THURSDAY, May 12 (HealthDay News) — People with HIV can reduce the risk of infecting their sex partners by more than 90 percent if they start treatment with antiretroviral drugs when their immune system is still relatively healthy, researchers announced Thursday.

The study, which included 1,763 mostly heterosexual couples from nine countries, was supposed to last until 2015, but the results were released early because of the significance of the findings. The research confirmed a belief held by many scientists and physicians — that starting drug therapy early can help to limit rates of transmission of the virus that causes AIDS.

“We set out to prove that if you took earlier therapy you could benefit your own health and you could prevent the transmission of HIV,” said lead researcher Dr. Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill.

“Both of those hypotheses were realized,” he said.

The study, which started in 2005, randomly assigned the couples to two treatment groups: In the first group the HIV-infected individual began taking a combination of three antiretroviral drugs immediately. In the second group, the HIV-positive person delayed drug therapy until their CD4 T-cell count — a blood test that measures immune system health — either dropped below 250 or an AIDS-related illness (such as pneumocystis pneumonia) set in.

Both groups also received HIV care, which included counseling on safe sex, free condoms, treatment for sexually transmitted infections, regular HIV testing and evaluation, and treatment for any HIV-related complications.

The trial was conducted at 13 sites in nine countries including the United States, Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand and Zimbabwe.

In looking over the preliminary findings, the data and safety monitoring board shepherding the study identified 39 new cases of HIV among the previously uninfected partners. In 28 of these cases, genetic analysis confirmed that one partner had infected the other.

Of these 28 infections, 27 — or 96 percent — occurred among couples in which the HIV-infected partner did not start antiretroviral therapy immediately.

Cohen cautioned that the findings don’t apply to all HIV-positive people. “Our couples had big advantages,” he said. “We enrolled couples who probably have a low overall transmission [HIV] rate,” he said.

The researchers also made sure that the patients were taking their antiretroviral medications. And, the medications were carefully selected. “The drugs are important,” Cohen said. “We didn’t use any combination possible — we used ones we thought would sterilize the genital tract,” he said.

Commenting on the study, Dr. Alexis Powell, an assistant professor of infectious diseases at the University of Miami Miller School of Medicine, said that “it’s nice to finally have evidence-based information that clearly shows that earlier treatment with antiretrovirals can benefit the individual who is HIV-positive, but also protects sexual partners who are HIV-negative.”

Most doctors would like to treat HIV patients sooner, Powell said. “We clearly understand that patients benefit with earlier treatment,” she said. “And this is another reason to start early.”

Powell said she’d like to put HIV patients on antiretrovirals as soon as they are diagnosed, but there are barriers. They include criteria for treatment set by insurance companies and lack of funding to treat those without insurance, she said.

“When you start talking about the dollars and cents of every day clinical practice, that’s when we are really going to see what we are going to be allowed to do,” Powell said.

Another barrier is convincing some HIV-positive people to take the drugs. Some are reluctant to start taking medications that they will have to take for the rest of their lives, while others are wary of side effects. Some people think the drugs make you sicker than the virus. And still others distrust the medical system to act in their best interest, Powell said.

She cautioned that the study findings do not mean that people can stop practicing safe sex. Men, especially, need to use a condom to protect themselves or their partners, Powell said.

More information

For more on HIV/AIDS, visit AIDS.gov.

SOURCES: Myron Cohen, M.D., director, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill; Alexis Powell, M.D., assistant professor, infectious diseases, University of Miami Miller School of Medicine; May 12, 2011, news release, U.S. National Institutes of Health

Copyright © 2011 HealthDay. All rights reserved.

This is a story from HealthDay, a service of ScoutNews, LLC.

There’s no direct proof linking the medications to the higher stroke rate, but previous research has suggested that HIV drugs can boost cholesterol and triglyceride levels, both of which contribute to stroke risk.

“Until we have a better idea what’s happening, this is a call or reminder to clinicians to be cognizant of these risk factors for stroke in these HIV patients,” said study author Dr. Bruce Ovbiagele, a neuroscience professor at the University of California, San Diego.

For their study, published online Jan. 19 in the journal Neurology, Ovbiagele and colleagues examined a database of hospitalizations for stroke from 1997, when a new generation of AIDS drugs was in its early days of use, through 2006.

They found that while overall hospitalizations for stroke fell by 7 percent, the number of stroke hospitalizations in HIV-infected people rose by 60 percent in 2006. (The researchers adjusted their numbers to account for factors such as age and gender.)

The researchers also looked at the two kinds of stroke — ischemic (when a blood vessel is blocked) and hemorrhagic (when a blood vessel bursts). There was no change in the percentage of hemorrhagic stroke patients who were HIV-positive, but the rate went up from 0.08 percent to .18 percent — more than doubling — among HIV patients who had ischemic strokes.

The latter number suggests, but doesn’t prove, that more HIV patients are suffering from blockages in their blood vessels. Some previous research has suggested that HIV patients have higher levels of heart attacks, which also occur when vessels clog up.

“We know that many of the drugs that are used for AIDS treatment have metabolic complications, which include the addition of belly fat and an increase in serum triglycerides,” Ovbiagele said. Both increase the risk of heart problems.

It’s possible that HIV patients are living longer and simply getting to the age at which strokes are more common among all people, said Ovbiagele, who was at the University of California at Los Angeles, when the research was conducted. But the study also found that HIV patients had strokes earlier, on average, than other people.

Overall, the risk that an HIV patient will have a stroke remains low. However, patients who are on AIDS drugs should be aware that stroke is “highly preventable,” Ovbiagele said, and they should work with their doctors to keep their weight and cholesterol levels under control.

Dr. Alejandro A. Rabinstein, a professor of neurology at the Mayo Clinic in Rochester, Minn., said that even while the link between AIDS medications and stroke isn’t proven, HIV patients should go on low-fat, low-sodium diets and be monitored for high blood pressure and other risk factors.

However, he said, strokes will remain rare among patients on HIV drugs. “The risk may be increased, but it is overall a small risk,” he said.

MONDAY, Oct. 4 (HealthDay News) — One in four people infected with HIV suffer from neurological complications, new Canadian research reveals.

And those that do have such problems harbor double the risk of dying compared with HIV patients who are not plagued with neurological diseases, the study authors reported in the Sept. 28 issue of Neurology.

“The good news is that people with HIV are living much longer now that we have antiretroviral therapies,” Dr. Chris Power, a professor of neurology at the universities of Alberta and Calgary, said in a news release from Alberta Innovates–Health Solutions, a new agency funded by the government of Alberta, Canada.

But the bad news is that “this study proves without a doubt that neurological disease is a major cause of disability for people with HIV,” added Power, who is also the Canada research chair in neurological infection and immunity.

Power and his colleagues based their assessment on work they conducted with 1,651 HIV patients who were receiving treatment between 1998 and 2008.

Of these, 404 had neurological problems, such as seizures, dementia, nerve pain in the limbs, memory loss, headaches/migraines, opportunistic infections of the central nervous system and movement disorders.

The study authors also found that brain disorders appeared to be twice as common among patients with full-blown AIDS compared with those whose HIV infection had not advanced to that stage.

“That motivates us to look closely at which drugs are working well, design optimal drug combinations to reduce brain diseases, and to explore in the lab new drugs that we can use to protect the brain,” Power said.

More information

For more on AIDS and neurological complications, visit the U.S. National Institute of Neurological Disorders and Stroke.

A new study shows that HIV-positive babies with stabilized infections “will do just fine switching to a regime of nevirapine, a reverse transcriptase inhibitor,” from a more expensive protease inhibitor, Scientific American’s “Observations” blog reports (Harmon, 9/7). So far, HIV treatment options for children in the developing world “have been limited by concerns over the possible development of resistance to drugs they received as infants during failed attempts to prevent their infection in the first place,” according to HealthDay/U.S. News & World Report (Mozes, 9/7). The study, published in the Journal of the American Medical Association, “followed 195 randomized babies and toddlers under 2 for a year” and determined that “[a]bout two thirds of the children with HIV that had switched to the nevirapine were able to maintain a level of fewer than 50 copies of the virus per milliliter of blood,” the lowest level technology could detect, “Observations” reports (9/7).

FRIDAY, Aug. 27 (HealthDay News) — The brain can be a convenient hiding place for HIV, the virus that causes AIDS.

That’s the finding of Swedish researchers who analyzed samples from about 70 HIV-infected patients who’d been taking anti-HIV drugs. The tests showed that about 10 percent of the patients — a larger proportion than expected — had traces of HIV in their spinal fluid but not in their blood.

Another study by the researchers found that 60 percent of 15 HIV-infected patients treated with medication for several years showed signs of inflammation in their spinal fluid, although the levels were lower than they were without treatment.

Anti-HIV drugs can prevent the virus from multiplying, but the virus also infects the brain and can cause damage if the infection isn’t treated, according to lead researcher Dr. Arvid Eden, a doctor and researcher at the Institute of Biomedicine at the Sahlgrenska Academy at the University of Gothenburg.

“Antiviral treatment in the brain is complicated by a number of factors, partly because it is surrounded by a protective barrier that affects how well medicines get in,” Eden said in a university news release. “This means that the brain can act as a reservoir where treatment of the virus may be less effective.”

It is unclear whether small quantities of the virus in spinal fluid represent a risk for future complications, researchers said. Still, the findings indicate that “we need to take into account the effects in the brain when developing new drugs and treatment strategies for HIV infection,” Eden added.

More information

The U.S. National Institute of Allergy and Infectious Diseases has more about HIV/AIDS.

SOURCE: University of Gothenburg, Aug. 23, 2010, news release.

Copyright © 2010 HealthDay. All rights reserved.

This is a story from HealthDay, a service of ScoutNews, LLC.

Media outlets continued to reflect on news from the International AIDS Conference-AIDS 2010, which attracted over 19,000 participants from 197 countries to Vienna last week, according to the conference blog.

The Washington Post reports that “concerns about [the] costs” of global HIV treatment programs “dominated the talk” of the conference. The newspaper notes that some HIV/AIDS advocates used the conference as an opportunity to voice their criticisms of the Obama administration, which “many … say is reneging on a commitment to continue big annual increases in global AIDS spending.”

The article examines how under the Obama administration, global HIV/AIDS funding has been folded into the president’s $63 billion, six-year Global Health Initiative [GHI]. Whereas, “[t]he portion devoted to HIV and tuberculosis, an infection to which AIDS patients are particularly prone, is $44 billion,” the rest of the funds will be focused on malaria, maternal and child health and strengthening health systems, according to the newspaper. ”Although larger than Bush’s revolutionary President’s Emergency Plan for AIDS Relief (PEPFAR), Obama’s GHI is spread across more agencies. It is less a bullet aimed at the heart of AIDS than a net cast to capture a flock of health problems,” the Washington Post writes.

Though the U.S. is “the biggest donor” to combat HIV/AIDS in developing countries, ”last year providing 58 percent of the $7.6 billion given by governments,” HIV/AIDS advocates point to flatlining of international HIV/AIDS assistance in 2008 and 2009 as a sign “big gains in generosity and economizing have mostly stopped.”

According to the newspaper, “Although there’s argument about the exact numbers, there’s little doubt the Obama administration is on track to spend less than planned by either the GHI or the Lantos-Hyde Act of 2008, which renewed PEPFAR and authorized spending $48 billion from 2009 through 2013. Many other donor countries are taking a similar go-slower approach.”

The article includes comments by Joanne Carter, director of the anti-poverty group RESULTS and board member of the Global Fund to Fight AIDS, Tuberculosis and Malaria; Paul Zeitz, director of the Global AIDS Alliance; and references recent comments in defense of the president’s global AIDS strategy made by Gayle Smith, Obama’s special assistant for development and democracy, and Ezekiel Emanuel, the president’s special adviser for health policy, published in two blogs last week (Brown, 7/29).

NPR’s Talk of the Nation also examines the major news out of AIDS 2010, through conversations between host Tony Cox and Jon Cohen, a correspondent with Science magazine and Steffanie Strathdee, associate dean of global health at the University of California San Diego. Cohen and Strathdee discussed the results of the recent microbicide gel trial, where things stand on progress towards developing an HIV vaccine, the search for an AIDS cure, injection drug use and the aims of Vienna Declaration as well as funding for HIV/AIDS (Cox, 7/27).

Vaccines; Global HIV/AIDS Patient Survey

Meanwhile, Nature News/Scientific American examines “the results of a handful of successful, but small, early-phase clinical trials for therapeutic vaccines – once thought to be a dead end for tackling HIV” that were presented at AIDS 2010. “Normal vaccines are designed to prevent infections, but so far none has worked for HIV,” the news service writes. “Therapeutic vaccines, in contrast, aim to treat infected people – in the case of HIV, by boosting ravaged immune systems.”

The article examines the potential advantages a therapeutic vaccine could have over current HIV/AIDS treatments and details several approaches companies are taking towards the development of therapeutic vaccines.

“All of the vaccines, which were developed by several small biotechnology companies, modestly but significantly reduced viral levels in the blood of patients, who responded for months or longer,” the news service writes. “In some cases, the vaccines also increased levels of CD4+ T cells – the vital immune-regulator cells that HIV depletes. In theory, the vaccines would only need to be administered every few months.”

“The ultimate value of the vaccines will only become clear as larger phase III trials roll out over the next few years. For now, leaders in AIDS research are cautious about the results,” Nature News/Scientific American continues. The piece includes comments by Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), who expresses cautious optimism about the potential for therapeutic vaccines in treating patients with HIV/AIDS, and Carl Dieffenbach, head of the NIAID AIDS division (Abbott, 7/27).

In related news, ”The AIDS Treatment for Life International Survey (ATLIS 2010) of more than 2,000 HIV-positive patients in 12 countries around the world, found that most respondents also had health conditions such as depression, hepatitis C or kidney disease, which could affect their antiretroviral (ARV) treatment, but less than half had ever discussed these with their healthcare providers,” IRIN/PlusNews reports. “Similarly, about half the respondents said their ARV medication had had a negative impact on their lives, but only 43 percent had ever asked their doctor about new treatment options with fewer side effects,” according to the news service. The survey, released at AIDS 2010 last week, also documented gaps in patient knowledge about drug resistance (7/26). According to a press release (.pdf), survey participants were interviewed ”January-March 2010, via a combination of Internet, phone, and in-person recruitment methods” (7/20).

In the study, Canadian researchers surveyed 159 HIV-positive women in the province of Ontario. Forty-five percent of the women were born in Canada, while 55 percent were born elsewhere, mainly in HIV-endemic areas such as sub-Saharan Africa and the Caribbean.

The study participants were asked about their personal background, HIV treatments, mental health and whether they felt they were being negatively judged by health-care providers, family and friends for their desire to have children.

“We do have strong evidence that women are feeling they are being judged negatively by health-care providers for wanting to have babies,” study co-author Trevor Hart, director of the HIV Prevention Lab in the psychology department at Ryerson University in Toronto, said in a university news release.

Family and friends didn’t play a major role in perceived stigmatization, the study authors found.

The study findings, scheduled for presentation this week at the International AIDS Conference in Vienna, Austria, were also published in the June issue of the journal Archives of Women’s Mental Health.

New antiretroviral drugs mean that HIV-positive women can conceive without transmitting HIV to their newborns, and health-care providers should know this and be informing patients, Hart explained in the news release.

“There needs to be more efforts to make physicians aware of the practically nil chance of HIV-positive women transmitting HIV to their newborns as long as the women are continuing to receive appropriate medical treatment,” he stated.

“There also needs to be continuing medical education to reduce the stigma perceived by HIV-positive women, which will improve their mental health and well-being,” Hart added.

More information

The American College of Obstetricians and Gynecologists has more about HIV and pregnancy.

SOURCE: Ryerson University, news release, July 21, 2010

Copyright © 2010 HealthDay. All rights reserved.

This is a story from HealthDay, a service of ScoutNews, LLC.

Summary: KP-1461, an experimental HIV drug already in a phase II trial, works so differently from other antiretrovirals that at first glance it looked like science fiction, and we found it hard to take seriously as a current possibility today. In fact this drug is highly credible, and based on elegant science that goes back at least 25 years. KP-1461 is the only antiretroviral in human use or testing that can eradicate HIV from laboratory cell cultures. No one knows how it will work in people — but we might know by the second quarter of 2008, when the current phase II trial could be complete. AIDS Treatment News interviewed Dr. Stephen Becker, a leading AIDS physician and researcher who is vice president of clinical development at Koronis Pharmaceuticals, in Seattle, Washington.

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Summary: KP-1461, an experimental HIV drug already in a phase II trial, works so differently from other antiretrovirals that at first glance it looked like science fiction, and we found it hard to take seriously as a current possibility today. In fact this drug is highly credible, and based on elegant science that goes back at least 25 years. KP-1461 is the only antiretroviral in human use or testing that can eradicate HIV from laboratory cell cultures. No one knows how it will work in people — but we might know by the second quarter of 2008, when the current phase II trial could be complete. AIDS Treatment News interviewed Dr. Stephen Becker, a leading AIDS physician and researcher who is vice president of clinical development at Koronis Pharmaceuticals, in Seattle, Washington.

Background: The scientific story began when Mansfeld Eigen (who had already won a Nobel Prize in chemistry for other work) applied his chemistry and mathematics background to problems in biology, and with Peter Schuster and others developed the concept of quasispecies. Standard Darwinian evolution predicts that the fittest strain of an organism, the one that reproduces fastest in a given environment, will displace the other strains there. But a virus like HIV is different; it is always mutating, and can mutate back and forth between different strains. The result is that HIV, in a patient with advanced infection or AIDS, exists as millions of related strains within the same patient (usually only one was transmitted, and then it evolved within that individual into countless slightly different variants).

This makes HIV hard to treat, because some members of the quasispecies probably already have resistance mutations to a new drug even by chance alone, and these resistant viruses are ready to be selected and become much more prevalent when the drug is started. The conventional approach to this problem is to use combinations of different drugs, hoping to suppress HIV to such a low level that little mutation and evolution can take place. This may suppress the virus for years, but has never succeeded in eradicating it, so patients usually have to stay on treatment for life.

Quasispecies follow different rules than Darwinian evolution. For example, it is possible at least in theory for the strain that reproduces fastest to be replaced entirely by strains that individually reproduce more slowly, but are more fit as a quasispecies. Eigen and Schuster also wrote a well-known book, The Hypercycle: A Principle of Natural Self-Organization, published in 1979 on quasispecies and related concepts.

A way to attack a quasispecies as a whole is to increase the already-high mutation rate, leading to an “error catastrophe” and collapse of the population. This approach was used to design the drug now in a phase II trial, KP-1461. KP-1461 is a nucleoside analog, like AZT, 3TC, and the others; once inside the cell it is chemically modified (triphosphorylated) into its active form (called KP-1212), which can replace one of the four bases used to make DNA. (The four bases are adenosine, cytodine, thymidine, and guanosine — some say that the initials ‘ACTG’ for the government AIDS clinical-trials network were not just coincidence.) In DNA the bases are paired, forming the famous double helix; cytidine always pairs with guanosine, and thymidine always pairs with adenosine.

KP-1212 can replace cytidine when the viral enzyme reverse transcriptase is building a new copy of HIV, and pair normally with guanosine. It does not terminate the DNA chain. But KP-1212 was chemically designed to be a flexible molecule, such that it can also look like thymidine and then pair with adenosine. This introduces an error that then is locked into the viral DNA.

These errors happen at random, anywhere in the virus; and when they do not kill the virus outright, they accumulate over generations in the DNA of the viral population. The result is eventually an error catastrophe that can wipe out the entire quasispecies, at least in laboratory tests. If you then take the drug away, the virus does not come back. And the cells on which the virus grew are still alive — cured of the infection.

AZT and the other approved nucleoside analogs terminate the growth of the DNA chain, killing the copy of virus being built. But that copy is easily replaced by other copies that do not have an abnormal error accumulation, so the population as a whole is not damaged. In contrast, KP-1212 continues to add new errors to the population, in addition to the errors that are already there due to the very high normal mutation rate of HIV.

For detailed scientific background, see [1].

* * *

AIDS Treatment News interviewed Dr. Stephen Becker in mid September 2007. Dr. Becker, who has been well known for years as a leading AIDS clinician and scientist, was hired last year by Koronis Pharmaceuticals, a small company in Seattle, Washington, to design and conduct the clinical trial that could lead to proof of principle of KP-1461.

Interview with Dr. Becker

AIDS Treatment News: Am I correct in believing that KP-1461 causes lots of mutations of HIV?

Dr. Becker: Yes. KP-1461 is a nucleoside analog [a false building block of the viral DNA]. It is a cytidine analog. But unlike all the conventional HIV nukes, it is not a chain terminator, it does not inhibit reverse transcription in the way that all of the conventional nukes do. It is incorporated by reverse transcriptase, and once it’s incorporated, just as the transcription process would dictate, there is base-pair matching that goes on.

KP-1461 is actually a prodrug [a medicine designed to be orally usable, which changes into its active form inside the body]. The active drug, intracellularly triphosphorylated like all the other nucleosides, is KP-1212. But for ease of discussion we may call it KP-1461, even though we know that’s the prodrug.

Once KP-1212 is incorporated by reverse transcriptase into the copy strand, it can appear in one of two forms. It can appear as its native cytidine, but also can appear as a thymidine. This happens because of the flexible structure of the drug. It is able to tautomerize (the chemical term); it is incorporated as a cytidine, but then appears ambiguous to the complementary base. If it appears as a cytidine it would normally pair with a guanosine (following Watson-Crick base-pairing rules). But when it appears as a thymidine to the complementary base, it winds up pairing with adenosine, causing a base-pair mismatch. So the drug actually brings about base-pairing errors, usually guanosine->adenosine errors.

Once the wrong base is incorporated and a base-pairing error exists, it is locked into the proviral DNA. With every replication cycle, this base-pairing error is perpetuated. As the drug continues to be administered, there is a progressive accumulation of errors, throughout the viral genome. There is no preferential hot spot for incorporation; so base-pairing errors will appear in all the viral genes.

Each mutation that the virus acquires tends to reduce its fitness — the viability, the infectivity, of the virus. So a mutational accumulation (as the theory held, and as we demonstrated in test-tube cell cultures) brings about the collapse of the viral population. If you progressively add too many mutations, you exceed an error threshold, or a threshold of viral viability, and the population collapses.

The theory for this came from Manfred Eigen — who won the Nobel Prize for chemistry in 1967 for something called fast reactions. In the 80s and the 90s he applied his chemist’s and mathematician’s brain to problems in biology. At Harvard he asked biologists to tell him about the problems they wrestled with, and he came up with the theory of viruses including HIV which exist as a quasispecies — meaning that it exists with many viral variants (‘strains’) in a population. Some of the strains will be very fit, infectious and pathogenic; others will be weak or have lesser degrees of fitness or infectivity. The virus has an advantage in this population form, because having certain strains with resistance mutations allows the viral population to evade selective killing pressures of HIV drugs, or of the host immune system.

So Dr. Eigen developed the concept of viral quasispecies, and suggested that if you hypermutate the virus, you could push it to the state of non-viability; you could exceed error permissiveness, you could bring about an error catastrophe in the population, and the virus would collapse. This theory has been out there for a while; Eigen published during the 1990s. And scientists from the University of Washington and MIT, (Jim Mullins, the HIV virologist, Larry Loeb, a DNA polymerase expert, an MD PhD also at University of Washington who studies mutations and cancer, and a chemist at MIT, John Essigmann), came up with the idea of fashioning a drug that could induce mutations in HIV, and helped develop KP-1461. Several series of in vitro experiments were done in cell cultures, using a very nasty strain of HIV, a homogeneous, highly fit virus. And after an average 15 serial passages, that virus was irreversibly extinguished — repeatedly. Repeated, published experiments have demonstrated that you can collapse the viral population with KP-1461.

You and I both know that none of the HIV drugs currently marketed have been able to extinguish the virus in laboratory cultures, and certainly not in humans. They may be very potent inhibitors, but when the drug is taken away, the virus re-grows. That did not happen with KP-1461. It’s distinguishing feature, from a therapeutic perspective, is that it is capable of viral eradication in vitro. We don’t know if that will happen in humans; this is exactly what the current phase II clinical trial is designed to determine.

I came to Koronis Pharmaceuticals almost a year ago, to design and execute the trials that would demonstrate proof of concept of the drug. That’s precisely where we are at this point. There is an ongoing phase II clinical trial; it is a very hard trial to recruit. But we have enrolled 8 patients out of a projected enrollment of 32. They will be dosed with KP-1461 as monotherapy for four months.

The serial passage data showed extinction of the virus after 15 serial passages in the laboratory. If you use that with the David Ho – Alan Perelson calculations of HIV kinetics (and all you really can do is a back-if-an-envelope type of calculation), we think it will take a couple months to bring about an effect in humans. So the four months was chosen in part reflective of this couple months of dosing, and the fact that there is animal safety data that will permit a study of four months.

We’ve gone through phase I studies; a phase IA study in healthy volunteers, and a phase IB study in 50 HIV-infected individuals, similar in description to the current phase IIA subjects. They were triple-class-experienced individuals; the drug was given in the 1B study for 14 days, because that is all the animal safety data there was at that time. The bottom line for the phase I studies is that the drug appears safe and quite well tolerated.

The findings from the IA and IB and the strength of the in vitro data, including genotoxicity and mutagenesis studies done in the preclinical stage, took us to performing phase IIA studies.

ATN: What keeps KP-1461 from harming human DNA?

Dr. Becker: There are two very fundamental safety questions that people have, and this is one of them. The question is how specific a viral mutagen is this drug, to what extent is it capable of mutating host DNA, which of course would not be a good thing. The answers to that are as follows.

Genotoxicity depends on how much of the drug is incorporated by human DNA polymerase, and how much of it is excised [cut out]. In the case of human DNA in the nucleus of cells, KP-1461 is very poorly incorporated — a log [about 10 fold] less than any of the other nucleoside analogs.

But it is incorporated to a modest degree, about as much as 3TC or tenofovir, by gamma polymerase in human mitochondrial DNA. However, it is very quickly proofread and excised. We have done those experiments, and we and the FDA are satisfied with them for dosing, at least this far in our development program.

ATN: What is the other safety issue?

Dr. Becker: The other key question that people rapidly come up with is, could you create a supervirus?

This needs to be considered. It is a concept that most of us are not familiar with. In HIV therapeutics we are trying to avoid mutations and avoid viral diversity. KP-1461 is a drug intended to create mutations and increase viral diversity. The question of whether you could create a supervirus is one that, at this time, has much less data than the viral vs. host DNA selectivity question.

We can only speak in terms of virology, HIV virology, and evolution. And these studies suggest that of 100 mutations, 49 of them are non-coding; they don’t result in an altered protein in any way. These mutations do not change viral enzymes. So they are basically silent.

Fifty of the 100 mutations will reduce viral fitness. We see this all the time with HIV. A mutation in response to a drug impairs the fitness of the virus. Sometimes that fitness hit is greater (as with K65R or 184V mutations), and sometimes less; but they all impair viral fitness.

One percent of mutations are believed to increase viral fitness. So could we create a supervirus? On theoretic grounds it is possible but not likely at all. HIV has evolved to become the supervirus. Mother nature has been testing billions of mutations for decades. For example, compared to Ebola, HIV is successful because it does not kill its host in days. Evolution has selected against the most pathogenic strains that would kill the host too quickly before the virus could be transmitted throughout a human population, which is of course exactly what the virus from its perspective is trying to do. So one could argue that mother nature has in some ways already created this supervirus. The most efficient and effective virus already exists. And 99 of 100 mutations are going to reduce the virus’s fitness, not increase it.

Current Clinical Trial

ATN: Our main question is on the inclusion criteria for the trial. Patients must have had extensive antiretroviral experience, but have been off all antiretrovirals for at least 16 weeks. This seems to be difficult to find. Could you describe not just the criteria, but also the kinds of patients — maybe they have used antiretrovirals and don’t have good options, so they stopped?

Dr. Becker: I can see three general patient populations that would be suitable for this study.

One group of patients might qualify because they were treated too early in their infection, treated with less than suppressive regimens, or were not fully compliant when they were given a suppressive regimen. In the 90s we treated people with 700 T-cells and a viral load of 5,000 — at the time, that was what we were supposed to be doing. In retrospect that was probably too early; we didn’t even know whether that patient was a progressor or not. So one category would be patients who may have been treated too early, with less than fully suppressive therapy, who now have stable T-cells; they are off therapy, but they have resistant virus.

Another category of patients would be those who for whatever reasons cannot construct a regimen expected to be suppressive. That could be because they participated in an integrase trial and have integrase resistance already, or their insurance company will not cover the Trofile assay and it’s not clear that they can use maraviroc — or they are not ready to go back onto a combination of conventional antivirals — they don’t really have as many options as a genotype or phenotype might suggest, because of intolerance or allergy to some of the drugs. So that is a second general category of patient.

And the third might be patients who just do not tolerate a 3-drug or 4-drug antiretroviral regimen. If you need to use ritonavir, there are some people who cannot even take 100 mg of ritonavir without getting sick.

Those are the three general categories of patients I think would be potentially suitable for consideration. Of the eight patients we’ve enrolled so far, a couple fall into that treated too early, non-suppressive regimen category. And we actually have one individual who was infected with triple-class resistant virus. Even though they are not treatment experienced, I provided a waiver for that patient, because they had a terribly ugly genotype of triple-class resistant virus, though by transmission, not prior therapy.

But I wanted people to be off of therapy for sound reasons — in this post-SMART era where almost nobody should be off therapy. I wanted to make sure that these were folks who felt, with their clinicians, that there was a solid reason to be off of antiretrovirals. I wanted them off for 16 weeks, so that they would have gone through whatever sort of reversion to wild type, and may be at a new CD4 and viral load steady state. I did not want somebody who was about to have immunological or clinical progression because their virus was suddenly very active and very pathogenic. That is why we are requiring 16 weeks off of therapy.

We require a CD4 count of at least 250 because we wanted patients who were not at proximate risk for an AIDS-defining event. Somebody with 50 T-cells would be too much at risk, and I think ought to be on some conventional therapy. One could argue that we could have set it the limit at 200 or 150, but we picked 250 for the moment.

We know that this will be a very hard study to enroll. So for 32 patients, we have 23 sites up throughout the U.S., and we will have in total probably 30 sites. So we are just looking for one or two patients per site. We want quality not quantity; this is a different kind of study, so we approached it from the perspective of many sites with low enrollment.

ATN: How can potential volunteers find a site near them?

Dr. Becker: On http://www.clinicaltrials.gov search for KP-1461. This shows the current sites, and whether they are recruiting, as of the date of the last changes, which is posted on the site. Check back in case none are near you, as we are still adding more sites.

Summary

ATN: How would you summarize the importance of this study?

Dr. Becker: This drug is clearly different in concept, and clearly different in the laboratory. It must be tested; we have seen so many drugs that looked good but did not work. While the current generation of antiretrovirals is really good, eradication of the virus has been taken off of the agenda. Maybe the current drugs cannot achieve that. But we have to have eradication remain as a therapeutic imperative. It is up to creative scientists, chemist and virologists, to create drugs that can eradicate HIV. We have many things to contend with — sanctuary sites, and latent resting reservoirs — but who is to say that the next generation of drugs should not have eradication as its goal?

I think we will have clinical data by the second quarter of next year, to indicate whether or not we are on the right track. I want the community, doctors and patients, to be fully aware of this drug, aware of its laboratory demonstrations, and know that we are trying to test it in early stage clinically.

We don’t know whether four months dosing will be enough. We came up with four months based on a back-of-the-envelope projection, and animal safety data. But it could be that 4 months is right, or 2 months is sufficient, or that your really need 10 months. We won’t know that until we complete these studies.

But we will make KP-1461 available to any individual who participates in the phase II studies, should it be apparent that the drug is effective and safe, but maybe needs to be given for a longer duration. We will work with the FDA to establish a protocol that will provide drug for those who participated in our early development trials should they need further treatment. Often patients who participate in early stage studies are excluded from further access to the drug. We have committed, and put into writing, that we will establish a protocol for those who might benefit from further KP-1461 therapy.

Koronis Pharmaceuticals is a private company; there are only 17 of us. It is a very small group of people wearing many different hats. Our aspiration is not to become the next Gilead. But if this drug is active we would love to partner with larger pharma, to conduct late-stage HIV trials, which as you know is a fully international several thousand patient venture. That is nothing that a company like ours could possibly do alone.

References

1. Harris KS, Brabant W, Styrchak S, Gall A, and Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Research. July 2005; volume 67, number 1, pages 1-9.

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