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.

In keeping with the main theme of the AIDS 2014 conference ‘Stepping up the pace’, the first day of plenaries, oral abstracts and symposia sessions (amongst many other activities) focused on the so-called ‘Holy Grail’ of HIV medicine – finding a cure!

This largely focused on how can we identify HIV viral reservoirs and how we can eradicate them. While much of the science presented seems well beyond the scope of primary care, I felt the theme underpins the current debate of whether commencing treatment sooner rather than later is of individual benefit.

The opening plenary by Salim S Abdool Karim (Director of the Centre for the AIDS program of Research in South Africa) summarised the global response to HIV/AIDS over the last 30 years and pleasingly showed a global decrease in the number of new HIV infections in adults and children since the early 2000s. Less pleasingly though was the noticeable decrease in condom use in MSM in Australia between 2007 and 2011.

He also did theorise that the concept of elimination and eradication is not readily applicable to AIDS with the millions of people living with HIV/AIDS and that there is no cure available and that the key to the end of AIDS is ‘epidemic control’.

Jintanat Ananworanich, a paediatrician, immunologist and HIV researcher and now the Associate Director of HIV Therapeutic Trials at the US Military HIV research program in Maryland, USA, then outlined where we are in terms of an HIV Cure and where are we going. She introduced us to the concepts of the persistence of HIV in latent reservoirs and the difficulties of monitoring the elimination of HIV due to the fact that we do not have biomarkers to determine HIV remission.

She suggested that success will likely require combination approaches including early antiretroviral treatment.

This theme was continued in a special session on ‘The Future of Science in the HIV Response’ by Dr Anthony Fauci, Director, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethseda, USA, where he further outlined the complexity of the HIV reservoir in terms of having qualitative and quantitative characteristics. Qualitative components including the body (e.g. gut, peripheral lymphoid cells, brain), cell type (naiive and memory CD4 cells, monocytes, macrophages and follicular dendritic cells) and the status of the virus (defective or replication competent) and the quantitative aspect simply indicating the quantity of viral reservoir which increases after infection.

HIV viral latency is believed to form very early in HIV infection and the various methods to eradicate HIV include:

  • ‘flush out’ the virus or the so called ‘shock and kill’ method (use of latency activator therapies such as Panobinastat)
  • immunotoxic therapy
  • stem cell transplant
  • gene therapy to eliminate CCR5 (Zinc-finger-nuclease modification of CCR5)

Dr Fauci also emphasised that a combination approach would be needed to achieve sustained virologic remission; early treatment initiation would “stack the deck in favour of eradication” by limiting the seeding of the reservoir, while use of novel immunotherapies (including passive transfer of HIV specific antibodies or therapeutic vaccination) would help eliminate HIV and HIV-infected cells. In addition, he outlined that recent advances in our understanding of the ‘broadly neutralising antibody response’ as particularly important in controlling the virus.

These concepts were further discussed in an afternoon abstract session that will be covered in another post.

 

 

 

 

 

 

 

 

 

 

 

 

Tagged in: AIDS 2014 IAS2014

Katherine Luzuriaga presented data showing that early cART (initiation before 6 weeks of age) leads to a restricted latent reservoir of HIV, and although the reservoir decays over 2 years, HIV remains detectable. There continues to be a 4-12 fold reduction in this latent HIV reservoir from 2 years through 14-18 years of age. Abstract #53

Early effective cART in infants leads to:

- clearance of HIV specific antibodies

- durable HIV RNA suppression

- markedly reduced HIV related mortality

- preservation of immune function

- lack of viral evolution over time in replication competent virus

- reduced HIV infection of long-lived CD4+ T CM cells

The use of early ART does not distract from the need to focus on preventing HIV transmission (viz. there were 260,000 new infant infections worldwide in 2012)

Tagged in: CROI2014

HIV-1 infection and Type-1 interferon

The interaction of HIV-1 and Type-1 Interferon (IFN-1) is complex. High levels of IFN-1 during acute HIV infection results in viral suppression. Administration of IFN-1 in primary infection can result in a drop in viral load, but this effect is not seen if administered later in the disease course and there is variability in response between individuals. Continued elevation of IFN-1 in chronic HIV infection is associated with long-term immune dysfunction, including viral expansion and T cell depletion. Abstract #119

 

Early treatment in acute SIV Infection limits the size and distribution of the viral reservoir

Compared with starting ART at 6 weeks after infection, initiating treatment at 7 days post-infection results in a 2-log decrease in peak viral load. Initiation at 10 days results in a 1-log drop in peak viral load. Researchers also found early initiation of treatment led to improved viral control, suppression of cell associated viral RNA, and decreased levels of SIV DNA in circulating lymphocytes, suggesting a lower established reservoir of SIV in CD4 memory T cells. There was a direct correlation between peak plasma viral load and total SIV DNA in peripheral blood mononuclear cells (PBMC) at 32 weeks. Very low levels of replication competent virus were found in circulating lymphocytes of early treated animals. Viral rebound still occurs after prolonged control in these early treated animals, but there was a slower dynamic of rebound, suggesting a degree of immune mediated control. Abstract #136LB

 

CD4 T cell subset composition reservoirs in gut, lymph node and blood during HAART 

Higher levels of HIV DNA were found in rectal mucosa, particularly in CD4 T EM cells. Peripheral blood showed a higher percentage of HIV DNA in CD4 T CM cells, and lymph nodes demonstrated a greater percentage of infected naïve CD4 T and CD4 T TM cells. Abstract #137

 

Proliferation of cells with HIV integrated into regulatory genes is a mechanism of persistence

HIV was found to be frequently integrated into multiple chromosomal sites, particularly into genes that control cell activation, differentiation and proliferation. The results from the study strongly suggested that the genes disrupted by HIV integration may impact cellular proliferation and survival. Proliferation of these infected cells with disrupted DNA contributes to the persistence of HIV in cellular reservoirs, particularly as the integrated HIV modifies gene function, facilitating prolonged persistence of specific infected cells. Abstract #138


"Kick and Kill"

The use of latency reversal agents (LRA) such as Histone Deacetylase inhibitors (HDACi) are being investigated to purge latently infected T cells. The theory is to reverse the latency in the infected cell, then induce an immune response to kill the cell. Researchers are finding that combinations of LRA may be required, as single agents may be insufficient to force the cell into expressing viral markers. Also, although initial administration of an LRA (Vorinostat studied in this case) may cause a transient burst in transcriptional activity, prolonged administration over 14 days results in compensatory mechanisms associated with transcriptional repression and cell survival. Abstracts #139 and #140

 

Cyclophosphamide (CTX) enhances SB-728-T engraftment to levels associated with HIV RNA control

CCR5 is a major co-receptor for HIV entry into cells. As found in the Berlin patient and two Boston patients, the CCR5 Δ32 mutation produces non-functional proteins where homozygotes are resistant to HIV infection and heterozygotes have slower disease progression. Researchers used CTX to enhance the engraftment of CCR5 modified autologous CD4 T cells transplanted into HIV positive subjects on ART. Subjects achieved a reduction in HIV viral load after treatment interruption, but this was not sustained. Abstract #141

 

Stimulation of subdominant cytotoxic lymphocyte (CTL) response is required for the elimination of HIV-1 latent reservoir

Plasma HIV-1 develops CTL escape mutations to evade the body's immune response. CD4+ T cells infected by these escape variants are insensitive to epitope-specific CTL clones, but can be killed by a broad spectrum CTL response. Research is underway to identify and stimulate subdominant CTL clones in chronically infected patients which can recognise and kill autologous target cells infected with these escape variants, and eliminate the latent viral reservoir. Abstract #142

 

Dendritic cell bases HIV therapeutic vaccine increases residual viraemia in individuals on ART

Vaccination with an autologous dendritic cell-HIV vaccine did not prevent viral rebound after treatment interruption and caused increased residual viraemia in 40% of subjects despite continuous ART. The vaccination may actually increase HIV-1 replication or expression from latent reservoirs. Abstract #143

 

HIV-1 rebound following allogenic stem cell transplantation and treatment interruption. 

Two subjects underwent allogeneic hematopoietic stem cell transplantation (HSCT) from CCR5 wild-type donors, while remaining on ART. With HIV-1 remaining undetectable from blood and rectal tissue biopsy from large samples of PBMC, analytical treatment interruption (ATI) was performed. One patient had no detectable virus for 3 months and the other for 8 months before viral rebound occurred. Both patients developed symptoms of acute retroviral syndrome. Symptoms rapidly resolved with initiation of active ART with subsequent viral suppression. Researchers propose that long-lived tissue reservoirs, such as host macrophages that may be replaced more slowly than T-lymphocytes following HSCT may have contributed to viral rebound. Abstract #144LB

 

Impact of Systemic Cytotoxic Chemotherapy for Malignancies On HIV-1 Reservoir Persistence

HIV infected individuals undergoing cytotoxic chemotherapy for malignancies (including haemopoetic malignancies) were studied for the persistence of HIV reservoirs. Generally there was a persistence of peripheral blood reservoirs, although decreases in CD4+ T cell associated HIV-1 DNA were seen. Chemotherapy may have an impact on the viral reservoir size, but the effect depends on the type of malignancy, chemotherapy given and viral factors. Abstract #418

Tagged in: CROI2014

HPV Vaccines: Progress to date and future worldwide directionsAbstract #19

Douglas R. Lowy presented on current effects of HPV vaccination and future directions for second generation vaccines. Interestingly, the current HPV vaccine has unprecedented immunogenicity for a protein based sub-unit vaccine. Even with one dose, persistence of antibodies to HPV 16 lasts for around four years. However, the antibody effect is orders of magnitude lower than if 2 or 3 vaccines are given.

Administration of two vaccine doses has just been licensed in Europe for the bivalent (Cervarix) vaccine and approval is expected soon for the quadrivalent Gardasil.

Second generation vaccines are expected to provide broader protection and/or be less expensive. Examples of possibilities are simplified administration regimens (e.g. add HPV 16 L1 to measles vaccine) or broader protection against more serotypes.

Merck is currently trialling a 9-valent vaccine with the 5 next most oncogenic HPV subtypes 45, 31, 33, 52, 58. So far results look promising.

Currently, HPV vaccines are against L1 proteins, which are serotype specific. Future possibilities are for vaccines against HPV L2 proteins, which contain cryptic cross-neutralisation epitopes. If a successful vaccine was created, then there is the potential for a pan-HPV vaccine. However, no vaccine has ever been developed against cryptic epitopes.

 

Response to early ART initiation in infants - Abstracts #922, #923, #924, #925, #926

This series of presentations demonstrated the role for early ART in infants. Where there is early treatment, infants become seronegative. Use of antibody status should not be used for diagnosis of HIV if ART started before 6 months of age. Where there is older ART initiation, infants show higher anti-gp120 IgG, which is associated with higher cumulative viral loads.

The age of ART initiation influences the degree of viral suppression and virologic control after viral suppression (better results where initiation is before 6 months of age).

Early viral suppression also correlates to better neurocognitive outcomes in HIV infected children with better testing scores (WISC III and IV), which becomes statistically significant around age 4-5 years.

An interesting point raised that the lack of antibodies in early treated infants reflects a lack of inflammation or immune activation. This may represent a functional cure, and may lead to better clinical outcomes.

Tagged in: CROI2014

Hi. I'm Ken Hazelton, a GP S100 prescriber from Orange NSW, and the grateful recipient of an ASHM scholarship to CROI,  Boston 2014. HIV is important to my daily General Practice, but not my main work.

I don't  think my blog is for anyone who is full on with HIV medicine, I think it might be of more interest and relevance to GPs who see a few patients or are interested in where HIV is going, and who might relate to the things that get my attention.

Having cleared the decks.....day 1 of CROI started with positive messages about the likelihood, sometime, of a cure for HIV. The qualification was that cures would probably start with subgroups like babies, and that there are still major barriers to eradicating the last of virus from reservoirs in lymph tissue and macrophages. The famous cure of Tim Brown, the  "Berlin patient", is a one off, involving whole body irradiation and 2 sequential stem  cell transplants from a donor with a HIV-favourable genotype. None of this is feasible for others, as fascinating as it is medically.

The other really interesting but frustrating session for me was an interactive Hepatitis C treatment decision panel. The annoying thing was the right answers from a US perspective were always Sofusbuvir and Semepravir, and that Telepravir and Bocepravir were old hat. This was on the basis of inferior effect, and much nastier side effects, but the latter two are the agents we are only now getting funded access to in Australia. More another day.

Tagged in: CROI2014

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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