Showing posts with label dolutegravir. Show all posts
Showing posts with label dolutegravir. Show all posts

Wednesday, August 21, 2013

ViiV goes for gold: US premium pricing may threaten dolutegravir use in Europe

On 12 August 2013, the FDA approved dolutegravir in the US. i-Base reported the news with an article linked to previous clinical trial results that noted not only the potential advantages but also some of the cautions.  One of the concerns was how the price, which didn’t accompany the original company press statement, would be critical for whether dolutegravir finds a significant market. While pricing is complex, the first indications of where ViiV have set their new drug are not encouraging. Unfortunately, dolutegravir has been priced as a second- rather than first-line option, with a US Wholesale Acquisition Cost (WAC) price of $1175 per month for 30 tablets ($39 per day, $14,105 per year).  When used by someone with integrase resistance the dose increases to 50 mg twice a day, presumably doubling the cost.

Read more here

Tuesday, April 30, 2013

Report from CROI-2013- My Personal Picks

CROI 2013 Report

Nelson Vergel



I was happy to attend  CROI-2013 in Atlanta on March 3-6, 2013.  These are areas of great interest to me and in no way attempts to summarize the main findings reported at the conference.  For abstract information, refer to http://www.retroconference.org/AbstractSearch/default2.aspx?conf=22


A baby girl gets cured
 
The most popular media story of the conference on retrovirus and opportunistic infections that took place in Atlanta was the story of a baby that was cured of HIV infection. The baby was born in Mississippi from a street drugs using mother that didn't have HIV care during pregnancy. The hospital where she went to give birth did not have HIV medications to give her prior to birth to prevent HIV transmission to the baby.  Immediately after birth two different viral loads were obtained and the baby was started on triple antiretroviral therapy. The baby had an HIV viral load in the 20,000 copies/ml range, and rapidly became undetectable after her doctor managed to get HIV treatment for her within 3 days. The baby continued the treatment for at least 18 months, then her mother and baby were lost to follow up and decided to discontinue their HIV treatment on her own. A few months later, when they were found and the baby returned to care, the HIV viral load remained negative and there was no evidence of ongoing replication or infection with HIV. The baby has been followed for several months off therapy without evidence of the virus returning. This aggressive treatment probably worked because the baby was very recently infected, and did not have a chance to establish a significant reservoir, and because of that the antiretroviral treatment was capable of clearing the infection. The amount of memory T cells in a newborn is very small, and those cells constitute the best characterized HIV reservoir. 
  
This case shows that if we could prevent reservoir formation by using anti-retrovirals alone we may be able to eliminate the virus.
  
New studies will aggressively treat newborns within a few hours of birth with triple antiretroviral therapy immediately after birth, and if infection is confirmed maintain this treatment for at least a year, and then discontinue it and see how many children can be cured with that strategy. These studies will have to be done in Africa because in the United States there are not enough positive infected children since most infections are prevented by giving antiretrovirals to HIV+ pregnant women. This fortunate case may have a dramatic impact on eliminating HIV from newborns all over the world. It will be our first massive cure initiative!
  
Neurocognitive impairment
 
HIV+ aging patients may present mild cognitive impairment even after long term successful HIV treatment.  There is a lot of controversy about whether or not using HIV antiretrovirals that penetrate the central nervous system (CNS) better may make a difference.

Dr. Letendre of San Diego created a system that scored HIV drugs according to their penetration in the CNS. He hypothesized  that treatments with better CNS penetration scores would be better in preventing the development of neurocognitive impairment.
 
Two studies were presented at CROI that looked into this hypothesis in different ways. In the first study, presented by Ron Ellis, individuals that were starting a new antiretroviral regimen were randomized to a regimen with good CNS penetration and compared to patients that were randomized to a not CNS targeted regimen. The study was a small and with slow accrual. The selection of CNS targeted regimen did not make a difference at 16 weeks, either in sophisticated neurocognitive testing or in biological markers in the cerebral spinal fluid (CFS). In fact 87% of the patients randomized to a “non-CNS targeted” regimen reached virological suppression in the CSF, versus 68% of those receiving a CNS targeted regimen.  Since the study only lasted 16 weeks no one knows if an effect would be seen in the longer term.

We are seeing more evidence that it is probably not a requirement that an antiretroviral drug has to penetrate the CSF to be able to exert a beneficial effect in brain function. Also, some of the better CNS penetrating drugs like efavirenz may also have CNS related side effects that may mask the potential benefit provided by its better penetration.

Another study called PICASSO  evaluated the cognitive function of patients were on monotherapy of boosted darunavir (Prezista)  or Kaletra versus  a combination of two nucleoside analogues with these boosted protease inhibitors. Darunavir/ritonavir and Kaletra do not have CNS penetration, so the hypothesis was that those patients taking those drugs as monotherapy should have some neurocognitive deterioration as a consequence. However, this was not the case which is yet another punch to the theory that CNS penetration can prevent or improve cognitive problems.

Another study showed that mega HAART (more than 3 HIV medications in combination)  did not improve the neuropsychological performance compared to stand on antiretroviral therapy in patients recently infected with HIV infection.

I think these studies have all failed to monitor patients’ quality of life of the different regimens to see any association on sleep quality, fatigue, gut issues, etc on cognitive function beyond the effect of CNS penetrating antiretrovirals. 
 
New HIV Medications

Several studies were presented on new HIV medications:
 
1. Dolutegravir. This new once a day unboosted integrase inhibitor has been proven to reduce HIV viral load rapidly and effective when compared to current standard of care. It also seems to present the same lack of interactions as raltegravir. The pharmacologic properties of dolutegravir were the topic of several presentations. Poster 178LB investigated concentrations in the CSF, and found that CSF concentrations were the same as  blood concentrations in HIV+ naïve patients.  The dolutegravir+ abacavir+3TC achieved an impressive -3 log CSF viral load reduction at 16 weeks similar to that in plasma. This combination is currently being formulated as a one-pill once a day regimen.Poster 531 assessed drug concentrations in colorectal tissue, as well as in male and female reproductive tracts. Low drug concentrations were observed in reproductive tract secretions of both men and women. Interestingly, however, tissue concentrations in female reproductive tract and rectum in the same people were adequate.  It is important to note that integrase inhibitors as a class seem to penetrate reservoirs a lot better than other drug classes (NNRTIs are almost as effective in doing so).

 
2. Merk’s new once a day non-nucleoside MK-1439. Poster 527 assessed the PK of this drug on HIV- people. The PK profile of the drug is conducive to daily dosing.  A drug interaction study with midazolam showed that MK-1439 was not an inducer or inhibitor of CYP3A. Other studies are being performed to asses any potential drug interactions. Presentation 100 described a monotherapy study comparing both 25mg and 200mg daily doses of MK-1439 with placebo for 1 week in HIV-infected individuals. During these 7 days, no serious adverse effects judged to be associated with MK-1439 were observed. Adequate viral load reductions in the range of -1.26-1.37 logs were attained in 7 days. We await further studies on this non-nucleoside that may present a new resistance profile that may possibly help treat HIV with several non-nucleoside resistance mutations. I hope it does has the same lipid profile as others NNRTIs without the rash and CNS issues.
  
3. Cenicriviroc. Week 24 analysis of cenicriviroc (CVC) was presented in abstract 106LB. CVC is an entry inhibitor given once daily CCR5 and CCR2 antagonist. Two different doses of CVC (100 mg and 200 mg once daily) were compared with efavirenz, both in combination with Truvada in treatment-naïve adults. The percentages of individuals experiencing virologic success were similar between the CVC and EFV groups. However, virologic non-response was higher with CVC than with EFV. It seemed to be better tolerated than efavirenz. We will see if the inhibition of the CCR2 receptor will translate into reduced inflammatory markers when compared to Atripla. The best dose is yet to be selected for phase 3 studies.
   
4. Tenofovir pro-drug - tenofovir alafenamide fumarate (TAF).Formerly known as GS-7340. This prodrug promises similar efficacy than tenofovir but fewer kidney issues. Posters 529 and 540 examined the effects of TAF on the kidneys. Unlike tenofovir (TDF), TAF does not concentrate in the kidneys. Patients with renal impairment receiving TAF had less than 2-fold increases in peak blood level concentration and drug exposure, which is not considered clinically relevant (TDF presents a problem in these patients). These findings suggest TAF may be able to be used in individuals with renal dysfunction without needing to reduce the dose as currently done with TDF.
 
Presentation 99LB described a phase 2 trial comparing  elvitegravir+cobicistat+ emtriva with TDF or with TAF. At week 24, the TAF-containing regimen had similar efficacy, and an improved side effect profile than Stribld. The group receiving TAF experienced no renal side effects, and a significantly smaller decline in bone density. I am looking forward to more data!

  5. Long acting formulations. Previous data have been presented with long acting formulations of a monthly intramuscular (IM) injection of rilpivirine  and injectable formulations of the integrase inhibitor GSK744 (a second generation integrase inhibitor, both IM and sub-cutaneous) where therapeutic drug levels are sustained for well over a month. Another drug that has been studied for a few years is the monoclonal antibody ibalizumab as a CD4 receptor entry inhibitor to overcome drug resistant HIV is based on intravenous delivery every 2-4 weeks.

 Oral abstract 24LB presented data on a long acting nano-formulation of GSK744. The drug was administered via a single intramuscular injection to HIV- vounteers and found to have a half-life of 21 to 50 days, which may allow a once monthly or even once quarterly dosing schedule. To assess the efficacy of this long acting GSK744 formulation for PrEP, 8 macaques received intramuscular doses of GSK744 at two time points 4 weeks apart. All eight of the control macaques receiving placebo became infected with SHIV. None of the 8 treated macaques had detectable virus 3 weeks after the final viral challenge.

 Long acting regimens including one or more injections of three compounds monthly may require  oral lead in periods to assess tolerability and easy withdrawal in case of side effects  Also, careful guidelines for treatment discontinuation will be important if the three compounds have different half lives.  

  Dr Puliguji from University of Nebraska presented results on a nanoformulation of atazanavir/ritonavir that in a mouse study which resulted in ten-fold higher concentrations in plasma and tissue and sustained for two weeks following a single intramuscular injection. It will be interesting to see studies on nanoformulations of darunavir and other popular HIV antiretrovirals in the future.  

In my opinion, this is one of the most exciting areas of HIV drug development in the present that may change the paradigm with improved adherence, great pre exposure and post exposure protection, and hopefully side effect profile.

Thursday, March 14, 2013

New HIV Drugs and Formulations in the Near Future (CROI 2013 Presentation)


All of the presentations in this section were great.

The one on new drugs is contained in the last set of slides (blue slides at 1:22:46)


http://webcasts.retroconference.org/console/player/19437?mediaType=podiumVideo


For individual reports on each drug (Thanks to Natap.org):


NEW HIV DRUGS at CROI

Monday, December 17, 2012

Six Promising HIV Drugs in the Pipeline (2013-2014)





By Warren Tong
December 5, 2012

Introduction
What new HIV medications do we have to look forward to over the next few years? How will these newer drugs improve upon the older ones? To shed some light on these questions, Roy Gulick, M.D., provided an overview at ID Week 2012 of drugs in development.
Since the first HIV medication, zidovudine (AZT, Retrovir), was approved in 1987, 26 other antiretrovirals have been made available in the U.S. for treating HIV -- a history that Gulick recapped in song during this conference. Our best regimens today are potent, convenient and relatively non-toxic.
However, according to Gulick, there is potential to make medications even better than those we have today. Newer drugs should build upon some of these aspects, he said:
  • Improve convenience (reduce dosage frequency, less than once a day).
  • Improve tolerability and reduce toxicity (even the best drugs today still have some of these issues).
  • Penetrate reservoirs more effectively (such as the genital tract and central nervous system).
  • Exploit new targets, thereby improving activity (particularly against drug-resistant viruses).
  • Improve formulation.
The list of drugs in the pipeline continues to be full of antiretroviral agents, whether they are in early development or undergoing clinical trials.
Gulick highlighted six of the most promising drugs.

GS-7340 (Also Known as Tenofovir Alafenamide, or TAF)
GS-7340 is an investigational nucleoside agent that is a prodrug of the approved formulation of tenofovir (TFV, Viread). A prodrug is a medication that, when metabolized in the blood, breaks down into the active form of the compound. The NRTI sold under the brand name Viread is actually tenofovir disoproxil fumarate (TDF), a prodrug that breaks down into tenofovir.
GS-7340's antiretroviral activity was first presented in a study by Martin Markowitz, M.D., and others at CROI 2011. In a small, 14-day study, Markowitz and his team found that GS-7340 performed slightly better than the "old" TDF, with greater decreases in HIV RNA at lower dosages (GS-7340 at 50 or 150 mg vs. TDF at 300 mg).
These findings were further supported by study results from Peter Ruane, M.D., and others at CROI 2012. Ruane and his team compared GS-7340 (at dosages of 8, 25 and 40 mg) with TDF (at 300 mg) in 38 treatment-naive patients over 10 days of monotherapy. GS-7340 again performed better than TDF, showing 0.76, 0.94 and 1.08 log reductions in HIV RNA, respectively, while TDF only showed a 0.48 log reduction in HIV RNA. The findings were statistically significant for the 25-mg (P = .017) and 40-mg (P = .01) dosages.
Ruane and his group also found that the plasma concentrations of tenofovir, when the prodrugs were metabolized, were 10 to 100 times higher for TDF than for any of the three dosages of GS-7340. This finding suggests that, because GS-7340 delivers less compound to target tissues, it could reduce toxicity levels in the organs, Gulick said.
On the other hand, when comparing intracellular concentrations of tenofovir in peripheral mononuclear cells like lymphocytes (which is where we want the drugs to be), GS-7340 achieved up to 20 times higher levels than TDF, Gulick noted.
In both of these studies, GS-7340 was generally well tolerated and no serious adverse events were reported.
A third study of GS-7340 was presented at ICAAC 2012. It found that GS-7340 had high potency against 26 HIV-1 isolates representing 7 subtypes. The drug also showed high potency against three HIV-2 isolates. In addition, GS-7340 maintained its viral potency longer than TDF, showing its better stability.
Further GS-7340 studies are in progress. Particularly because of its low dosage and high potency, it can be readily co-formulated with other agents.
Gulick pointed out two studies exploring such coforumulations. The first study will compound GS-7340 with emtricitabine (FTC, Emtriva) plus elvitegravir (EVG) plus cobicistat, and compare that to elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild). The second study will compound GS-7340 with emtricitabine, darunavir (Prezista) and cobistat (which would be the first one-pill, once-a-day protease inhibitor-based regimen), and compare that to tenofovir/emtricitabine (Truvada) plus darunavir plus cobicistat.

Dolutegravir (DTG)
Of the six highlighted compounds, Gulick stated that dolutegravir is the furthest along in development. Dolutegravir is an investigational integrase inhibitor, but it has distinguished itself from the two approved integrase inhibitors, raltegravir (Isentress) and elvitegravir.
Dolutegravir has a long half-life of 15 hours, indicating it can be taken once a day. Gulick emphasized that it does not require pharmacokinetic boosting. He noted that resistance does occur, but that dolutegravir showed activity against raltegravir- and elvitegraivr-resistant viral strains.
Its antiviral potency was shown in a phase-2a study by Sherene Min, M.D., and others. In 28 treatment-naive patients receiving either 2, 10 or 50 mg of dolutegravir, there was an average of a 1.51 to 2.46 log reduction in viral load after only 10 days of once-daily dosing. Seven of the 10 patients receiving 50 mg dosages achieved a viral load less than 50 copies/mL. Min and her team reported low pharmacokinetic variability and good short-term tolerability (the most common side effects were diarrhea, fatigue, and headache; adverse events were mild to moderate in severity).
According to Gulick, phase-3 results are complete and will be submitted to the U.S. Food and Drug Administration by the end of the year.
One of the phase-3 studies, known as SPRING 2, found dolutegravir to be non-inferior to raltegravir. The study followed 827 treatment-naive patients with a viral load above 1,000 copies/mL over 48 weeks. They were given either 50 mg of dolutegravir or 400 mg of raltegravir. Both groups were successful at achieving viral loads below 50 copies/mL (88% for dolutegravir and 85% for raltegravir). Both drugs were also very well tolerated, with only 2% in each group having to discontinue treatment because of adverse events.
Furthermore, a dolutegravir-based regimen consisting of abacavir/lamivudine (Epzicom, Kivexa) plus dolutegravir was actually found to be superior to tenofovir/emtricitabine plus efavirenz (Sustiva, Stocrin), according to the results of a companion phase-3 study by Sharon Walmsley, M.D., and others. In 822 treatment-naive patients studied over 48 weeks, 88% of the dolutegravir group achieved a viral load below 50 copies/mL, compared to 81% of the efavirenz group.
Gulick pointed out that the difference was because of tolerability: 10% of the efavirenz group discontinued treatment because of adverse events, compared to just 2% of the dolutegravir group. He commented that this would mark the first real challenger to efavirenz's long-held dominance in treatment-naive studies with a 48-week primary endpoint.
In terms of renal safety, the study found dolutegravir did interfere with tubular secretion of creatinine. However, Gulick noted, the increase in creatinine was only about .1 to .15 mg/dL, and occurred only within the first two weeks after starting dolutegravir, then stabilized over the rest of the 48-week study. As the Walmsley study noted, dolutegravir does not affect actual glomerular filtration rate.
In terms of resistance, dolutegravir appears to have a higher barrier to resistance than the other integrase inhibitors. In the Walmsley study, among both the dolutegravir and efavirenz groups, only 4% experienced virologic failure (18 and 17 individuals, respectively). Of the nine in each group that had genotypic test results available, "You see no nucleoside and no integrase mutations in the dolutegravir group. And as you would expect in the efavirenz [regimen], there were some nucleoside and non-nucleoside mutations detected," Gulick stated.
Because dolutegravir showed activity against elvitegraivr- and raltegravir-resistant viral strains, as shown in a study by Masanori Kobayashi and others, Joseph Eron, M.D., and others studied the use of dolutegravir for patients who had developed resistance to raltegravir. Their pilot study, known as VIKING, followed 51 patients with three or more class resistances, including demonstration of raltegravir mutations. The patients were given 50 mg of dolutegravir, either once or twice a day, for 10 days. A virologic response was defined as either a viral load below 400 copies/mL or a 0.7 log reduction. As Gulick explained, "The best responses were in the twice-a-day group. Whether you looked at all patients, those with the specific Q148 or other mutations, you can see response rates, over a short 10 days of therapy, exceeding 90%."
The VIKING study went on to follow the patients over 24 weeks. After the initial two weeks, the patients added an optimized background regimen. These follow-up results were presented by Vincent Soriano, M.D., Ph.D., at the 2011 European AIDS Conference. Soriano and his team found that by the end of the 24-week period, 41% of the once-a-day group and 75% of the twice-a-day group were able to re-suppress their viral load below 50 copies/mL.
Further studies of dolutegravir in the setting of other integrase inhibitor resistance are ongoing.

S/GSK-1265744 (or simply "744")
S/GSK-1265744 is an integrase inhibitor, similar to dolutegravir. Results from two studies presented at ICAAC 2012 found that 744 had high potency and an exceedingly long half-life. When given orally at once-daily doses of 30 mg, patients showed a median 2.6 log reduction in viral load.
More impressive, when using nanotechnology to formulate 744 to be injected subcutaneously or intramuscularly, a single dose showed a half-life between 21 and 50 days.
Remarkably, after a single dose, patients still had detectable levels of 744 up to 48 weeks after injection.
Similar to dolutegravir, 744 seems to have a high barrier to drug resistance. According to Gulick, using site-directed molecular clones (molecules created with specific mutations) associated with integrase inhibitor resistance, these mutations showed high levels of resistance to raltegravir and elvitegravir, but remained susceptible to 744 and dolutegravir.
In terms of safety, there were some injection site reactions and nodules associated with subcutaneous dosing. But conceivably, 744 could be taken as infrequently as every three months for treatment, or even as PrEP (pre-exposure prophylaxis). Research is ongoing.

HIV Entry Inhibitors
HIV entry inhibitors block HIV at the point at which they attach to CD4 cells. Many of the other classes of drugs, including protease inhibitors, NRTIs and NNRTIs, fight HIV after it has infected a CD4 cell.
Among the entry inhibitors, there are presently three sub-classes. We already have approved drugs in the first two sub-classes: CCR5 antagonists and fusion inhibitors. In the CCR5 antagonist sub-class, we already have maraviroc (Selzentry, Celsentri), and a new drug called cenicriviroc is being investigated. The fusion inhibitor class has long featured only enfuvirtide (Fuzeon), but a new drug called albuvirtide is being studied.
The third sub-class is an investigational one: CD4 attachment inhibitors. These new drugs are being developed to either bind at the location of HIV's gp120 protein (such as BMS-663068) oron the CD4 receptor itself (such as ibalizumab, a once- or twice-a-day drug that's still under investigation for both treatment and prevention).
Gulick offered a closer look at a few of these drugs in his overview.

Cenicriviroc (CVC)
Cenicriviroc is an investigational CCR5 antagonist. Not only does it antagonize CCR5 binding, it also antagonizes CCR2 binding. CCR2 is a receptor that sits on the surface of macrophages and may be involved in inflammation.
Cenicriviroc showed potent antiretroviral activity in a small study by Jacob Lalezari, M.D., and others. They followed treatment-experienced patients who had not been on treatment for at least six weeks, had a CD4+ cell count above 250 and a viral load above 5,000 copies/mL. They were randomized to receive either 25, 50, 75, 100 or 150 mg of once-daily cenicriviroc. At the highest doses, after 10 days, patients showed a 1.5 log reduction in viral load.
An update on the follow-up study was discussed by David Martin, M.D., at CROI 2012. In Martin et al's phase-2b study, they randomized 150 treatment-naive patients into three groups to receive tenofovir/emtricitabine with either cenicriviroc (at 100 or 200 mg) or efavirenz. Cenicriviroc was administered using a new, 50-mg formulation. In preliminary data from 18 patients, cenicriviroc was found to be well-absorbed and within the expected therapeutic range of potency. Further study will assess the safety, efficacy and effect of CCR2 inhibition on inflammatory biomarkers.

Albuvirtide
The only approved fusion inhibitor, enfuvirtide, offers a lot of activity against HIV, but the obvious downside is that it requires twice-daily injections. Albuvirtide, on the other hand, is an investigational fusion inhibitor that when given intravenously has a long average half-life of 11 days, warranting weekly dosing.
Albuvirtide has a similar design to enfuvirtide. It is a peptide that is an analogue of gp41, one of the envelope proteins on HIV's surface, and thereby blocks HIV through CD4 membrane fusion.
Two proof-of-concept studies by Dong Xie and others were presented at ICAAC 2012. In the first study, albuvirtide was given to 54 treatment-naive patients in a single dose; doses ranged from 20 to 640 mg. They found that albuvirtide's half-life ranged between 10 and 13 days, and that the drug suppressed plasma viremia for between 6 and 10 days. Albuvirtide was generally well tolerated, with no injection-site reactions and no serious adverse events.
In the second study, albuvirtide was given to 12 treatment-naive patients in multiple doses of either 160 or 320 mg. Doses were given on days 1, 2, 3, 8 and 15. The participants averaged viral load decreases of 0.68 log copies/mL (at 160 mg) and 1.05 log copies/mL (at 320 mg). Similar to the first study, there were no injection-site reactions and no serious adverse events. No anti-albuvirtide antibodies were detected in patients for up to 42 days.

BMS-663068 (a.k.a. BMS-068)
BMS-068 is an HIV attachment inhibitor. It is an oral prodrug that breaks down into the active compound BMS-626529 (a.k.a. BMS-529). It inhibits CD4 binding by specifically binding to gp120, one of HIV's envelope proteins that binds to CD4 cells. Gulick stated BMS-068 could be taken once or twice a day without boosting, but noted, "There is decreased baseline susceptibility in some patients due to envelope polymorphisms."
BMS-068 taken over 8 days with or without ritonavir (Norvir) resulted in substantial declines in plasma HIV RNA levels and was generally well tolerated, according to a study by Richard Nettles, M.D., and others. The study followed 50 patients with a CD4+ cell count above 200 cells/mL and a viral load above 5,000 copies/mL. They were either treatment-naive or not taking any treatment. The median change in viral load ranged from a 1.21 to a 1.73 log reduction, demonstrating that CD4 attachment inhibition can be quite potent and effective.
In terms of resistance, a study presented by Neelanjana Ray, M.D., at CROI 2012, found little resistance after the eight days of monotherapy. Ray and his team analyzed the changes in phenotypic susceptibility and known attachment inhibitor resistance substitutions that may have occurred during the Nettles study. Of the 48 patients that completed the study, 42 had at least a 1 log drop in viral load, showing that BMS-068 was effective. However, the other six (about 12%) had no virologic response, even though their baseline IC50 (a measure of the effectiveness of a compound in inhibiting a biochemical function) levels were quite high.
"When they took a close look and they sequenced gp160, which is broken down into gp120, they showed that a mutation (M426L) was associated with resistance," explained Gulick. "You can see that in patients with virologic response, very few (only 6%) have this mutation, whereas in those without virologic response, 5 of the 6 had this mutation. So it looks like this will be important in screening for activity of this compound as its development moves forward."

New Fixed-Dose Combination and Antiretroviral Formulations
Gulick pointed out three one-pill, once-a-day formulations being developed:
  • GS-7340/FTC/elvitegravir/cobicistat.
  • GS-7340/FTC/darunavir/cobicistat.
  • Abacavir/lamivudine (3TC, Epivir)/dolutegravir.
In addition, three other in-development formulations that Gulick mentioned were:
  • Lopinavir/ritonavir/lamivudine.
  • Atazanavir (Reyataz)/cobicistat and darunavir/cobicistat (both in clinical trials).
  • Rilpivirine long-acting (RPV-LA).
Regarding the last drug in those lists, a small pilot study presented at CROI 2012 found that RPV-LA could potentially be given once a month in its long-acting nano-formation. It would likely need to be paired with other drugs, but research is ongoing for its use in treatment and prevention.
Warren Tong is the research editor for TheBody.com and TheBodyPRO.com.
Copyright © 2012 Remedy Health Media, LLC. All rights reserved.

http://www.thebodypro.com/content/69959/six-promising-hiv-drugs-in-the-pipeline.html


 This article missed the drug ibalizumab:

 TMB-355(Ibalizumab) is a humanized monoclonal antibody (mAb) and a member of an emerging class of HIV therapies known as viral-entry inhibitors. This drug candidate is distinct from other entry inhibitors in that it binds to the CD4 molecule, the primary receptor for HIV infection, thereby interfering with the penetration of the virus into the cell. It is the first entry-blocking humanized mAb to treat HIV/AIDS. TMB-355 caught the attention of the scientific community in February 2003, when results from the phase-1, single-dose clinical trial showed a transient but clinically significant reduction in the patients’ viral load. Moreover, it was well tolerated with no evidence of adverse effects on CD4 T-cells of treated subjects unlike the majority of approved drugs for HIV. The U.S. FDA granted TMB-355 fast track status in October 2003. The phase-2a clinical trial was successfully completed in 2006, with the results showing a clean safety profile and clear antiviral activity (10-fold reduction in viral load).  The Phase-2b clinical trial was also successfully completed in 2011. TaiMed Biologics is concurrently developing a subcutaneous injection dosage form and a phase 1 human pharmacokinetics bridging study is completed in 2012. Currently, TMB is developing a phase I/II study for HIV-negative and new HIV-positive subjects to begin by the end of 2012.

Saturday, December 01, 2012

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

Thursday, May 31, 2012

Ten News Items That Have Made Me Happy During the Past Month

These past several weeks have been great on many fronts. While taking a shower this morning, I counted a few of the great pieces of news that have come our way amidst all the negative news that the media dwells on to increase ratings. 

http://www.thebody.com/content/67329/ten-news-items-that-have-made-me-happy-during-the.html

Monday, May 14, 2012

Shionogi-ViiV Healthcare announces initial data from pivotal phase III study of dolutegravir in HIV


This drug will compete against raltegravir (Merck) and elvitegravir (Gilead). 


It will be dosed once a day for treatment naive patients and twice a day for treatment experienced.

Issued: Monday 02 April 2012, London, UK
Press release issued by Shionogi-ViiV Healthcare LLC, a joint venture between ViiV Healthcare Ltd (a global specialist HIV company established by GlaxoSmithKline and Pfizer, Inc.) and Shionogi & Co., Ltd.
SPRING-2 study meets primary endpoint of non-inferiority of dolutegravir compared to raltegravir over 48 weeks in treatment-naïve HIV patients
ViiV Healthcare and Shionogi & Co., Ltd. today announced that initial results have been received from the SPRING-2 (ING113086) Phase III study of the investigational integrase inhibitor dolutegravir in treatment-naïve adults with HIV-1. The study met its primary objective, demonstrating non-inferiority of dolutegravir to raltegravir. Through 48 weeks, 88% of study participants on dolutegravir were virologically suppressed (<50 copies/mL) vs. 85% of participants on raltegravir [with a 95% confidence interval (CI) for the difference, -2.2% to + 7.1%; the lower end of the CI (-2.2%) was above the prespecified -10% non-inferiority limit]. 
SPRING-2 is an ongoing non-inferiority study designed to compare the efficacy and safety of dolutegravir 50mg administered once-daily versus raltegravir 400mg administered twice daily, both with two nucleoside reverse transcriptase inhibitors(NRTIs); 411 treatment-naïve study participants were randomised in each arm. The primary endpoint of the study was the proportion of study participants with undetectable HIV-1 RNA (<50c/mL) through 48 weeks.  The tolerability of dolutegravir was similar to that of raltegravir, with rates of adverse events leading to withdrawal at 2% in both arms. Drug-related nausea was reported by 10% of patients in each arm; no other adverse events related to study medication were reported by more than 5% of participants in either arm. 
“The SPRING-2 findings indicate that once daily unboosted dolutegravir may offer people living with HIV an additional treatment option in the future. These are the first large-scale safety and efficacy data in naïve patients, and we look forward to seeing further data in 2012 to build a more comprehensive picture of the role of dolutegravir” said Dr John Pottage, Chief Medical Officer, ViiV Healthcare. 
“At ViiV Healthcare we have a total focus on the needs of people living with HIV, and as a result we see the continued need for new, effective and convenient therapies.  We are committed to building connections and collaborations, like the Shionogi-ViiV Healthcare dolutegravir programme, to meet these needs.” said Dr. Dominique Limet, Chief Executive Officer, ViiV Healthcare. 
“The SPRING-2 study has met its primary endpoint for dolutegravir in treatment-naïve patients.  This marks an important milestone for the development of dolutegravir and the Shionogi-ViiV Healthcare joint venture. We look forward to completing further Phase III studies in a variety of clinical settings in order to fully understand the potential clinical benefit for a range of HIV patient populations” said Dr. Tsutae "Den" Nagata, Chief Medical Officer, Shionogi & Co., Ltd.
Full results of this study, including the full results of the secondary endpoints, will be presented at an upcoming scientific meeting.  SPRING-2 is the first of four Phase III studies that are due to be reported in 2012. Data from the clinical trials SINGLE (ING114467), VIKING-3 (ING112574) and SAILING (ING111762), will be received throughout the year and will allow further determination of the profile of dolutegravir.  These studies are designed to support a future regulatory file for dolutegravir. 
About SPRING-2
SPRING-2 (ING113086) is a Phase III, randomized, double-blind, multicentre, parallel group, non-inferiority study. The study included 822 HIV-1 infected treatment-naïve participants. The study compares the efficacy and safety of dolutegravir and raltegravir as part of an overall treatment regimen; both treatment arms are administered with investigator-selected dual nucleoside reverse transcriptase inhibitor therapy (either abacavir + lamivudine or tenofovir + emtricitabine).
The primary objective for SPRING-2 is to demonstrate the antiviral activity of dolutegravir 50mg administered once-daily compared to raltegravir 400mg administered twice daily over 48-weeks. Secondary objectives include the assessment of antiviral activity of dolutegravir compared to raltegravir at 96-weeks, to compare the tolerability, long-term safety and antiviral and immunologic activity of dolutegravir to raltegravir and to evaluate viral resistance in study participants experiencing virological failure.
About Dolutegravir
S/GSK1349572 (dolutegravir) is an investigational integrase inhibitor (INI) currently in development by Shionogi-ViiV Healthcare LLC for the treatment of HIV. It is currently the only once-daily, unboosted INI in Phase III clinical development.Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Given the stage of development of this investigational HIV therapy, the full picture of the efficacy and safety of dolutegravir has not been conclusively determined.

Monday, March 05, 2012

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.

Friday, February 10, 2012

Activists Caution HIV+ Patients and their Physicians About Monotherapy in Upcoming Access Program


FOR IMMEDIATE RELEASE: February 9, 2012

Contact: Nelson Vergel (NelsonVergel@yahoo.com)

Activists Caution HIV+ Patients and their Physicians About
Monotherapy in Upcoming Access Program

New York, February 9, 2012—AIDS activists and physician advocates welcome the news that ViiV Healthcare will be providing  expanded access of dolutegravir (DTG), a new investigational integrase inhibitor for HIV patients with few remaining HIV treatment options.  However, they warn patients and physicians to avoid functional monotherapy, or the introduction of dolutegravir as an "add-on" to a failing treatment regimen if the patient’s virus is resistant to all other currently available antiretroviral drugs (ARVs).  Functional monotherapy has been shown to permit rapid HIV resistance to new medications, which can result in more rapid disease progression, health deterioration, and death.

Currently, the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines recommend three ARVs be given in combination to suppress HIV.  But many patients have HIV that has mutated rendering their virus multi-drug resistant (MDR-HIV).  Those with MDR-HIV cannot construct a viable HIV suppressive regimen with current FDA-approved and commercially available ARVs.  "The DHHS guidelines specify that patients that have developed HIV drug resistance to all commercially available antiretrovirals require access to at least two new active drugs to maximize their chances for treatment response.  However, “another new drug to combine with dolutegravir will not be commercially available for at least two years, and some patients cannot wait that long,” said Nelson Vergel, an activist founder of SalvageTherapies.org.  "For them, access to another research drug in combination with DTG is the only hope for survival," added Vergel.

In studies to date, dolutegravir (DTG) appears to be the most potent integrase inhibitor soon to enter the ARV market.  Unlike Gilead's upcoming elvitegravir, DTG has been shown to be effective against HIV that has developed resistance to Merck's Isentress (raltegravir), the only FDA-approved integrase inhibitor currently on the market.

Fortunately, another new ARV that can help patients with MDR-HIV is in active development and clinical trials.  Ibalizumab, a monoclonal antibody from a small biotech firm, Taimed Biologics, may soon be available via patient participation in research studies.  While ibalizumab has yet to enter phase three studies, it can also be provided to patients at risk of death via a named (or single) patient access application permitted by the FDA via a physician’s direct request to Taimed.  However, it is for the company to approve such requests for compassionate access.

There are no documented estimates of how many people have MDR-HIV in the United States.  A report in the Journal of Clinical Infectious Diseases estimates that about 260,000 patients are being treated with HIV in the United States.  However, it is virtually impossible to know how many are now without sufficient treatment options since no registry for such patients exists.  But most experts agree that this population is probably small – possibly up to 10% of the total in treatment.

"With little immune function left and resistance to all approved HIV medications, I have tried desperately to get access to two new drugs to help save my life,” said Christopher Cacioppo, a patient with MDR-HIV in  San Diego who believes he is running out of time. “My doctor tells me that I have little choice but to wait for the dolutegravir expanded access program and some as yet unknown and unavailable second new drug."

A coalition of activists and physicians have been in discussions with Taimed and ViiV for nearly two years to obtain compassionate-use access to their new ARVs in combination for those with MDR-HIV in greatest need of new treatment options.  The AIDS Community Research Initiative of America (ACRIA), a New York City-based community research and education organization, and physicians in San Francisco have proposed solutions to overcome this “two-drug access barrier” in an effort to secure urgent access to patients across the country.

Physicians and providers with patients with MDR-HIV in need of two new ARVs are urged to complete this form.

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