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.

Meredith Williams

Meredith Williams

Meredith Williams is a general practitioner/ s100 prescriber working at East Sydney Doctors and the Kirketon Road Centre in Darlinghurst, Sydney.  She has particular interests in preventative health and working with marginalised populations.

 

Dr Deborah Konopnicki from Belgium gave a fantastic overview of the current research in prevention and treatment of HPV-related malignancies in HIV positive men and women on Day 3 of the Glasgow Congress.

 

HPV-associated infections and lesions are more frequent and their outcome is more severe in persons living with HIV.  The prevalence and incidence of precancerous lesions of the cervix/vulva/vagina are 6 times higher, and of the anal region are 15 times higher than in HIV negative people.  Recurrence of these lesions is also twice as frequent after treatment. Rates of cancer of the cervix are three times higher than in the general population, and rates of anal cancer are 40-100 times higher.  Mortality rates from HPV-associated cancers are high, particularly in the case of anal cancer.

 

Antiretroviral therapy against HIV decreases HPV-associated infections and lesions after several years of optimal viral control and immuno-restoration of high magnitude.

 

A new preventative vaccine that targets 9 different strains of high risk HPV was approved by the FDA in 2014/5 (Gardasil9).  The newer vaccine is associated with a greater reduction in rates of squamous intraepithelial lesions in women (79% reduction versus <30% reduction) and AIN in men (89% versus 62%) than the vaccines targeting genotypes 16 and 18 alone.

 

Due to its high cost, it has been suggested that perhaps one or two, rather than three, doses of the vaccine could be administered, but there is no evidence for the effectiveness of fewer than three doses of the vaccine in the HIV positive population.  It has unequivocally been proven that HPV vaccination is beneficial for both primary and secondary prevention of HPV-related lesions in this population, although guidelines vary regarding the upper limit of age at which they should beneficially be administered as primary prevention.

 

Recent changes in cervical screening in the general female population in high resource settings are also application to HIV positive women:  under the age of 30, HPV prevalence is too high to warrant the use of HRHPV screening; after 30, HPV testing has good negative predictive value for women with CD4>500, so future screening may potentially be conducted at lower frequency than current guidelines in this population. 

 

A new approach to cervical screening studied in limited resource settings in South Africa, Botswana and India over the past few years has been the “screen and treat” intervention.  This involves visual inspection of the cervix and high risk HPV screening – the results are available within two hours and high grade CIN can be treated on the same day with cryotherapy of trichloracetic acid.  This approach has been shown to significantly decrease the incidence of HGCIN and cervical cancer at 3 years.

 

Another interesting development in this area has been the use of topical Lopinavir to treat CIN.  A single-arm, proof-of-concept trial was conducted by Lynne Hampson et al in Kenya, in which vaginal self-application of Lopimune (Lopinavir/Ritonavir) gel was used to treat high grade CIN in 23 HIV-negative women.  The intervention was well-tolerated and systemic absorption was weak; cytological response at month 3 was 82%, with 64% resolution of the CIN and 18% regression to a lower grade.  The effect of the gel was thought to be due to Lopinavir’s local anti-proliferative effect on cells, and similar cervical concentrations would not be achieved with oral Lopinavir treatment.

 

There are limitations to anal cancer screening – although high resolution anoscopy is the gold standard it is costly and time-consuming, and so far no RCTs have shown a reduction in mortality from anal cancer with any screening program. Results from two RCTs on the use of anoscopy that are currently underway are due in 2018 and 2022.  Dr Konopnicki stated that her clinic in Belgium incorporates both cervical screening and anoscopy as part of routine care for HIV positive patients, however.

 

Finally, therapeutic vaccines made of the E6 or E7 oncogenes (genotype-specific) or their DNA to induce cellular immune response against E6 or E7 are in development, and in the future they could contribute to less aggressive ablative therapy for HPV associated lesions.

 

 

 

 

On Day 3 of the Glasgow Congress, Dr Teymoor Noori from the ECDC in Sweden spoke about his organisation’s efforts to increase HIV testing rates among MSM during European HIV Testing week in 2015 and 2016 using pop-up messages on mobile phone apps.  In the EU, MSM account for over 40% of all diagnosed cases of HIV, and it is the only group where increasing HIV rates are being observed.  

 

The ECDC rolled out push messages for a one-week period on commonly-used hook-up apps – Hornet, Planet Romeo and Grindr – which linked to the AIDSMAP website where users could locate their nearest HIV testing facility.  In the week of 23-29 November 2015, they had over 70,000 page views, although it was not possible to track whether this led to increased testing.  In 2016 they are planning to expand the message to include viral hepatitis and STI testing sites. 

 

This intervention was large scale and was free, due to the enthusiastic support of the CEOs of the app companies approached for improving public health initiatives.  There are plans to work together with app owners to creatively embed test finders in their apps.  A lot of work has been done in this area by the Terrence Higgins trust and SOAIDS in Sweden, who are developing guidelines for sexual health and HIV organizations to cover issues related to promotion, education and marketing via social media, mobile apps, and the internet. 

 

Tarandeep Anand from the Thai Red Cross AIDS and Research Centre, Bangkok, gave a fascinating presentation on the use of the internet and public apps to address the HIV epidemic in Thailand, where 1 in 3 MSM are HIV positive.  Studies have shown that MSM and transgender people in Bangkok spend an average of 7-8 hours per day online, and are accessing the internet on average once every two minutes.  The website Adam’s Love is being used as an electronic health record portal to screen high-risk populations for PrEP, book clinic appointments (using the Eventbrite system), provide free online counseling, and provide test results and customized daily reminders to take tablets for PrEP.  Tarandeep commented that there has been more success adapting already-popular websites to provide these services rather than custom-build health websites or private apps. 

 

Later in the morning, Dr Francois Houyez, from the European Organisation for Rare Diseases in Paris, spoke about the use of medical apps and privacy issues.  He stated that medical data is high in the list of favoured information targeted by hackers, according to IBM, and legislation related to the use of new technology in this area is evolving and is still “catching up” to new uses.  

 

 

One of the focuses of Day 3 of the HIV Drug Therapy Glasgow Congress was co-morbidities and HIV management, and how this affects patient care.

Dr Edouard Battegay from the University Hospital in Zurich presented in the morning on multimorbidity in HIV infected people as they age.  He stated that multimorbidity (the presence of multiple concurrent medical conditions) often occurs in clusters, and the complexity of managing the conditions, including potential drug-drug interactions, increases exponentially with each additional condition.  Common clusters in HIV–infected people include hypertension and dyslipidaemia, and pain and depression. 

 

The EACS guidelines for 2016 are one of the first sets of guidelines to systematically address comorbidities in DDIs in a specific disease.  Dr Battegay’s presentation prompted discussion of the relative and overlapping roles of HIV specialists, primary care physicians and specialists in managing these multiple conditions as the focus often shifts from the HIV infection, which is often stable, to management of the individual’s comorbidities.

 

Expanding on this exploration of the needs of the ageing HIV-positive population, Dr Charles Cazanave from France spoke about the results from a cross-sectional analysis of the ANRS CO3 Aquitane cohort.  He described the evolution of chronic non-HIV related disease and their risk factors in 2,138 patients included in this cohort between 2004 and 2014.  The mean age of the cohort increased from 42 to 52 years and the majority (71%) were male. 

 

He found that there was a significant improvement in HIV markers over the ten-year period, but also an increase in renal and cardiovascular risk scores, with rates of dyslipidaemia increasing by 40%, and rates of hypertension increasing by 37%.  There was also a high rate of smoking in this cohort (40%), reinforcing the importance of addressing lifestyle factors in comprehensive HIV management.  One of the limitations of this analysis was that there wasn’t a HIV-negative control group for comparison to see what happens to the rates of these conditions in the general population over a similar ten year period.

 

Is HIV-related lipodystrophy associated with an increase in the risk of morbidity and mortality?  Dr Estaban Martinez’s 20 year longitudinal cohort study asked this question and found that, contrary to their initial hypothesis, lipodystrophy or lipoatrophy (but not lipohypertrophy alone) was associated with a reduced risk of death in the group studied.  This was thought to be due to the fact that in the cohort studied, the presence of lipodystrophy is a proxy for effective viral suppression with antiretroviral medication.  LA, LD and LH were, however, all associated with an increased risk of hypertension and diabetes. 

 

Finally. Dr Davide de Francesco reported on results from the POPPY study in UK and Ireland, which showed that the HIV-positive people studied exhibit poorer cognitive scores when compared to controls, and there is a correlation with increased scores on depression-rating scales.  He concluded that reduced cognitive function may be mediated by depression or the two conditions may in fact be related to the same, as-yet unelucidated, pathophysiological process.   

 

 

 

Day 2 of the HIV Drug Therapy Congress in Glasgow began with an excellent presentation by Dr Julio Montaner  from the British Columbia Centre for Excellence in HIV/AIDS on “HIV treatment as prevention: from a research hypothesis to a new global target and beyond.”  He argued that the “treatment as prevention” approach reduces morbidity, mortality and HIV transmission, and is also the most cost-effective approach to managing the HIV epidemic.  Is the current UNAIDS target of 90:90:90 by 2020 feasible?  This would equate to 91% of people with HIV diagnosed as HIV positive, 81% of all people with HIV being on ART, with 73% of all people with HIV being successfully virally suppressed.  The current global figures fall far short of this, being 57%, 46% and 38% respectively. 

Dr Montaner emphasised the importance of being alert to picking up clusters of increased incidence in specific populations quickly, with efforts to identify networks, increase contact tracing and testing, and make use of PrEP and rapid institution of treatment.  He also talked about the importance of political support and mentioned previous tendencies of government in various regions to lose enthusiasm for addressing the HIV epidemic when rates appeared to be waning.  He said that the piecemeal approach won’t work, and control of the HIV epidemic globally is clearly the work of a generation, not a few years. 

 

Dr Jens Lundgren of the Rigshospitalet in Copenhagen reviewed the insights gained from the START study and the substudies related to it.  This study was especially important in that it is globally applicable, being conducted over 4 years in 35 countries (250 sites), with a sample size of 4600 people, randomised to either early ART or deferred ART (until CD4 count less than 350cells/mm3).  It has changed the management of HIV globally, with all subsequent guidelines advising immediate rather than delayed treatment.

 

Some of the unexpected results of the START trial were that in the deferred arm there were both increased rates of opportunistic infections (although CD4 counts were often in the order of 500-600) as well as increased rates of various malignancies.  It had been hypothesised that the immediate treatment arm may see a reduction in CVD risk due to reduction in inflammation, but this was not the case – in fact there was no change in CVD risk.  A substudy published earlier this week in the Lancet Respiratory Medicine journal showed that, if anything, the deferred arm had reduced rates of COPD.  Another substudy on bone mineral density has clearly shown that early treatment leads to more accelerated decline in BMD. 

 

Later in the day, Dr Jean-Michel Molina from Saint-Louis Hospital and the University of Paris presented a case study of the use of PrEP in a thirty year old female patient with a HIV-positive male partner.  The various options for reducing transmission of HIV to the female partner (who wished to become pregnant) were discussed; the most important point being of course effective viral suppression of the male partner’s HIV, as well as condom use and also the possible addition of PrEP for the female partner as an additional precaution when she wishes to conceive.  The previously-favoured approach of IVF with sperm-washing was no longer seen as the most appropriate treatment, as rates of pregnancy are much lower with this approach than with natural conception and the panel commented that an undetectable viral load was reliably associated with lack of transmission of HIV to the negative partner in studies of serodiscordant couples as well as their clinical experience of similar cases.

 

One of the highlights of the first day of the Glasgow 2016 HIV Drug Congress was a brilliant presentation by Dr Andrew Hill of St Stephen’s AIDS Trust in London on the cost of novel direct-acting antivirals (DAAs) for chronic hepatitis C (HCV).  His group extracted data from an online database of Indian export ledgers for per-kilogram prices and volumes of DAA active pharmaceutical ingredients (APIs) exported from India over Jan-Jun 2016.  Generic DAAs are being produced by manufacturers in India and a limited number of other countries under voluntary licences offered by Gilead, the originator company of Sofosbuvir; however, these countries only represent 50% of the worldwide epidemic and current high prices elsewhere limit access to DAAs both globally and in high-income countries. 

 

Dr Hill and his research team combined the cost of per-pill API requirements with estimated costs for formulation and excipients and packaging, and finally a profit margin of 50% was added to estimate a price at which generic producers could profitably enter the market. 

 

Their graphs of cost per kilogram of DAAs showed that production costs for these medications have been falling rapidly since 2015.  The difference between generic production costs and the current price paid for non-generic DAAs in developed countries is enormous.  For example, 12 week treatments of sofosbuvir can currently be manufactured for $62, sofosbuvir+ledipasvir $96, daclatasvir $14, sofosbuvir+velpatasvir $181-216.  These prices include the estimated 50% profit margin for generic suppliers.  In contrast, the cost of a 12 week course of sofosbuvir available via the non-generic manufacturer in the US is $49,860 – 84,000; of daclatasvir is over $50,000; of sofosbuvir+ledipasvir is $56,700 – 94,500; and of sofosbuvir+velpatasvir is $74,760.

 

Dr Hill made the point that the estimated generic prices for DAAs are comparable to those that allowed massive treatment scale-up in HIV/AIDs.  He also commented that governments are often unaware of the degree of mark-up being charged on medications they are purchasing, although this information is in fact available via the methods his study team used.  He stated that the common reaction to talk of these huge profit margins was that pharmaceutical companies need the money to invest in further research and development: his response was to state that Gilead, for example, posted a profit of over 10 billion dollars in the past year, and to pose the question: exactly how much money do such companies need to make to fund further research and development?

 

 The first day of the HIV Drug Therapy conference in Glasgow today featured presentations and panel discussions of a number of complex clinical cases focussing on antiretroviral treatment choices in the context of other comorbidities, particularly Hepatitis C infection. 

 

Dr Alessia Dalla Pria from Chelsea and Westminster Hospital presented the case of a male patient with HIV-associated B cell lymphoma infiltrating the liver, complicated by HCV-related cirrhosis and acute renal insufficiency.  The timing of treatment of both the lymphoma and Hepatitis C infection was discussed, with the two conditions in this case being treated concurrently.  The take-home messages: it is important to consider not only CYP3A4 drug-drug interactions, but also P-glycoprotein P and other trans-membrane transporters in considering DDIs, as the concentration of R-CHOP chemotherapy can be increased by Hep C treatment leading to increased toxicity.  Interferon and Ribavirin are also contraindicated during cancer treatment due to overlap toxicity with chemotherapy and the unknown effects of interferon on lymphoproliferative disorders.  Protease inhibitors shouldn't be used in patients with Child-Pugh B or C decompensated cirrhosis.

 

The differences in rates of diagnosis of HIV, linkage to care, retention in care, appropriate ARV treatment and successful viral suppression (the HIV care cascade) in Italy, the USA and the UK were highlighted by Dr Cristina Mussini from the University of Modena.  The rates in the USA were surprisingly poor relative to those of Italy and the UK, with a large percentage of HIV positive people being lost to follow-up, emphasising the importance of universal health care in improving accessibility of HIV treatment and management of the HIV epidemic.  

 

In a study of the HIV care cascade among 12 infectious diseases clinics in Italy in 2013, approximately 7-9% of patients were lost in each successive column of the care cascade, prompting discussion on how retention in care can be optimised - in particular, clinic protocols for systematically monitoring retention rates and contacting patients who don’t attend planned reviews.  A study done at Chelsea and Westminster Hospital in 2011 showed that of patients presenting late with opportunistic infections, 62% had had a positive HIV test previously but had failed to be retained in care. 

 

Dr Laura Waters reported on a study conducted in the USA using point-of-care HIV tests administered in pharmacies in the community.  Of 1000 tests done, 1.5% had a positive result, at an overall cost per positive test (new diagnosis of HIV) of around $30.  This may be a potentially cost-effective approach to improving access to HIV testing if high-risk groups are targeted.

 

Linda-Gail Bekker from the Desmond Tutu HIV Centre in Cape Town talked about a study currently underway of the use of PrEP in 300 female sex workers in South Africa.  She reported that between 45 and 70% of female sex workers in the region are HIV positive, making this a particularly vulnerable group.  Elsewhere it was reported that non-oral forms of PrEP (such as injection, implant or ring, if available) would be preferred by 55% of African women due in part to the stigma associated with taking anti-retroviral medication.

 

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

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