Starting HIV Medications Within 10 Weeks from Infection Can Create Elite Controllers After 3 Years of Treatment

Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption

Presented by Charline Bacchus (France).

C. Bacchus1, L. Hocqueloux2, V. Avettand-Fenoël3, A. Saez-Cirion4, A. Mélard3, B. Descours5, A. Samri1, C. Blanc6, B. Autran1, C. Rouzioux3, VISCONTI and ALT ANRS study groups

1Cellular and Tissular Immunology Laboratory, Pierre and Marie Curie University, INSERM UMR-S 945, Pitié-Salpêtrière Hospital, Paris, France, 2Infectious and Tropical Diseases Department, Regional Hospital, Orléans, France, 3Virology Laboratory, René Descartes University, Necker Hospital, Paris, France,4Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France, 5Human Genetic Institute, Molecular Virology Laboratory, CNRS UPR1142, Montpellier, France, 6Flow Cytometry Platform CyPS, Pierre and Marie Curie University, Pitié-Salpêtrière Hospital, Paris, France

Background: Virological and Immunological Studies in CONtrollers after Treatment Interruption (VISCONTI) are required to understand the benefits of an early treatment at acute HIV-1 infection on the HIV reservoir. We studied the distribution, magnitude and inducibility of the HIV reservoir in VISCONTI patients.
Methods: The prospective VISCONTI study included twelve patients controlling HIV for a median of 76[IQR:67.5-84.5] months after interruption of a 3[IQR:1.7-5.9] years long HAART initiated within 10 weeks post-infection. Circulating resting CD25-CD69-HLADR- CD4+T cell subsets were sorted as naive (TN), central-memory (TCM), transitional-memory (TTM) and effector-memory cells (TEM) for further cell-associated HIV-DNA quantification by ultrasensitive real-time-PCR, and viral inducibility by culture with anti-CD3/anti-CD28/IL-2/IL-7. Reservoir distribution was compared to the one observed in 8 untreated Elite-Controllers for whom 90% of HIV-RNA measures was undetectable (below 200 copies) over 12[9-14] years.
Results: In the VISCONTI group, activated CD4+T cells had significantly higher HIV-DNA levels than resting ones (median 2.7[IQR:2.4-3.4] and 2[IQR:1.8-2.5] log copies/million cells, p=0.005). HIV-DNA was detected in all subsets from all patients except for 8 out of 12 TN-sorted cells, which were 10 fold less infected than all memory subsets (median TN:1.5[IQR:1.2-1.6], TCM:2.5[IQR:1.8-2.9], TTM:2.6[IQR:2.2-2.8] and TEM:2.4[IQR:2-2.8] log copies/million cells, p< 0.007). TTM was the major subset contributing to 56% of this reservoir. The same HIV reservoir characteristics were observed in Elite-Controllers in term of magnitude and distribution, except that both TCM and TTM equally contributed to the Elite-Controllers HIV reservoir. The VISCONTI HIV reservoir was inducible after TCR-stimulation in all sorted memory subsets from all patients, except in TN where no virus was recovered in 6 out of 8 patients.
Conclusions: In VISCONTI patients, treatment initiated at primary HIV-1 infection leads, after treatment interruption, to a low -but inducible- durable HIV reservoir distributed mainly in short-lived memory CD4+T cells that mimicks the natural distribution observed in Elite-Controllers.


Two more men with HIV now virus-free. Is this a cure?

They are still taking HIV medications, so we won’t know until after they interrupt their HIV treatment…

Two More Patients HIV-Free After Bone Marrow Transplants
http://abcnews.go.com/blogs/health/2012/07/26/two-more-patients-hiv-free-after-bone-marrow-transplants/

Two more men with HIV now virus-free. Is this a cure?
http://www.msnbc.msn.com/id/48338421/ns/health-mens_health/t/two-more-men-hiv-now-virus-free-cure/#.UBG2nI6TNUR

HIV Undetectable in 2 Men After Bone Marrow Transplants: Study
http://health.usnews.com/health-news/news/articles/2012/07/26/hiv-undetectable-in-2-men-after-bone-marrow-transplants-study

2 HIV patients in Boston show no signs of virus after bone marrow transplant
http://www.boston.com/whitecoatnotes/2012/07/26/hiv-patients-boston-show-signs-virus-after-bone-marrow-transplant/OsWbGbCtDq70CoWOZ0A2tI/story.html

GSK is Exploring a Once a Month Injectable HIV Treatment Regimen

Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults

         Presented at the International AIDS Conference in Washington this week

Discussion 
— S/GSK1265744 long acting parenteral administration prolonged plasma levels (apparent t1/2of 2150days; Figure 4) compared with oral administration (oral t1/2of 30-40 hours)
— AUC(0-∞)appeared to increase in a dose-proportional manner; Cmax increased greater than proportional to dose following 800 mg IM, suggesting the rate of absorption was higher for this dose (Table 2)
— 800 mg IM achieved a mean S/GSK1265744 Cday 1021-fold above PA-IC90; this exposure is comparable to exposure observed with 30 mg oral, once-daily dosing, which produced a -2.5 log10decrease in HIV RNA following 10 days of monotherapy in HIV-infected subjects. Mean Cday28following 800 mg IM was 14-fold above PAIC90, making this a viable loading dose for S/GSK1265744 LAP
— Modeling and simulation (not shown) suggest S/GSK1265744 LAP 200-400 mg monthly is an appropriate maintenance dose for HIV treatment
Conclusions

S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated in healthy adult subjects. Both IM and SC routes of administration will be evaluated in repeat-dose clinical trials 

Single SC or IM doses of the long-acting formulation yielded sustained S/GSK1265744 plasma concentrations previously shown to produce robust antiviral activity as oral monotherapy and suggest monthly to quarterly dosing intervals using clinically practical dose volumes
Study results support continued development; S/GSK1265744 is under evaluation for both HIV prevention as pre-exposure prophylaxis as well as HIV therapy with a partner antiretroviral agent, rilpivirine (TMC278-LA)
Abstract
Background: S/GSK1265744, an HIV integrase inhibitor with proven antiviral activity following oral monotherapy, is under development as a long-acting parenteral (LAP) depot formulation. Antiretrovirals dosed monthly to quarterly may provide clinical utility for HIV treatment and prevention. This study evaluated pharmacokinetics (PK), safety, and tolerability of single S/GSK1265744 LAP doses in healthy adults.

Methods: This was a phase I, randomized, double-blind, placebo-controlled, dose escalation study. S/GSK1265744 200 mg/mL nanosuspension was administered by intramuscular (IM) gluteal injection (100 mg, 200 mg, 400 mg, 800 mg [400 mg x2]) or subcutaneous (SC) abdominal injection (100 mg, 200 mg, 400 mg [200 mg x2]) to cohorts of eight (6 active/2 placebo) subjects. Safety and PK were assessed prior to dose escalation and continued until plasma S/GSK1265744 was <0.1 μg/mL by LC/MS/MS; PK parameters were determined by noncompartmental methods. 

Results: 25 females and 31 males were dosed; S/GSK1265744 LAP was generally well tolerated with mild-moderate, self-limited injection site reactions (ISR) reported as the most common adverse event (AE); ISR erythema and nodules were more frequent following SC dosing. Systemic safety was good with no drug-related serious AEs or grade 3-4 AEs. S/GSK1265744 was detected in plasma up to 48 weeks and exhibited absorption-limited kinetics; mean apparent terminal phase t1/2ranged 2150days vs. 40 h following oral dosing. S/GSK1265744 AUC(0-∞) appeared to increase proportionally to dose. Split dosing increased the apparent absorption rate. Mean S/GSK1265744 Cday 10 following 800 mg IM was similar to geometric mean CÏ„,ss of 3.28μg/mL associated with -2.5 log10mean change in plasma HIV RNA following 10 days of 30 mg PO QD monotherapy. 

Conclusions: S/GSK1265744 LAP single dose IM or SC 100-800 mg was safe and generally well tolerated. Achievement of sustained plasma concentrations previously shown to produce >2.5 log10mean reduction of HIV RNA as monotherapy suggests S/GSK1265744 LAP may exhibit prolonged antiviral activity at clinically practical doses and supports continued development.
S/GSK1265744 is an integrase strand transfer inhibitor in development as both an oral formulation and LAP injection. The compound has attributes that enable formulation and delivery as a nanosuspension for injection: 
— High potency: deliver monthly or longer dose in clinically practical volume
— Low aqueous solubility and correct particle size to control release kinetics
— Low metabolic clearance: reduced drug input requirement
— Formulation prerequisites: withstand nanomilling forces, stability in formulation with excipients and stabilizers, a sterile product
Prior clinical studies have demonstrated S/GSK1265744 oral monotherapy produces a vigorous antiviral effect in HIV-infected subjects at 5 or 30 mg once daily for 10 days (Figure 1). In vitro resistance studies suggest a favorable profile. The current study was undertaken to evaluate the safety and PK of single IM or SC doses of S/GSK1265744 LAP formulation in healthy adult subjects


    New HIV, Hepatitis C and TB Medications in the Research Pipeline’ Report from TAG and I’Base

    I highly recommend this excellent pipeline report for an update of what drugs are in the development pipeline for HIV, Hepatitis C and TBÑ

    2012 Pipeline Report

    Fw: Hot Topics at TheBody.com’s “Ask the Experts” Forums

    From: “News at The Body” <update@news.thebody.com>
    Date: 17 Jul 2012 18:51:45 -0400
    To: <nelsonvergel@yahoo.com>
    ReplyTo: “News at The Body” <update@news.thebody.com>
    Subject: Hot Topics at TheBody.com’s “Ask the Experts” Forums

    If you have trouble reading this e-mail, you can see the online version at: www.thebody.com/topics.html

    July 17, 2012 Visit the Forums “Hot Topics” Library Change/Update Subscription



    Living With HIV  To Drink or Not to Drink Grapefruit Juice: What’s the Final Verdict?
    It seems for years I have heard that grapefruit juice is to be avoided if one has HIV and is taking meds. The forum is filled with listings concerning this question. Most answers deal with specific medications, but I’m confused as to which ones. I take Isentress (raltegravir) and Truvada (tenofovir/FTC) along with many other meds and supplements. I bought and enjoyed a bottle of grapefruit tangerine juice. Will it do me harm?

    Benjamin Young, M.D., Ph.D., responds in the “Choosing Your Meds” forum
    Mixed-Status Couples  What Can My Baby-Making Partner Do to Increase His Sperm Count?
    I’m trying to have a baby with a partner who’s HIV positive. We’re doing sperm washing and cervical cup insemination to conceive, but it’s not cheap so I want to maximize our one or two tries by enhancing his sperm quality. Do you know of any supplements or techniques that have been shown to increase sperm count and motility?

    Nelson Vergel responds in the “Nutrition and Exercise” forum
    Insurance, Workplace & Legal Concerns  Can I Keep My Social Security Benefits While in Graduate School?
    I’ve just been accepted to a graduate school program, and they offered me a $10,000 teaching assistantship. I have been on social security disability insurance (SSDI) and supplemental security income (SSI) for over 15 years and don’t want to get the school’s insurance. Is it possible for me to stay on SSDI and SSI while in school?

    Christa Douaihy, Esq., responds in the “Legal Issues and HIV” forum

     Should I Continue Pursuing a Career in Nursing?
    I’m HIV positive and a nursing student. Do you think my HIV status will stand in the way of my being hired as a nurse after graduating and obtaining my license? Should I choose another career path, or will nursing be as safe as any other career?

    Jacques Chambers, C.L.U., responds in the “Workplace and Insurance Issues” forum
    Visual AIDS: Art from HIV-Positive Artists
    Image from the July 2012 Visual AIDS gallery Detail from:
    “Wave, 0-9 (Detail #3),” 1996
    Robert Blanchon

    Visit the July 2012 Visual AIDS Web Gallery to view our latest collection of art by HIV-positive artists! This month’s gallery, "Overnight Wave (For Arthur)," is curated by Rick Herron.


    HIV/AIDS Treatment  What Is an Appropriate Level of HIV Care?
    I tested positive for HIV two years ago. I take Atripla (efavirenz/tenofovir/FTC) and have an undetectable viral load, a CD4 count of about 500 and a CD4 percentage of 35. When I see my HIV specialist, what kind of exam should be done? How often should I go? I currently go every six months and my appointments only last 15 minutes. Usually we go over my lab results, my doctor says “You’re doing great!” and that about covers it. He hasn’t done a complete physical exam since I was diagnosed. Does this sound appropriate, considering my condition?

    Benjamin Young, M.D., Ph.D., responds in the “Choosing Your Meds” forum


     Do My Depression Meds Interact With My HIV Meds?
    I currently take Intelence (etravirine), Isentress (raltegravir) and Truvada (tenofovir/FTC). Can I take trazodone for depression along with this regimen?

    Joseph P. McGowan, M.D., F.A.C.P., responds in the “Choosing Your Meds” forum


     Why Am I Having Trouble Walking and Speaking Clearly?
    I was diagnosed with HIV in January 2010. My CD4 count was 339 in February of this year and I started taking Atripla (efavirenz/tenofovir/FTC). Lately I’ve noticed my speech is slurred and I stagger a lot when walking. I can’t jump or run, either. Could these effects be related to my HIV meds?

    Keith Henry, M.D., responds in the “Managing Side Effects of HIV Treatment” forum


    More Questions About HIV/AIDS Treatment:

    Other Health Issues & HIV/AIDS  Does Being a Bottom Put Me at Risk for Peritonitis?
    I have HIV and my new partner does as well. I am also on peritoneal dialysis, and about six weeks into our relationship I came down with peritonitis. Just days after completing a 21-day antibiotic regimen, I ended up in the hospital with another bout of peritonitis. One of my doctors suggested abstaining from sexual relations for about a month to allow my body to recover. Do you think that being the receptive partner in anal sex puts me at a high risk of developing recurrent peritonitis?

    David Fawcett, Ph.D., L.C.S.W., responds in the “Mental Health and HIV” forum

     How Can I Treat a Serious Infection if I Have Drug Allergies?
    I was injected with Bio-Alcamid (poly-Alkyl-Imide) in 2007 to treat facial wasting. Over the past four years the implant has dropped, and several days ago the spot above the implant was tender and soon became red and swollen. I would like to have the infection treated with antibiotics without affecting the implant, but my doctor doesn’t seem to know what to do. I’m also allergic to penicillin and sulfa-based drugs. How should I manage this infection?

    Gerald Pierone, M.D., responds in the “Facial Wasting” forum
    Connect With Others My Man Is Back After Rejecting Me: Why Do I Keep Pushing Him Away?
    (A recent post from the "Relationships and Dating" board)

    I started seeing this real nice guy a month or so before I tested positive, and informed him the same day of my test results. I thought or hoped that he would be more supportive when I told him, but he wasn’t. Said that he never wanted to talk to me again and not to contact him again, which I didn’t.

    I was hoping that if I gave him some time that he would come back around, which he did … He’s also tested negative, but here’s the problem. He’s willing to accept me the way I am, and wants me to be a part of his life again. I feel the same way, and know I’m very fortunate that he still loves me the way I am, but it’s like subconsciously I keep trying to push him away and it wasn’t like that before I tested positive. …

    Does anybody have any idea why I’d do this? Do you think I just need to give it time? I know that I don’t want to lose him again! — thebird1959

    Click here to join this discussion, or to start your own!

    To do this, you’ll need to register with TheBody.com’s bulletin boards if you’re a new user. Registration is quick and anonymous (all you need is an email address) — click here to get started!

    Understanding HIV/AIDS Labs  Why Isn’t My Viral Load Higher in Acute Infection?
    I was recently diagnosed HIV positive after being notified anonymously that I’d come in contact with the virus in the last two months. I’d had zero symptoms, with the exception of slightly swollen lymph nodes under my neck around the time of infection. I’m confused with my lab results: a CD4 count of 389 with a CD4 percentage of 38 and a viral load of 14,000. I’m told people in the acute stage of HIV infection develop a similar low CD4 count then rebound, but their viral load is usually much higher than mine. What’s the explanation for this?

    Mark Holodniy, M.D., F.A.C.P., C.I.C., responds in the “Understanding Your Labs” forum
    HIV/STD Testing & Transmission  Does Syphilis Increase My Chance of Transmitting HIV?
    I am an HIV-positive bottom with an undetectable viral load. I recently discovered that I have syphilis from a partner I had about a year before my current boyfriend. I had no symptoms and no idea I had it. Does my having syphilis increase the probability of passing HIV to my current boyfriend, who is HIV negative and a total top, when we have unprotected anal sex? If there are no sores, can syphilis still be transmitted? If so, how?

    Nelson Vergel responds in the “Aging With HIV” forum
    Strange but True  Could My Childhood Big Fish Story End With HIV?
    When I was about 4 or 5 years old, I was at a fishing expo with my family. There was a fish-gutting ceremony going on at one point. I wandered off and hid underneath a man’s cutting board just as he was chopping the head off a fish. I looked up just in time to be covered with a cascade of fish blood, some of which made its way into my right eye. I now suffer from a lazy right eye. Could this have something to do with HIV coming into my body when fish blood made contact with my cornea?

    Lisa B. Hightow-Weidman, M.D., M.P.H., responds in the “Safe Sex and HIV Prevention” forum

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    An HIV Drug Helps Cancer Patients

    NEJM paper: http://www.nejm.org/doi/full/10.1056/NEJMoa1201248

    http://www.forbes.com/sites/matthewherper/2012/07/11/immune-reversal-unsuccessful-pfizer-aids-drug-might-help-transplant-patients/

    Immune Reversal: How A Pfizer AIDS That Disappointed Investors Drug Might Help Transplant Patients

    A Pfizer drug that failed to thrive as a treatment for HIV may now present a great hope for a deadly consequence of the bone marrow transplants used to treat blood cancers such as leukemia, myeloma, and lymphoma, according to a small study of 38 patients published this evening in the New England Journal of Medicine.

    Transplants of stem cells found in the bone marrow can treat and even cure these cancers. Cells from a donor, often a family member, are injected into the patient after their own bone marrow has been wiped out. The result is that the patient has a new immune system that can attack cancer cells.

    But sometimes – in fact, all too frequently – that new immune system attacks the patient, too. This occurs at least 30% of patients where the stem cells are “matched,” coming from a family member, and at least 50% when they are not. The main step to prevent this internal attack, called graft versus host disease, is giving the patient medicines to suppress the immune system, increasing the risk of infection.

    Ran Rashef, an assistant professor of medicine in the blood and bone marrow transplant program at the University of Pennsylvania, thought there might be a better way. Instead of just shutting down immune system cells like white blood cells, why not tell them where not to go? These cells “don’t just wander around randomly into tissues and the blood stream,” he says. “There is a very well orchestrated process.”

    The key to that process, earlier studies had shown, was the C-C-chemokine receptor type 5 (CCR5), a cellular switch on the surface of white blood cells that detects chemical signals coming from damaged cells. Blocking CCR5, Rashef thought, might prevent graft-versus-host disease. Luckily, the Pfizer drug, Selzentry, was already on the market. Pfizer provided the drug for his study and helped fund the clinical trial.

    Rashef expected mainly to be able to see that the CCR5 inhibitor was affecting the movement of white blood cells. But the results were incredibly encouraging. Instead of the a third or more of the patients having graft-versus-host disease, only about 15% did – far fewer than expected, and a sign that the medicine may be extremely effective. “We were surprised we got some good efficacy for the study,” he says. “This was a pilot study that went wild.” Still, he emphasizes, larger clinical trials will need to be done to confirm the result. A Pfizer spokeswoman adds: “These findings are preliminary and it is too early to speculate on any future plans.”

    Selzentry was approved in 2007 as a treatment for HIV patients whose HIV had entered their cells using CCR5 as a gateway. At the time, industry analysts expected Selzentry would generate $500 million in annual sales in 2011. In 2010, it generated only $128 million, far short of those expectations and far less than other AIDS medicines such as Merck‘s $1.1 billion Isentress and Gilead’s $6 billion HIV drug franchise.

    If the results pan out, it will be one of the best examples yet of an idea known as drug rediscovery. One of the potentially big results from research emerging from the study of human genetics, this is the idea that existing drugs could treat new diseases. In some case, as with Merck’s Cozaar, which has shown promise against Marfan syndrome, a hereditary disorder, this can mean a relatively cheap medicine can help a population of people who were not thought of as large enough to warrant a big pharmaceutical research effort.

    But the idea of “rediscovering” a drug can also create business challenges, because drugs are priced based on the diseases they treat. In one case, Celgenedramatically raised the price of thalidomide after it was found to be effective not just against complications of HIV and leprosy, but the blood cancer multiple myeloma. If Selzentry is effective against graft versus host disease, Pfizer might have reason to try a similar approach. The U.S. patent on Selzentry lasts at least until the end of 2019.

    Informative Questions and Answers at TheBody.com

    Gynecomastia problems: http://www.thebody.com/Forums/AIDS/Aging/Q223555.html

    Shingles Vaccine for HIV+ People:
    http://www.thebody.com/Forums/AIDS/Aging/Q222619.html

    Recently Diagnosed with HIV:
    http://www.thebody.com/Forums/AIDS/Nutrition/Q223309.html

    Taking Egrifta and Gaining Weight:
    http://www.thebody.com/Forums/AIDS/Nutrition/Q223414.html

    How Do I Improve my Sperm Count?
    http://www.thebody.com/Forums/AIDS/Nutrition/Q223473.html

    Wormwood and HIV
    http://www.thebody.com/Forums/AIDS/Nutrition/Q223420.html

    Parotid Gland Inflammation and HIV
    http://www.thebody.com/Forums/AIDS/Nutrition/Q221140.html

    Winstrol (Anabolic Steroid) and HIV Medications
    http://www.thebody.com/Forums/AIDS/Nutrition/Q220965.html

    Other Options for Lipodystrophy Besides Egrifta
    http://www.thebody.com/Forums/AIDS/Nutrition/Q221875.html

    How to Gain Muscle
    http://www.thebody.com/Forums/AIDS/Nutrition/Q217583.html