In the last 30 years, human immunodeficiency virus (HIV) infection has been transformed from a devastating disease causing acquired immunodeficiency syndrome (AIDS) and early death, to a well-understood and treatable condition. This tremendous progress has occurred as a result of effective antiretroviral therapy, which blocks HIV replication and as a consequence leads to restoration of immune function, the prevention of AIDS, and improved quality of life. Despite these great advances in treating HIV-infected individuals, there is a great deal of controversy surrounding when to start antiretroviral therapy. While some experts advocate starting therapy early in order to reduce viral replication and inflammation, others are concerned over the long-term side-effects of treatment, and advocate that treatment be deferred until it is absolutely needed.
International guidelines are divided in their recommendations about when to start therapy. The US guidelines recommend starting therapy in essentially everyone, whereas a number of European guidelines advocate deferring therapy until a patient’s CD4 count drops below 350 cells/mm3. This controversy is addressed by two debate articles in BMC Medicine by Michael Saag from the Center for AIDS Research at the University of Alabama, USA, and Jens Lundgren from the Department of Infectious Diseases, Denmark. Saag recommends an early start, whilst Lundgren favors a deferred approach.
Here we talk to two experts from international guideline committees, to explore the reasons behind the differing global recommendations. Steven Deeks from the University of California San Francisco, USA, is a member of the US guideline committee viewpoint, and a strong advocate of early therapy. Caroline Sabin from University College London, UK, represents the British HIV Association (BHIVA) guideline committee, which is in line with European guidelines.
When do US guidelines recommend starting HIV therapy?
SD: In the late 1990s, clinicians and their patients became increasingly concerned about the toxicity of the antiretroviral drugs commonly used during that time. The prevailing philosophy for the next decade was to delay therapy as long as possible. This perspective began to evolve a few years ago, when most clinicians and clinical researchers began to realize that more modern regimens are far safer and that subtle but perhaps permanent harm was occurring during untreated HIV infection. The risk-benefit analysis had clearly shifted from one where treatment was bad to one in which treatment was good. Around 2011, the guidelines at the US DHHS (Department of Health and Human Services) shifted the recommendations towards earlier therapy. The most recent set of guidelines now recommends that therapy be strongly considered for everybody, with some rare exceptions.
How do the US guidelines differ from other guidelines worldwide, such as in Europe?
SD: I think this is largely a philosophical issue. It depends on your default perspective. If your default perspective is ‘we should treat until you prove that we should not treat’, then you go with the American guidelines. But if your default perspective is ‘you should not treat until we prove it’s actually better to treat’, then you should wait. There are no definitive, randomized, clinical trial data showing that you should treat people whose CD4 counts are above 350. Everyone agrees that such data is lacking. So what certain guideline panels have done is say that in the absence of definitive therapy, we’re just going to assume that untreated disease is more benign than treated disease. That is philosophically quite distinct from the perspective that the American guidelines have taken, which is the complete opposite.
When do UK guidelines recommend starting HIV therapy?
CS: For anybody with a CD4 count that is less than 350 cells, in the UK we would recommend starting therapy immediately. In addition to that, if there are people who have a clinical AIDS event or an HIV-related comorbidity or, for example, a malignancy where they’re going to have immunosuppressant therapy, then those people as well would also get treatment immediately, regardless of their CD4 count.
If somebody has a CD4 count that is above 350 and they also have hepatitis B or C co-infection, then our guidelines may also recommend that they would start treatment. Finally, people with primary HIV infection, if they also have neurological involvement or an AIDS event or a low CD4 count, would also be recommended to start treatment.
For people who are asymptomatic and have a CD4 count that is above 350 cells, however, treatment would not be recommended for their own benefit. However, there is a clause in the BHIVA guidelines where for all patients, the clinician is encouraged to discuss the possibility that treatment might reduce transmission. The evidence should be presented to the patient and should be discussed; there should be an assessment of what their own risk is for transmission, and if the patient then wishes to start treatment for that benefit and they’re aware of the fact that there may be no benefit to them from a clinical perspective, then treatment can be started.
In patients with CD4 counts greater than 350, what are the main arguments for deferring therapy?
CS: I think that at present, we really don’t have any idea about what the risk-benefit ratio is in that group of patients. For people with a CD4 count less than 350 cells, we know that their risk of clinical progression from HIV-related diseases is relatively high. Although the drugs themselves have some side effects – some of which may be life-threatening and may lead to loss of quality of life – in this group, the risk of those side effects occurring is more than outweighed by the benefits that that person may get from starting treatment through the prevention of AIDS-related diseases.
However, for people with a higher CD4 count who are asymptomatic, we don’t believe that the evidence is yet strong enough to be able to reliably inform patients that this is the case. We know that the risk of clinical events from HIV-related conditions is very low at that higher CD4 count anyway, so even if treatment is deferred for a short while, their actual risk of having an AIDS-related condition is very, very low. The risk of side effects from the drugs may also be low but at that point it may be that the risks start to outweigh the benefits. That’s why in people with a higher CD4 count, who are asymptomatic, BHIVA have made the recommendation to defer therapy.
The US Office of AIDS Research Advisory Council does not recommend deferring therapy and takes the opposite stance. What are the main arguments for starting therapy as soon as possible?
SD: There are several major arguments. The first is the recognition that in almost any study that has compared treatment versus no treatment – in the context of randomized clinical trials, or observational cohort studies – those on treatment did better than those who were not on treatment. The strength of this data is unquestioned in people whose CD4 counts are below 350. However, as you get to earlier stages of the disease, particularly with CD4 counts above 500, the quality of the data is suspect and the conclusions are not definitive. But in general, whenever anyone has looked at this question, treatment has always been better than no treatment.
Then there is the data suggesting that HIV replication causes irreversible damage to the immune system even before the onset of clinically-relevant immunodeficiency. This damage to the immune system leads directly or indirectly to chronic inflammation, which in turn causes harm to blood vessels and a variety of organ systems. Chronic inflammation has been associated with early onset of cardiovascular disease, cancer, osteopenia, kidney disease, liver disease and neurologic syndromes.
There is also the emerging story that individuals with early stage disease, when they are viremic and off therapy, are infectious. If you put those people on therapy, their ability to transmit virus to others is greatly diminished. Finally, there is a growing consensus that the drugs given to treat people in the modern era are a lot safer and have fewer drug-drug interactions than the drugs that were given five-to-seven years ago.
All of this has led to the argument that the default choice when people show up in the clinic is to treat them, unless there is a good reason not to.
What are the public health implications of starting treatment early?
SD: We’ve known for many years that one of the major predictors of viral transmission during sexual interactions is the amount of virus in the infected person; the larger the viral load, the more likely they are to transmit virus to others. This hypothesis was tested in a landmark randomized clinical study of serodiscordant couples. The HIV-infected partner was randomized to immediate versus deferred antiretroviral therapy. Transmissions were exceedingly rare in the treated arm and not uncommon in the untreated arm.
This has led to this paradigm that if you could treat everybody in the world – a big ‘if’, but if you could – you’d stop the epidemic without a vaccine.
In my clinic, the major motivator for patients seeking early therapy is to protect their partners. People really do not want to be infectious, which makes great sense. Although some may argue that treating early has as not yet been convincingly shown to reduce transmission rates from a public health perspective, its impact on an individual level is unquestioned, and the guidelines show in my opinion to be focused on the individual’s needs.
Studies have shown clear benefits for the early treatment of HIV in the prevention of transmission. How can this be reconciled with the UK stance of deferring treatment in certain cases?
CS: It’s certainly true that the results from the HIV Prevention Trials Network (HPTN) 052 trial have demonstrated clearly that individuals who are treated successfully seem to be at very low risk of transmitting HIV to their partners. There has also been published data showing that the proportion of people on treatment and with a suppressed viral load is inversely correlated with the incidence of new HIV infections. But that doesn’t seem to be the case in all settings.
Certainly in the UK, we actually have a very large proportion of people who are diagnosed, who are in care, who are on treatment and have a suppressed viral load. Yet we’ve seen record numbers of new infections over the last few years, particularly in the population of men who have sex with men (MSM), which is quite probably the population where we can intervene most effectively. Although we know that we have a very good record of getting people on treatment and viral loads are largely suppressed, it doesn’t seem to be translating into a reduction in the risk of incidence in the UK. I think the same may well be true in other Western European countries.
Now, why is that? Well, there are a couple of hypotheses. Firstly, we know that in the UK the people who are likely contributing to the epidemic are those who are not yet diagnosed. They don’t know they’re infected and of course they can’t then take any steps to reduce onward transmission of the virus. It may be that, unless we can identify that group and get them into care and on treatment, the impact of an increased number of people on treatment in terms of preventing transmission in the UK, may be quite minimal.
I think that in certain settings, it really does seem clear that there may be a public health benefit to starting earlier, but it is not clear that it’s going to have the same public health benefit everywhere. Certainly in the UK, we’re still looking into that to see if there is any impact.
The factors to be considered in the debate of when to start HIV treatment can vary across nations. When it comes to resource-limited settings are there any special considerations?
SD: You need to factor in that the healthcare systems may not be able to afford to treat everybody, or may lack infrastructure to deliver these drugs to everyone. In those settings in which you simply cannot afford to treat everybody, it is reasonable to treat those with the greatest need.
CS: I think there are special considerations because there may be settings in which the public health benefit of earlier treatment certainly is stronger. It has been said, particularly by some of the investigators in the US, that putting people onto treatment actually engages them in care and ensures that they come back for their medications. Certainly, that is a reason for starting treatment earlier because it allows people to come into care and they benefit in lots of other ways; not only through preventing transmission of the virus to other people, but also by ensuring their own health is really cared for. I imagine in resource-limited settings that may be a powerful argument for getting people on to treatment earlier. However, this is not easy to do in these settings; you have to find a way to identify people to get them diagnosed, and then there are the financial issues around getting all those people on to therapy. There is a very strong argument within resource-limited settings for early treatment – it could have a very big impact on controlling the epidemic as well as on the health of those people – but I think there are a lot of feasibility issues that have to be worked through.
Why do think there are differences in recommendations on when to start HIV therapy from the different guideline committees?
CS: Some of the guidelines say that their decision is based on trial evidence, whereas others acknowledge that this decision isn’t based on trial evidence, but rather expert opinion and beliefs about the potential public health benefits of earlier treatment.
The trials that are out there at the moment, which have been cited as contributing to this discussion and look at deferral of treatment versus non-deferral, have often been conducted in very different populations. The deferral may be to a very low CD4 count, a point at which certainly in Western Europe we would have initiated treatment anyway. I think there has been some confusion, certainly between the guideline committees, as to what constitutes high quality evidence.
There are some observational studies that have addressed this issue. Four large cohort collaborations in particular have looked at whether deferral is likely to lead to an increased risk of clinical outcomes or at least mortality in AIDS-related events. But again, the results from those studies are very inconsistent, and there is a lot of confounding in observational studies that is just impossible to remove.
However hard we try, and whatever fancy statistical methods we use, ultimately it comes down to whether we believe that that confounding has been removed. I think many of us feel that it is virtually impossible to do that, even though we contribute to those observational studies and have been involved in some of those analyses.
What further work needs to be done to resolve the controversy about when to start therapy?
CS: There are two trials: the START trial is a large randomized trial which has randomized people either to start treatment early or to start treatment at the level that we would consider treatment at the moment. That trial is now recruited and we’re waiting for the follow-up. The problem with that of course is that the data probably won’t be available until 2016 at the earliest, so we have got to wait a few years before we get the results from that trial. But it will directly address the risk-benefit ratios for starting treatment earlier and I think that when the data is available, it will be very strong evidence in one direction or the other. There is also another on-going trial in a resource-limited setting, the TEMPRANO trial in Côte d’Ivoire, which should report its findings in the next two to three years and which will also contribute to the discussion, but maybe for a very different population where the issues may be quite different.
SD: Hopefully the START study will be able to provide some definitive data regarding the optimal time to start antiretroviral therapy. My concern is that it may in fact show no difference because it is studying a group of people who are relatively young – I think most of the people in these studies are in their 30s and 40s – and these people are going to be followed for a relatively short period of time (several years) for a disease process that is going to play out over five decades.
This leads to a related issue: there are epidemiologic data, as well as strong theoretical considerations, that suggest the harm associated with delaying therapy will not emerge until years later, when patients are much older. That is to say, if a decision is made to defer therapy in a person in their 30s and 40s, the consequences of that deferred therapy is not going to be measurable until people are in their 60s and 70s. This leads to the issue of whether or not this question will ever truly be definitively addressed. No-one can afford, and no-one really wants, a study that will play out for decades to prove this conceptual issue.
There are three potential outcomes from the START study; you could show that early treatment is beneficial, harmful of neither. I predict that the study will likely find no real difference, given the age of the subjects and the duration of observation. If this happens, I suspect the default position in the United States will remain the same, and the guidelines will continue to recommend early therapy, assuming the patient is motivated.
Questions from Claire Barnard, Senior Editor for BMC Medicine.
Caroline Sabin is Professor of Medical Statistics and Epidemiology at University College London, UK, and initiated the UK Collaborative HIV Cohort (UK CHIC) Study of more than 45,000 HIV-infected individuals in the UK – one of the largest clinical cohorts of HIV-infected individuals worldwide. She has been closely involved with many other large HIV cohort studies and collaborations both in the UK and abroad.
Steven Deeks is a Professor of Medicine in Residence at the University of California San Francisco, USA, and a faculty member in the Positive Health Program (AIDS Program) at San Francisco General Hospital, USA. With two decades of experience in HIV research and clinical care, Deeks is an expert on the role of chronic inflammation in untreated and treated HIV disease.
BMC Medicine 2013, 11:148
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BMC Medicine 2013, 11:147
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