9 November 2011 

Varenicline—An Ontario study assesses safety in HIV-positive people

Varenicline (sold as Champix in Canada, the European Union and many other countries, and as Chantix in the U.S.) is approved for the treatment of smoking cessation when used together with counselling. As it is a relatively new drug, at this time there are virtually no published studies on its safety and effectiveness in HIV-positive smokers. Since its approval several years ago by regulatory authorities, there have been limited reports of unexpected mental-health side effects in HIV-negative people who used this drug. Therefore, there are compelling reasons to assess the safety of varenicline in HIV-positive people who smoke tobacco because, as mentioned in our previous CATIE News story, tobacco smoking is highly addictive and harmful.

Researchers in the cities of Hamilton and London, Ontario, conducted an exploratory study to understand the safety of varenicline among 36 HIV-positive smokers. The researchers generally judged the drug to be “safe and effective,” although some side effects such as nausea were common. Varenicline did not weaken the effect of treatments for HIV infection. Researchers unexpectedly found that the CD4+ counts of participants increased by almost 70 cells 12 weeks after they ceased taking varenicline.

Study details

The average profile of participants at the start of the study was as follows:

  • 3% women, 97% men
  • age – 46 years
  • duration of HIV infection – 11 years
  • 86% used ART
  • 81% had a viral load less than 50 copies/ml
  • participants smoked about a pack of cigarettes daily for nearly 30 years
  • researchers estimated that 64% of participants had moderate to high levels of dependence on nicotine

Importantly, researchers described the participants as “stable” and none were being treated for depression or schizophrenia. The issue of mental health and varenicline is discussed later in this bulletin.

Varenicline was taken orally as follows:

  • Days 1 through 3 – 0.5 mg once daily
  • Days 4 through 7 – 0.5 mg twice daily
  • Day 8 through week 12 – 1 mg twice daily

Additionally, the study team gave participants counselling relevant to quitting smoking as well as helpful reading materials from the Ontario Cancer Society, the Canadian Lung Association and the city of Hamilton’s department of public health.

Participants were monitored during the study and physical exams and blood samples were collected for analysis.


During the study, 78% of participants reported adverse effects. The most common were nausea (33%) and abnormal dreams (31%).

A less common side effect, called “affect lability” by the study team, occurred in 19% of participants. This term encompassed one or more of the following:

  • irritability
  • mood swings
  • agitation
  • anger

Two participants (6%) reported depressed mood and one (3%) participant reported an increase in appetite.

Results—Other changes

Unexpectedly, CD4+ counts rose by 69 cells at the 24th week of the study, 12 weeks after participants had stopped taking varenicline. The reasons for this increase are unclear. Researchers performed many analyses to check for possible reasons for this (such as changes in ART, viral load, smoking cessation) but could not find any apparent cause for this increase

Varenicline had no impact on the effectiveness of anti-HIV therapy.

Levels of the liver enzyme ALT in the blood increased slightly, and this increase was statistically significant.

Blood pressure also increased very slightly.

Overall, participants had gained about 3 kg (6.6 lbs) by the end of the study. Participants who were underweight at the start of the study appreciated this change. (Marek Smieja MD, personal communication).

Premature discontinuation of varenicline

About 10 participants (28%) in the Ontario study prematurely stopped taking varenicline; six of these participants stopped taking the drug because of adverse events. No one was hospitalized because of adverse events. In studies with HIV-negative people, the rate of premature discontinuation of varenicline is usually about 13%. This is a significant difference between HIV-positive and HIV-negative people, at least based on data from the Ontario study.


In general, participants’ craving for cigarettes fell significantly during the study, even after they stopped taking varenicline. Indeed, while 17 participants were not able to quit tobacco during the study, their consumption of cigarettes fell significantly.

To assess participants’ ability to avoid smoking, technicians tested blood samples for the presence of cotinine, a compound produced as a result of ingesting nicotine. According to laboratory analysis in the first part of the study, 42% of participants were able to avoid smoking. In the second part of the study, this figure had fallen to 28%. This latter figure is similar to that seen in studies of HIV-negative people.


In the Ontario study of 36 HIV-positive people, although side effects were common, most were not severely bothersome and therapy could be tolerated for 12 weeks. The proportion of participants who reported abnormal dreams (31%) was greater than that reported in studies of HIV-negative people (9%). Nausea (33%) was a common side effect. The Ontario study did not recruit volunteers who had been diagnosed with depression or schizophrenia. Also, people with severely weakened immune systems were not recruited, so the results from the Ontario study cannot be generalized to HIV-positive smokers who have mental health issues or whose immune systems are weaker.

Abnormal dreams

Having abnormal dreams is a common side effect of the anti-HIV drug efavirenz (Sustiva and in Atripla). The Ontario team performed analyses in people who used efavirenz and in those who didn’t and found that there was no increase in abnormal dreams among varenicline users who took efavirenz. Interestingly, the study team noted that some participants were pleased to have abnormal dreams.

Smoking cessation, mental health and varenicline

In the recent past, regulatory authorities have issued several warnings about possible adverse effects of varenicline. Perhaps the most concerning to some readers are the warnings about the possibility of an increased risk for neuropsychiatric symptoms, ranging from depressed mood to hostility to suicide. These warnings and the resulting scrutiny of varenicline have generated controversy.

Yet, as alarming as these warnings sound, the actual number of people who have used varenicline and developed these problems is relatively small. Furthermore, before blaming varenicline for all of these issues, it is important to bear in mind that quitting smoking (without taking varenicline) can trigger one or more of the following effects as people struggle with nicotine withdrawal:

  • irritability
  • anger
  • depressed mood
  • anxiety
  • restlessness
  • difficulty getting along with family and friends
  • fatigue

As explained in our previous CATIE News story, nicotine from tobacco smoke may cause users to perceive a temporary improvement in their mood, ability to manage stress and concentration. So it ought not to be surprising that many researchers have found that smoking can be deeply addictive and is relatively common among people with mental health conditions such as anxiety, depression and schizophrenia. Smokers with these mental health conditions may face additional difficulty when trying to quit smoking. All people who plan to quit smoking should do so in consultation with their doctor and should also let close friends and family know so they can be monitored for any severe changes in mood. Although every smoker will experience different degrees of nicotine withdrawal, monitoring by a doctor as well as close friends and family members is important. There have been reports of severe depression among some people who experienced severe nicotine withdrawal.

Taking all of this into account, perhaps it is not surprising that mental health issues have been reported by people trying to quit tobacco and who also use varenicline. However, shortly after varenicline’s approval, isolated reports emerged of worsening pre-existing depression or schizophrenia in people who used this drug while attempting to quit smoking. Subsequently, several studies of varenicline in people with depression or schizophrenia did not generally find an increased risk of these problems when participants attempted to quit smoking and use varenicline. However, these studies were generally small and not placebo-controlled, so their results cannot be definitive. We now briefly review some larger studies conducted after varenicline was approved in high-income countries.

Large observational studies

An observational study of varenicline with 2,682 people in the UK found that psychiatric side effects were uncommon. There were two cases of attempted suicide, but the UK study team made this statement concerning those: “All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event.”

A more recent observational study from New Zealand with 3,145 people who used varenicline found that about 3% developed depression. There were also two cases of attempted suicide and two additional cases where participants reported thoughts of suicide after initiating therapy with varenicline. These four cases (two attempted and two thoughts of suicide) amount to 0.13% of participants in this study.

A much larger (80,660 people) observational study assessed the possibility that nicotine replacement therapy or bupropion or varenicline could be associated with attempted suicide, suicide, self-harm or depression. In that study, nearly 11,000 people received varenicline. There was no clear evidence that varenicline was associated with suicide (two cases) or attempted suicide (166 cases). However, due to the nature of the study design, an increased risk of suicidal behaviour associated with varenicline cannot be ruled out. But there was no increased risk of depression or thoughts of suicide among varenicline users; presumably these can be precursors of thoughts about self-harm.

Observational studies cannot provide definitive conclusions about cause and effect; that is, they cannot prove that varenicline did (or did not) cause suicide in some people. However, based on the collective results of the observational studies mentioned above, if there is a risk of increased thoughts of self-harm or attempted suicide with varenicline it is very, very small. Still, this means that to avoid the possibility of patients engaging in self-harm, the prescribing information for varenicline in Canada now carries the following warnings:

  • “The benefits and risks of all options for quitting smoking should be discussed with the patient before initiating treatment.”
  • “All patients attempting to quit smoking with Champix, as well as their families and caregivers, should be alerted about the need to monitor for depressed mood, agitation, aggression, hostility, suicidal ideation or behavior, or changes in behavior or thinking that are not typical for the patient.”
  • “Patients should be instructed to stop taking Champix immediately and contact their doctor if they experience, or if others observe, these symptoms. In many post-marketing cases, resolution of symptoms after discontinuation of Champix was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve."
  • Regarding alcohol intake: “Patients should be advised that alcohol intake may increase the risk of experiencing psychiatric adverse events during treatment with Champix.”
  • Regarding patients with psychiatric history: “Patients with concomitant psychiatric conditions, even if well controlled, or with a history of psychiatric symptoms, should be diligently monitored by a healthcare professional for new or worsened psychiatric events.”

Controversy about heart disease risk

In July, researchers in Baltimore reviewed 14 clinical trials of varenicline in which 8,216 people participated and published their findings in Canada’s premier medical journal, the Canadian Medical Association Journal, or CMAJ. The Baltimore team concluded that there was a very small yet statistically significantly increased risk of cardiovascular “events” associated with the use of varenicline. By “events” they meant any of the following—heart attack, abnormal heart rhythms, heart failure, sudden death or cardiovascular-related death.

The outcomes were as follows: There were 52 events in 4,908 people on varenicline (1.06%) and 27 events among 3,308 people who received placebo (0.82%).

The American study was not original in that it was a review of 14 other studies that were previously conducted using a statistical tool called a meta-analysis. None of these 14 trials were designed to specifically assess cardiovascular outcomes; the trials enrolled different populations and were held for different periods of time. All of these factors could have inadvertently led to bias when interpreting the results of their analysis. Due to these limitations, the findings by the Baltimore team are not definitive. But they do raise the possibility, that varenicline could be somehow associated with cardiovascular events in rare cases.

It is noteworthy that almost 1% of people assigned to placebo in the reviewed studies also experienced a cardiovascular event. Perhaps this finding suggests that nicotine withdrawal itself may play some role in exacerbating underlying cardiovascular disease.

Pfizer, the manufacturer of varenicline, contests the validity of the meta-analysis.

However, regulatory authorities in the U.S. have added cautionary statements about the use of varenicline in patients with “stable cardiovascular disease” while still noting that the risk of cardiovascular problems that may be caused by varenicline are “small.” Moreover, given the overall benefit of varenicline in helping people to quit tobacco (itself a risk factor for cardiovascular disease), the U.S. Food and Drug Administration (FDA) states: “The absolute risk of cardiovascular adverse events with Chantix, in relation to its efficacy, is small.” This agency encourages doctors to “weigh the potential benefits of [varenicline] against its potential risks when deciding to use the drug in patients with cardiovascular disease.”

Regulatory authorities in the European Union have taken a different approach, noting that due to flaws in the meta-analysis the European Medicines Agency (EMA) “could not draw robust conclusions from the meta-analysis.” Therefore the EMA made this statement: “the slightly increased risk of cardiovascular events reported by the study’s authors does not outweigh the benefits of Champix in helping people to stop smoking.”

Furthermore, instead of issuing a warning, the EMA has asked Pfizer to add more information about cardiovascular events to the medical information package for the drug used in Europe.

Varenicline vs. smoking

Researchers at the Mayo Clinic College of Medicine have reviewed data on varenicline and made this statement:

“Over half of all long-term smokers will die of a tobacco-related disease and the risk of a serious or life-threatening adverse event with tobacco cessation pharmacotherapy is vanishingly small. Pharmacotherapy for tobacco dependence is also among the most cost-effective preventive health interventions. Given these factors, the benefit : risk ratio is strongly in favour of pharmacotherapy for tobacco dependence treatment in virtually all smokers who are motivated to quit.”


Canadian Cancer Society: Smoking and tobacco

Canadian Lung Association: Smoking & tobacco

Santé et services sociaux Québec: Tobacco and your health

CATIE: Up in Smoke - The ifs, ands or buts of butting out


We thank Marek Smieja, MD, PhD, McMaster University, for his helpful review, research assistance and discussion.

                                                                                                           —Sean R. Hosein


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