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 

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

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Dolutegravir, Trii and new abacavir data- How it all ties together

By Nelson Vergel

Powerusa.org

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.

This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii.  This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).

The development of Trii for approval as a first line treatment seemed risky to me due  to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV.  These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients.  So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?

Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation,  the US Food and Drug Administration (FDA)  presented  a surprising poster on  March 2 that reported  no evidence of an association between abacavir  and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug.  The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.

It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines.  Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to  pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills.   Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.

As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.

Sources:

DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB

Ding X et al. No association of myocardial infarction with ABC use: an FDA meta-analysis.  Poster abstract 808.


More on:
http://www.retroconference.org/2011/Abstracts/42541.htm

http://www.thebodypro.com/content/art60708.html

More on CROI:
http://www.thebody.com/content/art60501.html

The Forgotten Minority: HIV+ Patients With No Available HIV treatment Options

Most successful HIV medication combinations require 3 medications that are fully active, but a small portion of long term survivors with long treatment history and accumulated HIV resistance mutations do not have the luxury of constructing a viable regimen to save their lives.

Several potent antiretrovirals (ARVs) in the past 4 years have enabled many patients with multidrug resistance (MDR) to suppress their HIV viral load.

Due to several factors, there is still a relatively small number of patients that have developed resistance or toxicity to the new ARV’s

To protect them from functional monotherapy, these patients are not allowed in pre- approval studies.

Some HIV ARV’s in phase II studies may potentially help those patients, but combining them after their respective approvals may take at least 3 or 4 years.

Some of these patients may be at risk of clinical decline and death if no viable regimen is available for them before 2012

We do not know how many of these patients there are in the U.S.

I performed a physician survey with the help of some researchers and activists to find out how many patients may be present in the U.S. with HIV multidrug resistance in deep salvage (one or zero active medications to treat their HIV).

These figures summarize our findings (click on figures to enlarge):

These are the HIV medications in current development. The ones with an asterisk are the ones that may work for patients with no options left.

The closest ones to approval are Taimed's ibalizumab ( an IV once every two weeks) which may be two years away from approval, and GSK's integrase inhibitor GSK572 (2-3 years) . Avexa recently stopped the development of   Apricitabine and Myriad may follow suit with their maturation inhibitor. A combination of at least two compounds will probably not be feasible until 2013.  Efforts towards creating an expanded access program using multiple investigational agents is currently under way but it may not be a possibility until 2011.  All companies and the FDA are welcoming the concept in its early stages.  I will provide an update during the last quarter of 2010.

I wish we could help patients who need help now.

Nelson Vergel