Scientific evidence is mounting for ART to be started at an earlier stage than currently recommended by WHO/NACO. But for healthcare systems in the developing world already struggling to meet existing demands, is this a viable option, asks Ajithkumar K

When should a person with HIV be started on anti-retroviral treatment (ART)? The controversy has erupted once more with the publication of studies indicating that starting treatment early will extend a person’s life. These findings question NACO’s current guidelines and also raise some important issues of public health and ethics.  Should we change our guidelines on the basis of these reports? 

HIV is different from many other diseases in that it does not need medical treatment in the initial days of infection. The question of when exactly treatment should start has been debated among experts from the early days of HIV treatment. Advocates of early treatment initiation suggest that it will prevent the deterioration of the affected person’s immune system. They also believe that reduction of HIV in the blood will reduce the chances of the virus being transmitted to others (through the normal modes of transmission).  

One criterion used to determine when a positive person should start on ART is the CD4 cell count. The CD4 cell is a kind of white blood cell which is targeted by the human immunodeficiency virus and is a measure of a person’s immune status. A normal count is at least 500/cc of blood; a person with a count of 350 is more vulnerable to illness and CD4 200 or below puts the person at high risk of dying.  

In developed countries, treatment is often started when CD4 falls to 350, in order to reduce the person’s vulnerability to illness. However, according to WHO and NACO guidelines, ART should generally be started only when the person’s CD4 count goes below 250. (People with certain symptoms may be started earlier even if they have higher CD4 counts.) 

Studies advocate early ART  

In April this year, reports of two studies were published in the New England Journal of Medicine and The Lancet, along with editorials on each study. One of the studies analysed information from 45,000 patients in Europe, North America and Argentina. The other looked at patients in North America. Both concluded that ART should be started when the CD4 count reaches 350 and not later. People starting treatment at lower counts were likely to fall ill earlier and die. 

Should these studies change the criteria for initiation of ART in the Indian setting? While considering this question, we must keep certain caveats in mind.  

First, both studies were retrospective – they looked at the histories of different groups of patients who started treatment at various CD4 counts, or did not get any treatment. Such studies can be biased as differences in these groups may affect the results though these differences may not be obvious. Though the researchers did their best to adjust for various biases in the analysis, they acknowledge this limitation.  

Second, ART used to be started early, but guidelines changed. As early as 1996, anti-retroviral therapy was recommended for all HIV-infected patients with a CD4 count of less than 500. But clinicians found that starting treatment early could make the patient resistant to drugs earlier. This happens because ‘treatment fatigue’ sets in the longer one is on therapy. This often leads to people skipping their daily medicines. Irregular treatment - less than 95% regularity - led to drug resistance and treatment failure. The drugs available at that time also caused many discomforts and had toxic side effects and this was a reason why many people took treatment irregularly. So, eventually, guidelines advised starting treatment in the later stages of the disease.  

Is the system ready to start ART early? 

The editorial in the New England Journal of Medicine concludes that it is prudent to start treatment when the system is ready. So the question is: is the Indian public health system ready to start early ART in the government programme? 

Till recently there was a general consensus that in the developing world it is better to wait till a person’s immunity is damaged to the point that s/he is prone to opportunistic infections. This strategy allows the public health system to prioritise medical support to individuals at higher risk of morbidity.  

But today this will mean going against the best scientific evidence which argues for earlier intervention, and thus denying a person treatment and effectively causing damage to his health. Is it ethical for the public health delivery system to delay treatment till an individual reaches a situation where he is likely to fall sick? Does this not amount to denial of his right to health and life? Should we accept double standards in HIV care between the developed and developing worlds?  

Obviously, if scientific evidence points to earlier intervention being of greater benefit, then that is the way to go. Equally obviously, the public healthcare system in India and other developing countries is in no condition to take on the extra burden. Before deciding, we should consider the following issues. 

First, the studies may not apply to the Indian situation. The NEJM and Lancet studies looked at developed countries with very different healthcare systems. Developed countries have the latest medicines, which have fewer side effects than the medicines used in developed countries. The newer medicines are also more costly than those recommended in developing countries. The health situation is different in developing countries, the support systems to deal with treatment complications, and the availability of second line medicines are also different. So it may not be possible to translate the results of these studies directly to the developing world.  

Second, the ART rollout in many developing countries is yet to cover even those who are eligible for ART by current criteria. So a sudden change in criteria to start ART at an earlier clinical stage may choke the evolving system and cripple it prematurely. 

Third, it is not enough to just start ART; it is even more important to sustain it with good levels of adherence. If this is not achieved, a rapid scale-up of ART can actually be counter productive by fostering early treatment failure or resistance to first-line drugs which will need support by more expensive and difficult regimens. Also, widespread development of resistance to first-line ART will present more difficult challenges.  

The reduction of death rates should be proportionate to the money spent and effort by the public healthcare system. So it may not be a sound public health strategy to start and sustain a large number of individuals on ART for a marginal decrease in death rates. 

There is also the question of the intense focus on HIV. How long can HIV continue as a disease which drains resources? It may take many years to learn if ART is really an effective prevention strategy. The ART rollout is yet to show any significant impact on transmission rates. Moreover, when we don’t have a good healthcare system to prevent diarrhoea and other common illness, should we invest more in HIV?  

There are counter arguments as well. For one, current evidence clearly states that early treatment is superior. It is therefore the responsibility of the community to provide this. Second, the system’s inefficiency is no excuse. It is important to establish systems which work. Third, once you decide to start early initiation of ART, you may be forced to establish a foolproof ART system which ensures proper follow-up so people take their medicines regularly, monitors complications to adjust treatment accordingly, etc. Fourth, investment in health, whether for HIV or diarrhoea, should become a priority. HIV should become a model for other areas of the healthcare system. Finally, most of the arguments now being used against introducing early ART were also made by experts before first-line ART scale-up. In that case, strong public opinion and political will pushed the scale-up of first-line ART. 

So where are we? What should we do to maximise the impact of publicly provided ART?  

We may have to eventually initiate steps to identify every possible HIV-infected individual at the earliest. There is mounting evidence that the later the treatment is initiated, the worse the result. It is also a person’s human right to have access to testing facilities and prevention methods. This again needs a much stronger public health system, better testing facilities, a more enabling environment, and mainstreaming of the epidemic response.  

Also it is important that we adopt less toxic and simpler regimens for treatment. There are much simpler, less toxic, once a day regimens which are possibly less liable for resistance than the WHO/NACO regimen available in the market for the last few years. The higher price of these regimens may be balanced by the fact that they are less toxic and also easier to follow, which means fewer systemic expenses. It should also be possible to integrate the HIV programme into the general healthcare system. It is also worth noting that there has been a gradual decrease in the price of ART as the market expands.  

Putting more and more HIV patients in the early stages of HIV disease on less toxic and simpler ART regimens, and integrating adherence management through horizontal programmes, should be seen as real options by WHO to balance medical, social and human rights criteria for initiation of ART. Also by putting more people on toxic regimens we should not inadvertently contribute to people’s illness and even death from drug-induced toxicity.  

We should not forget that the HIV epidemic is unique in that it brought ethics and human rights back into the field of epidemic response. The question of early initiation of ART is another opportunity to consider this issue. 

(Dr Ajithkumar K is a dermatologist with a special interest in HIV/AIDS-related problems, particularly mainstreaming care and support) 

References

1. Mari M Kitahata, et al. ‘Effect of early versus deferred antiretroviral therapy for HIV on survival’. New England Journal of Medicine. 2009;360:1815-26.
2. Sax PE, Baden LR. ‘When to start antiretroviral therapy--ready when you are?’ New England Journal of Medicine. 2009 Apr 30;360(18):1815-26.
3. Wood R, Lawn SD. ‘Should the CD4 threshold for starting ART be raised?’ Lancet. 2009 Apr 18;373(9672):1314-6.

InfoChange News & Features, July 2009