Wednesday, March 04, 2015

Starting HIV Medications Within First Weeks of Infection Decreases Hidden Virus


  1. Clin Infect Dis. (2015) doi: 10.1093/cid/civ171First published online: March 3, 2015

Impact of the Earliness of Antiretroviral Therapy Initiation During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA


Moussa Laanani1,2,
1Inserm, CESP Centre for Research in Epidemiology and Population Health, U1018, Paris-Sud University, Le Kremlin-Bicêtre, France
2APHP, Department of Epidemiology and Public Health, Bicêtre Hospital, Le Kremlin-Bicêtre, France

Abstract

Background. Combined antiretroviral therapy (cART) initiation during primary HIV infection (PHI) yields larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the earliness of cART initiation on CA-HIV-DNA decay.

Methods. We included patients enrolled during PHI in the ANRS PRIMO cohort, treated within the month following enrollment and achieving sustained virological response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation.

Results. 327 patients were included, accounting for 1,305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (IQR: 33-54). Median follow-up under cART was 2.3 years (range: 0.4-16.6). The earliness of cART initiation had significant impact on the first slope of decrease: the earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: -0.171, -0.131, and -0.068 log10 copies/106 PBMC/month when cART was initiated 15 days, 1 month and 3 months after infection, respectively.

Conclusions. This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection.

Tuesday, March 03, 2015

Most Important HIV Research Reports from CROI 2015





From Jules Levin: perhaps the biggest stories out of CROI from my perspective are the development of 2 new HIV therapies - the new attachment inhibitor & the new maturation inhibitors, as well as the safety & efficacy of TAF, and an important message out of CROI is that TAF can also be used in HCV coinfected patients as a replacement for TDF in their ART regimen which will likely provide key safety improvements. Equally important are the HCV coinfection study results from Harvoni, daclatasvir+sofosbuvir, and Abbvie’s 3D Viekira Pak, and at CROI are a number of presentations on use of simeprevir+sofosbuvir as this therapy was the most potent HCV therapy available in 2014. Merck is in phase 3 with their 2 HCV drug regimen and developing a triple drug regimen with the study of the 2-drug regimen in combination with the nuke they acquired from Idenix. J&J is studying the nukes they acquired from Alios, they have GSK’s NS5A inhibitor, and they have a non-nuke polymerase in-house as well as simeprevir. Abbvie & Merck reported 2nd/3rd generation drugs at AASLD in pre & early clinical - protease, NS5A. Achillion reported high SVR rates in their early clinical studies with their potent nuke, potent NS5A & they have 2 protease inhibitors. Aging & comorbidities were a focus at CROI as well, particularly noteworthy is the research from the Mass General group reported again that subclinical heart disease is ever present in HIV+, that it can results in plaque buildup, particularly of note in HIV+ it results in non calcified plaque buildup which can rupture; they reported Atorvastatin reduced coronary artery noncalcified plaque and that plaque buildup is associated with a leaky gut, microbial translocation. Statins got quite a bit of attention with several reports including one from Grace McComsey that Rosuvaststin arrests progression of carotid intima media thickness in HIV+Ken Lichtenstein reported the 4 heart disease algorithms underestimate risk for heart disease in HIV+ based on the SUN cohort. Bone disease is highlighted as well with Michael Yin reported modified FRAX underestimates risk for fractures among HIV+, and from HIV+ WIHS women experienced increased risk for fracture. Bigger font titles below indicate key reports, more NATAP reports coming including 9 specialized topical reports by expert researchers. Gilead has introduced a new HIV “cure” drug that appears to induce HIV reservoirs, TLR7, this immune based drug has been in ongoing research for several years at Gilead to treat HBV.

22nd Conference on Retroviruses and Opportunistic InfectionsSeattle WashingtonFeb 23 - 26, 2015


 Preventing one HIV infection in US saves $229,800 in modeling analysis - written by Mark Mascolini - (03/02/15) 

 Linkage to HIV care and viral suppression climb steadily in New York City - improvements to 76%, 73% - written by Mark Mascolini - (03/02/15) 



 Atorvastatin for 1 year trims coronary artery plaque volume and number in placebo trial - written by Mark Mascolini - (03/02/15) 



















Do gut flora play key role in cardiovascular disease with HIV? - written by Mark Mascolini - (02/27/15) 























Lower CD4 count, higher viral load tied to primary MIs in NA-ACCORD - written by Mark Mascolini - (02/26/15) 









Wider PrEP Use in San Francisco Could Cut New HIV Rate by 70% - written by Mark Mascolini - (02/23/15) 








Friday, January 30, 2015

Prezcobix and Evotaz: Two New HIV Fixed Dose Combinations Approved this Week


January 29, 2015

Janssen Therapeutics, Division of Janssen Products, LP (Janssen), today announced the U.S. Food and Drug Administration (FDA) has approved PREZCOBIX™ (darunavir 800 mg/cobicistat 150 mg) tablets, an HIV-1 protease inhibitor combined with a CYP3A4 inhibitor, for the treatment of human immunodeficiency virus (HIV-1) in combination with other antiretroviral agents for treatment-naive and treatment-experienced adults with no darunavir resistance-associated substitutions.
PREZCOBIX™ is a once-daily, fixed-dose antiretroviral combination tablet containing 800 mg of darunavir, marketed as PREZISTA® in the United States, and 150 mg of cobicistat, a pharmacokinetic enhancer or "boosting" agent, developed and marketed as Tybost by Gilead Sciences, Inc., taken orally with other HIV-1 medications and with food.



Bristol-Myers Squibb Company  announced today that the U.S. Food and Drug Administration (FDA) has approved Evotaz (atazanavir 300 mg and cobicistat 150 mg) tablets in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Evotaz is coformulated to be one pill, once-daily, combining the protease inhibitor atazanavir, which is marketed as Reyataz (atazanavir 200 mg/300 mg) capsules, and cobicistat, a pharmacokinetic enhancer marketed by Gilead Sciences, Inc. Today’s approval offers patients living with HIV an innovative treatment option that delivers proven suppression of HIV replication.

Saturday, November 15, 2014

Cost Effectiveness of Current HIV Cure Approaches


  • Published: November 14, 2014
  • DOI: 10.1371/journal.pone.0113031

Abstract

Background

We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART).

Methods

We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY.

Results

For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving.

Conclusions


Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.

Full paper:
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113031

Groundbreaking HIV vaccine's effects were real – and could be made to work better


Findings from further studies using a reformulation of the only HIV vaccine that has ever worked in a large efficacy trial were presented at the recent HIV Research for Prevention conference (HIVR4P). They showed evidence of stronger antibody responses, and in-depth analysis of these responses shows that by further developing a similar vaccine it may be possible to push the immune system into generating an antibody response to HIV that is sufficiently strong to prevent most infections.
The RV144 vaccine had such a slight beneficial effect that when its results were first announced, some people wondered if they were not just a statistical fluke. It did prevent four out of ten HIV infections that would otherwise have happened in its original trial in Thailand, but the results observed were only just statistically significant. This was largely because the vaccine’s efficacy appeared to wane with time – if the trial had been stopped a year after the first injection, its efficacy would have been 60%. It also seemed to have little effect in people at higher risk of HIV such as people who inject drugs and gay men.
At last year’s AIDS Vaccine conference in Barcelona, however, several studies were presented that showed the RV144 vaccine’s effects were real and depended on a very specific kind of antibody response to HIV that developed in some, but not all, vaccine recipients.

Vaccine produces better results in South Africa than Thailand

Glenda Gray, head of the South African Medical Research Council, presented the results from a small study, HVTN097, which gave a version of the RV144 vaccine protocol to 100 volunteers (51 men and 49 women).
The vaccine actually contains two components. One is a vaccine called ALVAC. This is a vector vaccine, consisting of HIV proteins encased in the shell of another virus. This 'fake infection' is intended to stimulate the cellular immune response (the part of the immune system that stimulates CD8 cells to attack other, infected cells). It was given in four components: zero, one, three and six months from the start of the study. The other component is called AIDSVAX. This consists of HIV envelope (sruface) proteins intended to stimulate the humoral immune response - the part of the immune system that generates the soluble proteins called antibodies that directly attack viruses. It was given at month three and month six.
Why has it taken so long to re-try a vaccine that produced positive results five years ago? The main problem is that expectations of the original study were so low that Vaxgen, the company making AIDSVAX, used all its stock and did not make more so the vaccine has had to be re-manufactured from scratch.
As was observed in the original study, the South African vaccine did not stimulate the cellular immune response to a useful degree. Some degree of immune response to HIV was stimulated in volunteers’ CD4 cells, and was more common and stronger in the South African trial: 69% of South African volunteers’ CD4 cells became sensitive to HIV as opposed to 50% of original vaccine recipients’ cells. However, there was little evidence of the desired CD8 response – only 5% of South African and 0.6% of the original Thai recipients had CD8 responses.
In contrast, and as seen in the original study, there was a strong and universal antibody response generated to the gp120 component of HIV. This protein forms the ‘knobs’ on the surface of HIV that attach to cells and is one of the components of AIDSVAX. There was also a near-universal (98.6%) response to a specific part of gp120 called the V1-V2 loop, a section of the protein chain that first attaches to cells. More analysis of the immune responses is underway and it looks as if the antibodies generated in the vaccine recipients in South Africa have a stronger effect against lab-engineered HIV viruses, being able, for instance, to neutralise (disable from reproducing) 25% more clade B viruses than Thai-recipient antibodies.
In January 2015 a new study, HVTN100, will give trial volunteers a vaccine based on RV144 but reformulated to contain proteins from the HIV subtype (clade) most common in south Africa, namely clade C instead of the Thai clade A/E. Depending on efficacy, this could then lead to a much bigger efficacy trial.

Thai vaccine boost regenerates immune response

In the original RV144 study, it had been found that an effective immune response to HIV depended on being on the right side of an antibody balance. Two different kinds of antibody response were generated, a dominant one of the antibody types called immunoglobulin A (IgA), and a less dominant one called IgG. The higher the ratio of IgG to IgA the more effective the immune response; indeed a high ratio of IgA to IgG actually enhanced vulnerability to HIV infection.
In a Thai study, RV305, volunteers for the original RV144 study were recalled and – eight years after they first received the vaccine – were given it again. Analysis showed that this boost produced a similar antibody response to the original vaccine; 70% of volunteers who received both vaccine components produced IgG antibodies to HIV and 56% of those who just received AIDSVAX, while 10% and 14% respectively had antibodies specific to the V1/V2 loop.
The IgA response was roughly ten times as strong as the IgG response but, significantly, no IgA specific to the HIV gp120 protein was found in rectal secretions. This suggests the vaccine could be ‘fine turned’ to produce more specific responses.
This immune response, however, is only active against varieties of HIV that are relatively easy to disable, so-called ‘tier 1’ viruses. The reason HIV vaccines are not more effective is that during infection, HIV and the immune system are locked into an arms race that HIV generally wins, staying one step ahead of the body’s response to it. While the body develops ever more elaborate antibodies, and about 35% of people eventually develop the so-called ‘broadly neutralising’ antibodies that can disable most transmitted viruses, the virus gets there first, always having mutations in hand of higher-tier viruses that are antibody-resistant.
Passive-immunity studies, in which volunteers are given injections of broadly neutralising antibodies, confirms that if we could get a vaccine to generate these antibodies from the start, they would be effective in repelling the vast majority of viral invaders. The problem is that cells capable of doing this are initially extremely rare and it is only the continued provocation of the presence of HIV that drives the production of broadly neutralising antibodies. An ideal vaccine would be one that would, so to speak, fool the immune system into thinking that it had already been dealing with a chronic HIV infection for ten years or more.

Could repeated vaccine boosts push the body into an effective anti-HIV response?

How far along this road are we? Michael Moody of Duke University told the conference that a truly effective antibody response against HIV would need to have four characteristics.
It would need to generate significant numbers of antibodies to the V1/V2 loop of the HIV gp120 molecule. It would needed to be able to 'deglycosylate' gp120, which means it would have to penetrate a sticky coating of sugars that gp120 coats itself in as a defence against antibodies. It would need to have a specific affinity for two amino acids in the V1/V2 loops.
And it would need to have an unusual characteristic that only the rarest, most broadly neutralising antibodies have; this is an extended 'prong' in the part of the antibody called the third heavy-chain complementarity determining region (H-CDR3), which is able to penetrate parts of the gp120 protein that are highly specific to HIV’s ability to infect, and therefore not mutable – they are “conserved” – but which are only exposed for a fraction of a second during the infection process. (Essentially, antibodies with long H-CDR3s almost literally throw a ‘spanner in the works’ of HIV infection.)
Moody said that the vaccine boost in the RV305 study more than doubled the proportion of antibodies, from 2.56% to 5.52%, that had mutations indicative of a shift towards being able to broadly neutralise HIV. A much higher proportion (11.6% versus 1.35%) had H-CDR3 loops more than 21 amino acids long, which indicates that they may possibly have broadly neutralising ability. In addition, 2.4% of the antibodies produced had mutations specifically adapting them to particular glucose molecules and enabling them to bind very strongly to gp120. However, these were not the same antibodies as the ones with long H-CDR3s, in the main, and when these antibodies were isolated and used against a panel of viruses, it was still only the ‘tier 1’ viruses they could neutralise.
However, one specific antibody called Ab8850, which represented 2.5% of the total antibodies produced, was molecularly near-identical to an already-studied broadly neutralising antibody called CH04 – its H-CDR3 loop was just three antibodies shorter, and this made all the difference.
Moody said that so far we had not seen, in the RV144 research programme, production of an antibody with all four characteristics needed for it to fully neutralise HIV, but had progressed from producing antibodies with two of these characteristics to ones with three.
He speculated that repeated boosts of AIDSVAX or a similar vaccine could have the effect of ‘pushing’ the immune system into developing broadly neutralising antibodies that might eventually fully protect an individual against HIV – the obvious problem being that, with the vaccines we have at present, this might take several years’ worth of inoculations at considerable expense.
It might also depend on individuals’ genetic make-up too much to be widely applicable, but the principal that it is even possible to do this has now been established.

References

Gray G et al. HVTN 097: Evaluation of the RV144 Vaccine Regimen in HIV Uninfected South African Adults. HIV Research for Prevention Conference, Cape Town. Abstract OA11.06LB. 2014.See webcast here.
Akapirat S et al. HIV-specific Antibody in Rectal Secretions Following Late Boosts in RV144 Participants (RV305). HIV Research for Prevention Conference, Cape Town. Abstract OA11.05. 2014. See webcast here.
Moody M et al. Induction of Antibodies with Long Variable Heavy Third Complementarity Determining Regions by Repetitive Boosting with AIDSVAX® B/E in RV144 Vaccinees. HIV Research for Prevention Conference, Cape Town. Abstract OA12.06LB. 2014. See webcast here.

Prevalence and risk factors of sleep disturbances in a large HIV-infected adult population.


Prevalence and risk factors of sleep disturbances in a large HIV-infected adult population.

Authors

Journal

J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19576. doi: 10.7448/IAS.17.4.19576. eCollection 2014.

Affiliation

Abstract

INTRODUCTION: Sleep disturbances are frequently reported in HIV-infected patients but there is a lack of large studies on prevalence and risk factors, particularly in the context of current improved immuno-clinical status and use of the newest antiretrovirals (ARV).
METHOD: Cross-sectional study to evaluate the prevalence and factors associated with sleep disturbance in adult HIV-infected patients in six French centres of the region "Pays de la Loire". Patients filled a self-administered questionnaire on their health behaviour, sleep attitudes (Pittsburgh Sleep Quality Index PSQI), quality of life (WHO QOL HIV BREF questionnaire) and depression (Beck depression Inventory (BDI)-II questionnaire). Socio-demographic and immunovirologic data, medical history, ARVs were collected.
RESULTS: From November 2012 to May 2013, 1354 consecutive non-selected patients were enrolled. Patients' characteristics were: 73.5% male, median age 47 years, active employment 56.7%, France-native 83% and Africa-native 14.7%, CDC stage C 21%, hepatitis co-infection 13%, lipodystrophy 11.8%, dyslipidemia 20%, high BP 15.1%, diabetes 3%, tobacco smokers 39%, marijuana and cocaine users, 11.7% and 1.7% respectively, and excessive alcohol drinkers 9%. Median (med) duration of HIV infection was 12.4 years, med CD4 count was 604/mm(3); 94% of Patients were on ARVs, 87% had undetectable viral load. Median sleeping time was 7 hours. Sleep disturbances (defined as PSQI score >5) were observed in 47% of the patients, more frequently in female (56.4%) than in male (43.9%) and moderate to serious depressive symptoms in 19.7% of the patients. In multivariate analysis, factors associated with sleep disturbances were depression,, infection , ARV regimen containing nevirapine or efavirenz.
CONCLUSIONS: Prevalence of sleep disturbances is high in this HIV population and roughly similar to the French population. Associated factors are rather related to social and psychological status than HIV infection. Depression is frequent and should be taken in care to improve sleep quality.

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