HIV AND AIDS

What is AIDS?

AIDS (Acquired Immune Deficiency Syndrome) is the name given to a state arising from infection with the human immunodeficiency virus (HIV, Figure 1). Infection with this virus, a member of a group of viruses called retroviruses, results in destruction of the immune system - especially a group of blood cells called T lymphocytes (T-cells). As the number of T-cells falls, people become increasingly susceptible to infections such as Pneumocystis carinii pneumonia - almost unknown in a healthy person. Infections by other organisms that cause disease, such as Candida, tuberculosis, cytomegalovirus (CMV) and herpes virus also become more common and serious, even life-threatening. Loss of T-cells also increases the risk of developing some tumours such as Kaposi's sarcoma and non-Hodgkin's lymphoma. It is the emergence of such complications, usually following a long period of HIV infection, that leads to a diagnosis of AIDS.

Since the introduction of the multi-drug regime HAART (Highly Active Anti-Retroviral Therapy) in 1997, the proportion of HIV-infected people going on to develop AIDS has declined markedly and life expectancy has increased. Death rates from AIDS have fallen by 80 per cent and the number of cases of Kaposi's sarcoma and non-Hodgkin's lymphoma has also decreased.

Who does AIDS affect and what does it cost?

The World Health Organisation estimates that 38.6 million people had been infected worldwide by the end of 2005, over 4 million of them in 2005 alone. Since it was first recognised in 1981, AIDS has reached epidemic proportions in parts of the developing world, especially sub-Saharan Africa (with an estimated 24.5 million people with HIV/AIDS, 63 per cent of the world total) and south and south-east Asia (estimated 8.3 million).

In the UK, a total of 80,556 cases of HIV infection has been recorded since 1982, with 7,472 new cases in 2004. Almost 22,300 cases of AIDS have so far been recorded in the United Kingdom, with over 16,800 AIDS-related deaths. Heterosexual contact (4,461 new cases in 2004, 53 per cent of the total) has now overtaken sex between men (2,279 new cases, 31 per cent) as the most common route of infection. Three-quarters of HIV infections in heterosexual men and women were probably acquired outside the UK. Currently, about four men become infected for every three women, but this ratio has been declining sharply for several years.

The lifetime cost per patient in the UK was estimated in 2000 at £135,000-181,000. A more recent estimate puts the cost of treatment at around £16,000 per person per year and the total cost of care in 2002-2003 has been estimated at £345 million.

Present treatments and shortcomings

Eighteen chemically distinct anti-retroviral compounds are available in the United Kingdom for use in HIV infections (see Table 1). Six of these antivirals are nucleoside inhibitors of HIV reverse transcriptase (NRTI), nine are HIV protease inhibitors and three are non-nucleoside inhibitors of HIV reverse transcriptase (NNRTI). Fixed combinations of some of these compounds are also available.

None of these compounds is, unfortunately, able to eliminate HIV. Used in combination, they reduce the amount of virus in the body, improve immune status and considerably slow down the development of more serious symptoms. The major problems with these medicines are their significant side effects, including damage to nerves and the heart, complicated administration schedules and the development of resistance. Development of once-daily and combination products has reduced the pill burden. However, the development of resistance is still a serious problem. The AIDS virus multiplies very quickly and resistant forms constantly emerge, often within a few weeks of the start of treatment with a new medicine. This extreme changeability of the virus also makes it difficult to design a protective vaccine that could prevent infections.

What's in the development pipeline?

Although nine reverse transcriptase inhibitors (RTIs) have already been authorised for use, new antivirals of this type are still being developed. The enzyme reverse transcriptase is central to the route by which the HIV virus spreads to infect new cells and inhibiting it as effectively as possible, and with the fewest possible side-effects, is seen as a key to preventing disease progress.

There are two principal types of medicines that are used to inhibit this enzyme: nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). New members of both classes continue to be developed, to meet the challenge of resistance and to provide better tolerated, more easily dosed and more effective treatments.

Gilead has developed a one-pill-once-a-day combination of tenofovir and emtricitabine (both NRTIs) with efavirenz, an NNRTI.

Tibotec has two NNRTI compounds (TMC 125 and TMC 278) in clinical development. TMC 125 is now in Phase 3 trial, in combination with a protease inhibitor, in patients with resistance to at least one other NNRTI. Statistically significant reductions in viral load after 48 weeks treatment in such patients have been reported for an earlier trial. Meanwhile, TMC 278 has reached Phase 2b trial in patients being treated for the first time. Both compounds have been shown to be active in vitro against strains of HIV that have become multiply resistant.

Two other NNRTIs are at an earlier stage of development. Pfizer's UK-453,061 is in Phase 2 trials and Boehringer Ingelheim has a compound (BILR 355 BS) that has reached Phase 1 trial. In addition, Bristol-Myers Squibb and Medivir have recently announced a collaboration to develop the NNRTI MIV-170, which is currently in preclinical research. A greater number of NRTIs is under development, and these are all currently in Phase 2 trial. Achillion Pharma's elvucitabine (ACH-126,443) may permit once-a-day use. Also in Phase 2 study are AVX-754 (Avexa), alovudine (MIV-310, Medivir), amdoxovir (RFS Pharma) and racivir (PSI-5004, Pharmasset).

With nine protease inhibitors (PIs) available, new developments are less numerous. However, the compound darunovir (Tibotec) has completed Phase 3 trials. Ambrilia Biopharma is developing another PI (PPL-100), which is in Phase 1 trial.

Going beyond these three traditional classes of anti-retroviral compounds that form the basis for current treatment, much research centres on compounds called entry inhibitors that prevent HIV entering its target cells, where it replicates. Each of the three distinct steps of entry - attachment, binding and fusion - can be targeted separately. The first of this type (enfuvirtide, Roche) was introduced in 2003 and is a fusion inhibitor, inhibiting the third stage of entry.

Other compounds in development mainly target the second stage of entry - binding of HIV to receptors (CCR5 and CCR4 receptors) on the target cell. The furthest advanced of these is maraviroc (Pfizer), which is now in Phase 3 trial, followed by AMD-070 (AnorMED), Schering-Plough's vicriviroc and TNX-355 (Tanox), all of which have reached Phase 2. Four more are at Phase 1: the oral TAK-652 from Takeda and INCB9471 (Incyte), and the monoclonal antibodies PRO 140 (Progenics) and CCR5mAb004 (Human Genome Sciences). Research has suggested that people lacking a functional CCR5 receptor are largely resistant to HIV infection and this class of entry inhibitors may be a very valuable addition to current medications.

Bristol-Myers Squibb is taking an alternative approach and has two inhibitors of the first step of HIV attachment - binding of the virus coat protein gp120 to CD4 cell receptor - in development. These are the orally available compounds BMS-488043, in Phase 2 trial, and BMS-378806, at Phase 1. The latter has also been considered in a topical form for prevention of HIV infection.

Some projects are designed to intervene at other stages in HIV replication. Merck Sharp & Dohme is developing an HIV integrase strand inhibitor MK-0518, which prevents the DNA made from viral RNA from splicing itself into the genetic material of the host cell nucleus. This compound has reached Phase 3 trials. Gilead is also developing an integrase inhibitor (GS 9137), which is in Phase 2, as is GlaxoSmithKline's S-364735. In other approaches, Koronis Pharmaceuticals is investigating a compound (KP-1461, Phase 1) that is designed to generate a high rate of mutation that is lethal to HIV survival, while Panacos Pharmaceuticals has a maturation inhibitor at Phase 2 (PA-457, bevirimat) that disrupts processing of a protein, producing defective (non-infectious) virus particles.

Anti-retroviral compounds are intended to prevent disease progression, largely by preventing virus replication. However, they are unable to eliminate the virus completely from the body, even though they are very effective in clearing it from the bloodstream. There is now evidence that HIV can lie hidden in cells in areas like the gut and then re-emerge in infectious form if therapy is stopped, or resistant strains of virus emerge. Eventually, therefore, disease progression to AIDS is likely to occur, although the time period before this happens is now much longer than it used to be.

If AIDS does eventually develop, there is a need for medicines to treat opportunistic infections and other complications. Several new compounds are in development for this purpose. For example, Immtech Pharmaceuticals has an oral antifungal (DB289) in Phase 3 trial for treating Pneumocycstis carinii pneumonia. HIV-associated defective metabolism of fat (lipodystrophy) is being addressed by two companies: Theratechnologies has TH9507, an analogue of growth hormone releasing hormone, in Phase 3 trial: Serono has somatotropin for this condition.

The longer-term future

HIV infection continues to spread in both developed and developing countries and there is a great need for a protective vaccine that could help stem the epidemic. There are many projects seeking to develop AIDS vaccines, but a viable candidate has yet to emerge, despite enormous efforts by the major vaccine producing companies and many non-profit organisations. The number of projects is large and many different approaches are being tried. Only a sample of such trials are mentioned here; more details are available on the websites of organisations such as the AIDS Vaccine Clearinghouse (www.aidsvaccineclearinghouse.org).

The largest current trial is being conducted in Thailand. This is a Phase 3 study, started in October 2003, using a priming dose of a canarypox-based vaccine from sanofi-aventis that carries HIV genes, and a booster injection of a vaccine from VaxGen. This project is being run in collaboration with the Thai Ministry of Health and the US National Institute of Health (NIH) and the Military HIV Research Program. Having recruited over 16,000 participants, it is expected to continue until 2008.

Merck Sharp & Dohme also has a preventive vaccine (MRKAd5) in advanced trial in North and South America. This uses an adenovirus vector carrying HIV genes. This vaccine is designed to stimulate CD4+ T-cells to destroy cells that have been infected with HIV, but does not generate protective anti-HIV antibodies. With a target of 3,000 participants, this study is also expected to run until 2008. The study is a collaboration with the HIV Trials Network (HVTN) and NIH.

At Phase 2, Targeted Genetics and various non-profit organisations are conducting a trial in southern Africa of a vaccine (tgAAC09) that uses an adeno-associated virus type 2 vector to carry HIV genes. Also, Vical and GenVec, together with HVTN and others, are testing a DNA-vaccine, boosted with an adenovirus vaccine, in a Phase 2 study in the US, Brazil, South Africa, Haiti and Jamaica.

A number of companies are engaged on trials at the Phase 1 stage, including Geovax (DNA-vaccine prime, modified vaccinia virus (MVA) booster), Therion (MVA-based vaccine), Novartis (micro-particle vaccines), Pharmexa-Epimune (recombinant protein vaccine), Wyeth (several projects), Alphavax (Venezuelan equine encephalitis vector vaccine), GlaxoSmithKline (recombinant gp120 vaccine) and Oxxon Therapeutics (a therapeutic MVA-based vaccine).

Today, the range of medicines for HIV infection is extensive and the disease is more treatable than it was ten years ago. As a result, life expectancy after HIV infection has increased from about 2-3 years in 1984 to over 10 years today. As a protective vaccine is still a long way from being available, the need for more effective and better tolerated medicines remains and the area is still the subject of intense research.

FOR FURTHER INFORMATION CONTACT:

The Terrence Higgins Trust
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London
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Phone: 020 7242 1010 (Helpline)
Website: www.tht.org.uk

Positively Women
347-349 City Road
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Phone: 020 7713 0222 (Helpline)
Website: www.positivelywomen.org.uk