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As soon as the virus was isolated and its replication mechanism
disclosed, the laboratories of pharmaceutical companies and of research institutions
have been working hard to find the drug that would stop the damage caused by the
infection. The external pressures were strong and the debate on ethical and rights
issues, related to eventual trials and access to therapy, stirred up the scientific
community and the activist groups.
In 1986, a double-blind clinical trial on the efficacy of azidothymidine or AZT,
the compound that at that time was showed effective against the virus (Yarchoan R.
et al. 1986), was interrupted after 24 weeks for ethical reasons. The group
receiving the real drug was doing much better than the one receiving placebo. From
then on, AZT became the standard treatment for people with HIV infection (PWH),
whose immune system was starting to show signs of weakening and for people in
advanced stage of disease. Not all the patients could tolerate AZT therapy and soon
was evident that the virus was able to mutate into new variants, resistant to
AZT.
Many other drugs have been studied and tested, but not real alternative was
available until the nineties, when new compounds reached the clinical practice. In
the last five years more drugs became available and the importance of multiple drugs
regimens was definitely proved.
Nowadays, in most European countries HIV infected people have access to what is
called the "triple therapy", a cocktail of three drugs, with different mechanisms of
action, that work sinergically in reducing the viral replication. The viral load can
consequently be decreased to undetectable levels and the immune system is allowed to
a progressive, even if uncompleted, reconstruction (Gazzard 1996). This regimen is
advised for symptomatic and asymptomatic subjects and acute or recent infections
(see guidelines released June 19, 1997 by the U.S. Department of Health and Human
Services).
The effects of the triple therapy, where people have access to it, are changing
the history of the disease: the progression to AIDS is delayed, the patterns of
morbility are changing, the survival time of people with AIDS is getting longer,
influencing the use and costs of health services and the need for assistance
(National Prospective Monitoring System 1999).
In this paper I will discuss the findings of a review of the recent medical
literature on the antiretroviral therapy, trying to analyse the new medical
discourse on HIV therapy and its underlying implications.
First I will try to sketch, how the technical developments and the
characteristics of the new therapy, as they are presented in the literature,
redefine the PWH as viral container, without a subjective identity. Secondly I will
show how this paradigm is normally negotiated in the clinical practice and looses
consequently much of its power. Finally I will discuss the research agenda and
present some questions raised by the changes in AIDS history.
I must stress that I could not revise the literature completely, my review is
done through the use of MEDLINE database and the search of web sites related to HIV
therapy, therefore is neither exhaustive nor in-depth, but I considered it a
starting point for a critical thinking about medical discourse on the subject.
I had been working as a physician in an AIDS clinic in Milan, Italy, from 1992
to 1995. During this period, I worked in the inpatient and outpatient departments
and had the opportunity to follow the medical and life history of some HIV positive
patients attending the clinic.
Some of the comments and conclusions in this paper are drawn from that
experience. The triple therapy was not routinely available at that time. In fact,
the randomised double-blind clinical trials on the protease inhibitors and other new
reverse transcriptase inhibitors were going on and these drugs were available just
to a limited number of patients.
In recent articles on HIV therapy the efficacy of the
multi-drug regimens or HAART (Highly Active Antiretroviral Therapy) is not
questioned, but protocols are elaborated to answer some unsolved management
questions (Garcia 1999): the current guidelines "emphasize early aggressive
treatment using multi-drug combination regimens", reported by Volberding (1999)to
be,"...one of the most recognized authorities in the clinical management of HIV
infection". The studies done until now assessed the efficacy of the therapy, but the
information available is enormous and often contradictory.
What are the main points about the therapy that can be noted from the available
articles?
Even if the participation of the patient is considered important, the main concerns in the decision making, regard the quantification of the viral load (the quantity of circulating virus particles), the CD4 count (the quantity of immune cells that are the main target of the virus) and the previous pharmacological history of the patient. The main markers of the efficacy of the drugs are virological and immunological, that means they can be established by blood tests. The follow up of a patient during therapy will be dependent on the possibility to execute those tests and from their results. This point has tremendous implications in the clinical practice as I will discuss later.
Due to high variability of its genetic material during the intense replication, HIV easily develops resistance to pharmacological compounds. The resistance of the virus to AZT is well known, but is clear that resistance to the newest drugs can also develop easily and new strains of the virus, resistant to all the available therapy have been reported already. These strains can be spread and give rise to a population infected by multi-resistant HIV, that will not benefit from the available drugs. There are tests to determine the patterns of resistance characteristic of each patient and some authors already advise to start and monitor the therapy guided by "resistance testing" (Boden 1999) and to plan in advance a "rational sequencing" with first, second and third line drugs and salvage therapy, in case of sequential failure of regimens (Moyle 1998). Concerning this issue I found an Italian web site advertising the advantage of this strategy and the technology to do it, with address and resource person to get more information and the resistance test.
The "undoubted benefit" of the HAART regimen are "at the cost of physical and psychological morbidity of the recipient" (Gazzard 1999). The intake of the drugs should follow very strict rules to guarantee absorption and consequent effect, suboptimal blood levels would not only be less effective, but also facilitate the onset of resistance. The drugs can cause many kinds of side effects: from gastrointestinal discomfort, headache and fatigue to more serious illnesses, like renal litiasis (stones), liver toxicity and a debated syndrome, called lipodystrophyc, that causes abnormal body fat redistribution, with accumulation of adipose tissue in the trunk and muscle loss in arms and legs, a total change in the body image. The protease inhibitors also may cause abnormal laboratory test results, including higher than normal levels of triglycerides (fats), cholesterol and glucose (blood sugar). The FDA has issued a warning about a possible link between protease inhibitor use and diabetes (see San Francisco AIDS Foundation web site). The long term effect of the drugs are not known. It is highly probable that people in triple therapy has to take as well other drugs (prophylaxis of opportunistic infections or therapy for other conditions): all these drugs interact in the body of the patients, influencing each other action and with effects still widely unknown. Some authors underlay the importance of these interactions, "likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV" (Barry 1999). Apart from the physical "trade-off" that the PWH has to endure, there is the psychological stress related to the strict schedule of the therapy, the loss of control on the body and the uncertainty of the whole condition. For these reasons some authors call for cautious assessment of the costs and benefits of the HAART in that specific patient. But, again, the author considerations. on risk, refer to a very technical and impersonal evaluation of the probability of disease progression in the next three years (Gazzard 1999).
Due to the importance of accessing the therapy and the problems in maintaining compliance/adherence to the regimen, some articles present results of studies and reflections on these subjects. Factors that can influence the compliance are evaluated and measured. The journal of General Internal Medicine, published a study in which the authors (Kalichman et al 1999) affirm that "education and health literacy were significant and independent predictors of 2-day treatment adherence after controlling for age, ethnicity, income, HIV symptoms, substance abuse, social support, emotional distress, and attitudes toward primary care providers (!). Persons of low literacy were more likely to miss treatment doses because of confusion, depression, and desire to cleanse their body than were participants with higher health literacy". The humanitarian concerns of physician are also expressed in the literature and the unequal access to the new drugs is often underlined. In the Annals of Internal Medicine, Lerner and colleges (1998) express their concern about "disadvantaged patients with multiple social problems", that may be less compliant and for this reason have the. treatment denied. They remind the readers of the negative effects of such judgmental behavior and call for active involvement of patients in decision making about the therapy and the respect of patients' rights.
This short review of the recent medical literature on the new
antiretroviral therapy allows some speculations about the actual medical discourse
on HIV infection.
In the biomedical research, mostly based on quantitative, statistical analysis,
the patient as a person is very often neglected, to become the case of a disease or
the acceptor of a new technology. In the first trials, HIV patients were defined for
their age, sex, epidemiological risk factor, social background, immunological status
and clinical manifestations (symptoms or opportunistic infections), not as unique
individuals, but at least, people, to whom one could attach some kind of identity
and related socio-cultural context, even if stereotyped and superficial. These
people could be related to suffering, to the enormous distress that HIV infection
can cause. These representation has been changing and in the most recent literature,
other, more biological characteristics, are used to define the "subjects" in the
studies. Virological and immunological markers became the main targets of medical
attention: the individual is managed as the carrier of a certain type of HIV.
Information about the virus are increasing, while characterisations of the sufferers
are decreasing: you can read about virus type, quantity, susceptibility and
resistance, replication, suppression, rebound, long term reservoirs (sometimes
called sanctuary) and activity. Also drugs are well described in terms of action,
combination, metabolism, concentration, interaction, profile, side effects and so
on. While the subjects in the study are only pictured through their previous
pharmacological history, risk of progression, development of AIDS, opportunistic
infection and immunological status. In many publications the patient regains an
identity because of his/her lack of compliance to the pharmacological regimen , thus
becoming a source of danger for the future and the community, as potential cause for
the development of resistant viral strains .
There is a progressive detachment from patients' real life, and the construction
of a new object, a biological container, that has lost even its human bodily
characteristics.
Still, many studies are based on "real life" situations: big cohorts of patients
have been followed up and only clinical outcomes (the appearance of AIDS related
symptoms or death for AIDS) considered, but the main concern is always to measure
the efficacy of the drug combinations, expressed as risk rates for AIDS progression
or death. I did not find any study concerning the possible change in the quality of
life or the determinants of the well being of infected people, even if the influence
of these factors on immune function are widely recognised.
As I mentioned at the beginning, in my clinical experience, I could appreciate
how complex is, in reality, the management and the relationship with "real" people.
Apart from the diversified needs, that go far beyond the antiretroviral therapy, the
decision making on drugs intake is a constant process of negotiation between medical
knowledge, patient's beliefs, desire, possibilities and tolerability. The people
with HIV/AIDS, that have been stripped of their individualities and even of their
bodies in the clinical trials, regain their uniqueness in the daily management of
their "clinical" life. It is worth noting that authors and Journal dealing with
clinical issues, therefore more in contact with the real life of PWH, are more prone
to remind to the medical community that, after all, the focus of the therapy is a
human being. But this process of negotiation has not been yet considered in
depth.
The paradigms used to explain HIV infection and related diseases have been
changing through time, reflecting the cultural dominant trends. Virology and
immunology have been competing in lending metaphors to represent the disease and in
guiding research, but "neither ultimately wins full explanatory power, and both must
account for the logic of the other" (Patton 1990).
The chosen paradigm influence, in turn, the modelling of clinical trials more
than the claimed "scientific rigor". As Rothman and Edgar (1992) argue in their
paper, was the use of the infectious disease paradigm, dominant at the time of AZT
initial trials, which determined the choice for placebo controlled trials, despite
the long standing experience in cancer research of comparison with historical
control group, considered more ethical in highly fatal conditions.
Nowadays, placebo controlled trials are very rarely done, frequently different
combinations or regimens are compared between each other to find the most effective
one. Still, I think there are ethical abuse in the design of some clinical trials.
The questions are many: how is the "rational" for a protocol evaluated? Is it ethic
to use still regimen of monotherapy, after the numerous results showing the
superiority of multiple drugs administration? Saying that the approval of a new drug
against HIV for a pharmaceutical company is big business, is even too easy; but some
trial designs and conclusions (Murphy 1999) are prone to be suspected of
"promotion". The suspension of a clinical trial for "ethical reasons" had already
happened in HIV research, when a drug or combination is having much better results
than the compared one. I assume that this event should not be predictable a priori,
or do we need to test even what we already accept as "scientifically" demonstrated.
Is this "scientific rigor or business reality"?
The changes in the medical discourse about HIV infection reflect the
technological achievements, are fostered by the promise of biomedical disengagement
and supported by economical interests. The medical discourse in turn influences the
development of the research agenda and the effects of the above mentioned changes
are already visible in the agenda of the AIDS Clinical Trials Group (ACTG). The
focuses of current and future research are in the development and study of drugs to
reconstruct the immune system, once the virus replication is under control and to
define the best rescue therapy for people with multi-resistant strains or for whom
the available regimen failed. The research for the management of opportunistic
infections is shrinking; there is no account of all the people who do not have
access to the HAART and will still experience the opportunistic infections as
before. The management of such conditions was far from being satisfying, but the
research on the complications of HIV infection is in any case considering only
patients taking the HAART. Great interest is reserved for "naïve" subjects,
those who never received any therapy, which are supposed to posses the "original"
strain of the virus, not yet "spoiled" by contact with drugs (ACTG web site).
No doubt, we are entering in a new era of HIV epidemic. Even if the people who
will benefit of the new drug regimen represent only a very small percentage, the
effects of this new possibility will influence dramatically the history of the
disease in the rich countries and will have strong repercussions on the rest of the
world. Many questions need to be answered to understand this change and to be
prepared for its impact: how is it influencing the representation and perception of
the disease for the sufferers and for the rest of the community? How will the
preventive strategies be elaborated now? How is it shaping the relationship between
sufferers and care givers? What about people who cannot access the drugs? What about
those who will not accept the trade off requested by the heavy regimens? What about
the costs and sustainability of this change? Who will pay the social costs and in
which way?