Dr Michael Seah

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.

Michael Seah

Michael Seah

Mike is a general practitioner and community s100 prescriber at Gungahlin Family Healthcare in Canberra. He has been involved in the clinical care of HIV positive people since 2003. Mike works closely with other health and community providers in Canberra to coordinate HIV care. He has participated in the panel adapting the US Antiretroviral Guidelines and lectured on lesbian, gay and transgender issues in the Australian Defence Force. Mike has a strong interest in men's health, HIV treatment and sexually transmitted disease prevention.

I tried something a little different this afternoon. The conference venue set up a simulcast of all concurrent sessions in a theatre-like venue with six screens displaying the slides from each session. Audio was provided by personal channel-selected headphones, much like the system used in some gymnasiums broadcasting TV audio to users. It was a great way to flick between sessions rather than having to run between rooms. Despite this great technology, the human limitation still applies, and you can only pay attention to one presentation at a time!

The themed discussion afternoon consisted of 4 or 5 short presentations, following by robust discussion with the audience. The session on CNS treatment strategies addressed the issue about HIV and the CNS, in particular the issue of the potential for neurocognitive deficits to persist despite apparent complete viral suppression on ART. This effect is likely due to reservoir seeding to a sequestered site, resulting in ongoing immunogenitic and inflammatory effects of HIV, as discussed at other points at the conference.


The CNS is an early target for HIV. HIV-associated Neurocognitive Disorder (HAND) encompasses the spectrum of disorders related to HIV infection and AIDS, and includes disorders of varying severities. What is known is that early identification and treatment improves HAND, and ART improves established HAND.

A study into whether delays in ART initiation would impair neurocognitive function compared initiation immediately after infection with a 24 week delay. Interestingly, early initiation led to a greater improvement in neurocognitive function over time. The observation has important implications to clinical practice and in discussions with patients about when to start treatment. Early ART initiation may prove to be an important treatment strategy to decrease the severity of HAND or lead to better improvement in HAND.  [TD-380]


 

The next presentation looked at the cognitive trajectories over 4 years of HIV positive women with optimal viral suppression. There was a lower baseline cognitive function in several neurocognitive domains (attention, learning, memory and global functioning) in the HIV infected group compared with demongraphically similar uninfected women. The difference observered was at least one standard deviation worse across these domains and persisted over time. In the domain of motor skills, where there was no difference at baseline, a decline was observed over the 4 year period.

In comparing women who were virally suppressed with those that were not, in some domains (eg. global function) there was no difference in the measured decline over time. Interestingly, in some domains (eg. attention and fluency) virally suppressed women actually performed worse than non-virally suppressed women.

The difference at baseline may be attributed to co-morbidities such a susbtance use, trauma and psychological risk factors. These, combined with a low cognitive reserve, are hypothesised to be contributing to accelerated CNS ageing.

The vulnerabilities in various neuropsychological domains provides a framework for further study into the pathophysiology of the CNS damage observed. Clinically it is important to understand how co-morbidities in HIV infected individuals may be contributing to the HIV specific effects.  [TD-350]


 

CCR5 blockade using Maraviroc intensification has been shown to improve cognitive performance in HIV infected adults on ART. CCR5 binds multiple chemokines and is a co-receptor for HIV.

Cenicriviroc (CVC) is an new oral dual CCR2 and CCR5 antagonist. CCR2 is a chemokine receptor for the monocyte chemoattractant MCP-1. Monocytes have been implicated with contributing to HIV-associated Neurocognitive Impairment (HIV NCI). In ART naive HIV infected adults, CVC has been shown to decrease viraemia and soluble CD14 levels (CD14 is a marker for monocyte activation). Additionally, in animal models CVC has been shown to have anti-inflammatory and anti-fibrotic activity.

The pilot study hypothesised that CVC will improve cognitive function in HIV NCI by reducing monocyte activation. The sample cohort was older (average age 55), ART experienced (average 16 years on ART) and had low cognitive performance at baseline. Depression was an exclusion criterion. Neuropsychological testing was conducted at entry and at 24 weeks, along with plasma markers of monocyte activation (neopterin, soluble CD14 and sCD163).

The study observed that CVC intensification improved global cognitive performance, along with specific improvements in the neurospsychological subdomains of working memory and attention. There was a positive trend seen in the domains of psychomotor speed and visuospatial. Monocyte activation was significantly decreased with all three markers measured, with a trend seen between neopterin and working memory scores.

Although only a small study (17 participants) the results are certainly promising. Even in virally suppressed, ART experienced individuals, the measured improvements in cognitive function at 24 weeks suggests that HIV NCI may be treatable. Additionally, neopterin may be a predictor of improvement in working memory. A larger randomised control trial in HIV infected people with cognitive abnormalities is required to explore these effects further.  [TD-381]

Tagged in: CNS CROI 2017 HAND

 

Dr Carl June presented how novel therapeutics have the potential for an HIV cure. His work in the development of Chimeric Antigen Receptor (CAR) T cells have been instrumental in the cure of lymphoid malignancies. There are similarities in CD4 cell dysfunction between cancer, which causes exhaustion of T cells, and HIV, which causes deletion of HIV specific cells.

CAR T cell therapies use synthetic biology, tools of genetic engineering and genome editing to install a competent immune system into an immunocompromised host. In cancer therapy, an individual's T cells are harvested and geneticically engineered to make the T cells stably express CAR, conferring novel antigen specificity. They are reinfused into the patient to become personal "serial killer" cells. In almost 400 patients accumlating 1500 patient years, there have been no acute T cell toxicity events (ie. no conversion to acute leukaemia). Success has been seen out to 5 years with complete cure of a paediatric patient with advanced ALL and an older adult with extensive CLL.

Unfortunately there are no CAR T cell trials in HIV currently in progress, but it is likely to be an area of future research, with work towards an HIV cure.

The issues faced with this sort of technology are based around time, cost and the need for an individual's cells to be genetically engineered for each patient. Consideration of a blood bank model or central manufacturing strategy could advance implementation. Automated genetic engineering methods could allow CAR T cell treatments to be scalable, with lower coats and increased access. A government-industry-philanthropic partnership for combined funding could be a way ahead.

Links to:
Video and slides
Audio and slides
Audio only

Tagged in: CROI 2017

Oral session 38: Discovery of a novel potent HIV Capsid inhibitor

GS-CA1 is a first-in-class small molecule Capsid (p24) inhibitor. GS-CA1 was demonstrated to be more potent than EFV, DTG and ATV with no measurable toxicity in target and non-target primary cells. It was also highly active against major HIV mutations, with high breadth and potency of action. The inhibitor acts at multiple steps in the HIV replication cycle, impairing Capsid core assemble, core disassembly and nuclear transcription. The binding site to the Capsid is highly preserved, and while resistance has been demonstrated, the HIV mutations have reduced fitness compared to wild-type HIV.

A single subcutaneous dose in rats have shown maintained plasma concentrations out to 10 weeks. The compound shows promise as a long-acting, low-dose monthly injection in humans.

Oral session 39: Confirmation of oral dose reduction potential of nanoparticles

Solid drug nanoparticles (SDN) have shown promise as a method to reduce drug dosage while maintaining therapeutic exposure. SDN Lopinavir and SDN Efavirenz were studied using population pharmacokinetic modelling strategies. Both formulations proved well tolerated at the studied doses. With the potential of a 50% dose reduction, there is an estimated saving of USD$243 million per year

Oral session 40: Pharmacology of the HIV integrase strand inhibitor Bictegravir and Oral session 41: Randomised trial of Bictegravir or Dolutegravir with FTC-TAF

Bictegravir (BIC) is a novel integrase strand transfer inhibitor (INSTI) that is currently in Phase 3 trials. The medication has been demonstrated to have low toxicity, no effect on the QT interval and no impact on glomerular filtration. It is well absorbed (>70%) and is highly plasma protein bound (>99%). It primarily circulates as the parent drug, with clearance through oxidation (CYP3A4) and glucuronidation (UGT1A1). There is low potential for drug-drug interactions, but as with all INSTIs, they are chelated by cation-containing antacids. Therefore administration should be staggered by at least 2 hours with antacids. BIC itself does not inhibit or induce CYP3A4 or UGT1A1. Phase 2 trials developed as a single tablet regimen with FTC/TAF demonstrated that there was improved bioavailablity and a reduced food effect for the 75mg dose of BIC chosen. Therefore the dose of BIC was reduced to 50mg for Phase 3 trials, with a formulation of BIC/FTC/TAF of 50/200/25mg.

A double blind randomised control trial of BIC vs DTG with FTC/TAF demonstrated the study drug being 97% successful at achieving virologic suppression after 24 weeks and 48 weeks. There was no statistically significant difference in the outcome between the study and control drug formulations. No resistance to study medication was detected in either arm of the study. There was a rapid and robust CD4 response in both arms. Adverse events, grade 2 to 4 laboratory abnormalities and mild changes to eGFR were similar in both groups.  The trial demonstrated BIC/FTC/TAF is safe and well tolerated

Oral session 43: Prevalence and impact of pretreatment drug resistance in the ANRS 12249 TASP trial

Early initiation of ART and improved access to HIV care will lead to long-term decreased morbidity and mortality. However, there is a concern regarding an increase of pretreatment drug resistance (PDR) could lead to a delayed time to viral suppression and an increased risk of virological failure after ART initiation. New advanced technologies - Next Generation Sequencing (NGS) - have become available for low-level variant detection (at around 1% viral population), however their impact on ART outcome is still controversial.

There has been limited study of PDR in low to middle income populations or resource limited settings. The ANRS 12249 TASP trial was established to evaluate the effect of early ART, initiated irrespective of CD4 count, on HIV incidence in the general population in the same setting. The study is being conducted in the KwaZulu-Natal province of South Africa. ANRS 12249 TASP included an analysis of PDR in chronically infected and and recently infected participants. The definition of PDR used was >20% of viral population, with separate analysis using NGS of resistant virus at 2% levels. 

The prevalence of PDR detected was about 9% in both recently and chronically infected participants, with two times more low-level variants detected with NGS. NNRTI use is mostly compromised by PDR but NRTIs are still active. About 10% of PDR have multiple drug resistance (3 or more up to 7), suggesting previous exposure to ART. Interestingly, PDR did not significantly impact the cumulative probability of achieving virologic suppression at the 12 months mark, with around 95% of subjects virally suppressed at 12 months, regardless if PDR was present or not. The two consistent predictors of poor viral suppression remain high baseline viral load and poor adherence. 

Oral session 44LB: Phase III SWORD 1 & 2 SWITCH to DTG+RPV maintains virologic suppression through 48 weeks

With the high resistance barrier of DTG, SWORD 1 & 2 evaluated whether the 2-drug regimen of DTG+RPV once daily was as effective as traditional cART. The primary endpoint at 48 weeks was a snapshot of subjects with a viral load <50 copies/mL. 

The 2-drug combination demonstrated non-inferiority to cART with comparable viral suppression rates, similar rates of adverse events, a neutral effect of lipids and a statistically significant improvement in bone turnover biomarkers. There were two confirmed virologic failures in both study groups, however no integrase resistance was found.

The study supports DTG+RPV being filed as a treatment regimen and leads the way for exploration of other 2-drug regimens in the future.

Oral session 45LB: Doravirine is non-inferior to Darunavir/r in Phase 3 treatment-naive trial at week 48

Doravirine (DOR) is a novel next generation NNRTI with a unique resistance profile, low potential for drug-drug interactions and can be taken once daily without regard to food. A Phase 3, multi-centre, double-blind randomised control trial was conducted in treatment naive HIV-1 infected adults. DOR was compared to DRV/r in combination with TDF/FTC or ABC/3TC. The demographics of study participants were almost identical in both arms of the study.

There was no genotypic or phenotypic drug resistance observed in participants with protocol defined virological failure through week 48. One participant discontinued due to noncompliance at week 24 and developed DOR resistance. Approximately 80% of subjects experienced one or more adverse event, with about 30% having drug-related adverse events. Study discontinuation was 2-3% due to adverse events. Similar proportions experienced adverse events of clinical interest -  rash (7-8%) and neuropsychiatric (11-13%). DOR had a neutral effect on lipids compared to DRV/r

DOR demonstrated potency with non-inferior efficacy with a low rate of resistance (1/383 subjects). DOR is generally well tolerated and safe. 

Tagged in: CROI 2017

Dr Jintanat Ananworanich presented the first plenary session on the emerging potential for an HIV cure. She disussed how information gained from adult and infant studies showed that early treatment, rapid viral suppression and sustained seronegativity results in less reservoir seeding and an extended time to viral rebound following cessation of ART. This has important implications for targeting persistent virus, particularly replication competent virus.

Early attempts at a "shock and kill" strategy have been unsuccessful at significantly  decreasing the amount of reservoir virus or killing affected cells. Fture strategies are likely to employ the use of multiple Latency Reversing Agents (LRA), the use of new classes of LRA and combination use with immune therapies. Trials in animal models using a TLR7 agonist with Ad26MVA vaccine demonstrated promise in animal models, with a reduced viral load in monkeys infected with SHIV following ART discontinuation.

Preliminary trials of VRC01, a broadly neutralising antibody (bNAb) has also shown to be ineffective. However, the more potent VRC07-523LS bNAb, combinations of bNAbs or combination with vaccines are more effective approaches being tried. A combination of VRC07+PGT121 (a vaccine) given to infant macaques 1-2 days after SHIV infection led to a complete clearance of the virus.

The final messages Dr Ananworanich presented were that new methodologies need to be considered in order to facilitate research, notably

  • Consider parallel animal and human studies for combination therapies;
  • Testing combinations with the same animal model;
  • Streamlining the regulatory pathways for the use of agents for different indications; and
  • Conducting psychosocial research concurrently with scientific studies

 

Tagged in: CROI 2017

Posted by on in Uncategorised Posts
CROI 2017: Opening Session

Dr Susan Buchbinder opened CROI 2017 with a powerful statement rejecting the recently halted US Presidential edict restricting entry into the US from seven Muslim majority countries. Apart from the obvious human rights aspect of the ban, the major impact of the travel ban would be on the free exchange of scientific information. The statement was particularly meaningful given that Federal Judge James L. Robart who launched the temporary restraining order is from Seattle.

Bernard Fields Lecture

Dr Jeffrey Lifsom presented the Bernard Fields Lecture on insights into HIV prevention, pathogenesis and treatment from non-human primate (NHP) models. Dr Lifsom helped develop the highly sensitive quantitative assays for HIV and SIV that are currently used in research and management. Drawing on Dr Bernard Field's work, Dr Lifsom described how NHP models had contributed to the understanding of HIV with respect to:

  • Transmission: eg. how early distal SIV RNA found in mucosal transmission correlated to tissue changes found in HIV
  • Pathogenesis: eg. the discovery of the gastrointestinail system as a major site of CD4 T cell and viral replication for SIV infection, which was subsequently extended to HIV in humans. In particular, how epithelial disruptions resulted in immune activation and inflammation that was not fully reversed or restored by ART
  • Vaccines: eg. the use of a CMV vectored SIV vaccine to provide a persistent immune response, demonstrating that an unconventional response appears to result in enduring protection. This may lead to the promise for novel vaccines, including for other intracellular infections such as TB and malaria.
  • Treatment: eg. the use of injected TFV/PMPA in NHP models was critical in the decision to develop orally bioavailable TDF. More recent developments are the use of a highly effective long-acting triple drug regimen which will influence treatment strategies.
  • Viral Reservoirs: eg. The role of immune privileged B-cell follicles and clinically expanded T-cell clones with the persistence of SIV and HIV infections

Dr Lifsom concluded by saying that thoughtful selection of NHP models matched to the question of interest can provide experimental advantages and yield important insights.

N'Galy-Mann Lecture

Dr James Hakim, prominent researcher and clinician from Zimbabwe presented a fascinating insight into how his country turned around a devastating medical and socioeconomic epidemic to be one of the leading research areas in the world for HIV today.

In 1986 Zimbabwe had an HIV prevalence of 29%, with an incidence of 4.7%. This has been turned around to a prevalence today of around 14%, with an adult incidence of 0.48%. There has been a significant collaboration with international organisation to implement a robust research agenda and build capacity in the Zimbabwean health and research workforce. The initiatives of PEPFAR and NIC have invested significantly in sub-Saharan medical schools, to empower them with an improved qualify of education, leadership and research capability.

One of the most disturbing statistics that Dr Hakim presented was that Africa has 24% of the world's disease burden with only 3% of the world's health workforce. Ongoing support and collaboration is required to continue progress towards the UNAIDS 90-90-90 targets - noting that in 2016 Zimbabwe is tracking at 74.2/86.8/86.5 against those aspirational targets - a remarkable achievement given when the country started from some three decades earlier.

Special award

The delegation was treated to a performance by Mr Oliver Mtukudzi, a musician and human rights ambassador who has championed the cause of HIV/AIDS in Zimbabwe. He was given a special award for his contribution towards raising the awareness of HIV/AIDS, and trying to reduce the stigma of the disease through his music. In his words, "Art speaks to people's conscience"

Tagged in: CROI 2017

Serena Spudich presented information about HIV infection causing ongoing active injury to the central nervous system (CNS) - comprising the brain, meninges and cerebrospinal fluid (CSF) - despite antiretroviral therapy (ART). Abstract #66

CNS injury can be measured by:

- Neurocognitive testing: persistent milder forms of HIV associated neurocognitive disorder (HAND) can be demonstrated in 18-50% of individuals on ART.

- Inflammatory biomarkers: examination of CSF shows elevated levels of neurofilament light chain (NFL) which is a marker for axonal injury marker

- Neuroimaging: structural or functional imaging shows persistent abnormalities of HIV positive individuals on treatment.

 

The mechanism of CNS injury is unknown, but is likely multifactorial:

 

- CNS injury prior to treatment. HIV is brought into the brain by infected lymphocytes (and perhaps infected monocytes) in the setting of immune activation. The viral load of CNS HIV is reflective of the plasma HIV levels in primary infection. Infection of brain cells occurs, with immune activation of microglia and macrophages, leading to breakdown of the blood brain barrier and release of cytokines. This results in axonal death and further HIV infection and mutation in the CNS of susceptible cells.

- Persistent compartmentalised infection. Despite suppressed plasma viral load, researchers can still demonstrate detectable virus in the CSF ("CSF escape"). Active CNS replication of HIV occurs despite apparent peripheral control. HIV in the CNS undergoes distinct evolution, with analysis of CSF showing that CSF HIV is distinct from plasma HIV during suppressive ART.

- Ongoing immune activation. Elevation of inflammatory biomarkers such as neopterin (a derived product of activated monocytes and macrophages in the brain) demonstrate ongoing immune activation.

- Contribution of vascular disease. Vascular immune activation and/or co-morbid risk factors contribute to vascular disease in HIV positive individuals on ART. Higher stroke rates are seen in HIV positive women and younger patients, compared to their HIV negative counterparts.

- Acceleration of normal brain ageing. Normal brain ageing may be accelerated in the setting of HIV and ART, with increased macrophage activation and increased permeability of the blood brain barrier.

- Effect of co-morbidities. Higher rate of cognitive impairment are seen in HIV positive individuals with concurrent depression and substance abuse.

- CNS penetration of antiretrovirals. Antiretroviral medications with higher CNS penetration show lower CSF viral loads, but this may not reduce the risk of CNS disease. 

 

Additionally, the use of mono/dual therapy may increase risk of CSF escape. Potential neurotoxicity is only seen with particular antiretrovirals such as efavirenz.

Apart from the persistent smouldering immune activation in the CNS compartment, viral latency and integration may be important. HIV-1 DNA can be found in microglial cells, macrophages and astrocytes. Animal models show that by day 4 of primary infection with treatment, SIV RNA is no longer found in CSF, but SIV DNA can be demonstrated.

In the future there may be the ability to block HIV entry into CNS during primary infection. While the exact reasons for CNS perturbations is unknown, and likely multifactorial, there is plenty of opportunity for further research.

Tagged in: CROI2014

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

Injectable GSK744 LA (long acting) is an analogue of Dolutegravir currently undergoing trials as a potential PrEP agent. Abstracts #39 and #40LB

Trials in rhesus macaques showed it to be 100% effective as PrEP. Quarterly injections protected against rectal SHIV infection, while monthly injections were protective against repeated vaginal exposure. 

Proposed dosage in man would be quarterly 800mg of GSK744 LA IM injection. Presented as 200mg/mL, it would be given as divided doses - 2x2mL gluteal injections).

Clinical evaluation in high risk MSM with phase 2 safety & tolerability trials begin in the northern hemisphere spring 2014.

Dapivirine (DPV) & Maraviroc (MVC) vaginal rings were trialled as a PrEP device in the MTN-013 study. Vaginal rings provide sustained drug delivery, minimal user action is required and they are discrete. The rings were well tolerated with primarily mild to moderate adverse effects. Abstract #41

With DPV, 100,000 fold higher concentration of drug was found in vaginal fluid compared to plasma. The levels of DPV in cervical tissue dropped to below the lower limit of quantification (LLOQ) 3 days after ring removal. Vaginal MVC levels were 2-4 times lower than DPV, and MVC plasma levels and cervical tissue were below LLOQ.

Researchers found that the anti-HIV activity of DPV ex-vivo from cervical biopsies correlated to the concentration of drug.

In the FAME-02 study, DPV film and gel were trialled as delivery mechanisms for vaginal PrEP. Abstract #42LB

Films were akin to Listerine strips that dissolve on contact. Researchers found that subjects had difficulty using the film, with sticking to the finger and poor placement noted on follow up. Cervical levels of DPV were equivalent to 1 month of vaginal ring use (10^6 pg/mL). Vaginal drug levels were about 4 fold higher - reflecting tissue surface adherence. Similar plasma levels were seen for both film and gel, comparable to the vaginal ring.

This study could provide lower cost, on demand PrEP for women. Modified film size/shape could improve placement issues.

Tagged in: CROI2014 PREP

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

 

Illicit drug use and HIV

Adeeba Kamarulzaman from Malaysia presented on HIV in people who inject drugs (PWID). Due to time constrains, PrEP and HCV co-infection was not discussed. Abstract#20

Overall illicit drug use causes 1% of global disease burden and is the 8th largest contributor to years lost to disability among males. In countries where HIV incidence is increasing, 70-80% of HIV cases are among PWID.

Effective strategies such as needle exchange programs and opiate substitution therapy have been shown to be effective in several countries. However, worldwide there is poor overall implementation of such programs. Globally for every 100 PWID only 8 are on opiate substitution therapy, and only 2 needles per PWID per month exchanged.

There are unmet needs amongst further marginalised groups - notably women, adolescents and men who have sex with men (MSM) drug users.

Prisons are a high risk environment for the ongoing transmission of HIV and other infectious diseases such as TB. Prisons do present an opportunity to treat, and when treated, AIDS related mortality reaches parity with the general population. However, this effect is not sustained once prisoners are released, as continuity of care cannot be guaranteed.

Treatment can be used as prevention in high income countries - as shown by studies in Vancouver and Baltimore. This is more difficult in lower income countries, where active drug injection, incarceration and lack of an HIV care provider result in poorer adherence to ART and poorer HIV suppression.

Addressing the stigma of addiction and HIV among PWID will not only have benefits for individuals, but lower the overall burden of disease for a country, leading to positive economic outcomes.

 

Effect of ART early in HIV infection

Increasingly the role of ART initiation at or soon after primary infection is gaining significance. Not only does early ART result in a higher chance of post-treatment control, but preservation of the immune system is seen, with more chance of a higher CD4 level and CD4/CD8 ratio ≥1. Correspondingly, there is a lower HIV reservoir established, with the potential for "functional cure".

Early HIV control is important because many of the long-term effects of chronic HIV infection and ART are related to chronic immune activation for example, diverse conditions such as cardiovascular disease, neurocognitive effects and various cancers.

 

Tagged in: CROI2014

Attending my first CROI in Boston, I am amazed by two things. Firstly, how cold it is during the day. I'm sure my eyeballs were going to freeze walking to the conference venue. More of that to come - it's only reaching a maximum of 0 degrees Celsius all week. At least the locals are warm and friendly.

Secondly, the scale of CROI is enormous. Over 4000 delegates this year and the main auditorium is imposing for any speaker. Thankfully there are large screens and excellent amplification. You can still sit way down the back and still see/hear what's going on.

This evening, Dr Paul D. Bieniasz from the Aaron Diamond AIDS Research Center presented the Bernard Fields Lecture on "Making and Breaking Barriers to Cross-Species HIV-1 Transmission". 

The lecture centred on the role of intrinsic host cell factors that directly inhibit viral replication. They work through a diverse mechanism of actions on invariant or genetically fragile viral features. For HIV these defences are called restriction factors. A number of restriction factors have been studied as potential inhibitors of HIV replication. Tetherin was used as an example - the expression of which causes retention of mature, fully formed infectious HIV-1 on surface of infected cells. Tetherin works by inserting its c-terminal anchor into viral envelope, trapping nascent HIV-1 virions by a direct tethering mechanism, leading to endocytosis and signalling.

The Research Center had created an artificial tetherin that was structurally similar but not the same protein sequence as the human protein. Remarkably, this artificial tetherin had action (not as good as real tetherin) to trap virions on the cell surface, preventing release of the virus and further viral replication.

However, viruses have evolved defence mechanisms to counteract these restriction factors. HIV has the Vpu protein that binds tetherin to overcome the cell's defence mechanism. The HIV-1 Vpu protein specifically evolved to work against human tetherin.

These defences are largely species specific, making it difficult to use animal models to study the actual HIV-1 virus. Many Simian immunodeficiency viruses (SIVs) do not encode a Vpu protein, and evolved a different mechanism - the Nef protein which interacts with simian tetherin via the protein's cytoplasmic tail.

Another HIV-1 restriction factor discussed was APOBEC3. APOBEC3 is antagonised by HIV-1 Vif proteins, which also has species specific action like Vpu. The researchers developed an HIV-1 strain with SIV Vif inserted that allowed the virus to replicate in pig-tailed macaque lymphocytes. Infecting successive groups of macaques, the researchers generated a terminal AIDS defining illness in phase 4 animals, when they artificially caused CD8 depletion at the time of infection using anti-CD8 antibodies. The phase 4 macaques developed a B cell lymphoma which showed marked CD4 depletion.

Interestingly, the HIV-1 Vpu in this modified strain adapted to antagonise the pig-tailed macaque tetherin, at the expense of the ability to antagonise human tetherin, providing an insight into viral mutation and cross-species infectivity.

Although Dr Bieniasz was hopeful on the ability to develop more realistic animal models for HIV-1, he cautioned against the use of such models for more advanced research such as vaccine development. While this adapted HIV-1 strain can cause AIDS in a non-hominid species, the adaptation is incomplete. Notably, in this experiment the researches needed to induce CD8 depletion at the time of infection, as the animal quickly adapted and post-infection depletion of CD8 was ineffective at inducing an AIDS defining illness.

 

Tagged in: CROI2014 IAS2013

RT @hepqld: Curing #hepatitis C is easy, and no longer needs a specialist to prescribe treatment. Community doctors play a pivotal role in…

ASHM ASHM