[Viva] Fwd: CATIE News - Ketamine use linked to liver and other problems in HIV-positive people

[Denise Becker]

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From: CATIE <mailer at newsletter.catie.ca>
Date: Tue, Aug 6, 2013 at 10:16 AM
Subject: CATIE News - Ketamine use linked to liver and other problems in
HIV-positive people
To: dbecker106 at gmail.com


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    CATIE News - Bite-sized HIV/AIDS news bulletins
       CATIE News - Ketamine use linked to liver and other problems in
HIV-positive people

Ketamine is a drug used as an anaesthetic in emergency departments of
hospitals and by veterinarians. It can cause hallucinations, feelings of
euphoria and floating, being in a dream-like state, out-of-body and other
experiences. As a result, it is also used as a club or party drug. In such
settings, ketamine has acquired the nickname “Special K.” Depending on the
dose and how it is taken, ketamine can have a relatively swift onset of
action, occurring within one to 30 minutes after ingestion. Ketamine’s
effect can last for up to three hours.

Ketamine can also cause paranoia, confusion, dizziness and feeling
disconnected from the body. Some of these effects may be responsible for
accidents and subsequent injuries reported among ketamine users.

Exposure to ketamine can become addictive, as users strive to repeat their
initial experience with the drug. This can lead to more frequent usage and
the consumption of larger doses over time. There have been growing reports
of ketamine toxicity when used recreationally, affecting the bladder and
causing pain, difficulty urinating, frequent urination, infections, blood
in the urine and urinary incontinence. Kidney injury from ketamine has also
been reported.

Reports from the UK suggest that the use of ketamine as a party drug is
increasing. As networks of substance users are connected, trends seen in
the UK may also be occurring in Canada and other high-income countries.

Doctors in Brighton, UK, have reported two cases of injury to the liver and
bile ducts that have been linked to ketamine use. In both cases the
affected men were HIV positive and it appeared that the concentration of
ketamine in their bodies may have been affected by their HIV treatment.
 Case 1

The first case was a 38-year-old man with what doctors described as “a
nine-year history of well-controlled HIV infection.” His CD4+ count was
nearly 800 cells and his viral load less than 40 copies/ml for the past
nine years. His HIV medications were as follows:

   - abacavir + lamivudine (a fixed-dose combination called Kivexa)
   - darunavir (Prezista) + ritonavir (Norvir)

 He was taking these additional medicines:

   - salbutamol for asthma
   - perindopril for managing blood pressure

 He sought medical care because of the onset of these symptoms:

   - nausea
   - vomiting
   - chronic abdominal pain

 He told doctors that he had episodes of these symptoms four times in the
past year.

His intake of alcohol was modest and he did not inject or use other
substances.
 Ketamine

The man disclosed that he had initially been taking ketamine orally at
relatively low doses two years ago. However, in the past year, he had
increased his intake to between 1 and 2 grams per day (self-prescribed), he
said, to help deal with the abdominal pain he experienced.
 Laboratory and other testing

Analyses of his blood found elevated levels of the following liver enzymes:

   - ALT (alanine aminotransferase) – three times the upper limit of normal
   - ALP (alkaline phosphatase) – nearly two times the upper limit of normal

 Technicians conducted tests for viral hepatitis, autoimmune or inherited
liver conditions but did not find anything remarkable.

Magnetic resonance imaging (MRI) scans of his abdomen did not find any
tumours, though it appeared that his common bile duct was inflamed. Doctors
inserted a small tube with a camera to assess his digestive tract but did
not find any lesions or gallstones. However, they did notice that the
muscle tissue (sphincter) controlling the opening and closing of his common
bile duct was swollen, so they removed the sphincter.
 Quitting ketamine

After this surgery, doctors advised the man to quit ketamine. He did and
within four weeks his symptoms and abnormal laboratory tests resolved.
Repeated medical investigation for 18 months after he stopped using
ketamine has not found any return of his symptoms or abnormalities in his
digestive tract.
 Case 2

Another HIV-positive man, 25 years old, sought care three times in eight
weeks because of recurring abdominal pain and nausea. He had been HIV
positive for three years, with a CD4+ count of 154 cells and a viral load
of 6,356 copies/ml. These results occurred despite the prescription of his
HIV treatment, as follows:

   - tenofovir + FTC (a fixed-dose combination called Truvada)
   - lopinavir-ritonavir (Kaletra)
   - Bactrim/Septra (trimethoprim-sulfamethoxazole)

 Doctors reported that this man’s ability to take his medicines exactly as
directed was “poor.” In reviewing his medical records, they noticed that he
had disclosed “occasional ketamine use” three years ago. However, in the
past year the man told doctors that he had increased his intake to between
1 and 2 grams, taken two to three times weekly. He did not inject ketamine
or other street drugs. However, his intake of alcohol was very high.

Lab tests of his blood revealed elevated levels of liver enzymes as follows:

   - ALT – 10 times the upper limit of normal
   - ALP – three times the upper limit of normal
   - GGT (gamma-glutamyl transpeptidase) – 15 times the upper limit of
   normal

 Based on these results and his disclosed alcohol intake, doctors advised
him to reduce his alcohol consumption.

He followed their advice but his symptoms persisted. Additionally, he was
also experiencing recurring bacterial infections of his urinary tract
(caused by *E. coli*).

As with the first case, investigation did not reveal viral hepatitis,
autoimmune or inherited liver disease.

Analysis of his urine found blood and ketamine.
 Scans and procedures

Ultrasound and MRI scans of the man’s abdomen detected a swollen common
bile duct. Visual inspection of his digestive tract and his liver and gall
bladder did not find any tumours or gallstones or any conventional cause of
his problems. Doctors removed the sphincter at the end of his common bile
duct. Liver biopsy did not reveal any scarring or tissue damage from
alcohol.

Doctors changed his HIV treatment to this combination:

   - Truvada + darunavir-ritonavir (all drugs taken once daily to help his
   adherence)

 A month after his scans and procedures, the man returned for medical care
because of abdominal pain. Doctors then advised him to stop using ketamine.
Two months after stopping ketamine, the pain and elevated liver enzymes
resolved. Subsequent blood tests and MRI scans have not detected any
abnormalities.
 Noteworthy

Putting together the data collected from interviews—focusing on periods
when ketamine was used as well as the development of symptoms—doctors noted
that “regular ketamine use” was linked to abdominal pain.

Other doctors have reported liver injury and swollen common bile ducts in
HIV-negative patients who have used ketamine recreationally. In such cases,
on average, the onset of abdominal symptoms took about four years to appear.

However, in the case of the two HIV-positive men, regular use of ketamine
occurred for one year before the appearance of symptoms.

The faster onset of symptoms in HIV-positive men may have happened because
they were taking ritonavir. This medicine can slow down the activity of
enzymes in the liver that process and break down drugs and substances. This
property of ritonavir is useful and is used by doctors because a small dose
of ritonavir is often prescribed with another HIV protease inhibitor in
these combinations commonly used today in Canada and other high-income
countries:

   - atazanavir (Reyataz) + ritonavir
   - darunavir + ritonavir
   - lopinavir + ritonavir

 The effect of ritonavir in such cases is to raise (or boost) and maintain
the concentration of the other protease inhibitor in the blood. Using
ritonavir in this way often allows for once-daily dosing of protease
inhibitors.

The Brighton doctors suggest that ritonavir may have elevated the amount of
ketamine in the blood of their HIV-positive patients, resulting in a faster
onset of toxicity compared to HIV-negative people. The increased levels of
liver enzymes detected in blood tests may have occurred because ketamine
can cause liver injury.
 Withdrawal management

The two men in this report were apparently able to overcome their addiction
to ketamine without difficulty fairly quickly. However, other long-term
ketamine users may require assistance such as: temporary prescription of
medicines for managing pain in their bladder and other places; gradually
reduced doses of anti-anxiety medicines to cope with ketamine withdrawal;
counselling about breaking free from addiction to help support mental and
emotional healing.
 Caution needed

Many medicines prescribed as part of HIV treatment—including but not
limited to protease inhibitors and non-nukes (NNRTIs)—and many other
prescription and non-prescription medicines have the potential to influence
the concentration of other drugs in the body by affecting the activity of
enzymes in the liver. This effect is called a drug-drug interaction. This
is particularly the case with street drugs.

Since the release of potent anti-HIV therapy (commonly called ART or HAART)
in the late 1990s, doctors have documented cases of serious, sometimes
fatal, toxicity caused by substances interacting with ritonavir and
possibly other protease inhibitors.

By building a trusting relationship with their healthcare team,
HIV-positive patients should, whenever possible, disclose all the drugs
that they are taking—both prescribed and non-prescribed (including street
or club drugs), as well as supplements and herbs so that their doctor,
nurse and pharmacist can advise them about possible interactions and ways
to stay healthy.
 “Special M”

Other researchers in the UK have reported that a street drug related to
ketamine, called MXE (methoxetamine) or “Special M” by users, has appeared.
This new drug has similar effects to ketamine but takes longer to exert its
effects when inhaled or swallowed. This carries the risk that some users
may inadvertently overdose. There are claims associated with MXE that this
analogue of ketamine is “bladder friendly.” However, researchers in the UK
who study substance use warn that it is too early to be certain about the
effects of MXE on the urinary tract. As MXE has not been formally tested in
people, its safety on the brain and other parts of the body are unknown.


*—Sean R. Hosein*

REFERENCES:

   1. Kirby T, Thornber-Dunwell M. High-risk drug practices tighten grip on
   London gay scene. *Lancet* 2013;381:101-102.
   2. Zhou J, Shaw SG, Gilleece Y. Dilated common bile duct and deranged
   liver function tests associated with ketamine use in two HIV-positive MSM.
   *International Journal of STD and AIDS*. 2013; *in press*.
   3. Winstock AR, Mitcheson L. New recreational drugs and the primary care
   approach to patients who use them. BMJ. 2012 Feb 15;344:e288.
   4. Middela S, Pearce I. Ketamine-induced vesicopathy: a literature
   review. *International Journal of Clinical Practice.* 2011
   Jan;65(1):27-30.
   5. Mason K, Cottrell AM, Corrigan AG, et al. Ketamine-associated lower
   urinary tract destruction: a new radiological challenge. *Clinical
   Radiology*. 2010 Oct;65(10):795-800.
   6. Turkish A, Luo JJ, Lefkowitch JH. Ketamine abuse, biliary tract
   disease and secondary sclerosing cholangitis. *Hepatology.* 2013; *in
   press.*
   7. Henry JA, Hill IR. Fatal interaction between ritonavir and MDMA. *Lancet.
   *1998 Nov 28;352(9142):1751-2.
   8. Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening
   interactions between HIV-1 protease inhibitors and the illicit drugs MDMA
   and gamma-hydroxybutyrate. *Archives of Internal Medicine*. 1999 Oct
   11;159(18):2221-4.
   9. Antoniou T, Tseng AL. Interactions between recreational drugs and
   antiretroviral agents. *Annals of Pharmacotherapy.* 2002
   Oct;36(10):1598-613.
   10. Corazza O, Assi S, Schifano F. From "Special K" to "Special M": the
   evolution of the recreational use of ketamine and methoxetamine. *CNS
   Neuroscience & Therapeutics*. 2013 Jun;19(6):454-60.


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-- 
www.denise-becker.com
Queen's Gold Jubilee Medal
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cell: 250-870-1714
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