India's National Magazine
From the publishers of THE HINDU
Vol. 15 :: No. 26 :: Dec. 19, 1998 - Jan. 01, 1999
MEDICINE
The quest for an AIDS cure
With no vaccine in sight and the possiblity of a total cure still remote, the only hope in the battle against AIDS has been a major finding by a team of U.S. scientists that has led to advances in multi-drug therapy.
R.RAMACHANDRAN
in New Delhi
THE Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS), which has infected an estimated 30 million people around the world, is perhaps the cleverest of the micro-organisms that afflict humans. As the names of the virus and the disease imply, the infection attacks the very root of the immune system, namely the T-cell lymphocytes (white blood cells that normally confer protection). It does not so much destroy the immune system as it thrives in it. Ongoing research seems to reveal that HIV usurps the immune response for its own replication in the human host; this situation makes both prophylactic and therapeutic interventions major challenges to biomedical research.
No wonder, therefore, that 17 years after the first case of AIDS was diagnosed, the world is far from being close to a cure or a preventive vaccine for the disease. Meanwhile the infection is spreading at a phenomenal rate of 16,000 cases a day (based on 1997 figures). Last year alone about 2.3 million people died of AIDS the world over, which was probably more numerous than the number of deaths due to malaria. A more worrisome fact is that the rates of prevalence of HIV in some countries in Asia have shown increases of over 100 per cent between 1994 and 1997. Today 90 per cent of the HIV-infected population is in developing countries: the World Health Organisation (WHO) estimates that more than four million people have been infected in India. Hence, a strategy to halt the spread of HIV is of utmost importance to developing countries, particularly India.
Dr. Jose Esparza, Director of Research, United Nations Programme on HIV/AIDS (UNAIDS), who was in New Delhi recently to attend the Tenth International Congress on Immunology (ICI) says: "We believe that behavioural intervention (among high-risk groups) alone would not be sufficient to control the HIV/AIDS pandemic and that a safe, effective and affordable AIDS vaccine may be our best hope." The first HIV vaccine was developed 10 years ago and till date Phase-I trials (for safety and immunogenicity) have been conducted for nearly 25 candidate vaccines. Two of them have entered Phase-II trials (in the United States and Thailand); one of them (developed by VaxGen) has recently been cleared for Phase-III (or clinical) trials as well in the U.S. and in Thailand.
Clearly, scientists are nowhere near realising Esparza's hope. Scientists such as Dr. Fritz Melchers of the Basel Institute of Immunology believe that developing a vaccine may even be impossible because the HIV undermines the very immune system that is supposed to mount a preventive immunity. In this scenario the only succour that is available today to HIV-infected persons and AIDS patients is "anti-retroviral" drug therapy. Even here, the recommended multi-drug therapy at best prolongs the survival of patients and delays the onset of the disease in HIV-infected persons by lowering the circulating viral load in the body. But a recent finding by Dr. Anthony S. Fauci and his colleagues at the National Institute for Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), Bethesda, U.S., may lead to a cure. However, the price of the cure will be heavy.
HIV is a retrovirus or a "slow acting" ribonucleic acid (RNA) virus, which integrates into the host cell deoxyribonucleic acid (DNA) and multiplies when the cell divides. In this form, called provirus, the infection remains lifelong. More significantly, HIV can also integrate into non-dividing cells such as nerve cells and brain cells and produce viral proteins even if it does not replicate. In HIV infection, as in other retroviral infections, the gestation period from infection to full-blown disease is long, between eight and 10 years. The virus, therefore, has ample time to infiltrate and "hide" in safe havens within the host's body before manifesting itself as and when the biological environment is conducive to that. Indeed, the time lag between infection and its detection - even in a screening of high-risk groups - would amount to a significant delay because the diagnosis is done by measuring the viral load in the blood plasma in which latent viral pools do not show up. Any effective cure, therefore, has not only to prevent the replication and expression of the virus but clear the system of the virus, from all its 'hideouts'. As regards the former, the frequent mutations of the virus and HIV's genetic variability seem to pose a major challenge. As regards the latter, the locations of these hideouts, or what are called the latent virus pools, are not known.
COURTESY: USIS
A finding
by Dr. Anthony S. Fauci (right) and his team of researchers in the U.S. may
lead to major advances in the treatment of AIDS.
In a major research finding reported at the ICI, Fauci's team has identified one such hideout. The team has also found a therapeutic mechanism to flush out the virus pool from there and purge it with the help of anti-retroviral drugs. However, as Fauci cautioned, the discovery does not mean that a cure is at hand. "First we have looked at only one reservoir whereas there could be many. Furthermore, even here we have to see that the viral load does not increase in the long term when the patients are put off drug therapy. This requires a carefully planned follow-up strategy," he said.
The drug regimen that has been found to work reasonably well, and is followed all over the world, is the Highly Active Anti-Retroviral Treatment (HAART), a combination of zidovudine (AZT), lamivudine (3TC) and crixivan (Indinavir). It is basically a dual approach in the sense that it uses two types of drugs, one a reverse transcriptase (RT) inhibitor and the other a protease inhibitor, to prevent virus replication and/or viral protein expression. Reverse transcriptase is the enzyme that helps the RNA virus to convert into a DNA form and integrate itself into the host cell DNA so that it can replicate. But HIV has been found to mutate in order to evade any intervention at this stage. Protease is the enzyme which aids in the maturation of the virus before the viral proteins can be expressed. The assumption underlying the therapy is that it is extremely unlikely that a virus will mutate in the same cell and at the same time to evade both RT and protease inhibitors. Therefore, closing both the gates should work. The regimen includes two RT inhibitors and one protease inhibitor. But the therapy fails to attack the latent reservoirs.
One of the "reservoirs" of HIV is believed to be the cells known as 'Resting CD4+ T cells', which are part of the immune system. CD4+ T cells are those lymphocytes which express on their surface the protein called CD4 that binds well to HIV. Resting CD4+ T cells are those among the CD4+ T cells which have not yet seen the target - the antigenic molecules - and hence have not so far been activated to take part in the immune response. The body has a total of about a trillion lymphocytes of which 'Resting CD4+ T Cells' that harbour 'replication competent HIV' constitute tens to hundreds of millions. The important thing is that this latent pool is formed immediately after the first infection and can remain latent for as long as 15 years.
One of the clinical observations that led to Fauci's research is that in patients with active infection, any intervention to treat (or prevent) opportunistic infections such as tuberculosis was found to enhance the circulating viral load in the body. He inferred that the cytokines (or regulatory molecules) such as Interleukin-2 (IL-2) that control proliferation, differentiation and the immune response of a number of immune system cells, notably T cells, seem to drive the replication of HIV from the latently infected cells. Fauci's team found that cytokines not only regulated the replication of the latent virus pool but enhanced the expression of latently infected cells. In other words, cytokines such as IL-2 seem to clear the virus out of its hideout in resting CD4+ cells and the virus then begins to replicate and express itself. The exact mechanism by which this happens is not quite clear yet but this suggested that if HAART is adminstered to HIV/AIDS patients in combination with IL-2, the latter could tease the virus pool from its hiding and purge it with the action of HAART.
The NIAID team studied two groups of patients: 12 patients receiving only HAART and 14 patients receiving a combination of IL-2 and HAART. IL-2 was administered either subcutaneously or intravenously; the dose was between three million and 18 million international units (IUs) a day during a five-day treatment cycle, which was followed by a rest period of eight weeks before the next treatment cycle began. The viral load before the start of the experiment was less than 50 copies of HIV per millilitre of blood. The median time that the patients in the IL-2 + HAART group were receiving IL-2 was 39 months.
In six of the 14 patients (42.8 per cent), the researchers did not find any detectable replication-competent HIV in 10-20 million resting cells taken from the patients' peripheral blood. When much larger numbers of resting cells were cultured, in the range of between 200 and 300 million, three of the six did not show any detectable replication-competent virus. By contrast, in patients receiving HAART alone, replicating virus was found consistently in all the 12 patients. In the former group, a biopsy of the lymph-node tissue (the seat of the lymphocytes) also showed no detectable replication-competent HIV. When patients responded well, the interval between cycles of IL-2 was extended. The NIAID study now has patients who require only IL-2 once in several months and even some who require it only once or twice a year. One of the patients in the study has responded so well that he has received IL-2 only once in the past two years.
PATRICK AVIOLAT / AP
An AIDS
patient displays her daily drug cocktail of 35 tablets.
Fauci says: "Our new data suggest that in HAART-treated patients, IL-2 may have a role in reducing this 'reservoir' of virus, where HIV would otherwise remain sequestered from the immune system." For the first time it has been demonstrated that a "reservoir" of dormant virus can be cleared and eliminated by therapeutic means. The finding also suggests that the concept of a "therapeutic vaccine", which would be administered to HIV-infected patients in a bid to control virus multiplication, may not work because, if Fauci's finding is correct, the vaccine, by triggering cytokines, would only help viral multiplication. Perhaps such a therapeutic vaccine will also have to be administered with HAART.
More important, Fauci says that there could be other hidden reservoirs of HIV, and these may include the brain, testes, CD4+ T cells in other lymphoid organs such as the gut, and other immune system cells such as macrophages. These clearly imply a formidable obstacle to the ultimate control or eradication of HIV from an infected person's body.
However, the hope is that since IL-2 is a very general kind of cytokine that regulates the functions in even these cells to some extent, only small latent pools may be left unflushed and the immune system may be able to handle smaller latent pools.
From the perspective of medication, this finding will only push the hitherto high costs of chemotherapy to phenomenally high levels. At present the three-drug HAART costs about $18,000 (about Rs.7.65 lakhs) a year. From the point of view of a developing country such as India, this is unaffordable even to the rich. And this does not include other costs of health care and support of HIV/AIDS patients. IL-2 does not come cheap. In fact, in comparison to its market price of about $10,000 per million IUs, the cost of HAART drugs is negligible. Assuming that about one cycle (50 million IUs of IL-2) is administered every two months, the extra monthly cost of chemotherapy would be some $25,000 - clearly out of the reach of people in developing countries.
Even for developed countries this calls for a cost-effective technique and facilities for large-scale production of IL-2 in order to bring down the cost of therapy. (The fact that there are some indigenous efforts to produce AZT and IL-2 will not alter the situation greatly.)
Of course, if the finding does lead to a cure, a patient may undergo this therapy only for a short period of, say, two years. Fauci, however, does not wish to hazard a guess as to how much the modified therapy would cost if IL-2, now marketed as a biochemical for research, becomes a drug. "IL-2 is still an experimental drug with regard to its use in HIV disease. It has not been approved by the U.S. Food and Drug Adminstration (FDA) for use in HIV disease. Therefore I do not have any idea what its price would be if it were ultimately marketed for use in HIV disease."
Fauci says: "Vaccine (for prevention, and not as therapy) is the only option for developing countries. Given the viral variations in the Indian population, the sooner India gets a sound vaccine development and testing programme going, the better for it and the rest of the world." But even from the perspective of the developed world, notwithstanding the first ever Phase-III trials of a vaccine about to get under way, major scientific challenges and problems remain. Not the least is an understanding of the immune system itself.
Home | The Hindu | Business Line | Sportstar