Tag - cognitive dysfunction

Aerobic Exercise Increases Cognition and Brain Volume in HIV+ People

Background: HIV infected (HIV+) individuals are now reaching an advanced age, through stable treatment with highly active anti-retroviral therapy (HAART). However, HIV and aging are still risk factors for cognitive decline and neuropathologic deterioration seen in magnetic resonance imaging (MRI). Healthy lifestyle factors such as regular exercise may provide benefits to HIV+ individuals. Few studies have shown definitive benefit of aerobic exercise (AE) to HIV+ cognitive status, and none have used MRI. In this study we determine if a history of AE is beneficial to brain integrity and neurocognitive test scores in a cohort of HIV+ individuals.

Methods: A cross-sectional cohort of 70 HIV+ individuals (19-82 age range) had neuropsychological performance (NP) testing, neuroimaging, and completed an extensive self-report AE questionnaire that split the cohort into physically active (n=22) and sedentary (n=48) groups. Student’s t-tests were used to analyze demographics. Analysis of variance (ANOVA) was used to study main effects of exercise on a brief NP battery, which consisted of the following tests: Trail Making Tests A and B, Hopkins Verbal Learning Test, Digit-Symbol Coding, F-A-S and Verbal Fluency. NP tests were grouped by executive and motor function for analysis. ANOVAs were also used to study the effects of exercise upon brain volumes. This included brain volumes affected by HIV, such as the caudate and putamen, regions affected by exercise, such as the hippocampus, and general brain regions like total gray and total white matter

Results: Active and sedentary HIV+ individuals were similar for age, sex, education, and laboratory values. Physically active HIV+ patients performed significantly better than sedentary HIV+ participants on NP tests of executive (p=.04, mean Z scores of -0.654 and -0.956 respectively, [95% CI, 0.27, 0.72]) but not motor function (p=.13, mean Z scores of -0.331 and -0.827, respectively). Additionally, physically active HIV+ individuals had a significantly larger putamen (p=0.028) across the lifespan compared to the sedentary cohort.

Conclusions: Across a range of ages, AE may maintain healthy brain volumetrics in HIV+ individuals and led to improved cognitive performance. Future studies should consider exercise as an adjunctive therapy to HAART for HIV+ individuals.

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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.

Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells

Popular HIV drug may cause memory declines

Johns Hopkins study
suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain
cells

The way the body metabolizes a commonly prescribed anti-retroviral
drug that is used long term by patients infected with HIV may contribute to
cognitive impairment by damaging nerve cells, a new Johns Hopkins research
suggests.
Nearly 50 percent of people infected with HIV will eventually
develop some form of brain damage that, while mild, can affect the ability to
drive, work or participate in many daily activities. It has long been assumed
that the disease was causing the damage, but Hopkins researchers say the drug
efavirenz may play a key role.
People infected with HIV typically take a cocktail of medications
to suppress the virus, and many will take the drugs for decades. Efavirenz is
known to be very good at controlling the virus and is one of the few that
crosses the blood-brain barrier and can target potential reservoirs of virus in
the brain. Doctors have long believed that it might be possible to alleviate
cognitive impairment associated with HIV by getting more drugs into the brain,
but researchers say more caution is needed because there may be long-term
effects of these drugs on the brain.
“People with HIV infections can’t stop taking anti-retroviral
drugs. We know what happens then and it’s not good,” says Norman J.
Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins
University School of Medicine. “But we need to be very careful about the
types of anti-retrovirals we prescribe, and take a closer look at their
long-term effects. Drug toxicities could be a major contributing factor to
cognitive impairment in patients with HIV.”
For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics,
researchers obtained samples of blood and cerebrospinal fluid from HIV-infected
subjects enrolled in the NorthEastern AIDS Dementia study who were taking
efavirenz. Researchers looked for levels of the drug and its various
metabolites, which are substances created when efavirenz is broken down by the
liver. Performing experiments on neurons cultured in the lab, the investigators
examined the effects of 8-hydroxyefavirenz and other metabolites and found
major structural changes when using low levels of 8-hydroxyefavirenz, including
the loss of the important spines of the cells.
Haughey and his colleagues found that 8-hydroxyefavirenz is 10
times more toxic to brain cells than the drug itself and, even in low
concentrations, causes damage to the dendritic spines of neurons. The dendritic
spine is the information processing point of a neuron, where synapses — the
structures that allow communication among brain cells — are located.
In the case of efavirenz, a minor modification in the drug’s
structure may be able block its toxic effects but not alter its ability to
suppress the virus. Namandje N. Bumpus, Ph.D., one of the study’s other
authors, has found a way to mod
ify the drug to prevent it from metabolizing
into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to
suppress the HIV virus.
“Finding and stating a problem is one thing, but it’s another
to be able to say we have found this problem and here is an easy fix,”
Haughey says.
Haughey says studies like his serve as a reminder that while
people infected with HIV are living longer than they were 20 years ago, there
are significant problems associated with the drugs used to treat the infection.
“Some people do seem to have this attitude that HIV is no
longer a death sentence,” he says. “But even with anti-retroviral
treatments, people infected with HIV have shortened lifespans and the chance of
cognitive decline is high. It’s nothing you should treat lightly.”
###
The study was supported by grants from the National Institute on
Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental
Health (MH077543, MH075673 and MH71150), the National Institute on Aging
(AG034849) and the National Institute of Neurological Disorders and Stroke
(NS049465).
Other Hopkins researchers involved in the study include Luis B.
Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin
McArthur, M.B.B.S., M.P.H.

Can an Alzheimer’s Drug Help HIV+ People with Cognitive Dysfunction?




CROI 2012 Paper #482.  Rivastigmine for the Treatment of
HIV-associated Neurocognitive Disorders: A Randomized, Double-blind,
Placebo-controlled, Crossover Pilot Study
The prevalence of
HIV-associated neurocognitive disorders (HAND) remains high despite successful
antiretroviral therapy.  This study
performed by researchers from the HIV Swiss Cohort aimed at looking at the
effect of rivastigmine on HAND in patients with undetectable HIV viral load in
blood and cerebrospinal fluid but who had symptoms of neurocognitive
dysfunction.
Rivastigmine (sold
under the trade name Exelon) is an approved agent used in  the treatment of mild to moderate dementia of
the Alzheimer’s type and dementia due to Parkinson’s disease.
 This was a 2-site, randomized, double-blind,
placebo-controlled, crossover study in 17 HIV+ patients (12 men, mean 54.7
years old, 660  CD4+) with HAND. All
patients had undetectable viremia in both plasma and cerebrospinal fluid at
study entry, and no lesions on brain MRI. Participants were randomized to
receive either rivastigmine by mouth (5 months) followed by identical placebo (5
months) after a 6-week wash-out period, or placebo followed by rivastigmine .
Dosage was progressively increased from 1 mg to reach 12 mg per day of
rivastigmine. Four study visits included neuropsychological examinations. The
primary outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale
(ADAS-Cog). Secondary endpoints were 8 cognitive measures of attention,
information processing speed, working memory and executive functioning, as well
as perceived quality of life (MOS-HIV). The difference between start/end values
during each 5-month study period was used as a combined outcome for each
subject.
Rivastigmine induced
mild to moderate adverse events in 9 patients that disappeared after slight
dose reduction. Four patients withdraw because of severe nausea,
nightmares/anxiety, and allergic reactions. One measure of attention/processing
speed improved on drug (Trail Making Test A). Executive functioning also
improved but did not reach statistical significance due to the small sample
size (CANTAB Spatial Working Memory). Patients showed a trend for a
self-reported enhanced cognitive functioning (MOS-HIV) on drug . There was no
significant improvement on the ADAS-Cog.
In small trials, drug
effects need to be very large to reach statistical significance. This pilot
study suggests that the use of rivastigmine in aviremic HIV+ patients with HAND
may improve cognitive functions that are typically affected in HAND, i.e.,
information processing speed and executive functioning.
This study used an
oral formulation.  It is known that a
transdermal patch formulation has been better tolerated in Alzheimer’s
patients, so it will be interesting to test this drug in a patch form in a
larger group of patients with HAND who have undetectable viral load.