LIVE FROM ISHEID 2016: THURSDAY, MAY 26
On the beginning of the 2016 ISHEID’s second day Emerging Infectious Diseases were addressed once again particularly focusing on Ebola.
Armand Sprecher (Brussels, Belgium) described the experience of “Médecins sans Frontières” (MSF). MSF has been responding to Ebola since 1995. The west African 2014-15 outbreak implicated MSF to care 5226 confirmed cases. MSF activities included not only the care of patients but also training, clinical trials, transit centers and rapid response teams. This needs a lot of coordination and explanations to the populations that are sometimes afraid of care givers (8 individuals from MSF were killed by villagers). Dealing with clinical trails in such an emergency situation was not simple, both for treatment and vaccine trials. MSF also demonstrated that the death rate is correlated to viral load.
Abdoul Habib Beavogui (Maférinyah, Guinea) talked about the lessons learned from this last Ebola outbreak. The main challenge was that the health system was weak with difficulties to have access to confirmed biological diagnosis. There was also strong community reluctance to the measures of prevention. Lessons learned comprise that international and political involvement are crucial. Community involvement is inevitable and it is necessary to engage early the population and explain them what is going on unless they constitute a barrier to the efforts done. Increased and continuous vigilance is definitely necessary.
Jean-François Delfraissy (ANRS, Paris, France) emphasized the difficulties to implement research findings during health crisis. For the first time health crisis is now in the agenda of politicians, Professor Delfraissy said. He also spoke about REACTing, a new network in France to deal with emerging infectious diseases. It is not focused on one disease or one particular research area, and not focused on northern or southern countries. REACTing in action started with the 2013 Chikungunya outbreak in the French Carribean. During Ebola crisis, the Prime Minister nominated Professor Delfraissy as the coordinator of the French task force. This allowed to discuss and decide what research was to implement first. Favipravir trial was one of the trials chosen to move forward. But the dosage of the drug in the trial was too low. Professor Delfraissy emphasized that the time of the research is longer than the time of the health crisis. Cohorts in such crisis are also important because they allow to ask questions 2 to 3 years after the health crisis that were not evident initially, like the existence of Ebola persistence in some patients who recovered from the disease. Finally, REACTing also has several ongoing projects on ZIKA that affects the French Carribean.
The session ended with a presentation from Kristi Williams (Leiden, The Netherlands) from Janssen on the development of an Ebola vaccine. Durable immune response, both antibody response and T cell response, was demonstrated until 240 days after prime-boost.
Ndeindo Ndeikoundam (French Institute of Health Watch, Saint-Maurice, France) opened the oral communication session this thursday morning in Marseille. He presented his work concerning recent trends and characteristics of STI in men having sex with men (MSM) in France from 2012 to 2014. He used a case based STI surveillance of the National voluntary network of clinicians (STI clinics and hospital outpatient consultations) and laboratories. Between 2012 and 2014 896 cases of LGV (95% increase), 3164 cases of syphilis (47% increase) and 3648 cases of gonorrhea (98% increase) were reported. This increase of STI essentially concerned HIV+ patients with a higher median age, and resulted of unprotected anal intercourse with a casual partner.
Patricia Enel (Sainte Marguerite University Hospital, COREVIH POC, South-East Regional HIV network committee, Marseille, France) presented a cross-sectional study aiming at HIV screening by means of Rapid HIV Diagnostic Test (RDT) of people frequenting shows organized by the erotic industry. In 4 large French cities (Lyon, Paris, Rouen and Toulouse) 943 individuals frequenting erotic industry exhibitions were proposed an anonymous self-reported questionnaire and an HIV RDT. Characteristics of these individuals were: 606 men (64%), mean age of 26 years, 387 (41%) had never been tested for HIV, 615 (65.8%) declare having sexual relations without a condom over the past 12 months, 101 (10.7%) had used cocaine or snorted over the past 5 years and 688 (73%) had experienced abusive consumption of alcohol. Those who had never had an HIV test were statistically younger, more often male, report more frequently no sexual relations over the last 12 months and more often heterosexual relationships. Out of the 943 RDT, 3 tests were positive (0.74%). This study demonstrates that a commercial backdrop can be useful as a potential site of a campaign of HIV/STI information and HIV screening.
Mathilde Coudray (SIS Observatory department of SIS Reseau, Montpellier, France) described results of a study based on self-administrated questionnaires available on Sida Info Service website, the French HIV/AIDS helpline, in order to collect informations about healthcare experience of PLHIV over 40 years. Between July and October 2015 194 questionnaires were gathered and analyzed: 75.8% individuals were male, of a mean age of 52 years, a mean time since HIV diagnosis of 18 years, 97.4% were on antiretroviral treatment, for 12.5 years on average, 92.8% had undetectable viral load, and 62.9% reported at least one comorbidity (dyslipidemia, cardiovascular diseases, osteoporosis, cognitive impairment, renal failure and diabetes). Age, time since HIV diagnosis and time since ART initiation were factors significantly associated with comorbidities. Screening of comorbidities does not seem to follow the French guidelines.
Mark Wainberg (McGill University, Montreal, Canada) analyzed effect of the DTG-specific R263K resistance substitution on integration during long-term infections. After measurement of levels of HIV integration in in vitro short-term infectivity assays, this experience showed that R263K substitution impaired HIV integration and was associated with a progressive decline in levels of integrated HIV DNA. Even further impairments were noted if both the R263K and H51Y substitutions were simultaneously present, with statistically significant differences.
In Abstract 012, Pasternak et al wished to examine the relationship between HIV disease progression and markers that might serve to guide the likelihood that this might occur. They first showed that viral load at baseline was not always a good predictor of progression in the absence of treatment, based on results obtained with a cohort of patients from a decade ago or more who did not promptly initiate antiviral therapy at diagnosis. They harvested viral DNA and RNA from the buffy coats of 56 persons in the cohort and were able to show that the best predictor of disease progression was the level of multiply spliced (MS) viral RNA in the samples. Patients were followed in this study over 24 and 60 weeks and the level of MS RNA was an excellent inverse predictor of a normalization of CD4:CD8 ratios following initiation of therapy. They conclude that MS RNA in these patient samples is reflective of a state of active viral replication, which explains why persons with the highest such levels take the longest times to normalize CD4:CD8 ratios after initiation of therapy and are most prone to rapid disease progression in the absence of therapy.
Abstract 013 by K. Suphaphiphat and colleagues was on the topic of broadly neutralizing antibodies (bnAbs) and the role that these might play in prevention of HIV transmission in a SHIV monkey model. They showed that a combination of three bnAbs preparations was most effective in this regard at prevention of viral transmission by SHIV-infected splenocytes and free virus. One of these Abs, 2G12, seemed to play an essential role in viral neutralization. All of them are directed against SIV Env determinants.
Interestingly, the IC50 of these Abs for cell-free virus neutralization was considerably lower than that required for neutralization of cell-associated virus transmission. This suggests that these Abs have a higher affinity for relevant epitopes that are expressed at the viral envelope compared with the surface of infected cells. These scientists hope that their model may serve as a model for blockage of HIV transmission.
In Abstract 014, M. Salas et al (presented by M-C Gaudoin) assessed conditions governing infection by SIV of newborn macaques. They infected 12 animals with SIV in an effort to establish a model of pediatric HIV disease. They attenuated the SIV by variously deleting Nef and/or Vpr and/or the V1 and V2 regions of env. Animals infected with many of these viruses showed evidence of strong Ab and CD8 T cell responses as demonstrated by ELISPOT and other assays and also displayed attenuation of the viruses that were used, suggesting that certain of these viruses might have potential as vaccines. No evidence of reversion with the most attenuated viruses was evident. These data indicate that impaired CD8 immune responses that are commonly seen in SIV infection are probably due to wild-type SIV infection in these non-human primate neonates.
Abstract 015 by Castera-Guy et al dealt with the development of a rapid single-step PCR assay for detection and quantification of hepatitis delta virus (HDV) RNA. There is a compelling need for such a rapid, sensitive, specific test and these scientists have apparently succeeded, based on results obtained with a reference panel of more than 3000 samples obtained with HDV infection whose status was first ascertained on the basis of a more standard test performed at the French reference centre for HDV (CNR). This work, that was performed collaboratively between Omunis SAS, which is a private diagnostic company, and the CNR has the potential to advance the field. This test probably has potential for widespread sales in regard to HDV diagnosis, also because it can detect infection by 8 different genotypes and multiple subgenotypes.
The second part of Managing HIV Infection began with Lucy Dorrell (University of Oxford, Oxford, UK) who detailed new immunological tools for HIV research and monitoring. CD4/CD8 ratio is re-emerging as a useful indicator of immune reconstitution, and normalized in individuals who started ART in PHI (46.8%) compared with individuals who started ART ?6 months after HIV seroconversion (13.5%) (Thornhill J AIDS 2016). This parameter doesn’t inform us HIV-specific immunity, because most people experience viral rebound when they stop ART, despite important drop in reservoir cells (e.g. 3 log drop in the Boston patients that rebounded after treatment interruption). Rare HIV controllers constitute a human model of successful immune response, maintaining low or undetectable viral loads without ART, smaller HIV reservoirs, but with no single immune parameter accounting for HIV controller status. HIV-specific CD8+ T cell responses are detectable in most patients but fail to clear infection. Different studies show that the ex vivo antiviral inhibitory capacity of CD8+ T cells may predict the rate of CD4+ T cell decline (predominantly due to lysis of infected CD4+ T cells), as well as viral load set-point. This CD8+ T cell antiviral activity is explained by preferential targeting of regions of vulnerability (regions that are susceptible to loss of function upon mutation) within the HIV proteome and may be modestly boosted by therapeutic vaccination in chronic ART-treated patients. Immediate or early ART may preserve relevant HIV-specific CD8+ T cell functions. New strategies aiming at improving CD8+ T cell function or harness non-HIV-specific CD8+ T cells may be crucial to HIV eradication.
Laurent Cotte (Croix-Rousse Hospital, Lyon, France) accentuated the persistent need of PrEP because of persistence of a high number of new HIV infections and STIs in France, especially in high-risk populations such as MSM. He made a complete overview of the most important PrEP studies. The concept of PrEP arised from animal studies. The first demonstration of PrEP efficacy in humans came from the CAPRISA study demonstrating a reduction in the risk of HIV infection by 39%-54% in women treated with a tenofovir vaginal gel. IPrEx was a second large study in MSM and transgender women using daily TDF/FTC, a strategy that demonstrated a global efficacy of 44%. The overall safety of TDF/FTC was very good, even if a slight decline of eGFR and BMD were observed. The TDF-2 study gave similar results in male and female heterosexuals with an effectiveness of 61.7%, but was followed by FEM-PREP and the VOICE studies that failed to show efficacy of the use of TDF, TDF/FTC or Tenofovir gel in African women, because of a very poor adherence to treatment. Partners PrEP showed the high efficacy (85-93% dependent on adherence) of both TDF and TDF/FTC in serodiscordant heterosexual couples. The Bangkok study demonstrated the efficacy of 48.9% not only of TDF in IV drug users, but also of the global approach on diminishing the sexual or other risks. The IperGay trial, initiated in France and Canada, is the only study based on a personalized regimen of oral PrEP, based on the number of unprotected relations of each patient. The efficacy was very high (86%), with a median consumption of 15 pills par month and no decrease in condom use in persons using PrEP during the blind phase, knowing that the use of condoms was in fact low already before entering the study. A slight increase in unprotected sex was yet observed during the open phase of this study, while the risk of HIV infection still decreased by comparison to the blind phase. As expected, a significant number of STIs were diagnosed during the study and were clinically asymptomatic. At last, the English PROUD study compared daily TDF/FTC PrEP either immediate, or deferred by 6 months, and also showed an efficacy of 86%. If we further compare the effectiveness of various strategies of prevention in the same diagram, we can then conclude that the most efficient strategy is the antiretroviral treatment, either as TASP or for the PMTCT, followed by daily on demand PrEP in MSM. The evaluation of the relationship between adherence to PrEP and efficacy of the strategy in the iPrEx study concluded that HIV incidence was reduced by more than 90% in patients taking more than 4 pills per week, which is also the median number of tablets taken by the IperGay participants. On the other hand resistance mutations have been described in the PrEP trials, mostly in patients starting PrEP during primary HIV infection, which reflects the subpopulation of patients having stopped the treatment for months. The overall risk of resistance appears extremely low, around 1 in a thousand exposed persons, and resistance mutations usually do not persist more than a few months following infection. Unfortunately PrEP did not work in the case of a patient infected while receiving TDF for chronic HBV infection, and in the case of a man infected with a multi-resistant strain of HIV, harboring resistance mutations to both TDF and FTC. The cost-effectiveness of PrEP depends on the price of the drug, the HIV prevalence in the population, as well as the balance between PrEP efficacy and risk of disinhibition. Medico-economic analyses suggest that PrEP will be cost-effective in high-risk populations. PrEP became available in the US in 2014 and in France at the beginning of 2016. PrEP awareness and use are regularly increasing in high-risk groups, driven by a huge community involvement, and results in real life are consistent with the trials, with a high efficacy in the reduction of HIV incidence, while the condom use and STI incidence are stable.
Léa El Khoury (Sorbonne University, UPMC Univ Paris VI, CNRS, Theoretical Chemistry Laboratory, Paris, France) presented her study of the inhibition mechanism of HIV-1 integrase by diketoacids molecules. Using fluorescence anisotropy titrations and computational chemistry calculations DTG shows better interaction and a higher affinity towards processed viral DNA than EVG. Design of DTG’s derivatives (substitution of F by NH2 or CH3NH group, shift of F and substitution of another F by NH2 or CH3NH group) strengthen the interaction with viral DNA and show a more specific interaction potential.
Patrick Philibert (European Hospital, Marseille, France) presented interesting results of a practice survey in a routine HIV clinical setting concerning comorbidities’ assessment by systematic screening approach from January to December 2015. Among the 163 patients screened 146 were male, with a mean age of 48.5 years, mainly MSM (85%) and a mean EPICES score of 35.8/100. Identified risk factors were cardiovascular (61%), tobacco use (34%), IST (40%), hepatitis coinfection (21%) and previous IVDU (10%). Among comorbidities the study group identified respiratory diseases (37%), chronic hepatitis (15%), cardiovascular diseases (14%), diabetes (5%), neurological diseases (3%), anal lesions (8.5%), and urogenital disorders (6%). 33% of the long-term smokers had a clinical event of COPD or asthma (p=0.02). EPICES score was higher in non-MSM (p=0.02) in a population with an intermediate pre
During the “Modern ART” session Santiago Moreno (Madrid, Spain) addressed the issue of new strategies for initial therapy. One purpose could be to increase the time to switch the initial regimen for another one, whatever the reason is: tolerability, failure, simplification. Santiago Moreno argued that including an integrase inhibitor in the initial regimen allows better tolerance, high potency with a high genetic barrier to resistance and a more convenient regimen to follow that those with a boosted PI. Mark Nelson (London, UK) focused on strategies for maintaining success. He proposed the concept of proactive switching to prevent things from happening. It is all now about maintenance, Mark Nelson said. He underlined the fact that we are still concerned about backbone tolerance, either with tenofovir or abacavir. There are strategies under study trying to get rid of nucleoside or nucleotide analogs, for example combining rilpivirine and an integrase inhibitor or 3TC and an integrase inhibitor.
Three exciting and interesting debates on important topics were held at the conference.
- PrEP and the risk of STD transmission
First, Alain Lafeuillade of Toulon France debated against Mark Wainberg of Montreal on whether the use of PrEP would lead to higher rates of STDs among the populations who used this approach, principally gay men at risk for acquisition of HIV. Dr. Lafeuillade pointed to a number of studies that suggested that this would be a concern, as individuals taking PrEP might also engage in higher risk-taking activity if they thought that PrEP was likely to work. Dr. Wainberg countered by showing that this does not appear to have happened in some of the studies that were carried out. Moreover, several studies reported only marginally higher rates of transmission of some STDs such a syphilis and gonorrhea in the men who took PrEP but that this was more than offset by >85% reductions in rates of HIV (which is also a STD) transmission in the PrEP-receiving populations. The recent successful ANRS Ipergay PrEP-on-demand study further highlights this point, since most of the individuals were highly educated, only took PreP as needed in anticipation and following anticipated sexual relations, and were not inclined to higher levels of risk-Taking behaviour. The question period suggested that there was now a consensus that PrEP now represented a key element of HIV control strategies, complementary to such prevention efforts as Treatment as Prevention.
- Do we still need triple drug regimens for treatment of HIV infection? In this debate, the affirmative side was taken by Stefano Vella of Rome who argued that triple therapy was still the gold standard and would remain so for the foreseeable future. He used Tuberculosis as a comparator and made reference to studies by Georges Canetti of the Pasteur Institute who described differences among individuals and TB sanctuary sites more than 60 years ago. inshort, he argued that TB treatment failed when fewer than 3 drugs were used in combination, that such a strategy led to development of TB drug resistance, and that the same thing could happen with HIV.
His opponent, Dr. Jose Maria Gatell of Barcelona pointed to a number of relatively small studies that nonetheless made the point that 2-drug regimens could sometimes be as successful as 3-drug regimens.
Examples are the Gardel study that compared lopinavir/r plus 3TC against lopinavir/r plus 2 nucleosides and the Paddle study that compared Dolutegravir plus 3TC against Dolutegravir/3TC/Abacavir. Of course, these studies, while showing equivalence, were only carried out for 48 and 24 weeks, respectively. Thus, little information is available as to the durability of these approaches. With time, the development of new effective ARVs will probably give rise to other studies of this type. Most observers felt that it would be easier to use a 2-drug approach or possibly even monotherapy once viral load has first been suppressed by more traditional means using induction-maintenance regimens. The field will definitely continue to evolve and it is possible that long-acting injectables may also have a role in future therapy in double drug regimens.
- Can we cure HIV infection?
In this exciting debate, Jean-Pierre Routy of Montreal pointed to a large number of studies that are aimed at the flushing or activation of the HIV reservoir, followed by the killing of all HIV in the body. He pointed out that some of these strategies that are collectively termed « Shock and Kill » are more controversial than others and that we are still lacking a safe and effective compound that will be able to reproducibly achieve this goal without being toxic, oncogenic, or teratogenic. On the other hand, it is clear that current global assistance programs in support of the purchase of HIV drugs are becoming non-sustainable due to high costs and the threat of drug resistance, particularly in developing country settings. Thus, we simply must find a way of attaining at least a functional cure of HIV infection that will permit us to remove patients from HIV therapy, while relying on their immune systems to keep viral replication in check. He delved into the possible roles that various arms of the immune system might play in this regard, including CD8 cells, NK cells, neutralizing antibodies, cells involved in antibody-dependent target cell killing and others.
Dr. Marie-Lise Gougeon of the Institut Pasteur painted a picture that was not significantly different from that of Dr Routy, although she pointed out the difficulties that are inherent in assuring the activation of all cells that comprise the HIV latency reservoir. She also stated that there was still much information that was still lacking in regard to the nature of all cell types and subtypes that comprise the reservoir and that different stimuli might be required for different cell types.
Dr. Routy stated that the « inflammasome » is now considered to play an essential role in efforts to control sequestered HIV. Dr. Gougeon expressed the opinion that the multiple layers of complexity that are apparent, even from studies on well-controlled populations such as Visconti, will make the attainment of a functional cure extremely difficult.
Roy Gulick (Cornell University, New York, USA) closed this second day in a touching ambience during the Joep Lange Keynote Memory Lecture about the future of HIV care. 16 million people currently receive antiretroviral therapy worldwide using 29 approved drugs in 6 mechanistic classes. Current ART guidelines recommend a first-line regimen consisting of a combination of 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) and a third drug, either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a boosted protease inhibitor (PI), or an integrase inhibitor (II). Current ART regimens have proved their virologic activity, their safety and tolerability, and their convenience. One pill, once-daily regimens are widely available and current virologic suppression rates can exceed 90% in clinical trials and cohort studies. Newer strategies consist in investigating on newer approaches (Nuc-lite, Nuc-sparing, PI/r+II), 2-drug regimens (PADDLE study, ACTG 5353), new formulations (co-formulations of drugs that reduce pill counts), long-acting injectable compounds (rilpivirine, cabotegravir), implantable devices and other new technologies. The investigational pipeline contains new agents in existing classes with less toxicity than current drugs (tenofovir prodrug TAF; doravirine) and new mechanistic antiretroviral classes (CD4 attachment inhibitors like BMS-663068, HIV maturation inhibitors as BMS-955176). Current scientific goal is the cure of HIV infection; while only one patient under extraordinary circumstances is considered cured to date, research develops strategies to specifically identify and decrease the latently infected HIV-cell reservoir. Meanwhile, tremendous improvements in life expectancy of PLHIV have been done and in some cohorts expected age of death is bigger than in the general population, certainly because of a regular medical surveillance. While awaiting the further exploration of HIV cure research strategies, we currently can control HIV infection long-term with potent, safe and convenient antiretroviral therapy.