Considering the hysteria created by the emergence of a major epidemic in most parts of the World, notably in the African and Asian Continents, there has been a great compulsion to ensure that therapeutic agents to treat the unfortunate victims of AIDS are discovered and developed. The advent of Drug Cocktails had given hope that by using the new drug regime, it is possible to extend the life of AIDS patients, improve their quality of life and reduce transmission rates of the disease.
However there is now increasing concern that these hopes are not fully justified. So too the possibility of developing an effective vaccine, suffered a set back with the failure of AIDSVAX which had reached Phase 3 trials.
In the early days after the discovery of the AIDS virus and even after reports of mortality from the disease in large numbers, the pharmaceutical industry was slow in taking up new drug discovery research on HIV/AIDS, primarily since it was felt that this therapeutic segment was not commercially attractive. In fact the first drug tried for the disease was Azidothymidine earlier developed as an Anti-cancer drug by Jerome Horowitz of Michigan Cancer Foundation. Once HIV had been isolated and characterized as a retrovirus, the knowledge on the relevance of retrovirus on Cancers, eg., on adult cell leukemia discovered by Gallo in 1981 came in handy to test out AZT against HIV.
The approval of AZT as an antiviral drug for AIDS in 1987 was considerably assisted by the Orphan Drug Act in U.S.A. (1984), which provides for incentives for life-saving drugs of little commercial importance. In the absence if industry interest, it was the National Cancer Institute (NCI) which initiated a major programme on screening for activity against this viral disease.
Subsequent years however saw the development of many new molecules for the treatment of AIDS. There are at present around 16 drugs used, specifically for HIV/AIDS in addition to the dozens which need to be used for combating the adverse drug reactions that these drugs produce in the patients Four of the proteins made by HIV are enzymes- which have been traditionally ideal targets for discovering new drugs right from the days of the discovery of sulfa drugs.
The two major classes of enzyme inhibitors are Protease inhibitors, which prevent T - cells which have been infected with HIV from producing new copies of the virus. The most favoured products in this class are Saquinavir (Roche), Ritonavir (Abbott), Indinavir (Merck), Nelfinavir (Pfizer) and Amprinavir (Glaxo Smith Kline) and various combinations of these. When one Protease inhibitor is combined with other anti-HIV drugs, usually a total of three, then such combination therapy can block the replication of HIV in a person's blood.
The second class are Nucleosides/Nucleotides Reverse Transcriptase inhibitors, of which around nine are approved by the U.S. FDA. These drugs prevent healthy T-cells in the body from getting infected by HIV. They are ideal drugs for combining with Protease inhibitors for arresting the replication of HIV in the patients blood stream. Zidovudine (Glaxo Smith Kline), Lamivudine (Glaxo SmithKline), Stavudine (Bristol Myers Squibb), Abacavir (Glaxo SmithKline), Tenofovir (Gilead Sciences), Zalcitabine (Roche) and Didanosine (Bristol Myers Squibb) have all been used primarly as components of combination therapy. In addition to these, cellular inhibitors such as Hydroxyurea (Bristol Myers Squibb) and the most recent class of fusion inhibitors such as Fuseon (Roche) are useful in therapy.
Fuseon is capable of protecting the cell from invasion by the virus unlike other AIDS drugs, which block replication of the virus after infection. The results of clinical trials with this drug showed that in 37% of the patients treated, there was a dramatic drop in viral load, compared with 14% with other drugs.
Apart from the anti-virals to which all the above classes belong, a totally different approach is the development of immune-based therapies. Essentially, the strategy here is to assist the person's immune system fight the virus on its own. For this purpose the preferred class of drugs belong to the cytokines such as Interleukin - 2 and Interleukin - 12, which help regulate growth and activity of various immune system cells.
Therapeutic vaccines are those which have a prophylactic role by improving the immune status of the host and also have therapeutic properties whereby the product assists the immune system in fighting the virus which has already infected the host. The well-known and tested Salk Vaccine has been one of the candidates tried for this purpose.
The role of human growth hormone in achieving these objectives is also being increasingly tested, since it is known to help the thymus gland to produce more T-cells. It has to be mentioned, however, that cytokines as well as the human growth hormone, both of which are produced through biotechnological processes today, are prohibitively expensive as far as using them as treatment options for AIDS are concerned.
Drug Cocktails for HIV/AIDS Treatment
After the initial paranoia of helplessness against AIDS was overcome with the first use of a nucleoside drug AZT, came a realization that the drug was ineffective in the long term. By 1995, after two new classes of drugs , the reverse transcripts inhibitors and the protease inhibitors were approved and it was recognized that these drugs in combination, was effective, the euphoria again returned. Those who were fortunate to have the financial resources either on their own or provided by Insurance companies or employers benefited and use of the cocktail drugs enabled many patients live a longer life with better quality in addition to preventing transmission of the disease from mother to child.
On the negative side, it became readily apparent that the drug cocktail had no cidal effect on the virus, the drugs had to and most importantly, it was unaffordable to the majority. Outside Europe and U.S.A it was estimated that less than 0.1 % of the patients had access to full regimen.
Traditional Medicines For HIV/AIDS
There have been several reports on the effectiveness of traditional medicines for the treatment of HIV infections and even of diseases which result from AIDS. Most of these claims have come from the Orient, particularly of Indian and Chinese origin. The ancient Indian Systems of Medicine (ISM) such as Ayurveda, Siddha and Unani claim in some cases on quantified reduction in the viral loads.
While some anecdotal evidence has also been presented in some publications umambiguous proof of efficacy is yet to be established. It is conceivable that even if anti-viral properties are not present in these preparations, they may help in raising the immune status of these mostly herbal based drugs, since their primary claim in healthcare has been through their immuno-modulating activities. Much work needs to be carried out before their usefulness is established through modern methods of evaluation including large-scale clinical studies.
Side Effects of Chemotherapy
Typical of any chemotherapeutic intervention for chronic diseases, the HIV/AIDS drug cocktail also has somewhat severe adverse effects. Metabolic changes including Insulin resistance and hyperlipidemia were found in almost 50% of the patients under treatment. This condition, called lipodystrophy can result in long term, cardiac diseases, stroke and diabetes.
According to the FDA, more than half the patients who developed lactic acidosis due to the multi drug cocktail therapy died. It was also claimed that about 1/3 of patients who were on cocktail a few years back have now increased viral loads, questioning the fundamental premise of these drugs being the long term answers for treatment of HIV/AIDS.
In addition, since many HIV infected patients suffer from concurrent Hepatitits B or C infection, since they lived longer with the drug cocktail, they succumb to the complications of chronic Hepatitis B & C infection, particularly hepatocellular carcinoma.
At a meeting of the American Society of Microbiologists in 1999, it was reported that the cocktail was losing its effectiveness, patients were dying from side effects of the drugs and drug resistant strains are on the rise. According to John Mellers of the University of Pennsylvania, " the concern is that there will be a new wave of disease."
Development of AIDS Vaccines
During the last decade, there has been several major efforts for the development of appropriate vaccines against HIV infection. While therapeutic intervention is essential to control the already infected cases, a long term strategy of prophyaxis alone will help the control of the disease.
A recent Conference (January 2003) of the International AIDS Vaccine Initiative (IAVI) discussed all the on-going efforts at vaccine development. Neutralising Anti-bodies (Nabs) are once again gaining attention since it is increasingly realized that cellular immunity alone will at best protect against the disease, but not the infection . The isolation of rare human antibodies that target epitopes of the HIV envelope protein (EnV) shows that humans can indeed produce such antibodies.
Questions are also being asked as to whether a combination of Nabs and cellular immunity could lead to protection against infection as well as the disease progression. While it is true that Nabs can work, the real challenge is to achieve adequate anti-body production in humans through vaccination. Such a vaccine could ideally be a therapeutic vaccine meeting the twin objectives of prevention of infection and at least some degree of remission in already infected cases. Overall, there are around 2 dozen vaccines under development in various laboratories, of which 7 are DNA-based, 5 recombinant viral vectors, 4 protein sub units and 3 lipopeptides. The only one which reached Phase III trials is Vaxgene's AIDSVAX.
Recent reports on this vaccine, however has been disappointing, since protection if any, has been marginal compared to Placebo. IAVI's leading vaccine candidate, which is a DNA-MVA (attenuated Modified Vaccinia Ankara) vaccine is currently in Phase I/Ii trials in London & Kenya. It is also expected that the next Phase III vaccine trial will begin in Thailand by the end of 2003 with an Aventis Pasteur Canary Pox Vaccine plus a Vaccine, such as AIDSVAX.
In summary, it would appear that, while some of the approaches and trials do show promise, the challenges are enormous, particularly in view of the fact the AIDSVAX showed (based on limited data) markedly different patterns of response among Caucasian blacks and Asians compared to other populations.
Conclusion
While use of drug cocktails could assist the viral replication and perhaps even the rate of progress of HIV infection to full blown diseases including opportunistic bacterial, fungal infections, neoplasms, notably Kaposi's sarcoma, there is no guarantee that this indeed as has been seen in recent times the answer to control of the disease, even if the drugs are readily accessible. Development of resistant mutant strains, unacceptable side reactions and high costs of treatment preclude adoption of this approach as the most appropriate and rewarding strategy.
While R&D on vaccines are on-going in many laboratories and over 20 vaccines are in various stages of development, it is not clear as to how soon any one of them will be ready for the market. It is also unlikely that the same vaccine will be useful across ethnic and geographically distributed groups. Considering the very high investments required for R&D and the high costs of drugs, even at subsidized rates, unless massive funding from public sources are available, the fruits of such activity will not be affordable to the majority of Countries where they are needed.
-- The author is one of India's top scientists and pharma industry observer