UK-CAB 26 – Meeting Report

TB and HIV — reporting adverse drug reactions — Theratechnologies

25 July 2008

Summary

Winnie Sseruma, a delegate to theUNGASS meeting on HIV in New York, gave her impressions of this meeting.

Feedback from the 17th Resistance Workshop, Sitges covered: integrase inhibitor resistance – how to use raltegravir safely, the new NNRTI etravirine and prediciting when it will work, pipeline drugs – IDX899, CHX157, bevirimat and what happens below 50 copies/mL – does getting viral load further down stop resistance?

Theratechnologies, a biotech company based in Montréal, presented data on tesamorelin, a Human Growth Hormone Releasing Factor analogue currently in a phase III trial as a treatment for visceral adipose tissue gain. Results from phase II studies indicate this treatment results in a reduction in visceral adipose tissue – but this is reverses after stopping.

The MHRA presented details of the Yellow Card scheme for reporting adverse drug reactions. The MHRA would like to encourage patients to report more and the UK-CAB to publicise the Yellow Card scheme.

There was an overview of TB and HIV coinfection, including incidence, testing, treatment, MDR-TB and XDR-TB.

UK-CAB has a new coordinator – Memory Sachikonye.

Contents

1. UNGASS meeting
2. Resistance Workshop, Sitges and other research feedback
3. Theratechnologies: tesamorelin
4. Yellow Card scheme: adverse drug reaction reporting
5. HIV and TB
6. UK-CAB business

1. UNGASS meeting

Winnie Sseruma presented her impressions of the United Nations General Assembly Special Session (UNGASS) on HIV in New York.

She attended with (among others) Moono Nyambe, Wanjiku Kamau, Nick Partridge and reps from the UK Internations AIDS Consortium and DfID. This meeting was essentially a catch-up meeting to check on progress towards goals set at the first UNGASS in 2000.

Themes that stood out:

  • Prevention
  • Mother to child transmission
  • HIV treatment – 3 million now have access to treatment, but progress needs to be accelerated to achieve anything near universal coverage by 2010 (as resolved at the 207 G8 Summit)
  • TB/HIV coinfection – more co-ordination needed between different health systems
  • Civil society involvement
  • HIV related travel restrictions – see below!
  • Most at-risk groups – not enough being done on access to treatment etc for men who have sex with men, sex workers and other women

Personal views:

  • I declared my HIV status and went through the proper formalities to get a visa waiver. It was a nightmare – long queues and intrusive interviews at the US consulate.
  • UNGASS is a political meeting, not a conference: there will be a summary report progress will be checked again at the next meeting in 2010.
  • Importance of involving civil society: until a last minute intervention DfID had no person living with HIV in its official delegation, then Moono was selected.

Q: How were you selected?
A: I applied via ICASO and they had a group of people who selected me. I represented the World Council of Churches.

Q: How many people HIV+ in the delegation?
A: 2 out of less than 10

Q: Do you feel that girls and women were highlighted in the meeting?
A: I did my best, I had four minutes to talk about bringing key HIV+ women into decision making processes. We have to be careful not to sideline men too.

Q: Are travel restrictions going to be dropped in Australia and New Zealand etc too?
A: I don’t know. The US has been the biggest culprit and it’s where UNGASS happens. I had to get the World Council of Churches to call the US Embassy who called me.

2. Resistance Workshop, Sitges and other research feedback

17th International Resistance Workshop, Sitges

Simon Collins reported on this small, specialised meeting. There were about 200 delegates and only two community places offered. Issues:

  • Integrase inhibitor resistance: how to use raltegravir safely
  • Etravirine: predicting when it will work
  • Pipeline drugs: IDX899, CHX157, bevirimat
  • What happens below 50 copies/mL – does getting viral load further down stop resistance?

Integrase inhibitor resistance

Integrase inhibitor (INI) resistance is closer to NNRTI resistance than PI resistance. Only two steps are needed in HIV integrase for the virus to become highly resistant. There also appears to be no residual benefit for staying on it in terms of maintaining a less fit virus.

There is cross-class resistance: if you are resistant to raltegravir you will be resistant to the second one, elvitegravir.

However we have hardly any data – the licensing trials were unusually small, and fewer than 100 people have failed raltegravir (RGV).

Q: How do people fail?
A: By having no other active drugs. Resistance may take maybe 3-4 weeks on RGV monotherapy to develop. Some people who apparently had no active drugs maintained an undetectable viral load on RGV but this is probably due to residual protease inhibitor activity: PI resistance is not ‘all or nothing’ and even if the genotypic resistance test says you have no sensitivity to PIs they may still help to suppress HIV.

There are new INIs that appear not to be cross-class resistant, but not available for several years.

There is probably a transitory viral fitness benefit conferred by 1-2 INI mutations, in the first month or two, but as more INI mutations arise viral fitness is regained.

Qs and As: Discussion of personal experience of patients/friends on RGV.

Etravirine

Etravirine (ETV, TMC 125) is a new NNRTI, recently licensed as Intelence – the first new NNRTI since efavirenz in 1999. Active against some efavirenz or nevirapine resistance.

Opinion on the amount of NNRTI resistance mutations you need before etravirine stops working has changed as time has gone along:

  • 2007: More than 3 [out of 13 listed NNRTI mutations] don’t bother
  • 2008: Different mutations confer different degrees of resistance. Needs expert interpretation before prescribing.

An Eetravirine weighted score for different mutations has been developed – see table.

Take home message is that a score of 4 or more on this chart means do not rely on this drug, but a piece of good news is that K103N, the most common of all the NNRTI mutations, is not on the list and does not add to etravirine resistance. Some mutations that by themselves increase sensitivity to etravirine (eg G190S) decrease sensitivity when they are part of a cluster of mutations. FC = fold change, ie it will take 12.5 times more etravirine to suppress HIV with the Y181V mutation in its reverse transcriptase enzyme than HIV with no resistance mutations.

Q: Anyone here on etravirine?
A: Yes.

Table: Genotypic weighting scores and associated phenotypic sensitivity to etravirine

Mutation FC in single site directed mutant Effect on FC in model Weight factor
Y181V 12.5 High 3
Y181I 17.4 High 3
K101P 6.2 High 2.5
L1001 1.8 Medium 2.5
Y181C 3.9 Medium 2.5
M230L 3.4 High 2.5
E138A 2.0 Medium 1.5
V106I NA Low 1.5
G190S 0.2 Low 1.5
V179F 0.1 Medium 1.5
V90I 1.5 Low 1.0
V179D 2.6 Low 1.0
K101E 1.7 Low 1.0
K101H 1.3 Low 1.0
A98G 2.5 Low 1.0
V179T 0.8 Low 1.0
G190A 0.8 Low 1.0

Pipeline drugs: IDX899, CHX157, bevirimat

IDX899: NNRTI with -2.0 log (100-fold) reductions in viral load at day 8. Very limited data but no CNS toxicity. Once-daily.

CHX157: a tenofovir ‘pro drug’ requiring much lower doses than tenofovir, active against tenofovir resistant HIV, and not renally metabolized so no kidney probs.

Beviramat (PA-457): the maturation inhibitor. It turns out that 50% of patients have natural mutations in their HIV gag protein that means they won’t be sensitive to this drug. If you do a test to identify mutations at baseline, then you get -1.0 log (10-fold) reductions.

What happens below 50 copies/mL – does getting viral load further down stop resistance?

Study: 6 patients on treatment for mean 4 years (range 1-10) added efavirenz or lopinavir/r (Kaletra) for 30 days to their existing combination therapy. There was no change to their existing viral load (average 4.5 copies). So you probably can’t get more potent treatment than triple-combo therapy.

80% of people with viral loads of less than 50 copies/mL have more than 1 copy. Median: 3-4: 60% below 5.

Previous studies have indicated that there is no ongoing viral evolution in patients with less than 50 copies/mL Cohort studies say as long as you stay below 50 (without being measured further) you don’t rebound.

Q: anything on resistance to maraviroc from Sitges?
A: Maraviroc failure is largely to do with tropism (CCR5 or CXCR4-using virus) which is a thing resistance tests can’t measure.

Tesamorelin

Simon Collins briefed the meeting on tesamorelin, a Growth Hormone Releasing Factor (GHRF) analogue.

Tesamorelin is taken as daily 2mg subcutaneous injection. In studies in people with fat accumulation, it produced an approximately 20% reduction in visceral adipose tissue but there was no further effect after six months’ use and after the end of treatment visceral adipose tissue returned to baseline values.

Suggested questions for Theratechnologies (tesamorelin manufacturers):

  • Is effect constant and predictable? Do some people get better effect?
  • Safety and side effects?
  • Dose effect? Other doses studied?
  • Maintenance dosing – what is proposed? Dose, frequency?
  • Access for trial participants?
  • Expanded access?
  • Regulatory timeline in US and EU?
  • Cost?

Diagram: visceral fat (visceral adipose tissue) v subcutaneous fat (subcutaneous adipose tissue) in lipodystropy

View visceral fat accumulation compresses organsView | View in new window

Visceral fat accumulation from lipdystrophy is inside the abdomen and around the organs rather than being directly under your skin.

3. Theratechnologies: tesamorelin

Company background

Chantal Desrochers, Marketing Director

Company background Presentation

Company background Presentation Download as a PDF file [184Kb]

Theratechnologies, based in Montréal, is a biotech company founded in 1993 a long lifetime for a biotech! Currently has 95 employees. It has $72m capital – about 18 months’ reserves – and is researching and developing a number of candidate products and product lines based on intellectual property bought from the University of Montréal.

Tesamorelin is a Human Growth Hormone (HGH) Releasing Factor analogue currently in a phase III efficacy trial. It has potential for additional clinical uses in other areas but is currently being investigated for the treatment of central fat gain/visceral adipose tissue (visceral adipose tissue) related to HIV and HIV treatments. However it is also being tested for non-HIV-related wasting and obesity and adult HGH deficiency.

Theratechnologies is also investigating a peptide drug for acute renal failure and has licensed out other discoveries, e.g. a diabetes type 2 drug to Johnson & Johnson.

Chantal commented: “HIV-associated lipodystrophy is an attractive ‘foot in the door’ indication for tesamorelin.”

It is estimated that around 250,000 people worldwide currently would benefit from and could have access to a drug for HIV-related visceral adipose tissue gain. Abdominal obesity in growth hormone deficiency, for example, would be potentially a much larger market. It is estimated that 178m people worldwide suffer from HGH deficiency.

Tesamorelin and lipodystrophy

Christian Marsolais, Research Director

Tesamorelin Clinical Program in HIV-Lipodystrophy

Long-Term Impact of Tesamorelin Download as a PDF file [825 Kb]

Visceral adipose tissue- fat accumulation inside the abdominal cavity, rather than subcutaneously – is a phenomenon seen in a number of metabolic syndromes, especially type II diabetes. It is associated with a very high risk of cardiovascular disease. In HIV patients, waist circumference and visceral adipose tissue are independent predictors of cardiovascular disease. Obese people with subcutaneous fat accumulation rather than central fat accumulation have less cardiovascular disease risk.

38.5% of HIV patients with ‘lipodystrophy’ (defined as any kind of fat redistribution) have disordered HGH secretion. Lipodystrophy is also associated with treatment failure due to dherence failure: the number of self-reported lipodystrophy symptoms is independently associated with adherence failure (see APROCO study).

Data from the D:A:D study shows that cardiovascular disease risk in people with HIV on protease inhibitors is raised by 40% a year over and above the general risk increase per year:

Diagram: data from D:A:D study to December 2007: relative risk of heart attacks related to years of PI/NNRTI exposure, adjusted for other risk factors

View elative risk of heart attack by years of PI/NNRTI exposureView | View in new window

Increased visceral adipose tissue is also associated with a higher risk of type 2 diabetes, and vice versa: HGH and GHRF levels have a negative feedback loop with another hormone associated with diabetes, insulin-like growth factor (IGF): the less of the former, the more of the latter.

The natural GHRF peptide is degraded within minutes. Tesamorelin has a molecular ‘tail’ added, similar to the pegylation of interferon for hepatitis C treatment, which slows down degradation.

Theratechologies have also done studies using tesamorelin with elderly hip fracture patients (no effect), and are doing ones on people with chronic obstructive pulmonary disease (COPD, emphysema) related wasting, and with sleep/cognitive disturbances related to low HGH levels. Studies of the effect on diabetes and the immune response are planned.

Tesamorelin studies

Two HIV fat accumulation phase II trials were done: 1 in the US and 1 in the EU.

US study

Slide: study design and results schematic

View study design and results schematicView | View in new window

  • The study was a double-blinded, double-randomised placebo-controlled partial crossover study. This means that 410 patients were initially randomised to receive either tesamorelin or placebo for six months. At six months, all patients who had received placebo were switched to tesamorelin for another six months. Patients who had received tesamorelin were again randomised and split into a group that carried on receiving tesamorelin and one that switched to placebo. So everyone at some point received tesamorelin: 25% received tesamorelin for twelve months and 75% for six months: and 75% were on tesamorelin at the time the study finished.
  • The primary endpoint: % decrease in visceral adipose tissue from baseline versus placebo by CT scan.
  • Secondary endpoints: blood lipids, serum IGF levels (very high IGF = glucose intolerance etc), patient-reported (subjective) outcomes on fat accumulation.
  • Statistically, the study was designed to have a 90% power to detect an 8% difference between arms.
  • To be included, subjects had to have a waist circumference of over 95cm in men and 94cm in women and a waist to hip circumference ratio of more than 0.94 in men or 0.88 in women. They also had to have fasting glucose of less than 8.33 mmol/L (ie no clinical diabetes).
  • 326 patients out of 410 (79.5%) completed the study: at 12 months 211 were on tesamorelin and 115 on placebo. The 20% dropout rate was described as “not bad for a daily injectable”.

Patient characteristics

  • About 85% were male and about 5% were African-American.
  • Mean body mass index was 29, ie just short of clinically obese.
  • 69% had an undetectable HIV viral load.
  • 55% of those who started on tesamorelin versus 64% of those who started on placebo were on protease inhibitor-containing regimens (not a significant difference). 53% ontesamorelin versus 41% on placebo were on NNRTIs (this was a significant difference, p =0.03, meaning it could have made a difference to the results.)
  • Total cholesterol was on average somewhat above the upper limit of normal at about 5.1 mmol/L – and triglycerides were significantly above the upper limit of normal at 2.75 mmol/L.
  • Visceral adipose tissue, defined as the area of fatty tissue seen in a CAT scan section at the lumbar vertebrae 7-8 level was 178cm2 in those starting tesamorelin and 171 cm2 in those starting placebo – reference range: 80-90cm2 in a normal person. Average subcutaneous adipose tissue area was 231cm2.

Results: 26 weeks

50/50 on tesamorelin/placebo at this point.

% change in visceral adipose tissue at 26 weeks was:

  • -15% in patients on tesamorelin
  • +5% in patients on placebo

or in area terms -27.8cm2 versus +5.1cm2.

Patients on tesamorelin lost 1kg of trunk fat while patients on placebo gained +0.41 kg. Lean body mass increased by +1.4% on tesamorelin. There was no effect on subcutaneous adipose tissue.

No difference in results was seen between men and women.

The more baseline fat, the more fat loss: patients in the lowest quarter of baseline visceral adipose tissue (25th percentile) lost 17cm2 of visceral adipose tissue on tesamorelin. Patients in the 50th percentile lost 26cm2. Patients in the 75th percentile lost 35cm2.

Lipid changes: there were significant changes in patients on tesamorelin in total cholesterol, HDL (‘good’) cholesterol and the total cholesterol:HDL ratio. These are probably not clinically significant as baseline values were near-normal. There were also significant reductions in triglycerides, and these probably would be significant. IGF went down by 81% on tesamorelin. There were no changes in glucose/insulin levels.

There were also positive changes in bone mineral density markers but it’s not known if these have clinical significance.

Results: 52 weeks

Long-Term Impact of Tesamorelin

Long-Term Impact of Tesamorelin Download as a PDF file [60Kb]

Over 52 weeks the visceral adipose tissue loss on tesamorelin was sustained but did not increase. However, and disappointingly, patients who went on to placebo regained fat, and quite fast too: 75% of fat was regained by the 13th week after changing to placebo (= week 39 of study).

Patient reported outcomes

At baseline patients reported their body fat changes as comprising fat reduction in the areas of the buttocks, legs arms and face and fat accumulation in the belly, breasts and neck/shoulder blades (‘buffalo hump’).

Changes in ‘belly distress index’ calculated from questionnaire answers at week 26 was +12 on tesamorelin versus +6 on placebo – ie both arms reported subjective improvements in their body image, but in tesamorelin patients the improvement was twice as great, and significant (p=0.03).

Adverse events

82% on tesamorelin versus 75% on placebo reported some adverse event (difference not statistically significant, p =0.12). Adverse events judged to be possibly trial-related were 53% on tesamorelin and 37% on placebo, with 12% on tesamorelin versus 3% on placebo discontinuing. This was significant.

There was more arthralgia (joint pain), edema (fluid accumulation), myalgia (muscle aches), rash, and hypoesthesia and paresthesia (numbness and dulling of sensation) in patients on tesamorelin.

2% of patients developed an apparent allergic/hypersensitivity reaction to tesamorelin consisting of hives and/or rash. 1 subject has a systemic (anaphylactic) allergic reaction. All subjects with a hypersensitivity reaction tested positive for anti-tesamorelin antibodies. These reaction did not occur immediately but after 4 or more months of treatment.

European study

Results not yet publishable. Similar reduction in visceral adipose tissue in tesamorelin patients seen, but slight visceral adipose tissue decrease in placebo arm seen too, so difference between tesamorelin and placebo not quite so impressive as in US study. Similar results with triglycerides.

Q: It is fat production or distribution that is affected?
A: Production, not distribution because no increase in subcutaneous adipose tissue.

Q: Patient satisfaction?
A: Yes, they really see a difference. Also the fact that they had to inject themselves for a year and there was only a 20% dropout indicates satisfaction.

Q: Could you make a depot formulation [long lasting injectable formulation]?
A: We’re looking at it, but depot formulation has proved to be very unsafe in the case of recombinant HGH: ‘non-cyclical’ HGH does not mimic natural production and leads to high levels of both HGH and IGF.

Q: What happened when the trials were over? Why did you stop the study medication when it meant that subjects would, in the end, regain fat and receive no long-lasting benefit?
A: Answer confidential to UK-CAB meeting.

Q: Does visceral adipose tissue have an effect of decrease in natural HGH secretion?
A: Yes; once over a BMI on 27, every one-unit increase in BMI means about 5% reduction in HGH.

Q: Did it reduce buffalo hump?
A: We saw something and there was a question in the quality of life questionnaire but only 5% saw a difference, ditto for improvement in fat wasting.

Q: How will regulators treat this drug? £270m to continue the treatment is not insurmountable.
A: It is to do with the company size. It’s difficult to launch a long term programme until you have efficacy data to support the regulatory minimum.

Q: Yes but people are ‘back to abnormal’ after you stop treating them. Better to have done a rollover programme. Why didn’t you roll over after end of study with a lower maintenance dose?
A: Answer confidential to UK-CAB meeting.

Q: Cost estimate?
A: Not into a costing mode right now!

Q: How about looking at the compound plus behaviour modifications and lifestyle changes
A: Could do that, though so far lifestyle change studies have produced little effect

Q: EMEA [EU regulatory authority] registration?
A: Answer confidential to UK-CAB meeting.

Q: And FDA [US regulatory authority]?
A: Meeting with them very soon. By early next year we will make licensing submission, their review usually takes 10 months so would have product approved by 2010 in USA.

Results from the 26-week Confirmatory, Phase 3 Trial of Tesamorelin

Phase 3 Trial of Tesamorelin Download as a PDF file [172 Kb]

4. Yellow Card scheme: adverse drug reaction reporting

Yellow Card leaflet cover

Susan Kenyon, Abidali Fazal and Jane Morley from the MHRA, the medicines safety watchdog, explained the Yellow Card scheme for reporting adverse drug reactions.

The Yellow Card scheme has been used for over 40 years to collect information on suspected side effects from all types of medicines. Following a successful pilot, the Scheme was extended to allow patient reporting in February 2008.

The Yellow Card scheme’s website is at:
http://yellowcard.mhra.gov.uk

History of drug regulation in the UK

UK drug regulation started in 1961 with the thalidomide scandal (withdrawn 2 December 1961). In June 1963 the Committee on the Safety of Drugs was established and the Yellow Card scheme was launched in 1964. In 1968 the Medicines Act established statutory regulation of medicines after it was found that voluntary control was not effective.

In 1969-1970 Committee on Safety of Drugs became the Medicines Commission and Committee on Safety of Medicines. Day to day activities run by medicines division of Department of Health (DH). In 1989 Medicines Control Agency (MCA) formed, an executive agency of the DH. In 2003 the MCA merged with the Medical Devices Agency to form the MHRA (Medicines and Healthcare products Regulatory Agency).

About the MHRA

The primary objective of the MHRA is to enhance and safeguard the health of the public by ensuring that medicines and medical devices work and are acceptably safe both at the time of licensing and in the post-marketing environment.

How drugs are licensed

There are 5 ways medicines can be licensed:

  • National – only in UK. No HIV medicines licensed this way.
  • Mutual recognition – licensed in one EU country. Can then apply for license in another. AZT and ddI were licensed this way.
  • Decentralised.
  • Centralised ie EMEA – all other ARVs (EU law says all HIV meds must be licensed by EMEA).
  • Traditional herbal medicine regulation.

The method of licensing depends on how drug is then regulated: for a nationally regulated drug the UK can decide to withdraw it, for a centrally regulated drug the whole EU has to decide.

When someone takes a medicine they expect:

  • Efficacy – the medicine will have a positive effect in patients
  • Quality – it contains the active ingredients in the stated doses, it contains the stated excipients, and the stability, dissolution, bioavailability etc will be acceptable
  • Safety…

The Yellow Card scheme

The scheme started in 1964. Only doctors and dentists could report. The first year there were c. 5000 reports. Addition of other healthcare professionals as reporters eg pharmacists (1997), nurses (2002).

Reports also received from pharmaceutical companies; they have a legal obligation to do this. Over 50% of reports are received directly from patients and healthcare professionals.

In 2004 there was a review of the Yellow Card scheme and in January 2005 pilot patient reporting was started. In February 2008 patient reporting was established. Direct patient reporting will help MHRA better understand the patient’s experience.

There are now 20,000 reports a year. Data is anonymised for the patient. The reporter’s details are kept but are not shared.

Reports can be made on prescription, over the counter medicines and alternative therapies (including herbals). We ask for reports of suspicions and look for signals.

Signal: “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely reported previously…”

Scheme not used for NHS audits or for disciplinary purposes.

Strengths of the scheme

  • Proven to identify unrecognised reactions
  • Sensitivity is potentially high
  • Inclusive (all drugs throughout marketing life)
  • Can work rapidly
  • Can be applied widely
  • Fairly cheap to operate

Weaknesses

  • Under-reporting: reporting rates are difficult to establish
  • It’s poor at detecting certain adverse drug reactions such as ones that develop over time or look like other illnesses, eg cancers
  • .It can’t establish frequency of the side effect or its causality. Data can be misenterpreted or abused.

Researchers may apply to use the data

Signal generation

Does the number of reports of an adverse reaction with drug X exceed expectations?

1. Strength of the case

  • Number of cases in relation to usage
  • Quality of the information regarding cases – eg history, patient details, positive re-challenge (using the drug again and having the same side effect)
  • Individual case assessment of causality – time sequence, re-challenge/de-challenge, any confounding factors?

2. Other evidence

  • Pharmacological effects of the drug
  • Known effects of other drugs in the class
  • Pre-clinical studies
  • Clinical trials
  • Epidemiological studies

3. Public health impact

  • Number of cases per year
  • Reporting rate in relation to usage
  • Health consequences (seriousness, sequelae)

Risk/benefit calculation

Is the benefit worth the risk?

  • What are the absolute benefits?
    • Quantitatively (eg prevent 5 cases per 1,000)
    • Qualitatively (eg mortality, cure, symptom control)
  • Comparison with alternative treatment options. Are they worse?
  • What is the context? Serious or life threatening disease? In that case more serious side effects might be tolerated.
  • Acceptability to the population at risk
  • Can things be done to avoid or minimise the risk?

Decision-making support

Decision-making helped by:

  • UK
    • Commission on Human Medicines (CHM)
    • Expert advisory groups
    • External CHM advisory panel for ad hoc advice
  • Europe
    • Pharmacovigilance Working Party
    • Scientific advisory groups
    • Committee for Medicinal Products for Human Use (CHMP)

Options for regulatory action

  • No action
  • Communication, eg ‘Dear Doctor’ letter
  • Changes to product info
  • Over-the-counter changed back to prescription only
  • Suspension of drug pending investigation
  • Revocation of drug

Table: Examples of major safety issues identified by the Yellow Card scheme

Year Medicine Reaction
1995 Tramadol Psychiatric reactions
1995 Quinolone antibiotics Tendonitis and tendon rupture
1996 Alendronate Severe oesophageal reactions
1999 Aristolochia (herbal) Renal failure
2003 Kava-kava (herbal) Hepatotoxicity

Communication options

  • Non urgent info cascade
  • Rapid alert
  • ‘Dear Health Professional’ letter (from CHM/MHRA, Chief Medical Officer or the drug company)
  • Targeted info for patients
  • Drug Safety Update – new MHRA monthly bulletin
  • MHRA website
  • Changes to product info

Slide: MHRA – key stakeholders in communication

View slideView | View in new window

Antiretroviral drugs

Many ARVs were granted special licences as quickly as possible on the basis of less data. We therefore have little data on the long term safety of these drugs. We are still licensing ARVs on much less safety data than most other medicines. For instance, in the case of raltegravir (Isentress) we only had data in a 1,000 patients for 24 weeks. We’d ideally like over 3,000 patients and a lot more on long term safety.

There are about 200-400 ARV reports a year out of 20,000. We received 1,000 reports in the 1st pilot year (2006) from patients. Only three were about ARVs. We had 3,500 reports in the 2nd year and only 1 was about an ARV.

Graph: Healthcare professional reports of adverse events – ARVs

View healthcare professional reports of adverse events - ARVsView | View in new window

Particular problems with ARVs

  • Is the cause of the adverse event the medication, the disease (HIV or coinfections), or lifestyle? We have already seen this debate around, for instance, the incidence of heart attacks in people with HIV.
  • Which medication? HIV drug regimens can be complex especially if other drugs are also added. An example is protease inhibitors getting blamed for lipoatrophy.
  • Drug interactions, especially with over-the-counter medicines or herbs.
  • Very long term side effects, including ones that may appear after drug cessation.
  • Diet.

Useful information to record

If you have what you think is an adverse drug reaction it’s useful to includes the following information. The more information you record the easier it is to determine if the reaction is drug-related.

  • CD4count now
  • CD4 nadir with date if possible
  • Baseline CD4
  • HIV viral load now and before therapy
  • Test results relevant to the possible adverse drug reaction, eg liver function
  • Drug resistance profile
  • Previous illnesses
  • Previous side effects
  • Previous medications including over the counter, alternative, recreational

Example of an ARV signal picked up by the Yellow Card scheme

Lactic acidosis is more common in men usually, but the scheme found more cases in women on some drugs, especially d4T.

Encouraging reporting – providing feedback

Given the tiny number of reports from patients on ARVs, the MHRA would like to encourage patients to report more and the UK-CAB to publicise the Yellow Card scheme.

  • How can the MHRA encourage more reporting from within the HIV community?
  • What’s the best way of ensuring high quality reports?
  • Would feedback from the MHRA on HIV-associated Yellow Card reports be useful and what would be the best way of providing this?

Q: Can you report side effects already known to the scheme?
A: Yes, you can report anything. We’d look for differences in already-known side effects such as changes in frequency and severity, type of person affected, interactions and so on.

Q: You’re not always going to get all the data you request from patients: some won’t know it.
A: We understand that. More data makes it difficult to deny that the reaction is drug-related.

Q: Can you also report that a drug doesn’t work?
A: Yes: ‘lack of efficacy’ cases are also important.

Q: Do you generally feel there is under-reporting by patients?
A: Yes, especially by people who have chronic and potentially life threatening illnesses. I think patients are prepared to put up with more and that sometimes patients are afraid that a drug will be pulled from the market.

Q: Every time there’s a regimen change because a patient has tolerability issues, shouldn’t that generate a yellow card?
A: That would be very useful.

Q: Do you also get phone lines reporting to you?
A: Yes we get reports on NHS Direct and it would be useful to have e.g. the i-Base Treatment Phoneline reporting to us.

Q: Do you have proactive ways of monitoring for certain long term side-effects such as cancers?
A: With the newer drugs we have risk management plans scanning for side effects that might be plausible.

Comment: Find a way of taking this forward: have a working group in the CAB to take this forward with MHRA

Q: How many reports do you need?
A: Well if it’s a very severe skin reaction and a very good report, even 1 might work.

Q: Any drugs that generate a lot of reports?
A: Clozapine (anti-pychotic: severe neutropenia is possible), Champix (anti-smoking), statins

Q: Herbal remedies?
A: Very badly reported, but we have alerted public domain to dangers of kava-kava and black kohosh.

Comment: It’s disappointing so little is reported in HIV. We should have a button on the front page of i-Base and NAM’s websites.

Comment: I’ve experienced a varied quality of communication via the scheme. I reported kidney stones and atazanavir and got useful info, efavirenz-related kidney stones and got one of these forms saying ‘How will you use the research?’

Comment: A fair amount of time at the BHIVA Conference is taken up with reports from junior doctors.

5. HIV and TB

Sanjay Bhagani, Royal Free Hospital gave a clinician’s perspective on HIV and TB.

  • 8.9m new cases of TB a year
  • 1/3 of the world carries the TB bacterium
  • 0.75m cases of active TB in people with HIV
  • 1.7m deaths annually of which 250,000 in people with HIV
  • Up to 1/3 of all HIV-related deaths in Africa are due to TB

TB has gone up in Africa especially in high prevalence areas and eastern Europe – down elsewhere. Big problem in sub-Saharan Africa but also former Soviet Union, SE Asia (especially Cambodia)

Slide: World TB incidence by area

View world TB incidence by areaView | View in new window

In Africa, HIV rate among newly diagnosed TB patients varies from 80% (Botswana) to 24% (Uganda). Direct link between HIV prevalence and TB notifications.

At Royal Free Hospital 30% of TB patients were found to have HIV. DH recommended 2 years ago that all TB cases should be offered HIV test – not a clear position on take-up.

Slide: HIV prevalence among TB patients – Southern Africa

View HIV prevalence among TB patients - Southerm AfricaView | View in new window

Testing for TB

Smear test – but will miss TB if not many bacteria in sputum

Skin test = no good if immunosuppressed or had BCG vaccine

Elispot – Expensive, also may not work if immunosuppressed, doesn’t distinguish active disease

TB PCR – Even more expensive

Q: Could you use primary and secondary therapy as prophylaxis against latent TB?
A: Not easily. In high endemic areas reinfection is so common people soon get reinfected and if they have active TB and we give a single drug they will get resistance. It would work if you could prevent reinfections. Botswana has started a programme.

Treatment

Standard 4-drug regimen. Rifabutin can be used instead of rifampicin to avoid some ARV drug interactions (it uses same CYP450 enzyme as PIs)

In the first 6 months of treatment we try to Directly Observed Therapy (DOT). But DH (unlike many other European and other countries) doesn’t fund DOT.

We’ve found MDR-TB that’s resistant to isonaizid and rifampicin, and XDR -TB resistant to fluoroquinolones and at least one injectable. There’s an easily identifiable test for resistance to rifampicin by sequencing the bacterium’s RPOB gene.

Q: Do you use pyridoxine?
A: Yes – this is vitamin B6 – used to prevent peripheral neuropathy in isoniazid-taking patients.

MDR-TB and XDR-TB

MDR-TB more common in HIV-positive patients. It’s less fit, but because of increased susceptibility, HIV-positive patients get more of it. Forms about 1.1% of new diagnoses, 7% in patients who’ve had previous TB medication.

XDR-TB is thankfully still uncommon and not apparently growing, just isolated outbreaks.

Q: How long do you need to be in contact to catch TB?
A: More than 8 hours – from airplane studies – in was only caught if the flight was longer than 8 hours. Apparently you have to be 10 rows or less from the index patient!

Q: How long does the TB bug survive?
A: 3 days.

Q: How long are you infectious on treatment?
A: After 3 weeks your infectivity should go down to zero.

Q: Why has the uptake of HIV testing in TB clinics/patients been so poor?
A: Because not all TB clinics are under the control of an infectious disease specialist.

Q: MDR-TB is very stigmatised in hospitals.
A: Yes, the risk of a healthcare worker getting MDR-TB is almost zero.

Q: Can I ask about hearing loss and TB treatment?
A: We used to use streptomycin which was associated with hearing loss – 2 current TB drugs can cause hearing loss but TB is a multi-system disease and can cause it too.

Q: Should there be routine tests for latent TB in people with HIV?
A: Probably not necessary, because getting your CD4 count up should be enough to prevent reactivation of latent TB.

Q: What do you think will change in the BHIVA TB guidelines?
A: They should make it mandatory for everyone with TB to have an HIV test!

TB studies

UK CHIC cohort study

12 clinics mainly in London (also Brighton, Bristol and Edinburgh)

TB annual incidence rates in HIV patients:

  • 0.33% pre ART, 0.3% post ART
  • Africans – 0.92% pre-ART, 0.74% post-ART

CD4 count has big influence on incidence

Graph: TB incidence by CD4 count and ethinic group

View TB incidence by CD4 count and ethnic groupView | View in new window

South African gold miners cohort study

28,522 men working in 34 gold mines in Gauteng

High rates of TB (1.8%). HIV rate amongst TB pts went up from 10% in 1991 to over 50% in 1996. Recurrence: 16% HIV-positive, 6.4% HIV-negative.

Slide: TB natural history in South African gold miners cohort

View TB natural history in  South African gold miners cohortView | View in new window

  • HIV-negative patients – relapse more common than reinfection (non-significant, p=0.3)
  • HIV-positive patients – reinfection much more common (significant, p=0.005)
  • Cumulative hazard incidence of TB after six years = 18% HIV-positive, 5.5% HIV-negative.
  • Exposure: 70/30 no infection/infection
  • Containment 60-95%
  • Early progression (1-2 years) 2-5% HIV-negative 40% HIV-positive
  • Late progression: 5% lifetime risk HIV-negative, 3-14% a year HIV-positive

Graph: South African gold miners cohort study – proportion with TB over time

View South African gold miners cohort study - proportion with TB over timeView | View in new window

6. UK-CAB business

UK-CAB has a new paid co-ordinator: Memory Sachikonye!

Action: Letter to DfID re concern about withdrawal of HIV-specific funding: guidance by Winnie

New applications for the Steering Group please! We need women and Africans especially

Message boards: noted that less people are using it since it changed from email list. Will change notification of topics from opt in to opt out and simplify structure.

Next meeting: Friday 24 October 2008

Attendees

Florence Akoshule
Elijah Amooti, The African Eye Trust
Gus Cairns
Chris Chimwanyi, CAFP
Simon Collins, i-Base
Ben Cromarty, North Yorkshire AIDS Alliance
Richard Day, The Our Project
Emma Hudson, Brunswick Centre
Svlen Konsow, i-Base
Robert James
Rupert Jones, West Yorkshire African Group
Mohamade Jowana, Brent PCT
Badru Male, CHAT
Michael Marr, UK-CAB and Waverley Care Gonzalo Mazuela, FEAT, Spain
Hope Mheresa-Byawijobi, Positive East
Grace Moyo, Waverly Care, Glasgow
Nyambe Mukelabai, Leeds Skyline Service
Nakamba Ng’ambi, Leeds Skyline Service
Maya Nonngpremma, PozFem UK
Mary Oresi, Leeds Skyline Service
Kingsley Oturu, I I H D – EMU Edinburgh
John Owuor, THT
Roger Pebody, NAM
Winnie Sseruma, i-Base
Carmen Terrades, ICW
Anthony Tukai, Oxfordshire County Council
Sepo Young, Leeds Skyline Service

Speakers

Simon Collins, i-Base
Winnie Sseruma, i-Base
Chantal Desrochers, Theratechnologies
Christian Marsolais, Theratechnologies
Susan Kenyon, MHRA
Abidali Fazal, MHRA
Jane Morley, MHRA
Sanjay Bhagani, Royal Free Hospital

Views expressed in this report are personal and do not represent the views of any organisation involved in the meeting. Reasonable steps have been taken to ensure this report is accurate but it is for information only and not a substitue for professional advice.

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Published: July 25, 2008
Last edited: December 19, 2010