The biology and impact of the world's worst pandemic
In the UK the plight of AIDS today gets much less attention from the public and the media than it did back in the 1980ís and early 1990ís. This often leads to the misconception that AIDS is no longer a problem in this country; in reality, the increasing prevalence of HIV in the UK proves that this is simply not true.
Worldwide, accepted definitions, facts and figures on HIV and AIDS include:
The history of HIV / AIDS in the UK
Throughout the 1980ís the number of newly diagnosed HIV infections per year in the UK rose steadily. The figure plateaued during the 1990ís, averaging about 3,000 cases per year, but then increased dramatically after 1999. By 2005, the annual number of newly diagnosed infections was more than 7,500, and an estimated 63,500 people over 15 years of age were living with HIV in the UK, 20,100 (32%) of whom were believed to be unaware of having been infected. Since the pandemic began there have been 17,161 known UK HIV deaths.
The science bit...
What is the natural history of HIV infection? What are the symptoms?
But then the immune system kicks in, and the virus largely retreats, hiding within lymphoid tissues and replicating only very slowly. The levels of virus in the blood stream become much lower, the patient is less infectious and feels well. Untreated, an infected individual usually remains "healthy" like this for 5 to 15 years.
However, the bodyís immune system only has a limited ability to control HIV. The virus makes mistakes when it copies its genetic code. Roughly once in every 10,000 genetic letters that are copied the virus introduces the wrong genetic base. Since the genome contains about 9000 bases in total, almost every genome copied will contain an error. The result is that these genetic mistakes alter the appearance of the virus and so make it harder for the immune system to recognise and keep up, because it is trying to hit a moving target. Eventually, through this progressive shape-shifting, the virus takes on a form that the immune system cannot respond to, and at this point the pace of the infection begins to accelerate and the number of CD4+ T cells begins to fall.
When the CD4 count falls below a critical threshold (400 per microlitre of blood) the body is no longer able to defend itself. At this point an HIV-infected individual is said to have AIDS, and patients usually begin to develop opportunistic infections caused by organisms that would not normally affect healthy people. These include mycobaterial infections (caused by bacteria related to tuberculosis), the lung infection PCP (pneumocystis carinii pneumonia), oral and genital thrush, complications of CMV (cytomegalovirus), chronic diarrhoea and weight loss, toxoplasmosis, meningitis, dementia, and polyomavirus (JC virus), which is associated with a disease of the brain's white matter known as PML (progressive multifocal leucoencephalopathy). At this point patients are often prescribed prophylactic drugs to help ward off some of these infections including co-trimoxazole, which can slow down the progression of PCP.
Without treatment the median survival time after developing AIDS is only about 9 months. However, the rate of clinical disease progression varies widely between individuals from 2 weeks to 20 years. Many factors affect this rate of progression, including age, quality of health care and the presence of co-existing infections. An individual's genetic make-up also plays an important role because it's now becoming clear that some people are resistant to certain strains of HIV and although they become infected they do not seem to develop AIDS, or they do so only extremely slowly. There are even people who seem to be totally immune to infection with the virus. They carry a mutated cell surface marker called CCR5-delta-32, which prevents HIV from locking onto and invading their cells. Scientists hope that understanding what makes these people able to resist the virus may hold the key to future therapies to block infection amongst susceptible individuals.
There are two types of drugs that block RT; these are known as nucleoside and non-nucleoside RT inhibitors. The nucleoside RT inhibitors are structurally very similar to normal DNA bases, but they lack a critical chemical group required to enable a DNA chain to grow. So when the viral RT inserts one of these altered bases into the copy that it's making of its genetic code, it can't finish the job because it cannot add the next genetic letter. An example of this type of agent is the drug AZT or zidovudine (azidothymidine). The non-nucleoside RT inhibitors, which include drugs like efavirenz and nevirapine, work slightly differently. They target the RT enzyme itself and bind to it, distorting its shape so that it cannot work properly. This stops the virus from replicating.
Protease inhibitors (PIs) only emerged more recently. They work by blocking the action of a protein-cutting enyzme carried by HIV, which is critical to the virus being able to assemble new infectious particles. If this enzyme is prevented from doing its job the virus cannot escape from the infected cell. An example of the PIs includes saquinavir, which is famous for being one of the first drugs produced by building a computer model of the shape of the viral enzyme and then designing a drug specifically to block it.
There are also agents known as fusion inhibitors, which are a newer type of drug that work by stopping HIV from binding with the CD4 receptors that it uses to enter cells. One being evaluated at the moment is called efurvatide.
Doctors have also recently been testing a new agent called raltegravir, which is an "integrase inhibitor". This prevents the virus from inserting a copy of its genetic material into the host cell genome. In a recent trial published in the Lancet doctors randomly allocated 179 patients with end-stage HIV / AIDS to receive either the active drug or a placebo. After 6 months the patients receiving raltegravir showed a 98% drop in the levels of virus in the bloodstream, compared with only 45% in the placebo group. The next step will be to test raltegravir in combination with other HAART regimen drugs in healthier patients who are not approaching the end-stages of their disease. It may make a considerable difference to the rate of disease progression.
So there are lots of drugs with which we can now combat HIV; but there's a problem. Because the virus frequently makes mistakes when it copies its genetic material it rapidly develops forms of the virus that are resistant to the action of these drugs. To slow down the rate at which this happens, rather than use them singly, a cocktail of drugs is used, often one from each of the three classes (nucleoside RT inhibitors, non-nucleoside RT inhibitors and protease inhibitors). This is known as HAART or Highly Active Antiretroviral Therapy (HAART) and it has dramatically reduced the evolution of viral resistance and prolonged the time during which an HIV-infected individual remains healthy and symptom free. However, it's worth emphasising that, whilst drugs help to control the spread of HIV to uninfected cells, unfortunately there is no treatment available at present that can eradicate HIV once integrated into a host.
Another problem with combating HIV is that a number of different strains of the virus can arise due to differences in selection pressures as the virus encounters different individuals, different drugs and different routes of spread. This can result in resistance to multiple anti-retrovirals and frequently occurs through a process called recombination. It occurs because each HIV virion carries two complete RNA genomic strands, meaning that homologous recombination can occur when a cell is coinfected with two different but related strains. The two strains may then exchange genetic material, including drug resistance traits. The process of recombination also therefore poses theoretical problems for the development of a safe vaccine against HIV.
The situation is also made worse by the fact that increasing numbers of patients are found to be carrying resistant forms of the virus at diagnosis, even before any drug therapy has been administered. Indeed, in 2004 an estimated 9% of new HIV diagnoses were found to be drug resistant strains, presumably acquired from individuals who had already received treatment. If patients then acquire additional strains of the virus with different resistance profiles the process of recombination can yield multiply-resistant viruses. In a case described recently in the Lancet this resulted in an individual producing a strain of the virus that was resistant to every available anti-retroviral agent. The patient in question also progressed to AIDS and died within six months of becoming infected.
The main ways HIV is transmitted in the UK
A reported 754 HIV-infected children had been born in the UK to infected mothers as of the end of December 2006. Aware of the increasing risk posed by HIV to newborns and care-workers, in 1999 the UK Government introduced routine antenatal testing for HIV amongst all pregnant women. In those found to be positive, the use of antiretroviral treatment can greatly reduce the chances of a mother passing the infection to her baby. Since 1996 the increased use of such treatment has caused the rate of mother-to-child transmission to fall substantially.
Early media coverage of AIDS in the UK focused on injecting drug users. During the early 1980ís it was a big problem, but in 1986 needle exchanges began to operate across the UK, providing clean needles and giving drug users information and support. These schemes were largely effective in reducing the prevalence of HIV among certain members of this population. However, while they account for a small proportion of people living with HIV in the UK, the prevalence of HIV among injecting drug users has risen significantly in recent years (from 1:110, in 2002, to 1:62, in 2006). This rise has been attributed to an increase in the use of drugs outside of London where needle exchange schemes and information about HIV are harder to access.
Government policy in the UK
This measure aimed to tackle health tourism, the process whereby people migrate to a country in order to take advantage of better healthcare services there. However, denial of treatment to people in these situations can effectively be a death sentence, especially if they are then deported to countries where no treatment is available.
There are certain 'notifiable diseases', for which a person will always receive treatment in the UK regardless of their legal status, in order to prevent the rapid spread of epidemics. HIV, however is not on the notifiable diseases list. If a woman has no legal right to be in the UK then she will only receive medication to stop her baby being born HIV positive if doctors decide it is an 'emergency'.
Financial costs to the UK health system
Why is HIV / AIDS still on the increase in the UK?
Another reason people are still dying of AIDS is due to many being diagnosed with HIV at a late stage of infection. In 2005 more than one third of adults diagnosed with HIV had a CD4 count lower than the recommended threshold for starting treatment. At this stage treatment is much less likely to work. This late diagnosis is alarmingly common, highlighting the need for greater awareness and for people to access testing services as soon as possible if they think they may have been exposed to HIV.
What is next?
In the absence of a vaccine researchers have turned to other approaches to try to combat the virus. A promising discovery, confirmed earlier in 2007, was that male circumcision can dramatically reduce, by 60%, the chances of acquiring HIV. The first clues that circumcision might be beneficial in halting the spread of HIV came after researchers noticed much lower prevalences of HIV infection amongst communities in which males were routinely circumcised. This hypothesis was tested recently in a series of randomised control trials in which HIV-negative volunteers seeking the procedure were randomly assigned either to undergo circumcision immediately or to wait for a period of time first. The patients were then followed up with regular HIV tests. The trial had to be stopped prematurely on ethical grounds when a large excess of HIV cases were found in the group of individuals asked to wait before undergoing the procedure. Scientists think that the foreskin represents a significant portal of entry for the virus because it is relatively enriched in cell types targeted by HIV, it provides an environment in which the virus can persist for an extended period thus maximising the risk of infection, and the mucosa of the foreskin can develop tiny fissures during intercourse and these facilitate viral entry and infection.
In response to these findings, the WHO / UNAIDS have recommended that it should be considered as an effective preventative measure. According to Kevin de Cock, director of the World Health Organisation's AIDS department, "This is an extraordinary development...Circumcision is the most potent intervention in HIV prevention that has been described". And according to Marie-Louise Newell of the University of KwaZulu-Natal in South Africa and Till Barnighausen of the Harvard School of Public Health "if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new infections could have been prevented in 2007".
But none of these strategies can be effective without education, particularly about safe sex. One in ten girls aged 16-19 in the UK is infected with chlamydia, which can only have been acquired through unsafe sex. This is clear evidence that large numbers of young people are placing themselves at direct risk of HIV, probably because they are from a generation who never saw the "grim reaper" television adverts of the 1980s when AIDS first hit the headlines. HIV is a very real threat and still very much a life sentence. Unless people can be made aware of this then the problem will only continue to get worse.