UK-CAB 5 – Meeting Report

Access to treatment – TB and HIV – Roche

2 May 2003

Contents

Members and attendees

  1. Introduction
  2. Access to treatment for asylum seekers – Badru Male and Linda McDonald
  3. TB and HIV coinfection – Dr Anton Pozniak
  4. BHIVA guidelines update – Dr Anton Pozniak
  5. Roche – T-20 (enfuvirtide, Fuzeon)
  6. Feedback from BHIVA conference
  7. Appendix

Members registered

Willys Akoko Africa Advocacy Foundation
Steve Atkinson HIV i-Base
Hope Byarugaba Hillingdon AIDS Response Trust
Polly Clayden HIV i-Base
Simon Collins HIV i-Base
Joseph Chambers THT, Cymru
Ben Cromarty North yorkshire Aids Action
Richard Day Yorkshire MESMAC
Esslen Djola Kodjo CGNI
Babs Evans Haemophilia society
Jenni Fredriksson AVERT
Richard Jacksdon THT, Bristol
Ben Hill-Jones AVERT
Cathal Gallagher Whipps Cross University Hosp
Emma Hudson BEGIN, Wakefield
Martin Leigh UK Networx HIV Network
Badru Male Brent and Harrow PCT
Chris Morley Body Positive Northwest
Christophe Palaggi THT
Jo Robinson THT
Kapula Simonde Waverley Care SOLAS
Christopher Sutton
Carmen Tarrades Intl Community of Women
Brian West Waverley Care SOLAS

Minutes and reports: Simon Collins

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1. Introduction

HIV i-base welcomed those attending the fifth meeting of UK-CAB and Treatment Advocates Network and everyone introduced themselves.

Training for the session on access to treatment was organised by Badru Male, based on request for this subject at the last UK-CAB.

Reading material for this meeting, together with full reports from both training sessions and the accompanying slides are all available.

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2. Access to treatment for asylum seekers and refugees

Badru Male introduced this session by describing changes in approach to healthcare work since the mid 1990s. The problem then for African communities was over access to HIV treatment. They didn’t take treatment, people were worried about being guinea pigs, and preferred to pray to overcome health problems. He would encourage them and advocate for access to treatment and trial drugs.

As advocacy progressed people started treatment and then the focus became adherence. Now we are back to access issues – and lobbying authorities for treatment for a new group of people who need it, namely asylum seekers, immigrants and other non UK-citizens who are in the UK.

Linda McDonald, an HIV nurse practioner, and studying access to treatment for a law PhD led the training. She works at a unit with 300 HIV patients at Central Middlesex Hospital, 90% of who are African, and 70% of those are asylum seekers.

Full transcription of the talk

The slide set accompanying this talk are available to download from:
http://www.i-Base.info/ukcab/may03/powerpoint/UK-CAB_Access_McDonald.ppt

This talk covered aspects of access to HIV care for refugees, asylum seekers, overstayers etc. The definitions and law suggest that legal access to treatment is available but interpretation of the law is key – and there are many different access situations.

In order to claim refugee or asylum status the onus is on the individual to prove that they were being persecuted or have reason to fear for their safety in their home country and many people arrive from abroad without papers so it is difficult to do this unless they previously has a high profile in their own country. Asylum can be clamed by refugees or directly (before being given refugee status).

Article 3 of the Human Rights Convention states:

An asylum seeker who would suffer torture or inhuman or degrading treatment or punishment if returned to his/her country of origin, should not be expelled from the UK.

For many HIV-positive people in the UK, this includes being returned to a country where they will not receive treatment, and where without this treatment they will die.

A recent case study of a man from St Kitts, who argued he wouldn’t have access to treatment, was not accepted by the Home Office. If there is officially any access to treatment in a country it is used by the Home Office as reason to deny stay in the UK. But many governments only make drugs available to a few people, and it is very common for this limited treatment to be for members of the government or the army. In practical terms cost means treatment is not available to the majority of the population.

Even when limited treatment is available there is rarely the infrastructure such as access to viral load and cd4 monitoring, support for side effects etc.

More individuals are now being refused leave to stay on compassionate grounds.

To submit a case that is likely to be successful you need good lawyer that is aware of any recent policy changes.

People who are eligible for treatment if they are:

– a permanent resident in UK
– a student longer than for longer than 6 months at a recognised college
– a refugee or asylum seeker who has made an application
– if they are in a holding centre
– have diplomatic status
– or are from a country with a reciprocal healthcare agreement

People who are not eligible (for HAART) include:

– visitors
– student on course <6 mo (or not on a recognised course)
– applicants who have not filled in their papers yet
– illegal immigrants and overstayers

Exceptions include:

– if you need critical care – when you can get treatment to stabilise your health but not ongoing treatment
– if there are public health reasons (ie some communicable diseases like TB but not HIV)
– compulsory psychiatric care
– district nursing, midwifery and health visiting should be free – but we hear of nasty cases in HIV-positive people where costs are tried to be reclaimed

This means that people are treated in hospital but then presented with a large bill when they are discharged and excluding treatment it costs approx £300 a day to stay in hospital. It can also lead to some people who have both TB and HIV being charged ‘in some hospitals’ for different parts of their care – and there is wide variation in how the rules are interpreted.

Some hospitals will argue for both to be free – others will not and because of the different interpretations it is important to phone first before recommended a hospital to a client

The difference in interpretation arise because HIV care is affected by two different sets of conflicting regulations.

Under VD NHS 1982 regulations

– HIV treatment should only be provided to those eligible to free care
– HIV testing though is available free

BUT Under Venereal Disease 1976 regulations, which GU clinics work under

– all treatment is free and provided as anonymous treatment
– therefore clinics should neither know or ask about asylum status
– but that this only covers out-patient treatment

Because only out-patient treatment is included if they are admitted to hospital this protection is lost and often because of the previous safety people are very shocked when they arrive on the ward.

Some GUM clinics are very liberal and always provide treatment

Other cases we hear of include where people are asked to attend a GUM clinic with their papers and passport – note: this is illegal but being done.

Treatment status and asylum decisions may also become related. If someone has a high CD4 and is not on treatment this can jeopardise asylum application. This creates a pressure for people to start treatment early than they would normally do

Registering at a GUM clinic using false personal details is not a problem for accessing care at first, but when using solicitors and asking doctors for letters of support for applications, this can cause confusion.

Dispersal

Lot of clients are dispersed out of London. A High Court hearing a few weeks ago said this was legal on basis that NHS care is equal across UK. No account is taken of social support etc – and that case was dismissed. We get calls to our clinic from patients saying ‘I’m in Cardiff now’. They are given no notice and often no drug supply – and these are people who are legally entitled to medical treatment. We then need to then find out where there are, and which is their local clinic, The problems this causes are very difficult.

Our worst case was women diagnosed +ve when 32 weeks pregnant, who disappeared at 36 weeks to somewhere miles away. Treatment was critical. Linked to a clinic with no HIV experience and no HIV drugs – and ended up with only 3-days treatment before delivery. Immigration authorities said that treatment wouldn’t be a problem. Clients also assume that letters from doctors will help, but often it makes no difference. With dispersal, the onus is on client to keep in touch. We actively warn that this may happen. We warn that test in hospital will be tracked. We also put people in touch with lawyers

The full report includes information about access across the UK and additional case studies.

Conclusion:

– The diversity between NHS and GU regulations mean +ve individuals may not be eligible, but can access care through GU.
– However NHS treatment is not free and will be tracked outside GU setting
– Interpretation varies – always check before referral.

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3. TB and HIV coinfection – Dr Anton Pozniak

The main subjects discussed in the talk were:

– prophylaxis – can you prevent TB by giving drugs to protect against it
– treatment and side effects
– when to treat people with coinfection, how, and with what
– MDR – multi-drug resistance
– IRIS

Full transcription of the talk

The slide set accompanying this talk are available to download from:

http://www.i-Base.info/ukcab/may03/powerpoint/UK-CAB_TB_Pozniak.ppt

The relationship between TB and HIV prevalence in adults is very clear – as HIV incidence rises so does TB – especially in the developing world.

It makes treating TB a major problem – and putting programes together is difficult. Any country with HIV will have TB – and in the travel and refugees from Africa and Eastern European raises this is as a health concern in the UK.

London figures from TB – increases from African and Asian visitors – and the Home Office dispersal policy makes this worse. Some units outside London have little or expertise of refugees or TB and this is an important issue for advocates.

Note:

TB is rising in the UK, with 7,000 formal notifications in England and Wales a year, up from the 1987 low point of just over 5,000 (if nothing like the 1913 figure of 117,000). Two-thirds of confirmed cases are in foreign-born patients, up from 45% in 1988, but disease surveillance reports, as with HIV/Aids and hepatitis, give no indication of immigration status. Doctors believe a substantial proportion of TB cases might be explained by poor housing, poor diet and limited access to medical services.

A recent pilot study by the Home Office screened 5000 asylum seekers in Kent but failed to find one case of potential infectious TB.

Ref: The Guardian, 7 Feb 2003:
http://www.guardian.co.uk/Refugees_in_Britain/Story/0,2763,890624,00.html

Use of prophylaxis treatment

One third of the worlds population has been exposed to TB but this is not the same as having active TB. There is often confusion between infection and active disease. This is similar to being exposed to chicken pox – most people are exposed to the virus as children. They then fight the infection and recover but they still carry the virus throughout their lives – though they no longer have active disease. Once you are infected with TB however, then there is the potential for the disease to reactivate in the future and the risk is much higher in people who are coinfected with HIV.

Given that treatment for TB are very effective, many people thought that the solution would be to identify patients at high risk of TB and treat them to prevent infection. Only a few doctors though this was not as straight-forward as it appeared – but studies have now shown that prophylaxis treatment is not effective either to prevent initial disease, or to prevent reinfection – other than in a few very contained situations (army, prisons, close family contact etc).

However, rates of TB by CD4 count show a direct relationship in all settings (ie Italy, US and South Africa) with CD4 count – both >200 and >350, so the best prevention for TB is to boost CD4. TB can occur at any CD4 count but the risk is greatly reduced and effect on TB incidence in countries using HAART is huge (up to 99% in the US).

Also works for other infections – therefore all programmes need to identify HIV infections and low CD4 – for all countries.

Therefore a summary of when to use secondary TB prophylaxis is in:

– countries with significant TB
– where there are HIV programmes
– for all when CD4 <200 – as PCP
– stop when CD4 has increased >200

Issues in treating TB in HIV-positive people

Although the talk was largely medical – for TB social factors like poverty, overcrowding, governments and political will etc are also important. With overcroding for example, you need to know that if somebody sneezes into the open air, then TB droplets stay in the air for 1-2 days (aerosolised). If they cover their mouth then the droplets fall to the ground and are not infectious.

If TB is in the larynx then it comes out with each breath – so someone singing can be highly infectious, especially as you be infected without symptoms for 1-2 years.

One of the major problems in treating HIV-positive people for TB, and which make TB different form many other OIs (PCP, CMV, lymphoma etc) where you would treat both HIV and the OI at the same time, is the interactions between TB drugs and HIV drugs.

Drugs are absorbed and processed in liver, where enzymes break drugs down (especially CYP3A4) – and the major enzymes breaking down nearly all drugs. One common example is that the enzyme for processing alcohol in reduced in Asian people – and that alcohol tolerance is therefore much reduced). Drugs are then eliminated in urine and faeces.

Rifampicin is a crucial TB drug – and you need to take for it 6 months – without rifampicin you need > 18 months treatment.

Rifampicin increases 3A4 to very high levels – (turning the liver from a Scoda to Lambourgini!) and as these are the enzymes used to metabolise PIs and NNRTIs, they are cleared really quickly from your body, and you only get a small fraction of the levels that you need. Reverse transcriptase drugs (nucleosides) are not affected.

However, given the benefits of reduced risk of TB, once CD4 is increased (as with other OIs) and that some people are diagnosed with very low CD4 counts, several HIV drugs may be possible.

Other studies have suggested using rifabutin at reduced doses:

Three reports at the 2003 Retrovirus Conference also reported some success:

Nettles R et al. 10th CROI, Boston MA, February 2003. Abs 137
Patel A et al. 10th CROI, Boston MA, February 2003. Abs 138;
Pedral-Samapio D et al. 10th CROI, Boston MA, February 2003. Abs 784

You can also make use of TDM to confirm drug levels of HIV drugs if you are able to get results back within few days or a week, especially for gender etc and NVP

Data on duration of treatment is similarly sparse. US say treat for one year but there is no data behind this – they say they ‘err on side of caution’ but then need to analyse data. 4/6 studies showed an acceptable (<5%) relapse rate after 6 months. 2 showed relapse >9% but whether this was relapse of reinfection was not studied in one and was found to be a new infection in another.

Generally 6 months treatment is thought sufficient in uncomplicated and drug-sensitive cases, with longer courses for CNS disease, MDR disease or non-rifampicin regimens.

Side effects of HIV treatment are increased with TB treatment.

Q-What advice to the global find to fight TB when there is no access to HIV treatment?

A-That if you just treat TB – and many coinfected people will not survive – this is only likely to spread MDR – the answer is to treat HIV.

When to treat HIV ?

Even fairly recently, the arguments against starting both TB treatment and HAART both together at the same time (and therefore delaying HAART) were fairly convincing:

– HIV is a chronic disease
– Adherence may be compromised
– Toxicity management is more complex
– Immune restoration may produce “paradoxical reactions.”

We used to wait for 2-3 months for TB drugs to work and then start HAART – but an important study [Dean et al, AIDS 2001] showed that 27/188 coinfected patients developed further AIDS complications – most or these people were not on HAART (24/27). Median CD4 count in this group was 70 cell/mm3 and 90% still have CD4 <100 after 4 months TB treatment. Of the 16/188 people died only 4 were on HAART. On the basis of this data we moved to treating all on HAART.

Guidelines (with little evidence) for timing of treatment is now therefore:

– TB treatment must be started urgently
– the urgency of HIV treatment therefore depends on CD4 count
o if <100 – start HAART asap (1-2 weeks after TB)
o if 100-200 – risk of progression is low – so start HAART at 2 mo when settled on TB treatment
o if >200 – don’t use HAART but monitor

Most decisions should be based on data but not always there. In Spain and Italy they say HAART can wait but wait but would treat with a low CD4 but they keep these people out of studies… A new UK study – looking at immediate vs 2 months will give an answer.

In summary treatment of TB/HIV coinfection is very complicated – for timing, duration, dosing and choice of both HIV and TB drugs.

The solution that many doctors choose – and it is not a stupid one – is to contact a specialist, such as Anton Pozniak at the Chelsea and Westminster Hospital.

You are dealing with a situation with complicated interaction of (at least) two potentially fatal infections, both of which may require immediate treatment, and the recommended first-line treatments for each interact with each other in a complicated way that could jeopardise the effectiveness of each.

In the UK there are few cases of coinfection so this is still possible and the structure within the NHS is strengthening the use of support networks in this way.

This is also recommended for us as advocates when we hear of cases of coinfection, which through policies such as dispersal of asylum seekers may be increasingly being managed by clinics with little experience of HIV and TB coinfection.

BHIVA guidelines for TB/HIV are about to be published.

IRIS syndrome – Immune Reconstitution Inflammatory Syndrome

Dr Pozniak then described a relatively newly reported disease, related to TB. Symptoms are an angry infected wound – a bit like an very serious boil but which can become very large and difficult to heal – often in neck, lymph glands, back – seen is most other parts of the body.

It is seen in people with TB – and starts with a swollen lymph node. This should not be operated on – if removed by a surgeon it can lead to a long term seeping wound – always refer to specialist.

The wound can also come back – and any puss should only be removed by needle.

Details of symptoms and causes are included in the main report form this training. In the US this is treated with steroids, which may improve symptoms but reverse when stopped. In UK at Chelsea and Westminster it is treated with IL-2 and Gm-CSF

It is important to use recurrent aspiration – DON’T biopsy – and don’t use plastic surgeon to remove scars afterwards (as nerves can be brought up into scar during the healing process)

Multi-drug Resistant TB (MDR –TB)

MDR-TB is very serious and very difficult to treat, and an example was given from a case in Buenos Aires where one nurse infected 162 patients on an HIV ward over 2-3 years – and only 16 people survived using tailored regimens.

102 were resistance to 6 or more TB drugs

8 resistant to >10 TB drugs (and most doctors cannot name 10 TB drugs)

Using genetic markers on 92 cases – showed that 77 of these 92 were from index case

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4. Update on BHIVA guidelines

Dr Pozniak then presented an outline of the main points likely to change in the next UK treatment guidelines:

– Resistance tests are now recommended before starting treatment
– Triple nukes no longer recommended
– TDF for first line, if approved for first line in Europe as is expected
– NNRTI preferred over PI
– 2NN study wont change much other than not recommending once-daily NVP
– STI – not recommended if alternatives are available, for salvage therapy STI is recommended as part of OPTIMA stud
– Stopping treatment is an option if you started early (ie CD4 200-350) and are currently having difficulty with treatment (side effects, lipodystrophy)
– TDM recommendations are similar to last guidelines
– A new drugs section will include information on drugs that are expected to be licensed in the next year, and include not using T-20 not as monotherapy etc
– Another section will be included for blood tests and routine management (note that in the recent BHIVA audit, approximately 50% people did not have blood pressure or lipids measured prior to starting treatment, and 14% did not know their HCV status)
– New-fill will be included as a treatment for lipoatrophy
– d4T is not to be recommended as choice as first-line therapy (side effects)

Final draft for comments will be posted in early June to:

http//www.bhiva.org

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5. Roche – T-20

The afternoon session was dominated by a meeting with Dr Leroy Benons, Medical Advisor from Roche, focussing T-20, a new drug just licensed in the US and about to be licensed in Europe. T-20 is also called enfuvirtide and its tradename isw Fuzeon.

Slides from this presentation including detailed trial results can be downloaded from the i-Base website.

T-20 is the first drug in a new family – it is a fusion inhibitor and works before HIV enters a CD4 cell. All currently approved drugs only work once HIV has already entered a CD4 cell. As well as working against all currently resistance virus, T-20 may involve fewer side effects – although it has to be injected subcutaneously, twice daily.

Manufacturing and developing T-20 has been a very difficult process. It is a very complicated molecule requiring 106 manufacturing steps and 45kg of raw materials to make 1 kg drug.

Results from the large Phase 3 studies (called TORO 1 and 2) showed that using T-20 lead to an additional 0.7-0.9 log reduction in viral load, in addition to optimal background therapy. This background therapy was chosen from results from resistance tests, and is very important as people who did not have any other active drugs – ie T-20 was the only active drug even thought they were taking 3-4 drugs in a combination – only achieved a short term response.

Although T-20 still helps, and can be used in this salvage situation, resistance will develop after around 6 months, and longer use still will develop cross resistance to T-1249 – the next fusion inhibitor in development.

T-20 should therefore ideally be used earlier in treatment failure with at least one or two active drugs.

Practical advise from a patient perspective was then provided by James Locke, who 2 years ago, was one of the first patients in the UK to use T-20.

James has been HIV-positive since 1984 and after using many different treatments had developed extensive drug resistance. He started the talk saying that this had been his last chance for effective HIV treatment. He also said that he was very worried about the idea of using a treatment that need to be injected.

However, with a little support and training he explained that this was something that quickly became very easy to do. There are some problems with injection site reactions (ISRs), but that these can be minimised with practise, ensuring the powder is fully dissolved, having a bath first, massaging and using ice afterwards, and only injecting under the skin and not into muscle etc. An anaestetic cream can minimise discomfort from the injection.

People with higher body mass index (BMI) have fewer reactions and it can be a problem if you have less fat.

98% patients get reaction – directly after injections – but most last only a few days and only 3% people discontinued the studies for this reason.

T-20 is prescribed with a shoebox sized travel bag and kit containing:

– 60 vials
– alcohol pads
– 60 x 3ml NMT safety syringe for sterile water
– 60 x 1 ml, syringe (these are self-retracting safety syringes)

Roche are using a homecare delivery system as option, and nursing service for training including 24hr helpline. Other HIV medications can be included with the home delivery. This is an added service bought in by hospital.

T-20 takes up to 45 minutes to reconstitute if from fridge, less if taken out of fridge earlier. but can reconstitute 2 vials in the evening so that in the morning you need less time. Has to be used within 24 hours.

A paediatric version is available, but it has not been taken up so far in UK studies because of the concern about injections. It may be more appropriate for children to enrol in studies of T-1249 which only requires one injection a day.

Safety similar to adults but in children tissue is less defined – cellulitis – and can travel down the leg because muscles are less defined – only two cases but in smaller group to start with.

US approval for T-20 was in March 03 and is expecting Europe in 2-3 weeks – with a launch in June.

When to use?

– before you run out of options
– when new drugs to use
– toxicity or intolerance to current drugs
– co-infection (no drug interactions or liver toxicity)

Roche are recommending early third line (after NNRTI and first PI failure)

T-1249 is also being developed by Roche. There is some cross-resistance to early T-20 failure – but using T-20 in a failing regimen for 6 months or more wil make T-1249 unlikely to work.

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6. Feedback report from BHIVA conference

Jo Robinson from THT London reported back from the BHIVA conference that had taken place in Manchester the weekend before.

This conference has more social-based research than normal – which made it easier to take in treatment reports. Also, over 50 community places were provided.

The following presentations were of particular interest:

– BHIVA audit and first line treatment

This audit – where clinic around the country report on treatment of their last 50 patients – is a survey to see how c loosely the BHIVA guidelines are being followed.

Main findings included:

  • that of people starting <200 – some are presenting late but some are still delaying.
  • 60% people start on NNRTI .
  • TDF/3TC/EFV was a popular first line despite not being approved
  • that 50% clinics are not running blood pressure or lipid tests before starting treatment
  • that 14% clinics are not running a hepatitis C test before treatment
  • Discussion of 2NN

Several presentations discussed results from this study – difference between NVP and EFV discussed but mainly a difference in side effects

– Experiences of African +ve women – result of this first survey that THT were involved in were presented with a good gender analysis

  • fears around pregnancy but also validates as women
  • lone parenting
  • many women felt ‘immoral because of their HIV status – and therefore not guardian of morals

– Seminal super shedders.

Levels of HIV RNA in semen – the study was mostly in gay men – usually correlates with viral load in blood when not on Rx – but small minority had higher levels.

– Heart disease was discussed by Jens Lundgren (DAD study) and David Cooper (Lipodystophy definition study) – tables of risk from ARV had Kaletra at top, and main conclusion was the importance of other risk factors – but for most people without other risk factors, benefits of HAART still clearly outweigh risks.

Andrew Philips – looked at whether lifespan affected risk/benefit for starting treatment and suggested that looking at lifetime risk it is still preferable to dealy treatment until CD4 count is around 200 cells/mm3.

– Changing mortality – study from Chelsea and Westminster – showed higher rates of death due to lymphoma, self harm, hepatitis, reduced from KS etc

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7. Appendix

Preliminary reading material, together with powerpoint slides from all the presentations are available on the web page for this meeting.

If you do not have internet access and would like a print out of any report please contact i-Base on 020 7407 8488.

Edit
Published: May 2, 2003
Last edited: December 19, 2010