The 1981 discovery of the HIV / Aids virus caused widespread panic in many Western cities. Since then, huge steps have been taken to develop new drugs to effectively suppress patients’ viral load, affording them a longer, more fulfilling life. Well-treated patients taking a steady combination of anti-retroviral drugs can live up to 50 years after infection. But the development of effective therapy is only part of the war on HIV.
In 2009, Nobel prize-winning virologist Françoise Barré-Sinoussi, who helped discover the virus in the early 80s, warned that advances in HIV treatment were contributing to rising complacency in the West about the dangers of infection. “Some people in my country, France, and other Western countries have become complacent,” she said. “They see HIV / Aids as a chronic disease, not as one that can kill.”
While effective therapy is making a huge difference to the lives of many of those living with HIV, massive challenges remain, not least in finding a cure. Within treatment, there is a huge disparity of access to drugs between the developed and developing worlds, meaning that the most effective therapies are mostly denied to the countries with the highest prevalence of HIV infection. Even for patients with access to good treatment, resistance and drug toxicity are problems that academics and drug developers are hard at work to assuage.
After treatment: resistance and toxicity
In the days after the discovery of HIV / Aids, inadequate treatment regimens were confounded by mutations of the virus that were immune to a particular course of drugs. Through the development of more effective HAART (highly active anti-retroviral therapy) treatments in the mid 1990s and the refinement of regimens to more manageable dosage levels, the incidence of resistance has dropped off significantly.
“In the early days of treatment, there was a lot more resistance than now,” says Dr Alan Winston, consultant physician and senior lecturer in HIV and genito-urinary medicine at Imperial College London in the UK.
“If you can’t suppress the virus, you get resistance very quickly. So effective treatment has to suppress the virus. 15 years ago, when we first had effective treatments, they were cumbersome and difficult to take, but now we’ve got much more sophisticated regimens; in fact some of them are just one pill a day because there are combination tablets.”
Today, there is even relative consensus on the best resistance testing method, with genotypic tests being generally accepted for the speed at which samples can be sequenced and analysed. “There were studies in the late 1990s comparing the different resistance testing modalities, and they all showed that it doesn’t matter what test you use, as long as you use one. So nowadays we use the easiest test, and the easiest test is genotypic because most labs can quickly sequence the virus. Some of the new drugs attack different parts of the virus, so one more recent complexity we have is to sequence areas of the virus we might not have had to in years gone by, because the drugs act in different areas now,” says Winston.
With patients generally living longer with the virus, a far more prominent issue is that of drug toxicity. As well-treated HIV patients now commonly survive into old age, new health problems are springing up. “We’ve now got an aging HIV-infected population because they’re well and they’re on stable treatment,” Winston notes. “As we get older, we develop other medical problems, and then we have difficulties because of the drug interactions and the way toxicities change. So one of the challenges is to get drugs with less toxicity for an aging population.”
Another problem exacerbated by the aging HIV-infected population is the prevalence of diseases like heart disease and stroke, possibly caused by inflammatory changes prompted by long-term HIV infection. With the incidence of resistance remaining steady, the thrust of drug development efforts from academic institutions and big pharma are likely to concentrate on reducing toxicity and making treatment regimens more tolerable for older patients.
Improving access: the role of generics
The development of increasingly sophisticated drugs for the generally well-provisioned, aging Western patient base bears little relation to the experience of HIV-infected populations in the developing world. According to recent statistics from the World Health Organisation (WHO) and UNAIDS, anti-retroviral therapy coverage is only 37% in sub-Saharan Africa, the region with the highest prevalence of HIV infection in the world.
Access is improving, with several low to middle-income countries achieving universal access to treatment by December 2009, including Botswana, Rwanda and Cambodia. Much of the success that has been achieved can be attributed to the accessibility of generic drugs, mass-produced versions of anti-retroviral therapies that don’t come with such a prohibitive price tag.
“That’s the big thing for the future. Looking for future drugs, you want a drug that can be manufactured by generic companies cheaply and easily, and some of the drugs don’t fall into that category,” says Winston. “Some of them you can make, if you like, in your back yard with a chemical set, but others are much more sophisticated.”
As drug development methodologies improve, sophisticated modern treatment options will become more viable for large-scale commercial manufacture. If more developing countries are to meet the international target of 80% HIV treatment coverage (the original goal date was 2010), encouragement of local and international generics markets will have a key role to play.
Prevention and cure: research hurdles
Effective treatment is good news for people suffering from HIV / Aids today, but what are the prospects of preventing infection or even finding a cure for those at risk in the future? Research on methods of prevention has proved extremely frustrating over the years, although promising discoveries have reinvigorated efforts into developing more reliable preventive measures.
Post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) are anti-retroviral drugs indicated for use before and after potential HIV exposure, respectively to prevent infection. These prevention methods have shown some efficacy in animal and human trials, but neither has produced results strong enough to be considered conclusive.
PEP has produced positive results in a trial among healthcare workers exposed to the virus through needle-stick injuries, reducing the risk of HIV infection by 81%, but at least 13 reported cases where PEP has failed to protect exposed healthcare workers from infection has called its efficacy into question.
Similarly, PrEP caused a stir in late 2010 when the results of iPrEX, an international Phase III clinical trial, showed that in 2,499 men and transgender women across several countries, taking PrEP reduced the infection rate by 44%.
Although rightly hailed as a significant breakthrough, many more large-scale studies are planned for different study populations (heterosexual women in southern Africa, for example) before any conclusion can be drawn.
Microbicides are also a promising research area for HIV prevention, as Winston explains. “A microbicide is a gel that is used like a sexual lubricant, but it has anti-HIV drugs in it. So there are big microbicide studies in Africa, which also empowers women, because if a woman has this microbicide, she can administer it in her vagina before she has sex, which could prevent her from getting HIV. The results of the microbicides have been disappointing, but there are some studies starting now and it looks like we might be turning a corner there.”
The Berlin case
The search for a cure has also been fruitless thus far. The only major discovery came in a 2007 case in Berlin, where an HIV-positive male was given a bone marrow transplant to help treat acute myelogenous leukaemia (AML). The donor stem cells were partly chosen for a mutation that is resistant to HIV infection, and after the transplant doctors discovered that HIV levels had been eradicated in the patient. Although the discovery has again boosted interest in discovering a cure, the anecdotal nature of the case and the extreme risk of bone marrow transplants (the survival rate for these procedures is less than 30%) mean that any meaningful impact is a long way off.
Although genuine expectations for a cure might be a long way off, anti-retroviral therapy for HIV / Aids has never been better, and several meaningful steps in research for prevention and cure have laid a foundation on which drug developers can build. “I would hope that in the next ten years, we’ve got some more insight and something may be on the horizon,” says Winston. “I think people are a bit more hopeful that we could be nearer that turning point than we ever have been.”