A new generation of HIV treatments drugs is likely to revolutionise combination therapy over the next year or two. How will they be used? And can we learn from previous mistakes in order to avoid resistance? Gus Cairns reports.
“A very exciting time”
“It’s a very exciting time,” says Dr Stephen Taylor, Lead HIV Consultant at Birmingham Heartlands Hospital.
“This has led to a paradigm shift in what we are trying to achieve, especially in treatment experienced patients,” he continues. “We now know that we can achieve an undetectable viral load even in those highly treatment-experienced patients who have resistance to the current three main drug classes.”
What Taylor is talking about is that we’re currently in the early stages of what promises to be the most revolutionary advance in HIV treatment since combination therapy became possible with the licensing of protease inhibitors in 1996.
How not to use the new drugs
So we have a unique opportunity to put together potent regimes that can vanquish the vast majority of resistant HIV, and may even come to replace current first choices. But we could blow the opportunity.
“One of the key and crucial points,” says Steve Taylor, “is that we have to use these drugs in the correct way to get the maximum benefit from them. That means constructing new regimens for our patients that include at least two active drugs.
“It would be a real travesty if they were used inappropriately, by adding them in one at a time into a failing regimen. If these drugs, however potent, are not used without support from other active agents, patients will develop resistance to them.”
This has happened time and again in HIV treatment, often for understandable reasons. Many long-term survivors of HIV still carry with them virus that’s resistant to most of the nucleoside (NRTI) drugs because, lacking anything else, doctors gave them AZT as their only drug, or AZT plus ddI, in the early days of treatment; regimes that weren’t strong enough to contain HIV. More recently, when Fuzeon came along, some of the first patients given it had resistance to all the other drugs available at the time, and unfortunately pretty quickly became resistant to Fuzeon too.
Now, however, we have a unique opportunity to put several new drugs together that should tackle the most resistant virus.
But which ones? Taylor comments that for these experienced patients a complete resistance test history should be taken. A recent test may fail to show up ‘archived’ resistance mutations. This is because non-resistant virus, which is usually better at reproducing, predominates, but the resistant viral strains are still there, in proportions too small to detect by conventional tests.
Taking every dose of the drugs will obviously be crucial too. Forgetting to take your pills is the single most significant cause of treatment failure, and a lot of patients with multi-drug resistance got that way because they found adherence particularly difficult.
Two new classes
So what are these new drugs? For a start, the end of this year will see the licensing in Europe of two drugs that target HIV in two totally new ways.
They are the integrase inhibitor raltegravir (soon to be licensed under the brand name Isentress) and the CCR5 entry inhibitor maraviroc (Celsentri, which has just been licensed in the European Union.)
The last drug of a new class that came along was the fusion inhibitor Fuzeon (T20) in 2003, but it was a fiddly and sometimes painful twice-a-day injection. These two are twice-a-day pills. Furthermore, there are once-a-day drugs of the same classes not far behind, though they’ll have to be given with a baby dose of the ritonavir (Norvir) to boost their levels in the body. These are the integrase inhibitor elvitegravir and the CCR5 inhibitor vicriviroc, though because these are further behind in development they may yet fall at the last fence.
Integrase inhibitors
The integrase inhibitors work by preventing HIV from performing the central action of its life cycle, where it splices its genetic information into our own, effectively becoming part of our cells. After a lengthy development period we now have at least one drug whose results, in Steve Taylor’s words, were “spectacular”. The latest results show that over half of a group of extremely treatment experienced patients remain undetectable on raltegravir (10% more if they were also taking T20) compared with one in six on the best alternative regime possible – see treatment news for more details.
That 54% might not sound brilliant; but these were patients who were without other treatment option. Besides, it bears out Taylor’s point. Because of lack of data on drug interactions, darunavir, tipranavir and maraviroc – see below – were not allowed in these patients’ regimens when the trial was started. In trials where raltegravir and darunavir have been combined, the results really have been amazing; a vast majority of patients have achieved undetectability who would previously have failed.
Raltegravir or elvitegravir could eventually become first-line drugs too: they appear relatively side-effect free, and in one trial raltegravir performed exactly as well as efavirenz, still the most potent single anti-HIV agent of the drugs we know well. However at least two years of data would be needed before doctors would consider using the drugs first-line, and they would have to be much cheaper.
CCR5 inhibitors
Maraviroc and vicriviroc are trickier customers. The CCR5 inhibitors are fascinating compounds because, for the first time, we have drugs that act against part of the human immune system rather than on HIV itself. Specifically, they attach to and block a molecule called CCR5 that sits on the surface of immune cells and which otherwise serves at one of the essential ‘docking points’ for HIV. This makes clinicians a bit nervous because CCR5 is there for a reason; it receives signals the body sends out that direct immune cells to sites of injury or infection. However some people have a gene that means they lack CCR5 and they seem to do fine without it (they are also immune to HIV, which led to the discovery of CCR5 blockers in the first place).
Secondly and crucially, the CCR5 blockers only work against one type of HIV: the type that locks on to CCR5. Some HIV is abler to use a different molecule called CXCR4 to gain entry into cells. Nearly all HIV that is transmitted is CCR5-using virus but it has a tendency to change, and half of patients with AIDS and/or who are very treatment experienced have at least some CXCR4-using virus, which is immune to CCR5 blockers.
Furthermore the only way you can tell what kid of virus you have is by an expensive test made by one company in California – though it’s rumoured maraviroc’s manufacturers, Pfizer, will offer this test for free to doctors considering the drug for a patient.
Lastly, maraviroc doesn’t seem quite as potent as raltegravir; the results in treatment-experienced patients are not quite as impressive (though still better than anything we’d have expected two years ago), and it didn’t do quite as well as efavirenz in a trial of patients new to HIV therapy.
However, the CCR5 blockers are a new class, 50% of even very experienced patients will be able to use them, and Steve Taylor says they could have a valuable role to play.
“CXCR4-using viruses probably pre-exist (although in tiny or undetectable quantities) in many patients,” he says. “The same is true of HIV carrying resistance mutations to the NNRTI drugs nevirapine and efavirenz. This is because mutations can arise naturally.
“However we don’t see patients on the NNRTIs failing because of this because, when a very small amount of resistance to one agent is present, the other active drugs in the patients regimen should be able control these resistant viruses as long as they are present at very low levels. The same should be true of patients with small amounts of CXCR4-using HIV.”
He also thinks the drugs may eventually find a use earlier on in treatment.
If someone fails their first line regimen, which always contains NRTI drugs (Truvada, Kivexa and the like), NRTIs are still prescribed in a second line regime, even though resistance may be there.
“People feel better with NRTIs around, even when there is documented resistance to them. Previously this was because there was little else available,” says Dr Taylor. “But you should now be able to devise an extremely potent second-line regimen using maraviroc or raltegravir, a protease inhibitor and maybe one of the new NNRTIs” (see right-hand page).
“However costs would have to come down significantly before doctors would be willing to do this.”
The good thing about the CCR5 blockers is that they seem to have an excellent side effect profile. “If maraviroc had come long a few years ago, we’d have all wanted it,” says Taylor. “We’re spoilt for choice now.”
MEDICAL NOTES
Sperm washing is “100% safe”, say researchers
Reproduction: Sperm washing, in which the HIV is removed from the sperm of an HIV positive man so his HIV negative female partner can have his child safely, is so effective that “the calculated probability of [HIV] contamination is zero,” according to researchers. In eight European centres, sperm washing was used for 1036 HIV-/HIV+ couples. A total of 580 pregnancies resulted, resulting in over 400 live deliveries and over 450 live births (because some women had twins or had sperm washing more than once). There were no HIV infections in the women. “These results support the view that sperm washing should not be denied to serodiscordant couples,” say the researchers.
Popping a pill could cut HIV infections by a quarter
Prevention: The use of pre-exposure prophylaxis (PrEP), in other words giving HIV negative people HIV drugs to stop them catching the virus, would prevent about a quarter of infections worldwide and could stop three million infections in Africa alone over ten years, a study in the Public Library of Science has found. The study found that in a fairly realistic scenario on which daily tenofovir was given to the sexually active population, if half of them actually took it and it prevented 60% of infections, then HIV cases would be cute by 25%. In a rosier scenario where 75% of people took it and it was 90% effective, 74% of infections would not happen. “Our data highlights the enormous potential public health benefit of PrEP,” said John Mellors of the University of Pittsburgh.
Darunavir
Then there are new, improved drugs in classes we already have. The ‘third generation’ protease inhibitor darunavir (Prezista) has already proved its potency in highly treatment-experienced patients, getting 70% of them undetectable in clinical trials compared with 20% of patients on other PIs. It achieves this power because HIV finds it extraordinarily difficult to develop resistance to the drug. Even if they do, there may be a backup in the form of the first third-generation PI, tipranavir, though that’s got significantly more side effects and is difficult to combine with some other drugs.
But a study that came out this week at the ICAAC conference in Chicago also showed that a reduced dose of darunavir worked better than Kaletra, still the protease inhibitor of first choice for many doctors, in patients new to HIV drugs, and with fewer side effects, including the blood fat rises that nix Kaletra for some patients. Darunavir’s manufacturers Tibotec are therefore applying for a licence for it to be used as a first-line drug.
The new non-nukes
Then there are the new non-nucleoside drugs (NNRTIs). At present we only have two in this class, efavirenz (Sustiva) and nevirapine (Viramune). They are potent and form the keystone of first-time drug regimes. But HIV finds it easy to become resistant to them and they have tricky side effects: with nevirapine, skin and liver damage in the first weeks on therapy, with efavirenz often longer-term psychological weirdness that some patients can’t live with, plus raised cholesterol. Soon to be licensed will be the twice-a-day etravirine; further behind is the once-a-day rilpivirine. While HIV only needs to mutate (change) once to become resistant to the current NNRTIs, it takes two more changes to develop resistance to these two drugs. And they have a better side-effect profile. In a trial in experienced patients, etravirine proved as good as Fuzeon when added to a darunavir-containing combination. And in another trial in patients new to treatment, rilpivirine was as potent as efavirenz, with fewer of the bothersome side effects. Etravirine is already being used at Taylor’s clinic and in some other UK centres in patients who can’t tolerate nevirapine or efavirenz.
Cost
Finally, however, there is the question of cost. Most of these drugs currently come with big price tags. The average triple combination in the UK now costs about £7,000 a year. However a source at one of the London HIV clinics (who didn’t want to be named) told PN that London clinics are currently paying £20 a day for darunavir – that’s £7300 a year in itself, for one drug. Although they are not licensed yet, raltegravir and maraviroc attract an ‘administration fee’ for patients who need unlicensed drugs and get them on an expanded-access or named-patient basis, and this price is often a guide to the first commercial price. This is currently in the region of £10,000 a year. The exception is etravirine, which currently costs about £4000 a year – though this is similar to the pricier protease inhibitors rather than the other NNRTIs.
Taylor says NHS Trusts are usually willing to pay these prices for the handful of truly multi-drug-resistant patients. After all, Fuzeon costs £13,000 a year, and patients who needed it got that.
“There are probably only about 300 patients in the UK who are resistant to three drug classes and require extreme salvage therapy,” he says. “But their use in more conventional second- and third-line regimes will be very much dependent both on on their price, and on long term safety data compared to existing drugs.”
The London clinic worker confirmed this. “At the moment it’s difficult to see where the money would come from to pay for these new drugs,” he says. “And Pfizer, especially, will absolutely shoot themselves in the foot if they set too high an initial price for maraviroc.
“But there’s going to be a lot of pressure to use these drugs more widely, and prices are quite likely to fall.” Expect some tense negotiations ahead between the drug companies and the NHS Trusts.
Further ahead?
The pace of HIV drug discovery doesn’t seem to be slackening, and it mustn’t; with this week’s extremely disappointing announcement of the failure of the most promising HIV vaccine candidate (see treatment news), we will need them for a long time to come. The search is now on for longer-acting agents that can be taken intermittently. For instance, the ICAAC conference heard about trial results from PRO140, a CCR5 blocker that could be delivered by injection once a week. Would you rather take that than a daily pill? What if it was once a month? Investigation into yet more classes of oral drug are also underway.
At the moment, however, and perhaps for the first time in the history of HIV, we’re not running to catch up: we have enough drugs to fix the vast majority of HIV infection, and that can only be good news.
Thanks to Steve Taylor
