Free 2013 Report: New HIV, HCV and TB Drugs, Diagnostics, and Vaccines in the Research Pipeline

HIV i-Base/Treatment Action Group 2013 Pipeline Report
calls on leaders to get the best HIV, hepatitis C virus (HCV), and tuberculosis drugs, diagnostics, and vaccines to the most people as quickly as possible
– Survey shows HIV pipeline healthy, HCV drug development surging,
while TB research moves forward much too slowly –

– Faster research, approval, and access demanded –

KUALA LUMPUR, Malaysia, 30 June 2013 – HIV i-Base and Treatment Action Group (TAG) called on global and national leaders, research sponsors, and regulatory authorities to work together to make the best HIV, HCV, and TB drugs, diagnostics, and vaccines accessible as fast as possible, according to a report released today at the 7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In the 2013 Pipeline Report, Polly Clayden of HIV i-Base (UK) and Mark Harrington of TAG (USA), set a seven-part agenda to speed the best medical products to all who need them everywhere. They call for research funders to continue investing in better products and to address global needs up front in their development. They demand that regulators expedite review of new medications in developing countries and close approval gaps between rich and poor countries and adult and pediatric indications. World Health Organization (WHO) and national guidelines groups must continue streamlining and simplifying treatment guidelines, they stress. Clayden and Harrington urge authorities in developing and developed countries to speed the rational use of the best possible drug combinations regardless of patent status or manufacturer and to expedite the transition to high-quality first-line generic products when preferred drugs go off patent.

Noting that the pharmaceutical industry has made billions from successful HIV therapies in the past two decades, Clayden and Harrington report that in the last decade alone, 47 new drugs and combinations were studied in phases II and III. An impressive 34 percent (16/49) were approved by the U.S. Food and Drug Administration (FDA), with 6.4 percent (3) awaiting approval and 21 percent (10) moving forward in phases II or III. “To get the best drugs to the most people as quickly as possible, global and national health leaders, regulators, and research sponsors must take concerted action to speed up the approval of pediatric, generic, and high-quality cross-sponsor fixed-dose combinations—as soon as they are available in rich countries—in those where they are needed most,” commented Clayden and Harrington.

Themes of the 2013 “Antiretroviral Pipeline” by Simon Collins (HIV i-Base) and Tim Horn (TAG) include the continuing wave of innovations bringing broader, and in some cases better, treatment options for people with HIV. They note “the possible conflicts these innovations will encounter due to global economic austerity.” Collins and Horn underscore “the potential for combining generic antiretrovirals as they move off-patent in many developed countries with innovator compounds to produce synergistic, often cross-sponsor, combinations and fixed-dose combinations (FDCs) that could offer people with HIV the best of the new and the old while saving cash-strapped health systems billions of dollars.”

Noting the current decade’s coming wave of patent expiries on first-line HIV drugs such as efavirenz and tenofovir, Collins and Horn note that, “savings from generics are essential if we are to retain public health services for those who remain uninsured or underinsured.” They call for generic manufacturers and governments to seize the opportunity posed by the coming wave of patent expiries to offer optimal combinations at prices much lower than for innovator compounds. It will be critical for rich and poor countries, to reinvest the savings generated by sensible use of generic-containing antiretroviral combinations into massively expanded HIV prevention and treatment programs to end HIV transmission and progression to AIDS and death and achieve an “AIDS-free generation” for everyone.
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In back-to-back chapters on pediatric HIV drugs and HIV treatment optimization, Polly Clayden calls for continued streamlining and rationalization of adult and pediatric HIV formulations and notes innovative partnerships such as those recently supported by the Drugs for Neglected Diseases Initiative (DNDi) and UNITAID to expedite production of optimized regimens for children. Clayden stresses the importance of developing generic combinations with the best target product profiles. “It’s time to move on from merely providing the world’s poor people with the cheapest medicines and time to give them the best – safest and most effective – treatments possible, and make them affordable” says Clayden.

Richard Jefferys (TAG), in his broad survey of research developments on preventive technologies, research toward a cure, and immune-based and gene therapies, calls for intensified basic and translational science on potential HIV vaccines and continued research on antiretroviral (ART)-based pre- and postexposure prophylaxis (PrEP, PEP). He stresses the need for immune-based therapy research to raise CD4 T cell counts among immunologic nonresponders to HIV therapy, and new research to address ongoing residual dysfunction of the immune system that persists in people on successful ART. Finally, Jefferys emphasizes further investigation of the role of very early treatment with potent ART combinations in infants and adults infected with HIV; better lab measurements to quantify the cells and tissue sources of the latent HIV-1-infected cell reservoir, the target for HIV cure research; and exploration of the potential contribution of therapeutic vaccine approaches as part of combination curative therapy.

In the 2013 “HCV Treatment Pipeline,” Tracy Swan (TAG) notes that the “confluence of a robust HCV drug pipeline, shortened regimens, and [shorter] posttreatment follow-up are extraordinary. The new FDA breakthrough therapy designation may speed things up as well. By the end of 2014, [new HCV drugs] from four different classes and fixed-dose combinations (FDCs) are likely to be approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), offering the potential for off-label mixing and matching.” An impressive 26 new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV.

Swan notes, however, that not all optimal combinations are being studied, with some sponsors preferring combinations of their own proprietary compounds, while many sponsors take too long to study their new drugs in people coinfected with HIV and HCV, and those with cirrhosis.

In her companion chapter, “Low- and Middle-Income Countries Defuse Hepatitis C, the ‘Viral Time Bomb,’” Karyn Kaplan (TAG) describes how a worldwide movement is forming to ensure that when new all-oral HCV cures are approved, that governments, health systems, and providers will be ready for them. Kaplan points to recent progress instigated by HCV activists in countries such as Egypt, Georgia, Thailand, and Ukraine.

In three chapters on tuberculosis (TB) diagnostics, treatment, and vaccine research, Colleen Daniels, Erica Lessem, and Mike Frick (TAG) find that lack of investment and political will make the TB pipeline the most anemic covered in the 2013 Pipeline Report.

Globally, one-third of active TB cases are never diagnosed, reported, or treated, meaning that 3 million people are walking around with undiagnosed disease, in danger of progression, death, and onward transmission.

Some progress has been made in rolling out new DNA tests, which can detect TB more rapidly. The tests still require high-tech laboratory equipment, electricity, and trained personnel though, meaning they are far from the majority of TB patients and those at risk. Manufacturers are trying out cheaper forms of DNA TB diagnostic testing with as yet little published data, and faster ways to detect TB mutations, which are associated with resistance to TB medications.

TB treatment is slowly moving forward following the first FDA approval of a new drug from a new class in over 40 years, and innovative combination TB studies under way for both drug-sensitive and drug-resistant disease. Most countries are not ready to review, approve, distribute, and assure rational use of new TB drugs and combinations, however, reinforcing HIV i-Base and TAG’s call for high-burden countries to modernize their regulatory research oversight and approval programs.

Research on TB vaccines remains slow and underfunded but there are some glimmers of hope, particularly on the basic science and early clinical front. Much more investment is needed in TB research and development overall, and in TB program scale-up to ensure access to the best diagnostics tests and preventive and curative therapies.
 

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The HIV i-Base/Treatment Action Group 2013 Pipeline Report: HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies in Development by Polly Clayden, Simon Collins, Colleen Daniels, Mike Frick, Mark Harrington, Tim Horn, Richard Jefferys, Karyn Kaplan, Erica Lessem, and Tracy Swan, edited by Andrea Benzacar, Tim Horn, and Scott Morgan, is online at:

            http://www.treatmentactiongroup.org/pipeline-report 

and as an interactive web report at:

            http://www.pipelinereport.org

About HIV i-Base – HIV i-Base is a London-based HIV treatment activist organization. HIV i-Base works in the United Kingdom and internationally to ensure that people living with HIV are actively engaged in their own treatment and medical care and are included in policy discussions about HIV treatment recommendations and access.

http://www.i-base.info 
About TAG – Treatment Action Group (TAG) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. We are science-based treatment activists working to expand and accelerate vital research and effective community engagement with research and policy institutions. TAG catalyzes open collective action by all affected communities, scientists, and policy makers to end AIDS. TAG is a nonprofit, tax-exempt 501(c)(3) organization.

http://www.treatmentactiongroup.org 

WORLD AIDS DAY: Time to Help Victims of HIV Drug Studies and Resistance

We have repeatedly heard the following statements about multi-drug resistant HIV (MDR-HIV) patients in a host of meetings on treatment access and HIV research: “These patients no longer exist – they’re either dead or have responded to the latest ARVs”; “Only patients who do not adhere to their HIV regimens have MDR-HIV”; and “Our clinic cannot provide expanded access programs (EAPs) due to cost and staff restraints.” However, after surveying physicians around the country, we have found that although these patients are in a minority, they do exist and are anxiously waiting for access to viable regimens that could save their lives.

No one can deny that many patients can now suppress their HIV with effective regimens that cause fewer side effects. However, a vulnerable and often forgotten minority of people are still struggling with MDR-HIV while they anxiously await for access to life-saving regimens that would finally control their virus replication. Although some of these patients may have developed resistant HIV due to lack of adherence or other issues, many of them have been strictly following their doctor’s orders for years.

They’re often veterans of drug development research who have accumulated HIV resistance as they repeatedly joined antiretroviral (ARV) studies or traditional EAPs of a single new drug out of desperation to control their HIV viral load. As they signed up for studies that helped companies get their drugs approved by the FDA, many of these patients were exposed to suboptimal HIV regimens (namely, functional monotherapy or the addition of a single new active ARV to a failing HIV regimen). It is time to create a new paradigm to break the vicious cycle of single drug access that has failed these patients.

More: http://www.poz.com/pdfs/gmhc_treatmentissues_2012_12.pdf

New HIV Drugs in the Pipeline - 2012

Gilead has completed and released 48-week data from ongoing phase 3 studies of a four-drug fixed dose combination (elvitegravir, cobicistat, tenofovir, and FTC- called QUAD), as it has with studies of the integrase inhibitor elvitegravir and the pharmacokinetic booster cobicistat.  QUAD  will likely be approved for treatment naive patients after August this year.

 Results from phase 3 studies of the integrase inhibitor dolutegravir (formerly S/GSK-572) have been submitted to the FDA. This drug may be approved later this year for treatment naive and experienced patients. This drug is now available via expanded access to patients who have developed resistance to raltegravir. As with any other drug, it has to be combined with at least one fully active medication and a background therapy for it to control HIV.  But some patients do not have another medication to use with dolutegravir, so they will have to wait for other new drugs to be available via expanded access or single patient access programs in the future. Another HIV medication with a new mechanism of action may not be approved in the next 2.5- 3 years.

Phase 2 studies continue or are expected for an attachment inhibitor (BMS-663068) that may work for HIV mutidrug resistant virus, and a CCR5 inhibitor (cenicriviroc, formerly TBR-652) for treatment naive patients. BMS also has a continued with the developement of Festinavir , a nucleoside reverse transcriptase inhibitor that is active against HIV resistant to both abacavir and tenofovir, making the drug a candidate for people with multi-drug resistant (MDR) strains of the virus. 

Phase 2 results for the attachment inhibitor ibalizumab were presented last September at the ICAAC conference.   Ibalizumab's manufacturer, Taimed Biologics, is also testing a subcutaneous formulation instead of the intraveneous one used up to now is their studies.  Both formulations are dosed every two weeks.  As other small biotech companies (Tobira, Avexa, and Progenics), Taimed is currently looking for financial partners to proceed to phase 3 studies. 

Phase 2 results for the NNRTI lersivirine (previously known as UK-453061) in treatment-naive patients were presented at the International AIDS Society's (IAS) Conference in Rome last summer.  GSK-ViiV is exploring this and other drugs as part of a long acting ARV regimen provided via subcutaneous injection (no oral drugs) every week or two weeks. This will revolutionize HIV treatment, in my opinion.

Three compounds had their development discontinued: vicriviroc (a CCR5 inhibitor), GSK-761 (an NNRTI), and bevirimat (a maturation inhibitor).

The drugs that may work for multidrug resistant HIV are ibalizumab, BMS-663068, dolutegravir,  and potentially lersivirine and apricitabine. However, only dolutegravir is now available via expanded access. As a salvage therapy research advocate, I am looking forward to hearing from BMS, Taimed, Progenics about their upcoming phase 3 studies and future expanded access programs. Stay tuned for an upcoming article in Treatment Issues  about salvage therapy access for the dwindling but vulnerable population of patients with extensive HIV multi-drug resistance.

As a side note, some preliminary cure related studies have started enrolling:
HIV Cure Related Studies 

ViiV Announces Expanded Access of New Integrase Inhibitor...But Activists Are Concerned About Its Potential Misuse

The dolutegravir expanded access program (EAP) has been designed to provide free access to Shionogi-ViiV Healthcare’s investigational integrase inhibitor, dolutegravir (DTG, S/GSK1349572) in an open-label protocol program to adults living with HIV who have documented raltegravir or elvitegravir resistance, who have limited treatment options, and who require DTG to construct a viable antiretroviral regimen for therapy. The dose is 50 mg twice a day for patients with multi drug resistance (the drug will also be eventually approved for once daily use for treatment naive patients)

But before you consider the use of this new drug, read the following warning: Activists Advise Caution About Access Program

Who can participate in the dolutegravir EAP (ING114916)?

The dolutegravir EAP is available to adults living with HIV who (Note: Not all inclusion criteria are listed):

• Are male or female age 18 years or older (female patients of child-bearing potential should use every precaution to prevent pregnancy)
• Have documented plasma HIV-1 RNA levels ≥400 copies/mL within 3 months prior to the screening visit
• Have documented raltegravir or elvitegravir resistance
• Are unable to construct a viable background regimen of anti-retroviral therapy with commercially available medications.

The dolutegravir EAP is not available to adults living with HIV who (Note: Not all exclusion criteria are listed):

• Have estimated creatinine clearance (CrCl) <30 mL/min
• Are pregnant or breastfeeding
• Have had a known or suspected allergic reaction to an integrase inhibitor
• Have an alanine aminotransferase (ALT) level >5 times the upper limit of normal (ULN)
• Have an ALT >3 times ULN and total bilirubin >1.5 times ULN
• Have evidence of severe hepatic impairment
• Are eligible for, and have access to, an actively enrolling DTG Phase III clinical trial
• Have any condition (including but not limited to alcohol and drug use) or any active clinically significant disease or findings during screening of medical history or physical examination, which, in the opinion of the treating physician would interfere with safety or compliance
• Requires or is anticipated to require any of the prohibited concomitant therapy.

*Please note: country specific criteria may also apply.

The dolutegravir EAP is now open and accepting participants in the USA and Canada.

For Europe and the International region, it's expected that the EAP will start to open in March/April 2012 as local regulatory and ethics approvals are obtained.

How to apply for participation

For adults living with HIV: Please discuss your possible participation with your healthcare professional. If the EAP is available in your country, check with your healthcare provider if he or she is a participating site. If not, your healthcare provider may contact PAREXEL for further details on how to access the program.

For healthcare professionals treating HIV: If you have an eligible patient(s), please contact PAREXEL at dolutegravir-eap@parexel.com for further details about the program.

What is dolutegravir?

Dolutegravir (DTG, GSK1349572) is an integrase inhibitor under development as a treatment for HIV-1 infection. Phase III studies to assess the safety and efficacy of dolutegravir in antiretroviral naïve and experienced adults living with HIV are currently underway. The safety and efficacy of dolutegravir has not yet been fully established or thoroughly evaluated by regulatory agencies.

For Doctors: How You Can Help Your Patients Who Are Running Out of HIV Treatment Options

By Nelson Vergel, B.S.Ch.E., M.B.A.

July 6, 2011

In a previous blog post, I reviewed the current situation for the minority of patients with HIV who have run out of treatment options.
Of the HIV medications in development with potential activity against highly resistant HIV (i.e., patients with GSS=0), two may become available within the next year: ibalizumab (formerly TNX-355), a monoclonal antibody currently under development by TaiMed Biologics, and dolutegravir (formerly GSK1349572), a second-generation integrase inhibitor made by ViiV Healthcare).
Ibalizumab has a completely new mode of action, so most patients should respond to it when using it with at least one other active agent. It is different from the entry inhibitor maraviroc (Selzentry, Celsentri) in that it blocks the CD4 receptor on T cells rather than blocking the CCR5 co-receptor. This means it could be effective against virus that uses either the CCR5 or CXCR4 co-receptor. It is a genetically engineered monoclonal antibody administered once every two weeks intravenously. TaiMed has finished its dosing phase 2b study and will be presenting the data in the near future. TaiMed is also developing a subcutaneous administration of ibalizumab; phase 3 studies should take place involving HIV-infected patients in eight to 12 months.
Dolutegravir has shown activity against many raltegravir (Isentress)-resistant viruses at a dose of 50 mg twice a day. Dolutegravir's phase 3 study, which is seeking patients with raltegravir resistance, is now enrolling nationwide. However, patients are required to have a GSS=1 to join the study. For those who do not meet the entry criteria, but need help, there may be another option: The company is planning to open an expanded access program for its drug by year's end.
However, "year's end" is not near enough for patients who are in dire need of new, active antiretrovirals. There are many patients who cannot join the phase 3 studies, and who cannot wait eight to 12 months for both drugs to become available through their respective expanded access programs.
In these extreme cases, physicians can apply for "single patient Investigational New Drug (IND)" access to either or both of these antiretrovirals. Both TaiMed and ViiV/GlaxoSmithKline have shown good faith in helping patients in deep salvage, and they are willing to provide their drugs for patients with declining health and high mortality risk.
The following steps must be followed by physicians for each drug they want to access on behalf of one of their patients.

How to Apply for Single Patient IND Access to an Investigational Drug

If the patient's HIV has evidence of resistance to all commercially available antiretrovirals and his/her viral load suggests that his/her HIV is not responding to the current drug regimen, a phenotypic resistance test needs to be performed along with a tropism test. It is important to also know if phenotypic resistance to enfuvirtide (T-20, Fuzeon) is present. Additionally, genotypic integrase mutations need to be characterized to assess the patient's potential response to dolutegravir.
Once the test results have confirmed that the patient has developed resistance to all commercially available or expanded access HIV medications, and provided the patient's health is at risk (i.e., CD4+ cell count under 100 cells/mL and declining clinical outlook), physicians can follow this procedure required by the U.S. Food and Drug Administration (FDA). (Note that the FDA has also changed its regulations to accept patient access for small groups of patients, which could save a lot of paperwork.)

1. The treating physician should call the company that is developing the investigational antiretroviral to find out if it is willing to provide the drug for free before it has been approved. (Drugs have to have gone through dosing and safety studies before they can be made available in this manner. Also, antiretroviral interaction data are valuable, although ViiV and TaiMed do not expect negative drug-drug interactions from the combination of dolutegravir and ibalizumab.)
2. After each manufacturer agrees to provide its respective investigational drug via single patient IND, the doctor should follow the procedure described on this FDA Web page to fill the required forms and get institutional review board (IRB) approval.

This procedure is hardly used by doctors in HIV care due to lack of information or concerns about its complexity. But in actuality, it's very straightforward: three simple forms, a signed patient consent form and IRB approval are needed. Many local IRBs will even expedite approval of this kind of request due to its urgency.
Also, single patient IND can be approved verbally by the FDA if the patient has an expected survival of less than 30 days (this is called emergency IND). This will allow the drug company to ship the drug in an expedited manner, but the forms I mention above will still need to be processed while drug shipment is taking place.
If you need a sample patient consent form and cover letter for IRB submission, I recommend using these, which were used in the past for access to darunavir (TMC114, Prezista) and etravirine (TMC125, Intelence) while they both were investigational drugs:

• Sample consent form (from salvagetherapies.org)
• Sample cover letter (from salvagetherapies.org)

ViiV and TaiMed can also make copies of consent forms for their drugs available if requested by the physician applying for access on behalf of his/her patient.
I welcome e-mails from physicians who need more information or would like additional help gaining access to investigational drugs for their HIV-infected patients whose virus is resistant to all currently available drugs. Please send e-mails to nelsonvergel@gmail.com.

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Is There a Future for HIV-Infected Patients in "Deep Salvage"?

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By Nelson Vergel, B.S.Ch.E., M.B.A.

May 3, 2011

"Only patients who do not take their medications as prescribed have multidrug resistance."
"Deep salvage patients no longer exist. The ones in that situation are already dead or have responded to the latest HIV antiretrovirals."
"Even if we give expanded access to multiple investigational agents to patients in salvage therapy, it will be a waste since most of these patients have adherence problems."
"It is too expensive and cumbersome for my clinic to provide expanded access."
"My institution no longer participates in expanded access due to costs and manpower problems."
These are statements that I have heard in different meetings that I have attended in the recent past to discuss access and research issues in HIV. Some of these statements are very hard for me to hear, since I am one of these "difficult patients" who have "failed" most commercially available medications -- despite the fact that I, like many of my peers, am certainly not a patient who lacks perfect adherence.
Most of us built resistance as we joined study after study that exposed us to functional monotherapy. In fact, I consider many of us who have been struggling with multiple drug resistance to be wounded soldiers from a time when we were recruited into studies we joined out of desperation to access a new drug. Even if we seem invisible due to our lower numbers, we are still here -- and we absolutely hate to be discounted as disposable in the current era of largely successful HIV treatment.
It is my opinion, and that of several clinicians that I have worked with, that it is the pharmaceutical industry's duty to provide access to multiple investigational drugs so that so-called "salvage patients," such as myself, can finally construct a regimen that may help us join the population of virologically controlled patients.
We all know that the management of resistant HIV disease has improved dramatically with the approval of a number of highly effective antiretroviral drugs, including darunavir (TMC114, Prezista), etravirine (TMC125, Intelence), maraviroc (Selzentry, Celsentri) and raltegravir (Isentress). Among this recent generation of antiretroviral drugs, perhaps the most promising is raltegravir, the first clinically available inhibitor of HIV integrase. When used in combination with other active drugs, raltegravir has proven to be very potent, well tolerated and highly effective. In phase 2 and 3 clinical trials, the vast majority of patients who were able to combine raltegravir with at least one other active drug achieved durable viral suppression. (Comparable efficacy has been seen in patients who received darunavir, etravirine or maraviroc with at least one other effective agent.)
Despite the impressive effectiveness of these drugs in clinical trials, a subset of patients has exhibited virologic failure while on these drugs. Most failures likely occurred because of the inability to construct a regimen that contained two to three fully effective agents. Adverse events, drug-drug interactions and non-adherence also likely contributed to the inability of some patients on these drugs to achieve durable viral suppression. As a consequence of these factors, the failure rates in the recent phase 3 studies -- DUET (etravirine and darunavir), MOTIVATE (maraviroc) and BENCHMRK (raltegravir) -- were in the 27% to 40% range.
The picture gets less encouraging when looking at longer-term data. As shown in the following figure, a longer-term study generated from following patients using raltegravir for 144 weeks showed failure rates of 40% to 56% even in patients with one or more active agents in their background therapy.

But I guess these patients disappear into the dark, since many physicians do not seem to know who they are. It is assumed that many of the patients who failed these recent studies were subsequently unable to construct a suppressive regimen, although the long-term outcomes of those failing these clinical trials are unknown.
The prevalence of multi-regimen failure in clinical practice is also unknown. Steven Deeks, M.D., and colleagues at the University of California San Francisco/San Francisco General Hospital have an ongoing observational cohort of patients who have developed drug-resistant HIV (the SCOPE cohort). Most of these patients have been able to construct a fully suppressive regimen and are currently doing well clinically.
However, of the original 300 SCOPE patients, approximately 40 now have evidence of having failed all six therapeutic drug classes. These 40 patients have a genotypic sensitivity score (GSS) of either zero or one, and they have no clear options for suppressing HIV replication. Many have advanced disease (with a CD4+ cell count of less than 100 cells/mm³) and hence may not be able to "wait" for the development and approval of multiple new options.
In an informal online survey I made with the help of a team of investigators and activists, which was presented in a meeting with the U.S. Food and Drug Administration (FDA), 83 physicians around the country reported having a total of 252 patients with a GSS of zero or one.

The most surprising finding was the wide geographical distribution of these patients. Physicians from 47 U.S. cities and towns reported treating them. Although the larger cities had the most patients with a low GSS, many patients lived in small towns that are far from research sites or large practices that are more equipped to handle the needed paperwork to apply for expanded access or single-patient emergency drug access programs.

Much of the expanded access program documentation and nurse/physician time is not reimbursable or paid for by studies, so most doctors participating in these programs are doing so from the goodness of their hearts. Many large medical schools and clinics have stopped providing expanded access help to their patients entirely.
The following chart outlines some of the reasons reported by survey participants for not applying for early access to investigational drugs for their patients. The most common reason was that they simply did not have the administrative support they needed to handle the required paperwork. Many also expressed frustration with an application process they felt was too complex.

Given that patients who are unable to construct a background regimen often fail therapy, the FDA and other interested groups have advocated that future clinical trials only enroll patients whose background regimen has a GSS or phenotypic susceptibility score greater than or equal to one. Although this is an ethically sound recommendation, one unfortunate consequence is that those patients who have now progressed to multi-regimen failure won't be able to access experimental drugs via clinical trials.
Unfortunately, the HIV drug pipeline in 2011 is a lot more limited than it has been in the past due to many factors, including the relatively small size of the U.S. market, drug development costs, and the difficulty in finding treatment-experienced patients with one or more active agents in their background therapy. Some drugs have already been abandoned due to these issues, as shown by this table.

Thankfully, the FDA has proposed a new trial design concept that will facilitate the development of medications for treatment-experienced patients, which may encourage pharmaceutical companies not to abandon HIV drug development. For more information about this novel trial design concept, refer to a presentation given by Jeffrey Murray, M.D., M.P.H., from the FDA at a recent meeting sponsored by the Forum for Collaborative HIV Research.
However, even with these efforts, the possibility of constructing a regimen with three active agents for the salvage population within the next four years is low, which will diminish the chances for survival in those with lower CD4+ cell counts.
I've laid out a grim scenario in this blog post, but in my next post, I'll discuss a potential silver lining: a program in the works that I hope will greatly expand options for deep salvage patients in need of access to investigational agents.

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New Drugs and New Combinations – How will They Change What We Do?

IAC Summary on New Drugs and New Combinations – How will They Change What We Do?

 Vienna July 18-23 2010

Joe Eron, Univ of North Carolina

This year’s IAC was one of the most exciting and data-filled International AIDS meetings since Vancouver in 1996.  The defining presentation of the meeting was the CAPRISA 004 study that demonstrated that a topical microbicide (tenofovir gel) prevented HIV infection in at-risk women in South Africa.  The excitement in the room during the series of presentations was palpable and the presentations were interrupted several times by applause.  Much as Vancouver signaled the beginning of the HAART era, perhaps CAPRISA 004 will signal the practical beginning of the Antiretroviral Prevention era.  Certainly a prevention intervention that can be controlled by at-risk women is a true breakthrough. The hallway discussions were about the magnitude of the effect (Did we expect more? Did we expect less?), the obvious importance of adherence and perhaps the challenging questions about whether a second confirmatory study was needed before this intervention could be made available to women and whether placebo arms should still be incorporated in further studies of microbicides and other pre-exposure prophylaxis (PrEP) studies in women. 

While CAPRISA 004 was a clear centerpiece of the meeting there were also several presentations of antiretroviral therapies (used as treatment in the old fashioned way) that were quite important and will certainly impact how we treat our patients over the next 2-3 years.

ECHO and THRIVE

The most important of these presentations was made by Cal Cohen who presented the Phase III data comparing rilpivirine head-to-head with efavirenz when both were combined with two NRTI (predominantly tenofovir DF/FTC fixed dose combination) in treatment naïve patients. These data are the most clinically relevant because this was one of only two presentations of phase III data in treatment naive patients, because it looks like rilpivirine is ready to be combined with TDF/FTC in a fixed dose combination and most importantly, because Tibotec has submitted the new drug application (NDA) for this drug on July 28^th 2010. The full details of Dr. Cohen presentation can be found in the detailed NATAP summary but there are several interesting nuances to the results that we will probably be discussing and debating for some time.  First and foremost in the primary analyses of both studies, which were independent well powered studies (EHCO used FDC TDF/FTC as the NRTI backbone in all patients, whereas THRIVE allowed the use of TDF/FTC, ZDV/3TC or ABC/3TC as the backbone though the majority of the participants received TDF/FTC), rilpivirine with 2 NRTI was non-inferior to EFV and 2 NRTI in intention-to-treat analyzes (VL <50 c/mL, ITT-TLOVR at Week 48).  Both arms in each study performed very well in a challenging population (median baseline viral load was 100,000 c/mL). In the analysis that combined the results of the 2 studies 84.3% of participants on RPV-based therapy had HIV RNA < 50 copies/mL at 48 weeks compared to 82.3% of participants on the EFV-based therapy.  The “non-inferiority” of RPV was well established with the lower bound of the confidence interval at -2.2%, way below the non-inferiority bound of -12%. Though I am sure this is not FDA-kosher you could almost call the two therapies (when viewed in the light of the combined results) “equivalent”.  However ….. RPV-based and EFV-based therapy produced such similar overall results for different reasons.

Bioequivalence of the Co-Formulation of Emtricitabine/Rilpivirine/Tenofovir DF - (08/04/10)

Tibotec Pharmaceuticals Submits New Drug Application for Investigational Once-Daily HIV Treatment TMC278 to U.S. Food and Drug Administration - (07/26/10)

RPV-based therapy was clearly better tolerated than EFV-based therapy.  In the results from the 2 studies combined, Grade 2-4 AE that were at least possibly related to study medication were twice as likely on EFV-based therapy (31% vs. 16%, p < 0.0001) and significantly fewer participants receiving RPV-based therapy discontinued study medication compared to those on EFV-based therapy (3% vs. 8% p = 0.0005).  These discontinuations of course are counted as failures in the TLOVR-ITT analysis.  As anticipated neurologic and psychiatric adverse events were significantly and substantially less common with RPV and unanticipated (at least by me) was that rash was also significantly less common (3% vs. 14% p < 0.0001). Grade 3-4 laboratory abnormalities were also significantly less common in RPV-treated participants.  While no single grade 3-4 lab abnormality was very common in either arm, grade 3-4 increases in ALT, LDL cholesterol, total cholesterol and triglycerides were all less common with RPV.  Mean change in all individual lipid parameters (including HDL) were greater with EFV with very little change in any of the parameters in those participants on RPV-based therapy.  Because HDL also rises on EFV-based therapy the total cholesterol to HDL ratios at week 48 were not significantly different between the two treatment groups in the combined analysis.

The flip side to the superior tolerability data for RPV-based therapy was that virologic failures (as defined in the TLOVR analysis) were approximately twice as common in participants on RPV (9.0% vs. 4.8% in the combined analysis, p value not reported but likely very significant). So in effect, the discontinuations due to AE (approximately a 5% difference) are balanced by VF (approximately a 4% difference).  There were some relatively small but curious differences in VF between the two studies with a greater difference in VF in the ECHO study (6.6%), where all participants received TDF/FTC, compared to THRIVE (1.8%), where there was a choice of NRTI.  We were told that response rates were not different in THRIVE by NRTI choice so we don’t really have an explanation for this difference in virologic failures.  Perhaps the participants in THRIVE were more likely to take their medications more consistently (the difference in discontinuations due to AE between the two arms was also somewhat less in THRIVE).

The resistance consequences were also different between the two treatment groups as one might expect. Sixty-two participants out of 686 on RPV had virologic failure with resistance data available compared to 28 out of 682 participants on EFV-based therapy.   In these participants with VF and resistance data, the likelihood of acquiring at least one mutation was greater in RPV recipients (71% vs. 57%) and while the proportion with NNRTI resistance was similar (63% vs. 54%), NRTI mutations were more common in RPV failures (68% vs. 32%). The most frequent NNRTI RAM in VF with resistance assays on the EFV arms was the well known K103N mutation.  However in participants with VF on the RPV arms the most common NNRTI resistance mutation was E138K.  Preliminary phenotypic information demonstrated that virus that developed resistance to RPV were likely to be cross resistant to etravirine. 

These data suggest that there may be a subtle difference in potency between efavirenz and RPV given at the dose chosen for the Phase III studies. Recall that higher doses of RPV (while well tolerated) were associated with QT prolongation on ECG. Therefore doses of 75 mg and 150 mg daily (as opposed to the dose of 25 mg daily that was chosen) were not acceptable for the Phase III studies.  If we examine the results in the sub-groups with viral load < 100,000 and > 100,000 we find support for the potency argument.  In the participants with lower viral loads (VL) RPV-based therapy performed very well as the tolerability advantage held sway. In fact, in the analysis of the combined study RPV-based therapy was actually superior to EFV-based therapy as the potential subtle difference in antiviral activity  was not a disadvantage in the lower viral load group. In higher viral load group the overall result was that RPV was still non-inferior though the proportion responding was numerically less in the RPV-treated participants.  The hypothesis is that the tolerability advantage is somewhat neutralized by more virologic failures.  The differences between the two trials also show up here.  In THRIVE there is little difference in overall response in the high viral load groups between RPV and EFV (79% vs 80% < 50 c/mL at 48 weeks by ITT TLOVR), whereas in ECHO the results were 76% and 82% respectively.  There was no obvious explanation for this difference between studies but one could imagine if there were modest difference in drug exposure (perhaps due to adherence) in the two studies that might explain the results. If RPV is more on the cusp of its concentration to activity ratio then small differences in exposure or very high viral loads might result in a greater risk of virologic failure. In contrast the response rates on efavirenz were very consistent across the two studies and in the lower and higher viral load groups. This result is very consistent with our experience with EFV-based therapy in almost all other studies. For now though my speculation is only one possible hypothesis, which perhaps will be confirmed with more detailed analyses that include drug concentration measurements and further sub-analyses of the two studies.

The results of ECHO and THRIVE and the combined analyses set up an interesting discussion about how we will use EFV/TDF/FTC and RPV/TDF/FTC if RPV (and perhaps the fixed dose combination) is approved in early 2011, which seems very likely. At some point next year we will likely have two “one pill once a day” therapies. There is a clear tolerability advantage to RPV, which is a substantial plus as we move to treating asymptomatic patients with higher and higher CD4 cell counts. On the other hand there will be concerns about the increased risk of virologic failure that may be more likely in patients who have higher baseline viral loads. Again the sequencing argument will be raised.  If you have virologic failure on RPV-based therapy it appears likely that the patient’s virus will also be etravirine resistant, whereas if you have virologic failure on EFV based therapy and the only mutation is K103N then etravirine will still have full activity.  We hate losing a drug, even if we weren’t planning to use it any time soon.  Alternatively the loss of etravirine in a small fraction of patients who start RPV-based treatment will have very little practical consequence as there are multiple antiretroviral combinations available for first line failures.  There will also be discussions of the better lipid effects of RPV, however we don’t have the very long term safety data that we have with EFV.  RPV has NOT shown any teratogenicity in lab based and preclinical studies and will likely be a category C medication.  Many care providers and HIV-infected women of child bearing potential may then prefer RPV based therapy.  Another potential option will be to switch to RPV-based therapy (especially when the combination pill is approved) once patients are suppressed.  Obviously this strategy has not yet been studied but I suspect it will be, once rilpivirine is available.  There also will be a lot more data forth coming from the ECHO and THRIVE studies including new sub-analyses and eventually the 96 week data. While I don’t think ECHO and THRIVE can be considered a “home run” I think we all look forward to having rilpivirine and another one pill once a day therapy available to us soon.

Pooled Week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, Phase III trials comparing TMC278 versus efavirenz in treatment-naïve, HIV-1-infected patients - (07/22/10)

THE “ING” STUDIES

We learned a lot more about another promising drug, the Shionogi GSK integrase inhibitor S/GSK 1349572.  This drug, “572”, was introduced last summer at the IAS meeting in Cape Town and was shown to be very potent in a short term monotherapy study in integrase inhibitor naïve subjects reducing plasma HIV RNA by over 2 log₁₀ over 10 days.  In Vienna we saw longer term phase IIb data in treatment naïve individuals and we saw the initial activity of this drug in raltegravir failures who had documented integrase inhibitor resistance.  

The treatment naïve study, called SPRING, was a partially blinded phase IIb 48 week study examining 3 different doses of 572 (10, 25 and 50 mg) with a comparator arm of efavirenz each combined with 2 NRTI (approx 2/3 TDF/FTC and 1/3 ABC/3TC).  Sixteen week data were shown and demonstrated very rapid suppression (consistent with previous raltegravir and elvitegravir data) in each of the three 572 arms with over 80% of patients suppressed to < 50 c/mL by week 8 and 90% or more < 50 c/mL at week 16 in each of the 3 arms.  Again consistent with raltegravir data the speed of suppression was significantly faster with 572 compared to efavirenz-based though it is likely that over 48 weeks the treatment arms will look similar in the relatively small study of 50 participants per arm.  572 was very well tolerated and there were no serious adverse events related to 572 and very few discontinuation in any of the arms.  The highest dose (50 mg once daily) was chosen for further development though the 3 572 dose arms in this study will be continued through 48 weeks as there are little long term data with this agent. The potential advantages of 572 in naïve patients over other integrase inhibitors include; once daily dosing that does not require a boosting agent, a low mg dose that will allow co-formulation and probable single pill therapy and a predictable concentration activity relationship (pharmaco-dynamic profile).  The drug seems very well tolerated over the short term, like other integrase inhibitors, which is likely to be an advantage even when comparing across class, though clearly longer term tolerability and toxicity data are needed as well as data on lipid changes and other laboratory markers. Based on the SPRING results the naïve treatment market is likely to get more crowded with multiple good choices over the next several years.

I had the good fortune to present the VIKING study, which examined the short term activity of 572 in patients with documented RAL resistance.  The results of this study were interesting and more complex than the very straightforward results of the SPRING study.  In this study participants had to have documented RAL resistance at screening and could either be on RAL-based combination therapy or combination therapy without RAL, having failed RAL in the past with persistent resistance. Based on in vitro susceptibility data there were 2 groups of subjects. One group had integrase resistance mutations at screening at codon 155 with or without others, 143 again with or without other mutations or a single mutation at the 148 codon. The second group had to have a mutation at the 148 codon but then also had one or more secondary mutations. In vitro most viruses with the 155 pattern or the 143 pattern remain fully or nearly fully susceptible to 572. In contrast viruses that have the 148 mutation plus additional mutations (usually 140S with or without others) have decreased susceptibility to 572, though the fold change of some of these viruses are in a range where 572 might still have activity.  All participants received 572 functional monotherapy for 10 days at 50 mg daily. Those who were on RAL (the majority) had RAL replaced by 572 with continued background. Those who had already stopped RAL and were on a stable combination regimen had 572 added for the 10 day period. On day 11 participants were allowed to optimize their background therapy and continue the 572.  Only the functional monotherapy data were presented. 

Twenty-seven subjects were enrolled, 18 in group 1 and 9 in group 2. At baseline the median CD4 cell count was 110 and median viral load was approximately 30,000 c/mL.  These were highly treatment experienced patients. They had received a median of 17 antiretroviral agents in the past and the majority had been exposed to darunavir, enfuvirtide and etravirine.  The median baseline fold change to RAL was 161 while the median baseline fold change to 572 was 1.5.  There was a clear relationship between the pattern of RAL resistance mutations and the baseline fold change with the highest fold changes seen when the codon 148 mutation was present with 2 or more secondary mutations. Viruses with the 143 mutation (with or without other mutations) had minimal if any shift in susceptibility to 572.  The primary endpoint of the study was at least a 0.7 log₁₀decline in HIV RNA from baseline or a viral load < 400 c/mL at day 11.  Response rates were consistent with the in vitro data and the baseline genotype and phenotype data.  All 18 participants in group 1 (virus with 155 or 143 complex mutations) met the primary endpoint with a mean change in HIV RNA of 1.82 log₁₀. Eight out of 18 had HIV RNA < 400 c/mL at day 11 and one was < 50 c/mL.  In contrast only 3 of the 9 subjects in group 2 with 148 plus at least one additional mutation met the primary endpoint, though all 3 did fall to < 400 c/mL. The mean change in this group was 0.72 log₁₀.  Overall there was a very strong inverse correlation between baseline fold change and the change in HIV RNA at day 11.  Importantly no participant had emergence of a new RAL resistance mutation over the 11 day period. In 17/18 subjects in whom baseline and day 11 resistance testing could be accomplished the change in susceptibility was < 2 fold.  A detailed resistance poster was presented by Bonaventura Clotet. He showed that the one subject who had a an approximate 6 fold decrease in susceptibility had a mixture of viruses at baseline and over the 11 day period the virus with the more resistance genotype (148 plus an additional mutation) became the predominant variant and likely accounts for the decrease in susceptibility that occurred over the 11 days of functional monotherapy.

Following the presentation there was a lot of discussion about the results and whether 572 fits the bill as a second generation integrase inhibitor.  Clearly some viruses with substantial resistance to RAL respond very well to 572.  The viruses with the 155 and 143 mutation patterns were not just early failures of RAL. Though the duration of previous RAL therapy for these subjects is known (though not reported in the presentation by Eron et al) the duration of RAL failure for each patient is not known. However, as was shown in the poster by Dr. Clotet, many of the viruses with the 155 and the 143 pathways had multiple mutations and had substantial resistance to RAL.  Participants with these viruses have very good responses over the short term and if adequate partner therapy can be given the response is likely to be durable.  The flip side is that the 148 plus 140 pathway is probably the most common resistance pattern with RAL failures especially if virologic failure has been ongoing for some time in the presence of RAL. The 155H mutation may show up early but in some patients the virus undergoes a transition to the 148/140 path.  These viruses did not respond as well to 572.  There was a decrease in HIV RNA in most of the patients that had 148 plus one or more mutations but the effect was modest (mean of 0.72 and an approximate median of about 0.5 log₁₀). 572 at the 50 mg once a day dose is not likely to have a major impact in individuals with these viruses unless there were several other active agents that could be combined in an optimized regimen.  The logical question (which was asked by Bernard Hirschel) was what about a higher dose. 572 has been well tolerated and the dose response curves that have been generated would suggest that a higher dose should have a greater activity.  The VIKING study is now enrolling a cohort 2 – which will test 50 mg twice daily.  Hopefully this second cohort will show us whether more robust responses can be seen again viruses that have moved down the 148 pathway.  An additional clinical point that could be taken from the VIKING results are that individuals who are on raltegravir and who are failing should probably be moved to an alternative regimen or have their raltegravir stopped if at all possible.  Prolonged failure in the face of raltegravir selective pressure may push the virus to greater cross-resistance to 572.

Once-Daily S/GSK1349572 as Part of Combination Therapy in Antiretroviral Naïve Adults: Rapid and Potent Antiviral Responses in the interim 16-Week Analysis from SPRING-1 (ING112276) - (07/22/10)

HIV Integrase Genotypic and Phenotypic Changes Between Day 1 and Day 11 in Subjects with Raltegravir Resistant HIV Treated with S/GSK1349572: Results of VIKING Study - (07/21/10)

Activity of the Next Generation Integrase Inhibitor S/GSK1349572 and Two First Generation Inhibitors Across a Broad Panel of HIV Subtype Isolates in PBMCs and MDMs - (07/21/10)

S/GSK1265744: A Next Generation Integrase Inhibitor (INI) with Activity Against Raltegravir-Resistant Clinical Isolates - (07/21/10)

 

NRTI-sparing

The last topic I want to touch on just briefly is the topic on NRTI-sparing regimens, in particular for treatment naïve patients. It had never really occurred to me but if you look at the DHHS guidelines there is not one single NRTI-sparing first-line regimen listed in any category (Preferred, Alternative, Acceptable, possibly Acceptable).  One could argue that perhaps we just don’t need NRTI-sparing regimens in first line therapy, but as our patient’s age and the very long term toxicity of nucleosides becomes apparent there is great pressure to keep looking. 

IAC produced several pilot studies of NRTI-sparing regimens.  The largest, called PROGRESS, compared LPV/r plus RAL both BID with LPV/r plus TDF/FTC over 48 weeks in over 200 subjects.  The bottom line is that the 2 treatment arms looked very similar virologically and there were very few virologic failures with resistance in either arm.  A strong word of caution though is that the baseline viral load was very low, less than 20,000 c/mL (remember ECHO and THRIVE had a median baseline VL of 100,000).  LPV/r plus RAL may be a very good NRTI sparing regimen but it needs to be challenged in patients with higher viral load.  In addition, the lipid levels were higher on the NRTI-sparing arm probably reflecting the lipid lowering effect of TDF.  In this modest sized short term study there were not major differences in toxicity.

The small pilot SPARTAN study which combined RAL and atazanavir (ATV) unboosted both BID provides a contrast to PROGRESS.  While the overall results were similar in this arm to ATV/r plus TDF/FTC at 24 weeks (2:1 randomization with 63 vs. 30 subjects in each arm), there were more subjects on RAL plus ATV who had virologic failure with resistance testing results. There were 11 VL failures (VL > 50 at week 24) on the RAL arm, 8 had baseline VL greater than 250,000 c/mL, 6 had HIV RNA > 400 copies and had resistance testing and 4 had RAL resistance mutations. In contrast, while there were 8 “virologic failures” on the ATV/r TDF/FTC arm only 1 had a viral load greater than 400 and that patient had no resistance mutations.  Bilirubin levels were also higher on the RAL/ATV arm and there was no suggestion that ATV concentrations on that arm were sub-optimal.  I think we need more data on the RAL plus PI (preferably boosted) in high viral load patients before we venture to far down this path in the clinic, despite the PROGRESS results. 

One other NRTI-sparing regimen that was tested was maraviroc (150 mg once daily) plus ATV/r compared to a reference arm of ATV/r plus TDF/FTC. Again this was a small study with 60 patients per arm.  At 24 weeks a greater proportion of patients on the NRTI arm were less than 50 c/ml (89%) though this is a very high number for ATV/r TDF/FTC – much higher than was seen in the CASTLE study for example.  MVC plus ATV/r had 80% < 50 c/mL at 24 weeks so perhaps this may be an NRTI sparing regimen to test in a larger number of patients.  The number of subjects with baseline VL > 100,000 in this study was small but MVC plus ATV/r seems to do similarly in low and high VL groups.

I don’t think NRTI-sparing is ready for clinic prime time on a large scale but perhaps there are situations where it is appropriate and again switching once suppressed may be a safer approach but to date we only have pilot type data in this setting too.  A large trial of DRV/r plus raltegravir compared to DRV/r plus TDF/FTC in treatment naïve patients is about to start in Europe and it should provide some answers – though we will have to wait for some time to see these results.

 Abbott's PROGRESS Study of Kaletra and Isentress Compared with a Standard HIV Regimen Meets the Pre-Specified Primary Efficacy Endpoint - Abbott Press Release - (07/19/10)

The SPARTAN Study: A Pilot Study to Assess the Safety and Efficacy of an Investigational NRTI- and RTV-Sparing Regimen of Atazanavir (ATV) Experimental Dose of 300mg BID plus Raltegravir (RAL) 400mg BID (ATV+RAL) in Treatment-Naïve HIV-Infected Subjects - (07/22/10)

Once-Daily Maraviroc (MVC) + Atazanavir/Ritonavir(ATV/r) vs. Emtricitabine/Tenofovir(TDF/FTC) + ATV/r in Treatment Naïve Patients: A Week 24 Planned Interim Analysis - (07/22/10)

AIDS 2010
18th International AIDS Conference (IAC) 
July 18-23 2010
Vienna, Austria