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“Hope Rx: History of HIV Treatment and Future” © 2009 Stephen Fallon www.skills4.org

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(c) 2009 Stephen J. Fallon, Skills4

Hope Rx A Brief History of HIV Treatment Strategies, an

Assessment of Today’s HAART Regimens, and a Preview of Possible Future Treatments

Stephen J. Fallon, Ph.D.

October 2009 update

For color handouts: www.skills4.org •  Click on button for Fact Sheets •  Go to Links, then click on HopeRx


•  We’ll look at where HIV treatments have stumbled, where they’ve succeeded, and what directions they might next take.

By the end of this session, you will be able to 1.  List ways that evolving treatments have

improved quality of life, and saved lives.

Goals for This Workshop

2.  Explain the benefits of “working through” non-threatening side effects.

3.  Identify the reasons that resistance (conferred or selected) arises, and how it affects treatment potential.

4.  Identify the crucial role that adherence plays in ensuring treatment durability, with hopes for future novel treatments.


Checking the Pulse Honest answers will help us gauge our knowledge base •  Window period •  Seroconversion •  Treatment naïve •  Treatment adherence •  Viral set point •  UDVL •  Pathogenesis •  Zinc fingers •  TLOVR •  HLA- B 5701



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Two Battle Fronts •  Treatment goal is to lower VL to undetectable,

or at least as low and sustainable as possible. •  This prevents further immune degradation

caused by HIV, allows immune system to reconstitute.

•  Successful therapy usually leads to rapid increase in CD4s, where memory cells are being restored.

•  Continued therapy leads to a slow increase in naïve cell counts. Hunt PW, Deeks SG, et al. “Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of

viral suppression on antiretroviral therapy.” AIDS 2003 Sep;17(13):1907-15.

•  Simultaneous goal: monitor any metabolic impacts from treatment to ensure health risks remain < than health benefits.


Learning Our Internal Systems •  We take our bodies for granted, until something goes wrong. •  Then diagnosing becomes difficult because so many internal systems interact. •  It’s a lot like starting your car in the morning. Just a metal box that gets you places …. until. •  Lesson? Necessity is the mother of comprehension.


“The Dark Ages” of HIV Treatment •  Monotherapy: AZT/Retrovir (1987), then ddI/

Videx (1991), then ddC/Hivid (1992), and d4T/Zerit (1994).

•  1995: dual combination therapy proven to outlast consecutive mono treatments.

•  1995: 3TC/Epivir, and 1st protease inhibitor, saquinavir (Invirase) on December 22nd.

•  But just 4%-8% bioavailability mutations. James J. “Grapefruit Juice and Saquinavir.” AIDS Treatment News Nov 17,1995; 235.

•  1996: 1st NNRTI, nevirapine (Viramune). •  Despite all this, very little increase in life expectancy. •  AIDS diagnosed in = average increased lifespan

1989-1992 2.8 months 1993-1996 3.5 months


False Hope? •  In scary times people reach for solace and

hope, but lies later explode to ruin lives.

"The storytellers at the city gate twist life until it looks sweet to the lazy and the weak, but this solves nothing, cures nothing, nor does it let the heart soar."

John Steinbeck, East of Eden


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Debunking the Myths You Can Heal Your Life,

Louise Hay-- "Disease is just dis-ease.”

The Cure for AIDS, Clark Hulga--Supposedly cured 72 people.

Embraced by the Light, Betty J. Eadie-- saw God welcoming her. All is predestined.

Conversations with God, Neale Donald Walsh—Hitler wasn’t evil, but littering offends God.

The Secret, Rhonda Byrne– Everything that’s coming into your life, you are attracting into your life.


“Industrial Revolution” Era of Meds •  1996: More PIs approved, ritonavir

(Norvir) and indinavir (Crixivan). •  1997: Another PI, nelfinavir (Viracept),

and NNRTI delavirdine (Rescriptor). •  1998: First combo medication, nuke

Combivir (AZT + 3TC). •  Prevalence of opportunistic infections . Furrer H, et al. “Discontinuation of Primary Prophylaxis against Pneumocystis carinii Pneumonia in HIV-1–

Infected Adults Treated with Combination Antiretroviral Therapy.” Swiss HIV Cohort Study, New England Journal of Medicine, 340:1301-1306; April 29, 1999. AND Feinberg J. “Withdrawal of prophylaxis against Pneumocystis carinii pneumonia.” EuroSIDA Study Group, The Lancet, 353:1287-1287, April 17, 1999.

AIDS diagnosed in = increased lifespan 1997-1998 4.1 years

Walensky, R. “2 Million Years of Life Saved: the Survival Benefit of AIDS Therapy in the United States.” 12th Conference on Retroviruses and Opportunistic Infections, Abstract 143LB, Boston, MA, February 25, 2005.


High Hopes for Hit Early & Hard

A small voice of dissent, 1997.

•  Push virus out in 2.3 - 3.1 years? Ho D. “Can HIV Be Eradicated?” 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997, Wash, DC.

•  Make that 18-20 years. Ho D. ”Lecture S16." 5th Conference on Retroviruses and Opportunistic Infections, February 1-5 1998, Chicago.

•  Or is it 60 years? Finzi D. “Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.” Natural Medicine 1999;5:512-517.

•  Or 73 years? Siliciano R. “Abstract L5.” 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago.

•  Actually, it’s impossible as long as HIV is in sanctuary sites. Siliciano R. 14th International Conference on AIDS, Barcelona, Spain, July 2002, Abstract: MoOr103.


When to Initiate Treatment   History of an AIDS-defining illness, or   CD4s < 350, with stronger recommendation if <200.   May consider even if > 350, IF special circumstances (i.e. still > than 350 but declining rapidly). •  Prerequisite for any initiation: “Barriers to adherence should be addressed before therapy is initiated.”

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Jan 29, 2008; 1-128. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

•  2001-2005 SC HIV/AIDS reporting system: 41.3% were “late testers” i.e. AIDS w/in 1 year of HIV diagnosis. For DC, 39%. Duffus W, et al. “Missed Opportunities for Earlier Diagnosis of HIV Infection --- South Carolina, 1997--2005,” Morbidity and Mortality Weekly Report, Dec 1, 2006 / 55(47);1269-1272. Levine S. "Study Calls HIV in D.C. a 'Modern Epidemic’.” Washington Post, Nov 26, 2007.


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When to Initiate Treatment (cont’d) •  NA-ACCORD study suggests those treating with > 350 have higher survival benefit for life. •  Some counter-intuitive results (higher untreated CD4 patients had more risk than lower untreated?), and possible self-selecting variable (early treaters may be different in other way). Kitahata MM, Gange SJ, Moore RD, and The North American AIDS Cohort Collaboration On Research And Design. “Initiating rather than deferring HAART at a CD4+ between 351-500 cells/mm is associated with improved survival. ICAAC/IDSA, October, 2008; Washington, D.C. Abstract H-896b.

•  More armchair philosophy than practical debate when average U.S. patient initiates between 200 - 276 CD4s. Keruly JC, Moore RD. “Immune status at presentation did not improve among antiretroviral-naïve persons from 1991 to 2006. Clin Infect Dis. November 15, 2007;45(10):1369-1374.


HIV’s Strategy: Resistance •  HIV reproduces average 10 billion particles every day; most are cleared. •  Average 1 new mutation in each new virus genome, untreated PLWH. Ho DD, et al. “Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.” Nature. 1995;373:123-126.

•  An infected cell makes 50,000 viruses.

"Los Alamos Lab Suggests HIV Spreads Faster than Thought.” Associated Press, April 14, 2008.

•  Meds don’t cause resistance. Mutations selective pressure. Richman R. “Drug Resistance.” 12th Conference on Retroviruses and Opp Infections Feb. 22, 2005, Boston, MA.

•  Resistance is the #1 cause of treatment failure. (p=0.004). Johnson J, et al. “Low-frequency mutations substantially increase the prevalence of transmitted drug resistance and greatly strengthen the relationship between resistance mutations and virologic failure.” 14th CROI 2007; Abs 639.

•  1- in -5 newly infected U.S. teens acquired drug resistant virus. Viani R, et al. “Prevalence of primary HIV drug resistance among recently infected adolescents; a multicenter Adolescent Trials Network study: ATN029.” 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abst 21.

(c) 2009 Stephen Fallon, Skills4

What Are Side Effects? •  All medications intend to produce a

primary effect: reduction of symptoms or cessation of illness.

•  Most medications have the potential for secondary or side effects as well

•  Side effects might be considered as  Quality of life effects: daily nuisances

that pose no serious threat. Examples?  Chronic, potentially serious effects:

sometimes experienced, other times only apparent in lab readings. Examples?


Know About Resistance? •  Survey of 385 physicians who treat HIV patients and 400 adults LWH/A. •  91% of physicians "extremely" or "very" concerned about HIV drug resistance, but just 54% of patients are. •  61% of patients rate selves “knowledgeable about HIV drug resistance,” but 59% did not know if their virus was drug-resistant. •  Among those with resistant virus, 45% did not know which classes of drugs were involved. “Survey Reveals Nearly Twice As Many Physicians Than Patients Are Concerned About HIV Drug Resistance.” PRNewswire, July 18, 2006. "HIV Patients Often Unaware of Drug Resistance.” Reuters July 19, 2006.


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Don’t Drop the Ball •  Most treatment “failures” in the HAART era due to treatment

interruptions (drug holidays, side effects, co-morbidity). Phillips AN et al. “Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in

previously drug-naïve individuals.” AIDS 15: 2379-2384, 2001.

•  Non-adherence is the main cause of treatment resistance. “Taking AIDS drugs exactly as prescribed is the best way to prevent HIV from becoming drug-resistant….”

Harrigan R. "Predictors of HIV Drug-Resistance Mutations in a Large Antiretroviral-Naïve Cohort Initiating Triple Antiretroviral Therapy," Journal of Infectious Diseases 2005;191:339-347.

•  London's College Medical School: 16,000 patients studied 1996 - 2002. Many skip, then switch too often.

•  5% to 6% of patients studied “have experienced treatment exhaustion."

Sabine C, et al. "Treatment Exhaustion of Highly Active Antiretroviral Therapy (HAART) Among Individuals Infected with HIV in the United Kingdom: Multicentre Cohort Study," British Medical Journal March 2005;330:695. (c) 2009 Stephen J. Fallon, Skills4

Side Effects Skipping Failure? •  Side effects alone don’t always make

people skip doses. Glass T, Geest S, The Swiss Cohort Study, et al. “Correlates of Self-Reported

Nonadherence to Antiretroviral Therapy in HIV-Infected Patients.” Journal of Acquired Immune Deficiency Syndromes 2006;41(3):385-392

•  But side effect distress has been found to lead to non-adherence.

Johnson MO, Catz SL, Remien RH, et al. “Theory-guided, empirically supported avenues for intervention on HIV medication nonadherence: findings from the Healthy Living Project.” AIDS Patient Care STDS 2003;17:645-656. AND Heath KV, Singer J, O Shaughnessy MV, et al. “Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy.” Journal of AIDS 2002;31:211-217.

•  Resistance is the #1 cause of treatment failure (p=0.004). Johnson J, Li JF, Wei X, et al. “Low-frequency mutations substantially increase the prevalence of transmitted drug

resistance and greatly strengthen the relationship between resistance mutations and virologic failure.” 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; LA, CA. Abs 639.

•  When did Noah build his ark? Before the rains.


Treatment Impact on Heart Health

•  The risk is still less than being male, being a smoker, having diabetes mellitus, or having had a previous cardiovascular event. The DAD study group. “Class of antiretroviral drugs and the risk of myocardial infarction.” New England Journal of Medicine 2007; 356: 1723-1735. Stein JH. “Cardiovascular risks of antiretroviral therapy.” New England Journal of Medicine 2007; 356: 1773-1775.

•  Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study group followed 23,437 followed 1999 - 2001. •  345 patients had experienced an MI. •  After adjustment for other treatments, cardiovascular risk factors, lipid levels, patients receiving PIs had 16% risk of MI per year, or 10% for those with existing risks (serum lipid levels, hypertension, and diabetes mellitus).


Tracking Diabetes •  Another D.A.D. study finding: cumulative

exposure to combination ART independently & significantly associated with diabetes risk.

•  Even after adjusting for other risk factors, CD4 count, lipids, and lipodystrophy.

•  Greatest risk predictors were d4T, followed by AZT.

•  “The two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.”

•  Overall risk average increase is 1.11 per year. De Wit S, MD, Sabin C, Weber R, et al. “Incidence and Risk Factors for New-Onset Diabetes in HIV-Infected

Patients: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.” Diabetes Care 2008; 31:1224-1229.


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Consequences of Lipoatrophy •  People living with HIV, reported that lipoatrophy led to:

  Poor body image   Low self-esteem   Social withdrawal   Being forced to tell others that they have HIV   Depression   Not taking all of their HIV medicine. Collins E, Wagner C, Walmsley S. “Psychosocial impact of the lipodystrophy syndrome in HIV infection.” AIDS Reader 2000;10:546-551.


Treating the Symptom •  Most current strategies for lipatrophy and lipohypertrophy

focus on restoring appearance (not causes). •  Theratechnologies Inc’s TH9507 stimulates a growth

hormone to burn off excess fat. •  15% reduction fat buildup in the abdomen and back. •  Merck’s cholesterol-reducing drug

Zetia (ezetimibe) 12% reduction in LDL ("bad cholesterol").

•  Sculptra and Radiesse: initial impressive facial swell is not lasting.

•  Results around 8 weeks are actual. Needs a touch up after 2-3 years.


Tackling Lipoatrophy’s Causes •  Research identifies one mechanism. •  PIs block a protein called ZMPSTE24 from converting prelamin A into its useful form for the body, leaving it “clumpy” in the cells. Same seen in early aging patients.

•  Not all PIs block this protein. Studies underway to see if unblocked leads to less lipoatrophy, as expected. Coffinier C, Hudon S, et al. “HIV Protease Inhibitor Blocks the Zinc Metalloproteinase ZMPSTE24 and Lead to an Accumulation of Prelamin A in Cells," Proceedings of the National Academy of Sciences, 2007; 104 (33): 13432-37

•  Other med classes also linked to lipoatrophy & lipodystrophy. Carr A. “HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management.” AIDS 2003;17 Suppl 1:S141-8.

•  But not through this mechanism. Further studies needed to find what other regulatory protein imbalance is causing lipo with NRTIs.


Diarrhea: Causes & Solutions •  Diarrhea still more common in PLWH than in general population. Odds ratio 6.65. Siddiqui U, Bini EJ, et al. “Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of HAART.” Journal of Clinical Gastroenterology 2007 May-Jun;41(5):484-90.

•  Greasy fast foods: major cause of diarrhea. •  Anti-diarrhea medications like Lomotil, Kaopectate, Imodium, or Pepto-Bismol help. •  Calcium supplements (500 mg, 2x/day) help. •  Surprise: laxatives like Metamucil help too, due to bulking. •  Supplements and food high in soluble fiber (not insoluble) help keep it from starting in the first place: oatmeal, Cream of Wheat, grits, psyillium fiber husk bars, ground flaxseed.


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Effects of HAART •  Swiss HIV Cohort Study, PLWH since1996, estimated hazard ratios for progression to AIDS or death (weighted Cox models). •  Beneficial effect of HAART on progression / death: p = 0.07 compared w/ no treatment, p = 0.48 compared w/ dual therapy. •  Compared w/ no treatment, HAART benefits with increasing time since initiation.

•  Beneficial effect greater if baseline CD4 was < 200. •  “The substantial beneficial effects of HAART … provide a context for considering adverse effects.” Sterne J, et al. “Long-term Effect of HAART in Preventing AIDS and Death Compared with No Treatment and with Dual Therapy: The Swiss HIV Cohort Study” 12th Conference on Retroviruses and Opportunistic Infections, February 22-25, 2005, Boston, MA. (c) 2009 Stephen J. Fallon, Skills4

“The Space Age” of HIV Treatment 1999: First once-daily med, NNRTI Sustiva (Efavirenz). 2000: First boosted PI, Kaletra (lopinavir/ritonavir). 2003: First fusion inhibitor, Fuzeon (enfuvirtide). 2006: First QD combination approved as possible total regimen,

Atripla (efavirenz, emtricitabine, and tenofovir DF). 2007: First integrase inhibitors, Raltegravir (Isentress) and elvitegravir (GS-9137). 2007: First CCR5 antagonists, Selzentry

(maraviroc), Vicriviroc. 2007: First maturation inhibitor, bevirimat. •  Results generally? Lower pill burden / dosing,

higher IQ, lower side effect profile. •  HIV almost “chronic, manageable.”


Reluctant to Hope Again? •  First AZT, then AZT/3TC combination, then triple therapy cocktails were all “proven” to stop HIV (in vitro). •  Each time, HIV’s adaptations confounded hopes of a complete victory. •  Now, some are scared to be “called on” premature optimism again. •  Yet each advance has cumulated to an astounding moment of opportunity.


Checking in on Adherence •  Build dose scheduling into an existing daily routine (i.e. for 1x daily--morning multivitamin or evening alarm setting. For 2x morning and evening tooth brushing). •  Remember that adherence means on time, too (i.e. 2x not at 7:00 a.m. and 11:30 p.m. 1x not dawn one day, midnight the next).

•  Celebrate adherence successes; forgive yourself for slip ups … but pick pragmatic solutions, too. •  Those who manage first treatment without interruption can stay on the same regimen for 20 years without viral rebound.. Lampe F et al. “Viral rebound after suppression with HAART: experience from 237 people with viral load <50 copies/ml followed for up to 4.4 years.” Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 536, 2002.


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Creating Real Potential

•  Marshmallows and jellybeans tell us the real “secret” to success.

“I wanted to live deliberately and not, when it came my time to die, realize that I had not yet lived.”

Henry David Thoreau, Walden

“So oftentimes it happens that we live our lives in chains. And we never even know we have the key.” Eagles, Already Gone

Impulsive Grabbers & Patient Planners •  One study gave patients a "dry run" to prepare for taking meds. They were given jellybeans to take on schedule.

•  Some complained of headaches or stomach upset, but most simply forgot to take jellybeans on time.

•  How many do you think took all of their “medicine”? Leider ML, Kalkut G. “Understanding Adherence to HIV Medication.” Annals of Internal Medicine. 2000;132:418

Impulsive Grabbers & Patient Planners •  Recalls the 1960s experiment, “The Marshmallow Test.” •  Willing to put aside immediate gratification for an important goals? •  Can lead to greater success, happiness, and fulfillment throughout life.

  Invest in your dreams … whatever is important to you.   The universe won’t just send it. But you can make it.   Ready to dream a little with me?


Here’s Good News! •  Treatments today bring huge improvements: AIDS diagnosed in = increased lifespan

1989-1992 2.8 months 1993-1996 3.5 months 1997-1998 4.1 years 1998-1999 9.7 years 2000-2002 10.3 years

•  Today’s therapies “can lengthen the lifespan of persons with AIDS by nearly 15 years.”

Walensky, R. “2 Million Years of Life Saved: the Survival Benefit of AIDS Therapy in the United States.” 12th Conference on Retroviruses and Opportunistic Infections, Abstract 143LB, Boston, MA, February 25, 2005.

•  Better yet, start treatment when CD4s are still ≥ 350, and average life expectancy is 24 more years!

Schackman B R et al. “The lifetime cost of HIV care in the United States in the current treatment era.” 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract WePe12.2C07 (poster).


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Take a Stand for Your Health •  Ask your physician to spend time explaining why s/he chose this regimen especially for you.

•  If you’re finding side effects interfere with your adherence, talk to your physician about changing your regimen.

•  Don’t just complain. Instead, detail. That will get your concerns taken seriously. •  Keep a log of your symptoms, side effects, concerns. •  Help your physician understand how to help YOU adhere to your regimen.


•  PLWH starting treatment 1996 to 1999. Checked pill counts and refills.

•  Taking > 75% of meds during year 1 proven 2.97x MORE likely to be alive at follow up.

Hogg R, “Intermittent Use of Triple-Combination Therapy is Predictive of Mortality at Baseline and After 1 Year of Follow-Up.” AIDS 2003; 17(18s):S128-S130.

•  Another much bigger study: 1,200 PLWH followed for a decade.

Adherence = Success

•  Those > 90% adherent are 3.87x MORE likely to survive the decade than a non-adherent patient on the same therapy.

García de Olalla; et al. "Impact of Adherence and Highly Active Antiretroviral Therapy on Survival in HIV-Infected Patients” Journal of Acquired Immune Deficiency Syndromes May 01, 2002; 30(1): 105-110.


•  Newest study: 903 PLWH. Adherence from 79% @ 6 mos to 72% by 2+ years.

•  Those PLWH > 95% adherent were 3.25x – 3.61x MORE likely to survive through five year study period.

Lima V, Harrigan R, Bangsberg D. "The Combined Effect of Modern Highly Active Antiretroviral Therapy Regimens and Adherence on Mortality over Time.” Journal of AIDS 2009, Vol. 50; No. 5: P. 529-536.

Adherence = Success

•  PLWH who keep doctor’s visits > 2x as likely to survive year. Mugavero M. “Missed Visits and Mortality Among Patients Establishing Initial Outpatient HIV Treatment,” Clinical Infectious Diseases 2009;48(2):248-256.

•  "I think we are done with the mortality of AIDS in treated people. Only five years ago hope was an abstract notion; now hope is a reality.”

Dr. Michael Kazatchkine, Global Fund to Fight AIDS, 4th International AIDS Society Conference in Sydney, July 2007. (c) 2009 Stephen J. Fallon, Skills4

Today’s Takeaway Lessons •  Improved medicines and treatment strategies

have greatly reduced AIDS mortality, and improved quality of life.

•  Even the best regimen cannot work when it’s not taken. Taking meds on time is the most important thing you can do to stay healthy.

•  For a full and long life, PLWH should try to quit smoking, exercise, and get help for chronic depression.

•  Keep your eye on the goal: an even brighter future. Examples ….


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25-30 Years: Everything Changes 1973 2009

•  Where will HIV treatments be in 30 years?

+

1975


Future Idea: Flip the Immune Switches

•  The molecule PD-1 shuts down the CD8s prematurely, preventing them from mounting killing attack against HIV. Massachusetts General Hospital, Press Release, “Molecular switch may turn off immune cells that target HIV.” August 20, 2006.

•  Now a regulatory protein also discovered, CTLA-4, which rises too high. It dampens immune response. PLWH often have high levels of CTLA-4. “Elite serocontrollers” do not. Massachusetts General Hospital, Press Release, “Researchers discover ‘switch’ responsible for turning off immune system’s response to HIV.” September 30, 2007.

•  BIG news: early tests suggest these are both reversible.

•  Researchers have discovered that two parts of the immune system fall out of whack, preventing the immune system from properly attacking HIV.


Chasing the Virus Down •  Early trials used anticonvulsant drug valproic

acid) to try to purge HIV reservoirs. •  Cleared 75% of cells @ 3 months, but need

to clear 99.9999% from sanctuary sites. Margolis D. "Depletion of HIV-1 Infection in Vivo: A Proof-of-Concept Study,"

The Lancet 2005;366(9485):549-555. And Margolis DM et al. “Coaxing HIV-1 from Resting CD4+ T Cells: Valproic Acid Induces Latent Viral Expression.” 11th CROI, San Francisco, abstract427c, 2004.

•  New research: use chemotherapy to destroy reservoir virus where it hides dormant in cells even with UDVL.

•  For PLWH with UDVL, the new treatment can target infected cells, and might be able to wipe out the last ones, so "the patient will remain virus-free for a long time or forever.”

Rafick-Pierre Sekaly and Jean-Pierre Routy, "HIV Reservoir Size and Persistence Are Driven by T Cell Survival and Homeostatic Proliferation,” Nature Medicine June 21, 2009; doi: 10.1038/nm.1972.


Science to the Rescue? •  New studies: introduce treatments

through injections with nanoparticles instead of orally through pill.

•  Tested with tests with LPV, EVF, CCR5 inhibitors, and TMC 278.

•  Held therapeutic levels for ≥ 1 mos. G van't Klooster, R Verloes, L Baert, et al. “Long-acting TMC278, a Parenteral Depot Formulation Delivering

Therapeutic NNRTI Concentrations in Preclinical and Clinical Settings.” 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract 134. AND Destache C. “Ritonavir, Lopinavir--, and Efavirenz--containing Nanoparticles: in vitroin vitro.” 15th CROI, 2008, Abstract F-128.

•  Introduction not through digestive track could alleviate primary adherence challenges (nausea, vomiting, diarrhea).

•  The end of daily, pill-based therapy? •  Could justify DOT for all.


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Believing in the Future •  New Univ of CA Phase II study demonstrates gene therapy to treat HIV is beneficial and safe. •  1/2 of HIV+ participants in OZ1 trial received stemcells with crippled virus containing a gene hoped to block HIV from replicating. •  No effect @ 48 weeks, but @ 100 weeks, VL in gene group was and CD4 count But stemcells deleted quickly. No adverse reaction to the therapy. "Phase 2 Gene Therapy Trial of an Anti-HIV Ribozyme in Autologous CD34+ Cells,” Nature Medicine 2009;doi:10.1038/nm.1932.


Believing in the Future (cont’d) •  Patient LWH also had leukemia, and needed

treatment. His physician performed a very dangerous allogeneic stem cell transplant.

•  German Central Bone Marrow Donor identified donors with dual CCR5 deletion.

•  A virtually total inhibitor of HIV infectivity and progression (except when XR4 tropism).

•  2 years later, no HIV detectable in blood, lymph nodes, or brain. Hütter G, et al. “Treatment of HIV-1 Infection by Allogeneic CCR5-∆32/∆32 Stem Cell Transplantation: A

Promising Approach.” 15th Conference on Retroviruses and Opportunistic Infections 2008. Abstract X719. Shoofs M. “A Doctor, a Mutation and a Potential Cure for AIDS.” The Wall Street Journal. November 7, 2008.

•  Again, the end of daily therapy, or even …?


Just Getting Started … Stick Around!


Thank You for Making a Difference! Stephen J. Fallon, Ph.D. President, Skills4, Inc. 1712 N. Victoria Park Road Ft. Lauderdale, FL 33305 [email protected]

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