Scientists develop two-drug combo pill to treat HIV

Scientists have developed a new delivery system for a combination of two HIV drugs that may serve as an effective treatment for the deadly virus. The discovery, which allows for a combination of decitabine and gemcitabine to be delivered in pill form, marks a major step forward in patient feasibility for the drugs, which previously had been available solely via injection or intravenous therapy (IV), researchers said.

 

"If you have a condition that requires you to take a medication everyday, as many patients with HIV do, you wouldn't want to have to take that medication via daily injection," said Steven Patterson, professor at the Center for Drug Design at the University of Minnesota.
"This finding is a big step in demonstrating this treatment could be taken as a pill, similar to other HIV drugs, and is suitable for eventual clinical translation," said Patterson. Researchers first announced decitabine and gemcitabine, both FDA approved drugs, could potentially combine to treat HIV in August 2010.
The drug combination was shown to work by lethal mutagenesis that could obliterate HIV by causing the virus to mutate to a point where it was no longer infectious. For some patients, human immunodeficiency virus (HIV)'s ability to quickly mutate and evolve can result in drug resistance, researchers said.
For patients who have developed resistance to currently available HIV treatments, the decitabine-gemcitabine drug combination could prove an effective alternative and secondary line of defence. In addition to a potentially effective treatment for humans with HIV, the combination also shows potential to treat cats with leukaemia, researchers said.
"There's still a lot of work that needs to be done to demonstrate the safety and efficacy of this drug combination before human clinical trials can begin," said Patterson. "But we're optimistic that we're moving forward," said Patterson.
The study, coauthored by Christine Clouser, Laurent Bonnac, Louis Mansky, and Steven Patterson, was published in the journal Antiviral Chemistry & Chemotherapy.

 

What Abnormal Results Mean

What Abnormal Results Mean

A positive result on the ELISA screening test does not necessarily mean that the person has HIV infection. Certain conditions may lead to a false positive result, such as Lyme disease, syphilis, and lupus.
A positive ELISA test is always followed by a Western blot test. A positive Western blot confirms an HIV infection. A negative Western blot test means the ELISA test was a false positive test. The Western blot test can also be unclear, in which case more testing is done.
Negative tests do not rule out HIV infection. There is a period of time (called the "window period") between HIV infection and the appearance of anti-HIV antibodies that can be measured.
If a person might have acute or primary HIV infection, and is in the "window period," a negative HIV ELISA and Western blot will not rule out HIV infection. More tests for HIV will need to be done.

ELISA/Western blot tests for HIV

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How the Test is Performed

A blood sample is needed. For information on how this is done, see: Venipuncture.

How to Prepare for the Test

No preparation is necessary.

How the Test Will Feel

When the needle is inserted to draw blood, some people feel moderate pain, while others feel only a prick or stinging sensation. Afterward, there may be some throbbing.

Why the Test is Performed

Testing for HIV infection is done for many reasons, including:

• Screening people who want to be tested
• Screening people in high-risk groups (men who have sex with men, injection drug users and their sexual partners, and commercial sex workers)
• Screening people with certain conditions and infections (such as Kaposi's sarcoma or Pneumocystis jirovecii pneumonia)
• Screening pregnant women to help prevent them from passing the virus to the baby
• When a patient has an unusual infection

Normal Results

A negative test result is normal. However, people with early HIV infection (termed acute HIV infection or primary HIV infection) often have a negative test result.

What Abnormal Results Mean

A positive result on the ELISA screening test does not necessarily mean that the person has HIV infection. Certain conditions may lead to a false positive result, such as Lyme disease, syphilis, and lupus.
A positive ELISA test is always followed by a Western blot test. A positive Western blot confirms an HIV infection. A negative Western blot test means the ELISA test was a false positive test. The Western blot test can also be unclear, in which case more testing is done.
Negative tests do not rule out HIV infection. There is a period of time (called the "window period") between HIV infection and the appearance of anti-HIV antibodies that can be measured.
If a person might have acute or primary HIV infection, and is in the "window period," a negative HIV ELISA and Western blot will not rule out HIV infection. More tests for HIV will need to be done.

Risks

Veins and arteries vary in size from one patient to another and from one side of the body to the other. Obtaining a blood sample from some people may be more difficult than from others.
Other risks associated with having blood drawn are slight but may include:

• Excessive bleeding
• Fainting or feeling light-headed
• Hematoma (blood accumulating under the skin)
• Infection (a slight risk any time the skin is broken)

Considerations

People who are at high risk (men who have sex with men, injection drug users and their sexual partners, commercial sex workers) should be regularly tested for HIV.
If the health care provider suspects early acute HIV infection, other tests (such as HIV viral load) will be needed to confirm this diagnosis, because the HIV ELISA/Western blot test will often be negative during this window period.

Alternative Names

HIV testing

References

Dewar R, Goldstein D, Maldarelli F. Diagnosis of human immunodeficiency virus infection. In: Mandell GL, Bennett GE, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2009:chap 119.
Sax PE, Walker BD. Immunopathogenesis of human immunodeficiency infection. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2007:chap 408.

Strategy developed that may help researchers design a future vaccine against HIV/AIDS

Designing an effective HIV/AIDS vaccine is something of a paradox: a good vaccine would be safe and look enough like HIV to kick-start the immune system into neutralizing the virus - but the problem is that this is exactly what the human immune system has trouble doing even when it's exposed to the real thing.
Now a team of researchers led by scientists at The Scripps Research Institute in La Jolla, Calif. has developed a strategy for inducing a key part of an effective immune response to HIV. By tracing the evolution of HIV-recognizing molecules called antibodies taken from the blood of rare individuals whose immune systems are naturally able to target and neutralize the virus, they may have found a way to replicate this for everybody.
At a talk at the American Crystallographic Association meeting in Hawaii on July 24, the team will present multiple crystal structures, which like detailed architectural blueprints show how the virus interacts with components of the immune system. Examining these structures has allowed them to reverse engineer molecules that specifically activate the precursors of effective, neutralizing antibodies against the virus - molecules that may be components of a future vaccine against HIV.
"What we tried to do was to learn how those [effective] antibodies developed over the course of natural infection and attempt to guide the immune response in the direction of what we know works in certain HIV-infected individuals," said structural biologist Jean-Philippe Julien, who is presenting the work in Hawaii.
He conducted the research under the direction of Professors Ian Wilson and William Schief of The Scripps Research Institute. The work was funded by the International AIDS Vaccine Initiative Neutralizing Antibody Center, the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and the National Institute of Allergy and Infectious Diseases (one of the National Institutes of Health). Additional support was provided through a Canadian Institutes of Health Research fellowship.
Julien cautioned that the work might not, by itself, be the final answer that shows how to make an effective HIV/AIDS vaccine - but it is a step in the right direction. Most likely, Julien said, any future HIV/AIDS vaccine would combine multiple biological components in order to give the broadest possible protection against the virus.
He added that their candidate molecule was able to achieve the desired immune reactions in the test tube, and they are currently testing it in animals to see if it is able to kick start the desired immune response. If those experiments go well, he said, further studies will examine whether it can protect animals against infection, and human trials for safety and vaccine efficacy would be next - though it may be years before those results are known.
While designing a vaccine against any pathogen is a long, hard process, HIV has been particularly difficult, and despite decades of efforts and hundreds of millions of dollars spent in the process, we still do not yet have an effective vaccine that can prevent infection.

Failure Of Latest HIV Vaccine Test: A 'Huge Disappointment'

The green dots are HIV virus particles on a human white blood cell.

CDC

The largest current study of an AIDS vaccine, involving 2,500 people, is being stopped.
After an oversight committee took a preliminary peek at the results this past Monday, they concluded there was no way would show that the vaccine prevents HIV infection.
Nor would the vaccine suppress the wily virus among people who get infected despite being vaccinated.
So they on HVTN-505, as the study is called.
"It was a huge disappointment," says study leader , who learned the bad news at 1:45 Monday afternoon.
Hammer tells Shots the blow was all the more crushing because just a month earlier the had met its goal for participants.
"It was a big traumatic event to put all this effort in and then have the vaccine trial stop because of futility a month after we completed enrollment," Hammer says. He's chief of infectious diseases at Columbia University College of Physicians and Surgeons and a leading AIDS researcher who's been fighting the virus since the pandemic's beginning.
Participants are being notified that no more shots will be given. They will be followed for up to five more years to glean as much insight as possible from the $77 million, federally financed project.
It's another swerve into the ditch for AIDS researchers' on the long road to devise a vaccine that can prevent HIV infection, or at least blunt it, in a significant proportion of people at risk.
The only success so far has been in a involving 16,000 volunteers in Thailand. Published in late 2009, it showed a reduction in the rate of HIV infection by only 31 percent — not enough to deploy as a public health weapon, but a glimmer that encouraged researchers to think a protective vaccine is possible.
However, the latest big hope was dashed by these numbers: Among those in the just-halted study who got the vaccine, 41 people got infected with HIV, compared to 30 who got placebo shots.
That doesn't necessarily mean that the vaccine actually increased people's risk of HIV infection, because the difference is not statistically significant. But Hammer acknowledges that possibility.
"It's clear evidence the vaccine didn't work and may in some fashion put them at greater risk — we don't know that," he says. "The major message is they were not protected."
It may put the kibosh on the future use of an weakened cold virus, called , that was used as a vector — a vehicle carrying selected HIV genes that was used as part of the complicated four-shot vaccine regimen.
The possible riskiness of using the Ad5 vector was raised by results of an earlier HIV vaccine trial called back in 2007. That study was halted prematurely because of evidence that those who got the vaccine had higher risk of HIV infection.
The designers of the big HVTN-505 study hoped they'd avoided that problem by enrolling only people who had no evidence of prior exposure to the Ad5 cold virus. They reasoned that antibodies directed at the cold virus could have interfered with its efficacy as a vaccine vector and somehow increased the risk of HIV infection.
Other, early-phased HIV vaccine trials are using the Ad5 vector. Those will be reevaluated in light of the new findings, Hammer says.
"My own feeling is it's curtains for the Ad5 vector," Hammer says.
Even more ominous is the possibility is that it's not the vector that may be increasing the risk but rather any vaccine component that stimulates immune cells to attack HIV.
Since that's precisely what vaccines are supposed to do, that would be a catch-22 and a serious setback for AIDS vaccine research. But it's too soon to jump to that conclusion.
Leading AIDS researchers were disappointed by the failure of HVTN-505 – but not necessarily surprised, given the history of previous attempts.
"In a lot of ways, we're not much farther down the road than we were a number of years ago," of the University of California, San Diego MedPage Today.
"We understand a lot more about how (HIV-infected) people respond to the virus," Schooley says. "We don't know as much as we need to know about how to make uninfected people make the same kind of responses."
AVAC, an pushing the development of an HIV vaccine, said this latest failure "is a reminder of how challenging it is to develop an effective AIDS vaccine."
"This trial has provided a clear, swift answer about a specific vaccine strategy," says Mitchell Warren of AVAC. "It's not the answer we hoped for, but the search doesn't end here."
In fact, the search will continue with a careful dissection of the data gathered by the latest study.
Hammer says researchers will look at whether some people who got the vaccine were protected, and whether the vaccine produced the expected immune response. "Did it put pressure on the virus, but then the virus escaped?" he wonders. "We've got a bunch of things to do to figure this out."
To help with that task, the researchers are going to be talking with all 2,504 volunteers in the hope they can be persuaded to be poked and prodded for at least another couple of years to follow their responses and their risk of HIV infection.
The researchers will also redouble their efforts to get study volunteers to avoid risky behaviors that could expose them to HIV, given the clear evidence that the vaccine didn't protect them, and could have increased their risk of infection.
Meanwhile, this latest bad news "will throw the field into another round of discussion" about what to do next, Hammer says.
What it will not do, he says, is reduce the drive to keep trying until scientists come up with a vaccine "that gives us solid protection" against multiple strains of HIV.
"That will be a very joyous day," he says.

Efavirenz in children: WHO dosing guidelines raise the risk of side-effects in Thai children

 Efavirenz in children: WHO dosing guidelines raise the risk of side-effects in Thai children


Taking efavirenz according to 2010 World Health Organization (WHO) guidelines ensures a higher proportion of children with HIV have drug levels in the blood above recommended therapeutic levels (1mg/L) compared to the US Food and Drug Administration (FDA) guidelines, but also results in a higher percentage with potentially toxic levels (above 4mg/L), according to a population pharmacokinetic (PK) model presented last week at the 7th International AIDS Society Conference (IAS 2013) in Kuala Lumpur.
This retrospective analysis looked at 623 blood samples from 190 Thai children with HIV. The children had a median age of 7.2 years (IQR 0.1-15.2), bodyweight of 16kg (IQR 5-42) and with efavirenz dose given according to FDA bodyweight band recommendations, 8% (16) had an efavirenz level below 1mg/L twelve hours after a dose (C₁₂) while 6% (12) had a level above 4mg/L. There were no adverse events reported among the children. 
Model simulations showed that the percentage of children with a drug concentration (C₂₄ – 24 hours after a dose) between 1mg/L and 4mg/L using FDA dosing guidelines was similar to 2010 WHO recommendations. While the percentage with sub-optimal levels was lower using WHO guidelines the percentage of children with levels above 4mg/L increased by 11%. 
Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) together with a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) is the preferred ART regimen for children with HIV aged three and over weighing over 10kg.
Relatively little is known about how well efavirenz is absorbed in children. Some studies have shown sub-optimal as well as toxic levels in children and a greater variability compared to adults.
Between 1 and 4mg/L is a suggested concentration target 12 hours after efavirenz dosing to ensure efficacy and minimise the risk of toxicities, the majority of which are central nervous system disorders.
Dr Cressey cited two studies, both evaluating efavirenz levels according to WHO 2006 guidelines in African children, which reported high proportions of children with sub-therapeutic levels of efavirenz in the blood. One reported 40% of children and a sub-study of the ARROW trial reported 38% of children having efavirenz levels under 1mg/dl at C₂₄.
A poster presentation at the19th International AIDS Conference evaluating the 2010 WHO guidelines using scored generic 600mg efavirenz tablets among Zambian and Ugandan children (a sub-study of the CHAPAS-3 trial) showed more variability than adult data but similar to previously reported paediatric values “demonstrating the challenges of fixed-dosing when the therapeutic range is narrow”.
However, in Thailand, a study evaluating dosing according to FDA guidelines reported a lower percentage (15%) of children with sub-therapeutic efavirenz levels twenty-four hours after a dose (C₂₄).

Efavirenz dosing guidelines in HIV-infected children

                       Body weight (kg)

Dose (mg)	FDA dosing guideline	WHO 2006 dosing guideline	WHO 2010 dosing guideline
200	10 to <15	10 to <14	10 to <14
250	15 to<20	14 to<20	}
300	20 to <25	20 to<25	} 14 to <25
350	25 to <32.5	25 to <30	}
400	32.5 to <40	30 to <40	} 25 to <35
600	≥ 40	≥ 40	≥ 35

The investigators, wanting to evaluate current FDA and WHO 2010 efavirenz dosing guidelines, developed a population pharmacokinetic model to describe efavirenz absorption over time in Thai children with HIV.
Of the 190 children, 40 had 24-hour pharmacokinetic sampling data available.
Bodyweight affected efavirenz clearance.
The estimated median area under the concentration-time curve (AUC _0-24) was 49 (IQR 8-296) h.mg/L. The area under the curve (AUC) is a measure used to estimate the concentrations of active drug available to suppress HIV. If the AUC falls too low virus levels will increase, leading to virologic rebound and virologic resistance.
Some studies have suggested AUC in children above 50 h.mg/L is associated with virological efficacy.
A predicted efavirenz C₁₂ was 2.3 (0.07 to 11.9) mg/L.
FDA compared to WHO 2010 dosing guidelines, across all bodyweight bands, consistently showed higher percentages of those with sub-therapeutic levels (under 1 mg/dL) at C_12: from 14<15 , 15<20, 25<32.5 and 35<40 kg were 16 and 8%, 14 and 11%, 16 and 12% and 15 and 8%, respectively.
Conversely WHO 2010 guidelines compared to FDA guidelines showed consistently higher numbers, across all bodyweight bands, of those with potentially toxic levels (above 4 mg/dl) at C₁₂ : from 14<15 , 15<20, 25<32.5 and 35<40 kg were 39 and 25%, 33 and 24%, 28 and 21% and 42 and 21%, respectively.
Genotyping for CYP2B6 polymorphisms was not done. An estimated 11% prevalence of CYP2B6 TT (associated with high EFV exposure) in this population may explain higher levels in this group.
While the model suggests drug concentrations may be appropriate, safety data on EFV in children are needed for those getting WHO 2010 weight-band dosing.

Reference

Homkham et al. Plasma efavirenz concentrations in HIV-infected children in Thailand: comparison between FDA and WHO 2010 dosing guidelines. Seventh IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, abstract MOAB0104, July 2013.
View this abstract on the conference website.
View details of the conference session, Expanding ARV Options for Children: First Line and Beyond, in which this abstract was presented, including some presentation slides and webcasting, on the conference website.

Two Men HIV-Free After Bone Marrow Transplants

Two HIV-positive men no longer have detectable virus in their blood after receiving bone-marrow transplants to treat Hodgkin's lymphoma. Timothy Henrich and Daniel Kuritzkes , from Brigham and Women's Hospital, Boston, USA, explained at the International AIDS Society Conference, Kuala Lumpur, Malaysia, that one patient has been off HIV medications for over fifteen weeks and the other seven weeks, and there are still no signs of the virus rebounding.

Completely ridding a patient of HIV is extremely difficult. The virus hides within human DNA in such a way as to become "untouchable". ART (anti-retroviral therapy) helps control the virus in the bloodstream. However, as soon as ART stops, HIV usually replicates rapidly.

The two patients had been HIV-positive for over thirty years. They had both developed Hodgkin's lymphoma, a blood cancer that requires a bone marrow transplant if chemotherapy and other treatments failed. Blood cells are made in the bone marrow - experts believe the bone marrow is a major HIV reservoir.

After undergoing the bone marrow transplants, one man has had no detectable HIV in his blood for four years, and the other for two years.

Lead researcher, Dr. Timothy Henrich warned against using the C-word (cure), saying it is still early days.

In an interview with the BBC, Henrich said:

"We have not demonstrated cure, we're going to need longer follow-up. What we can say is if the virus does stay away for a year or even two years after we stopped the treatment, that the chances of the virus rebounding are going to be extremely low."

Last year, Kuritzkes and Henrich announced that HIV was easily detected in the blood lymphocytes of the two patients before their transplants, but within eight months post- transplant the virus had become undetectable. At the time the patients were still on ART.

The two patients came off ART earlier this year. They are regularly monitored and have no detectable HIV virus. Henrich said "We demonstrated at least a 1,000 to 10,000 fold reduction in the size of the HIV reservoir in the peripheral blood of these two patients. But the virus could still be present in other tissues such as the brain or gastrointestinal track."

If the virus were to rebound, it would mean that the brain, GI tract, lymph nodes or some other sites are important reservoirs of infectious virus "(and) new approaches to measuring the reservoir at relevant sites will be needed".

Bone marrow transplant not the answer to HIV infection

Bone-marrow transplant as a way of curing people infected with HIV is unlikely to ever become standard clinical practice.

In this case, the two patients had blood cancer; the transplants were performed to treat the cancer, not the HIV infection.

Most HIV-positive people do not have blood cancer. Bone marrow transplants are costly and risky - patients face a 20% risk of death. Before undergoing a transplant, the patient's immune system needs to be weakened to minimize the risk of rejection.

A third patient, who also had lymphoma and was HIV-positive and had received the same transplant as the two Boston subjects, died from cancer.

With ART, a person with HIV can enjoy the same life expectancy as other people.

Doctors "cured" baby born with HIV infection

In March this year, doctors from Johns Hopkins Children's Center, the University of Mississippi Medical Center and the University of Massachusetts Medical School announced that an HIV-positive baby who was administered ART within 30 hours of being born had been "cured".

Deborah Persaud, M.D., explained that it is very uncommon to treat a baby for HIV-infection so soon after birth. She added that this was the first case of a functional cure in an HIV-positive infant. The medical team believes that the prompt administration of antiretroviral therapy led to the newborn's cure.

Dr. Persaud said "Prompt antiviral therapy in newborns that begins within days of exposure may help infants clear the virus and achieve long-term remission without lifelong treatment by preventing such viral hideouts from forming in the first place."

First apparent HIV-infection cure probably occurred in Germany, 2010

In December 2010, researchers from Charite - University Medicine Berlin, Germany, wrote in the journal Blood than an acute myeloid leukemia patient, Timothy Brown, who was also HIV-positive had been cured of HIV infection after receiving a bone marrow transplant.

The scientists wrote "Our results strongly suggest that cure of HIV has been achieved in this patient."

In 2007 Timothy Brown stopped receiving ART, had his own immune system effectively wiped out with high-dose chemotherapy and radiation therapy, and received a bone marrow transplant.

In this case, the donor had a very rare gene mutation - CCR5-delta32 - which protected him from HIV infection, meaning that Brown acquired that protection. In July 2012, scientists in California found traces of HIV in his tissue. However, Brown says that any virus that remains in his body is completely inactive ("dead") and cannot replicate.

Written by Christian Nordqvist
Copyright: Medical News Today