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."

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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.

For more information: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/jhu_nimh/researchers/nhaughey.html

FULL PAPER:
http://jpet.aspetjournals.org/content/early/2012/09/19/jpet.112.195701.full.pdf+html

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.