AIDS TREATMENT UPDATE

Issue 46, October 1996


In this issue:

- Blood tests to monitor HIV
- New medical Research Council trials
- Treatment Information phoneline
- Glossary
- Noticeboard

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BLOOD TESTS TO MONITOR HIV

Which tests can help with treatment decisions and what do the results mean?

By Edward King

Last month, AIDS Treatment Update examined some of the most difficult decisions facing people living with HIV - when to start anti-HIV treatment, what drugs to start with, and when to change treatment. Blood tests may play an important role in each of those decisions. This month we describe the different tests, how often each should be taken, and how to interpret the results.

CD4 counts are immunological tests, used to examine the current state of your immune system. Viral load tests are virological tests, used to assess the activity of HIV in your blood. Together, they provide a snapshot of the battle between HIV and the immune system, and may help to forecast how that battle will develop in future. This is called prognostic monitoring, and the test results are called prognostic markers.

The same tests may also be used to try to assess the effects of anti-HIV treatments. The ultimate goal of anti-HIV treatment isn't simply to cause changes in the test results but to change the course of the disease, preventing illnesses and prolonging life. A treatment that changed blood test results but had no effect on actual disease progression would be of no value.

However, the changes in CD4 count and viral load in response to a treatment may help to show how well it is working and predict its likely long-term effects. When used this way, the test results are called surrogate markers, because they are being used as surrogates (stand-ins) in place of the improved physical health that we are really interested in.

>>CD4 CELL COUNT

Among the body's white blood cells (or leukocytes) is a subgroup called the lymphocytes. CD4 cells are a type of lymphocyte that co-ordinate the immune system's response to certain micro-organisms such as viruses. HIV can infect and kill CD4 cells (as well as some other types of cell). The absolute CD4 cell count measures the number of CD4 cells in each cubic millimetre of blood. A normal count in a healthy, HIV-negative adult can vary but is usually between 600 and 1200 cells/mm3. In very young children the normal CD4 count is much higher.

CD4 cells are not the only type of lymphocyte (another type are CD8 cells, which kill abnormal or infected body cells). Instead of counting the number of CD4 cells per mm3, doctors sometimes assess what proportion of all the lymphocytes are CD4 cells. This is called the CD4 cell percentage; in HIV-negative people, a normal result is about 40%. A CD4 percentage below about 20% is thought to reflect a risk of opportunistic infections about the same as an absolute CD4 count of about 200. Some doctors argue that this is potentially the most accurate CD4 test, although it is not very sensitive to small changes.

A third approach is called the CD4:CD8 ratio, in which the number of CD4 cells in a sample of blood is compared with the number of CD8 cells. The result is given as a single figure, which indicates how many CD4 cells are present for each CD8 cell. A normal result is greater than 1 (i.e. there is at least one CD4 cell for every CD8 cell in the sample), but this tends to fall to below 1 if HIV disease progresses. Both the CD4 percentage and the CD4:CD8 ratio are also affected by changes in the number of CD8 cells, which tends to rise through the course of HIV infection.

The absolute CD4 cell count is the main test that doctors use to monitor your immune system. Most people with HIV find that over time their CD4 cell count falls, although there may be long periods when it remains very stable. If it falls below certain levels, you are potentially at risk from certain opportunistic infections so may be offered treatments to try to prevent them. Likewise, monitoring your CD4 count can help you decide whether to start taking anti-HIV drugs, to try to prevent any further damage to your immune system. For more information on starting treatment, see AIDS Treatment Update issue 45.

If you are taking anti-HIV drugs, the trend in your CD4 cell count may help to show how well the treatment is working. A steady fall in your CD4 count despite treatment may be an indication that it is time to change to a new drug combination; other reasons to change include evidence of disease progression such as new HIV-related symptoms, or intolerable side-effects from the drugs you are taking.

The frequency at which you are advised to have a CD4 cell count will depend on the current state of your immune system, and whether or not you are taking anti-HIV drugs. Among untreated people whose CD4 counts are above 500, tests are usually performed only every six to twelve months. At CD4 counts between 350 and 500, tests are likely to be performed about every three to six months, or maybe more often if recent tests suggest that the CD4 count is falling rapidly. People with counts between 250 and 350 may be offered a CD4 count more often, so that precautions such as prophylaxis against PCP (pneumonia) can be suggested if the count falls below 200.

If you are starting on anti-HIV drugs, your doctor is likely to recommend a CD4 count before you start treatment, followed by a second test after four to eight weeks to assess the immediate impact of the drugs. Thereafter, a CD4 count will probably be done between monthly and three-monthly. At the clinic visits, other tests such as full blood count and kidney and liver function tests are also likely to be offered to monitor for side-effects of treatments (see below).

Doctors voice several cautions about interpreting CD4 cell counts. First, it is crucial to follow the changes in the count over a series of tests, rather than to worry too much about an individual result. HIV isn't the only thing that can affect your CD4 count. Other infections, the time of day, whether or not you smoke and your stress levels can all have an impact on the test result.

Secondly, a CD4 test only indicates the number of CD4 cells in the blood. Most of the CD4 cells in the body are in tissues such as lymph nodes, rather than in the blood. Various factors can encourage CD4 cells to move into or out of the blood which would show up as a higher or lower CD4 cell count respectively, even though the total number of CD4 cells in your body remained unchanged. Again, this highlights the importance of watching the general trend, rather than single results.

>>VIRAL LOAD

Most of the viral load tests measure the amount of HIV's genetic material in a sample of blood or body tissue. In an HIV particle, the virus' genetic material is in the form of RNA, but once HIV infects a cell its RNA is converted to DNA. This means that a test for HIV RNA measures the number of virus particles, whereas a test for HIV DNA measures the number of HIV-infected cells.

Most viral load tests now available in clinics measure levels of HIV RNA in a sample of blood - their proper name is quantitative plasma HIV RNA assays. The results are given either as the number of HIV particles (or 'copies') per millilitre of blood, or using the logarithmic scale. The chart opposite (print edition only) shows what different log amounts mean in absolute numbers; for example, a viral load of 3.8 logs means that there are 6,310 copies/ml.

As the table shows, a one log change is the same as a ten-fold difference. Thus, a one log increase from 3.8 logs to 4.8 logs is an increase from 6,310 to 63,100. A one log decrease from 3.8 logs to 2.8 logs is a decrease from 6,310 to 631. For more information on understanding log changes, see AIDS Treatment Update issue 44.

Among HIV-positive people who have not developed symptoms, viral load is considered to be 'high' if it is above 100,000 copies/ml (5 logs). Viral load below about 10,000 copies/ml (4 logs) is considered 'low'.
The viral load is thought to give an indication of the rate at which HIV is reproducing in the body. In people who are not taking anti-HIV drugs, it predicts how quickly the body's CD4 cells will be destroyed and how quickly they are likely to progress to AIDS. As with the CD4 cell count, following the trend in your viral load count over time may help you decide when to think about starting anti-HIV treatment.

If you do decide to start treatment, testing your viral load beforehand (at baseline) and again after you have been taking the drugs for one to two months may indicate how well they are working. Effective anti-HIV regimens rapidly reduce the HIV viral load in the blood. Several clinical endpoint trials have suggested that the reduction in viral load two to three months after treatment begins is likely to predict how effective a treatment is at delaying the development of symptoms and/or prolonging life. If a new treatment regimen does not have a significant impact on your viral load, many doctors would recommend that you try a different combination instead.

As discussed in the article 'Changing treatment' in AIDS Treatment Update issue 45, your treatment regimen may be starting to fail if your viral load rises until it is close to or above the baseline level. However, many doctors remain unconvinced that an increasing viral load alone is grounds for a change in treatment.

In many clinics viral load tests are still not widely available, mainly due to their cost. Dr Bibhat Mandal, senior consultant at the Monsall Regional AIDS Unit in Manchester, said that he is currently negotiating the introduction of viral load testing with local health authorities. However, in the meantime he is taking samples of blood from patients who are starting or changing therapy and having them stored, so that they can be tested at a later date. If you cannot get a viral load test now, this may be a useful option to discuss with your doctor. Better late than never, it would provide you with an indication of your baseline viral load which you could compare with later levels.

Doctors told AIDS Treatment Update that in an ideal world where cost and availability were not issues, people who are not currently taking anti-HIV drugs would probably have their viral load measured at least once a year. For people on treatment, viral load tests should probably be performed at least every six months, and whenever a change of treatment is being considered.

However, as Dr Mike Youle of the Kobler Centre pointed out, no-one really knows how best to use viral load tests in the clinic. The Kobler Centre is collaborating with a clinic in Paris to conduct the Eurovir study, which aims to establish whether viral load tests are helpful in assessing HIV disease progression and in making treatment decisions. 300 people will be randomised to three different groups. Blood is taken and stored from all participants every two months; however, Group A and their doctors are only told the result of the baseline test, Group B and their doctors are told their viral load test result every two months, and Group C and their doctors get six-monthly test results. After two years the researchers hope to be able to tell whether people who know their viral load make better treatment decisions and so maintain their CD4 count at higher levels, compared with people who are not told their viral load.

Many of the cautions voiced about CD4 cell counts also apply to viral load tests. Various factors can cause a temporary blip in the viral load, especially things that stimulate the immune system such as infections or vaccinations. The same viral load test used on the same sample of blood can produce a different result because of the degree of variability in the test. Dr Ian Williams of the Mortimer Market Centre said that depending on the test, the variability may be up to 20%. That means that someone with a viral load test result of 50,000 copies/ml could in fact have anywhere between 40,000 and 60,000 copies/ml.

For all these reasons, some researchers argue that having your viral load measured should ideally consist of two tests on different samples of blood taken a few days apart, especially if the result may prompt important medical decisions. In practice, clinics are currently hard-pressed to find the money for single tests.
There are also continuing scientific debates about the significance of viral load in the blood. It is uncertain whether changes in viral load in the blood are a true mirror of changes throughout the body. A drug that reduces viral load to below the limit of detection in the blood could in theory be having no effect on virus levels in other parts of the body, such as the brain or the testicles.

>>OTHER TESTS

CD4 counts and viral load are by no means the only useful blood tests for monitoring your health. Other commonly used blood tests include:

- Full blood count. Used to detect shortage of haemoglobin in red blood cells (anaemia), shortage of all the white blood cells (leukopenia) or of specific white blood cells such as the infection-fighting neutrophils (neutropenia), and shortage of the platelets that enable the blood to clot (thrombocytopenia).

- p24 antigen test. This test measures the amount of a protein called p24 in a sample of blood. The p24 protein is part of HIV, and its level in the blood is seen as an indicator of the amount of HIV replication. Its usefulness is limited by the fact that many people have no measurable p24 in their blood even at relatively advanced stages of HIV infection, and that the test used in many clinics only says whether or not p24 is present, rather than measuring its level

- Kidney function tests. Urine and blood are tested for levels of a substance called creatinine, to assess how well the kidneys are filtering the blood.

- Liver function tests. A sample of blood is tested for enzymes produced in the liver cells; high levels suggest that the liver has been damaged.

- Serology tests. A sample of blood is tested for specific antibodies to see whether you have been exposed to infections such as CMV, syphilis, Toxoplasma or hepatitis in the past.

Different tests are needed at different times. For example, if you have just tested HIV-positive you should have the range of serology tests to establish whether you are harbouring infections in a latent state, which may later reactivate and cause disease unless prophylaxis is given. Although some infections such as CMV are relatively common in the population (and CMV is found in nearly all gay men), if you discover that you are uninfected with CMV you may decide to take careful precautions to minimise your chance of becoming infected.

Tests like full blood counts and liver function tests are more often used to monitor the side-effects of treatments, and can provide early warning of toxic side-effects that may require the drug to be stopped or the dose reduced.

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NEW MRC TRIALS

Two studies will test novel drugs and treatment strategies

By Edward King

The Medical Research Council has almost finalised plans for its next two clinical trials of treatments for people with HIV, which will hopefully start in early 1997.

The first new study is known as ADHOC, which stands for 'adefovir dipivoxil for HIV or CMV'. Adefovir dipivoxil is the new name for a drug previously known as bis-POM PMEA. In pilot studies it has shown signs of anti-viral effects against HIV, cytomegalovirus (CMV), which is a major cause of illness in people with advanced AIDS, other herpes viruses and hepatitis B virus.

To be eligible, you will have to have a CD4 count below 100 and no prior history of CMV retinitis or other forms of CMV disease. You will be randomly assigned to take either adefovir or a placebo once a day, in addition to your existing anti-HIV therapy. The aim is to assess whether people who receive adefovir live for longer, and whether the drug helps to prevent CMV disease.

ADHOC will recruit at least 500 participants at clinics throughout the UK after an initial pilot phase at some larger clinics; AIDS Treatment Update will print details as soon as they are available. The study is a collaboration which is likely to include France, Germany, the Netherlands, Ireland, Italy, Denmark, Australia, New Zealand and Sweden.

>>COMBINING PROTEASE INHIBITORS

The MRC is also planning another trial known as ProCom (Protease Combinations).

The study will first try to achieve a high level of suppression of viral load using a combination of two protease inhibitors or a four-drug combination (two protease inhibitors and two reverse transcriptase (RT) inhibitors). After 12 weeks, some of the participants taking four drugs will reduce treatment to either two RT inhibitors or two protease inhibitors, to test whether the suppression of viral load can be maintained over the longer-term using fewer drugs, with potentially less toxicity. You may be eligible for this study if your CD4 count is below 350, or if your viral load is above 20,000 regardless of your CD4 count.

ProCom will run at London clinics and selected major centres elsewhere in the UK. A full report, including background information on the effectiveness of combining two protease inhibitors, will be published in next month's AIDS Treatment Update. 

>>QUATTRO PROGRESS REPORT

Meanwhile the Quattro trial is still continuing, comparing the effects of three different regimens:

- four-drug combination therapy, in which participants take AZT, 3TC, loviride and ddC simultaneously
- cyclical therapy, in which participants take each of the four drugs on its own for 8 week periods, switching from one drug to the next in a continuous cycle
- two-drug combination therapy, in which participants take AZT and 3TC simultaneously

Each of the 100 participants receives 64 weeks' treatment in one of these arms, during which frequent blood samples are taken to be tested for viral load. The first people to be enrolled are now reaching the end of their 64 weeks, and the Quattro steering committee will shortly meet to discuss their subsequent therapy, such as the possibility of staying on their study regimen until the last person completes the study and the trial is ended. Unless the trial is stopped earlier than planned, this is likely to be in October 1997.

Quattro participants and their doctors are not told their viral load results at entry to or during the study, as the tests are done retrospectively on stored blood samples and not in 'real time'. However, the steering committee will also discuss whether participants who reach the end of the 64 weeks might then be told some of their viral load results, to help them make subsequent treatment decisions.


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TALKING TREATMENTS

How a new treatment information phone line can help you

By Raffi Babakhanian

Just one year ago AIDS Treatment Update was heralding the results of the Delta and ACTG 175 trials which showed that two anti-HIV drugs extended life and health better than one (AZT) alone. Back then there were only three drugs to choose from: AZT, ddI and ddC. Protease inhibitors were just beginning to show promise, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were widely regarded as failures. Very few people were advocating the routine use of viral load testing.

Today there are eight approved anti-HIV drugs in Europe (five nucleoside analogues and three protease inhibitors) - and two NNRTIs and another protease inhibitor should soon be available through expanded access schemes. That means that by early 1997, eleven anti-viral drugs will probably be available for doctors and patients to choose from. In some cases, combinations of these drugs can lower viral load levels below the limit of detection for at least a year, and today viral load testing is (slowly) becoming an accepted part of HIV clinical care.

Yet with all this choice and with all the hope that has accompanied each new medical development, many questions remain unanswered. Issue 45 of AIDS Treatment Update looked at three such issues: When should someone start treatment? What should you start with? When should you switch treatments, and what to?  
Sometimes it seems each new piece of information actually makes answering these questions more difficult. 

There are so many factors to consider when thinking about starting or changing treatments: Will I develop resistance or cross-resistance? How far should I seek to lower my viral load? Am I taking drugs which reach all the places infected by HIV? Do I risk developing serious side-effects? Can I comply with the dosing regimens? Are there potential drug interactions? And if I don't start (or change) treatments now, do I risk irreparable damage to my immune system?

This long list of questions only covers some of the issues associated with anti-viral treatment decision-making. Prophylaxis and treatments for opportunistic infection bring with them many additional considerations. Publications like AIDS Treatment Update or reference books like the NAM HIV & AIDS Treatments Directory are essential elements in providing the information an HIV-positive person needs to make treatment decisions. But written material can only go so far in addressing these needs.

>>THE ROLE OF ATP

AIDS Treatment Project was formed to help meet some of these other treatment information and support needs. The questions above show how complex  treatment decision-making can be, even with up-to-date information. Sometimes reading just isn't enough to sort out all the overlapping concerns.  

For this reason at the beginning of August ATP set up a weekly HIV/AIDS Treatment Information Phoneline. We take calls Wednesday nights from 6pm to 9pm. The number is 0645 470047 and local rates apply throughout the UK. We can answer specific questions about particular treatments and HIV-related conditions, or we can discuss how callers can answer broader treatment questions for themselves. We don't advocate any particular treatment or even treatment over no treatment. Often there are no absolute right or wrong answers to fundamental treatment questions - just informed or uninformed choices.

Sometimes people have a simple question or misunderstanding which has made it difficult for them to understand something they've read. For example, it's not obvious that CD4 and T-cells counts are the same thing (in HIV parlance at least).  

Some people also find it difficult to discuss their concerns directly with doctors, especially if they're not confident they have the facts right. One caller who had a rapidly falling CD4 count but an undetectable viral load wanted to know if he was right in asking for another type of viral load test. (Some viral load tests can't detect some of the HIV subtypes). He was able to get a different test which detected a high viral load of nearly 90,000 copies/ml.

The phoneline can also help to reassure people that they've understood what they've read, and that their resulting treatment decision is a reasonable one. For example, someone who called with a CD4 count of 50 wanted to know if she was right in considering taking ritonavir. Was it true that there was a study which showed that it extended life and health for people like her? (The answer is yes). We were able to send her copies of the clinical trial results which she and her doctor then discussed together.

Sometimes we can point out something that the caller may not have considered. One caller had heard that triple therapy with protease inhibitors was the best treatment against HIV and wanted to know where he could get it. He had a stable CD4 count of 400, and hadn't had a viral load test. We discussed double and triple combinations, drug resistance, cross-resistance and how viral load tests could be useful in helping to assess the short-term risk of progressing to AIDS. We probably didn't make his decision easier, but we hope he has a better idea of the potential risks and benefits of starting triple therapy now.

A treatments phoneline is just one of the ways ATP is trying to address the treatment information and support needs of HIV positive people. We plan to set up treatment support groups, so people starting or continuing on treatments can share experiences with each other. We're starting a project to bring up-to-date treatment information to people who get their care outside of the urban HIV specialist clinics. And we want to develop more audio/visual sources of information about HIV and HIV/AIDS treatments.

The last year brought a lot of progress on the HIV scientific and medical front. If we're to make the most of these gains during the next year we'll need creative and innovative ways of bringing treatment information and understanding into the daily lives of HIV-positive people. If you are interested in any of our projects or would like to volunteer with ATP please call us at 0171-793 7444. We welcome everyone.

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NOTICEBOARD


>>DENIED TREATMENTS?

The Terrence Higgins Trust, AIDS Treatment Project and Africa Advocacy Foundation are trying to monitor the problems people face in getting medical care. If you have been denied treatment or had to change clinic to get the care you want, they would like to learn from your experience. Please call Geraldine at THT on 0171-831 0330 (Monday to Wednesday); or AIDS Treatment Project on 0645 470047 (Wednesdays 6pm - 9pm); or Rita at Africa Advocacy Foundation on 0171-713 6616.


>>LIVING WITH HIV

The NAM book Living with HIV and AIDS  combines personal perspectives of people living with HIV or AIDS with practical advice on coping with a diagnosis and living with the virus. It has been written with the concerns of newly diagnosed people in mind, but it is likely to be valuable to anyone directly affected by HIV.

The content includes advice on who to tell about a diagnosis; obtaining quality services; treatment and the NHS; nutrition and weight loss; keeping healthy and avoiding infections; coping with illness and disability; planning for the future; and relationships, sex & parenting.

The book is free to individuals living with or directly affected by HIV or AIDS; o9.95 to others. To obtain a copy, contact NAM Publications at the address below.

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GLOSSARY

antibody A protein substance produced by the immune system in response to a foreign organism
asymptomatic Having no symptoms
CD4 A molecule on the surface of some cells onto which HIV can bind. The CD4 cell count roughly reflects the state of the immune system
CD8 A molecule on the surface of some white blood cells. Some of these cells can kill other cells that have been infected by foreign organisms
clinical event The occurrence of a physical sign or symptom, rather than an abnormality that can only be detected by laboratory tests
combination therapy Using more than one drug at a time
DNA The material in the nucleus of a cell in which genetic material is stored
expanded access scheme A programme that allows access to an experimental drug outside clinical trials for people in particular need
haemoglobin The substance in red blood cells that enables them to carry oxygen around the body
immunological Related to the study of the immune system
leukocyte Another name for white blood cell
lymphocyte A type of white blood cell that recognises foreign organisms to which the body has been exposed before
lymph tissue Tissue involved in the formation of lymph fluid, lymphocytes and antibodies
monotherapy Taking a drug on its own, as opposed to in combination with other drugs
nucleoside One of the building blocks from which DNA and RNA are made. Nucleoside analogue drugs such as AZT resemble one of these building blocks
prognostic marker An indicator of the likely outcome
prophylaxis Using drugs to try to prevent or delay an illness
protease An enzyme that HIV uses to break up large proteins into smaller ones from which new HIV particles can be made
quantitative Measuring the amount of something
retinitis Damage to the retina, the light-sensitive surface at the back of the eye 
reverse transcriptase A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV
RNA The chemical form in which HIV stores its genetic material
serology The study of blood
surrogate marker An indirect indicator of something such as the effect of a drug
viral load A measurement of the amount of virus in a sample
virological Related to the study of viruses

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AIDS Treatment Update is published monthly by
NAM Publications, 16a Clapham Common Southside, London SW4 7AB.
Tel: 0171-627 3200. Fax: 0171-627 3101. E-mail: atu@nam.org.uk
Internet: http://www.nam.org.uk/nam/

Copyright NAM Publications, 1996.

Editor: Edward King.

Medical Advisory Panel: Dr Fiona Boag, Dr Janet Darbyshire, Dr Brian Gazzard, Dr Diana Gibb, Professor Paul Griffiths, Dr Margaret Johnson, Dr Jacqueline Mok, Professor Tony Pinching, Professor Jonathan Weber, Dr Ian Williams, Dr Mike Youle.

Postal subscriptions are free to individuals in the UK affected by HIV or AIDS. Professional/organisational rate: L40/year. For all overseas subscriptions, within EU add L5/year; outside EU add L15/year.

Reproduction and distribution of articles from AIDS Treatment Update is encouraged on condition that it is on a non-commercial basis and that articles are reprinted unedited and in full, including these credits.
