had a half life of 13 hours.    

Injectable long acting rilpilvirine was trialed in two doses, 1200 and 600 mg.  Sampling of cervcocervical fluid, rectal fluid and tissue showed high levels in cervicovaginal fluid but low levels rectally.  There were high levels of drug at one month.  A higher BMI was associated with lower concentrations of rilpilvirine.  There were no reports of increased toxicity with any of the medications. 

When asked to express an opinion on the negative protection described in the FACTS 001 phase III trial of precoital tenofovir gel presented the day before, Marta thought that systemic PrEP was probably easier for users than local PrEP.  In that study of young women, mean age 23, many of them were living at home and questions of privacy were thought to be germane. 

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The PROUD and IPERGAY studies offer us 2 dosing options for effective HIV prevention in high risk MSM:

1. Daily Truvada (Tenofovir/ Emtricitabine) 1 tablet

or

2. On- demand Truvada at the time of sexual exposure as follows:

- 2 tablets 2-24 hrs before sex

- 1 tablet 24 hrs later

- 1 tablet 48 hrs later

( if additional sexual encounters then continuing the regime so that 2 tablets over 48 hrs are taken after the last sexual encounter)

With the addition of PEP provided on-demand

Some additional considerations:

  • Adherence to PrEP is obviously critical to its effectiveness
  •  Condom use should continue to be promoted. Although neither study showed an increase in incidence of STIs in the PrEP group there is an ongoing concern that increased risk taking behaviour on PrEP will increase STI incidence.
  • Side effects- most commonly GIT - nausea, diarrhoea, less common- headache, renal
  • Renal monitoring- baseline and ongoing (? Frequency)
  • Baseline and ongoing HIV and STI testing ( 3 monthly)
  • Possible targets for PrEP- High risk MSM. For example anyone- with an STI in the last 6 months, in a HIV discordant relationship, who has unprotected anal sex, who use recreational drugs and/or binge drinks.
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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

 

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 Greetings from CROI 2015

This is a big conference with a substantial focus on topics such PrEP programmes and Hepatitis C treatments. However I would like to write on the data looking at HIV pathogenesis and long term persistent systemic inflammation which contribute to increasing age related morbidity such as cancer and cardiovascular risks.

In current HIV care, age related HIV morbidities such as cardiovascular disease; cancers, neurocognitive and frailty not only have a huge impact on the patient but also on what the service can offer. It may impact the HIV drugs prescribed and the drug to drug interactions must be considered.  General practice and specialist HIV monitoring may need to be increased and multidisciplinary support for lifestyle modifications such as smoking cessation, diet, exercise etc.

Peter W Hunt of University of California convened and presented a workshop – Pathogenesis of HIV complications, which was an overview of HIV complications many of which present as HIV age related morbidities, immune modulated pathogenesis factors and the use of inflammatory bio markers.

What this session highlighted is the pathogenesis of HIV is complex with chronic inflammatory processes playing a significant role in the end organ disease. It also questioned if traditional HIV markers such as CD4 and VL have any predictive value for morbidity and illness such as cancer or cardiovascular events.

It is well documented that both primary HIV infection and chronic HIV infections have a direct and significant impact on the in the lymphatic system, especially when looking at the Gut Associated Lymphoid Tissue GALT. In this workshop it highlighted two pathways, firstly that persistent HIV infection and inflammation causes lymphoid tissue fibrosis, which changes the structure of lymphoid tissue and this in turn reduces lymphoid tissue availability for HIV naïve T cells and IL7 responses. A second suggested pathway is the HIV associated “leaky gut” which involves the lamina propria of the gut wall. This is a process effects the integrity of the gut immunity with specific depletion of T and B cells and disruption of the epithelial tight junctions, with impaired function and cytokine regulation.

In this overview workshop it presented a series of data looking at plasma inflammatory biomarkers (IL6 and D Dimer) in HIV positive individuals who were not on treatment, a second group who commenced treatment after longstanding HIV infection and a third group who started treatment early after primary HIV infection, these were compared to HIV negative control group. The IL6 and D dimer were markers were measured at baseline of treatment and subsequent follow up time intervals.

At baseline all HIV positive groups showed raised levels of IL6 and D dimer compared to controls. In the follow up of the second group (delayed HIV treatment), the levels improved but still remained elevated compared to the control group.  Interestingly for those individuals who commenced treatment soon after HIV diagnosis or during sero- conversion the D-Dimer and IL6 levels returned to a similar level as found in the HIV negative control group.

The take home message from this workshop is that the pathogenesis of HIV morbidity is complex and that a chronic persistent HIV with a chronic inflammatory immune response may contribute to the risk of developing HIV age related morbidity. Early HIV treatment is likely to have a positive impact on the process. Complex inflammatory markers have a role to play, but will not yet replace CD4, VL as the traditional markers for HIV management.

I would like to further blog on current research looking at persistent inflammation after initiation of HAART in acute HIV infection and HIV disease in the gut during acute HIV infection...

 

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CROI formally opened yesterday evening. The format for the opening session of this conference is reliable and runs to its own format. Very little formality, straight into the science and accessible.

This year the first plenary, dedicated to Bernard Fields, was on Hepatitis C, a tiny bit of co-infection but largely monoinfection. It was given by Charlie Rice from the Rockerfeller. Hepatitis C has increasingly been making inroads into CROI and I think this is a great move. Rice commented on the prominence of HCV in this program. While it is not a retrovirus, it is a common opportunistic infection of HIV and we were told that globally about a third of people with HIV also have hepatitis C.

Like all good plenaries the lecture was general enough to be understood by a wide audience, covered the history, outlined some of the challenges and did some speculating. If you are looking for a comprehensive timeline for HCV science have a look at the earlier slides in this presentation. I found it very informative.

Hearing about the problems scientists have experienced in working with the virus were interesting, but I couldn't help thinking "they can't have been that difficult or you wouldn't have got to a cure so quickly." Charlie then went on to summarise the great leaps in treatment efficacy, which I think most of the Australians are familiar with.

In closing he revisited his comments about the difficulties in not have animal models and the practical issues this causes in looking at things like:

  • why some people don't respond to treatment
  • why others do or don't have improvement in their liver health, and
  • why still other's go on to develop liver disease or cancer even if the virus is cleared.

At that stage I ate my words about cure.

The last few minutes of this talk were very poignant:

  • about a trillion visions are produced each day,
  • the drugs have the potential for resistance resistance, and
  • efforts have been focused on treatment rather than vaccine development.

Lastly, accompanied by a photo of the lab dog, he summarised some of the potential animal models. I recommend that you have a look at the presentation. It is up on the CROI webcast site http://www.croiwebcasts.org

 

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Pre-exposure prophylaxis (PrEP) was a focus this morning at CROI.
 
After the iPrex study and it's open label extension iPrex OLE established good efficacy of PrEP among individuals who adhered to the drug, there has been considerable focus on establishing the conditions for effective (real world) use of PrEP among people at high risk of HIV. In short PrEP needs to be targeted to people engaged in high risk practices and there need to be high levels of adherence to the drug. As we know, adherence is not necessarily simple or easy for everyone.
 
Two studies of PrEP effectiveness among gay men reported this morning. Both studies received considerable attention last year when they closed their control arms earlier than expected and moved to offer all their participants immediate PrEP, suggesting that this prevention approach is proving to be very effective. At the time, though, there was limited detail about how, why and the extent to which risk was reduced.
 
The PROUD study is based in England among gay men who were either provided Truvada immediately or after a delay. Dosing was dailly. They both reported an 86% relative reduction in risk of HIV infection among those on PrEP.
 
The IPERGAY study is based in France and Quebec and used intermittent "on demand" dosing with pills taken before and after sexual intercourse--two before and two after. Whether or not participants actually dosed intermittently (or took the equivalent of a daily dose) was answered with an average of 16 pills per month used. On occasions where PrEP was not used other risk reduction strategies were employed, showing that this approach can be mixed and matched by gay men as appropriate. 
 
Importantly neither study found evidence of risk compensation. Partipants' behaviors were classified as high risk on enrollment and this did not change while on PrEP. This underlines the importance of properly targeting the technology.
 
The other real world consideration discussed this morning was implementation, including cost. PrEP is currently only approved in the US and while many health insurers notionally cover it, many people are encountering high co payments for particular scripts or expensive plans to start with. Some community groups are training up 'navigators' to help potential PrEP users sort out the complex bureaucracy of insurance eligibility.
 
Meanwhile in countries with public insurance schemes like Australia, the drug manufacturer has been slow in seeking a license. Hopefully this will change in the coming year. Meanwhile ASHM and partners have published guidance for clinicians and individuals wishing to use PrEP including options for importation of generic drug. At around $3 per pill such drug is affordable to many Australians. Equity questions remain to be addressed for those who cannot afford it or who lack the wherewithal to obtain the drug in this way.
 
Meanwhile the news for PrEP among women in the form of Tenofovir gel was not good with the South African FACTS 001 study finding no HIV risk reduction among those using the drug versus those using placebo. In a thoughtful analysis Helen Rees concluded that socio-cultural issues play a large part in determining adherence and therefore effectiveness. Young South African women face a variety of structural inequity issues that limit their ability to reduce the risk of HIV. The study included a social science arm with qualitative interviews and it will be fascinating to see those findings in the future.
 
Finally, a study of PrEP as a bridge to ARV as prevention reported excellent results. The PARTNER demonstration study was based in sub-Sahran Africa among heterosexual serodiscordent couples. It aimed to get the HIV positive partner onto treatment and undetectable and in the meantime (6 months from treatment initiation) provided PrEP to the HIV negative partner. It showed a 96% reduction in the risk of HIV infection. This seems like a logical and cost effective way to dovetail the two technologies for prevention.
 
All this means that PrEP is likely to continue to be a hot topic in HIV prevention for some time yet.
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Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

ASHM ASHM