Blips matter, and should be avoided
Viral load ‘blips’ are brief episodes in which the HIV viral load rises above the limit of detectability (usually 50, depending on the test used) for short periods before becoming undetectable again. Many patients experience these, and clinical opinion has been that as long as the viral load doesn’t rise above 1000 and doesn’t last longer than a couple of months, there are unlikely to be any long-term consequences to the health, treatment success or drug resistance.
Alan Perelson of Los Alamos Laboratory in New Mexico disagrees. He has used mathematical modelling to demonstrate that ‘blips’ probably arise because immune cells are activated by other infections, that this activation causes them to become infected with HIV, and that this then ‘re-seeds’ the long-lasting reservoir of cells in the body that contain HIV.
Perelson believes that new cells become infected with HIV this way every time they ‘come out’ to fight another infection. This model fits his data better than another model in which cells already infected with HIV were ‘woken up’ by infection and so started producing HIV again.
Apart from avoiding infections, then, the aim of HIV treatment should be to keep the average viral load so low that even if an infection stimulates the immune system, there is not enough virus around to create a significant blip and a new wave of infection.
Perelson found that in order to avoid occasional blips of over 50, an average viral load no higher than 7 should be maintained – a figure well below the detectability level of standard tests.
• JAIDS 48(5): 483-493.
Experts “deeply disappointed” by HIV vaccine failure
Researchers and prevention advocates have reacted with dismay to the news that an apparently promising candidate vaccine against HIV has failed to demonstrate any effect.
The STEP Study involved vaccinating 3,000 volunteers in six countries in the Americas and Australia, but was stopped on 21 September with only 1,500 vaccinated, when the proportion who caught HIV proved to be the same – about three per cent – regardless of whether they received the vaccine or an inactive placebo.
Twenty-four cases of HIV infection were observed in 741 volunteers receiving the vaccine and 21 in 762 receiving placebo.
Hopes had been high that the Merck MRK-Ad5 Vaccine would offer at least some degree of protection against HIV. It had produced strong immune responses when given to monkeys and measurements of immune activation in humans had suggested a protective effect.
However these immune responses did not translate into long-term protection, and hard questions will now have to be asked about the way candidate HIV vaccines are evaluated.
Richard Jeffreys of the Treatment Action Group in New York said: “The results ...raise critical and difficult questions for the HIV vaccine field as a whole. It will be crucial to analyse the outcomes in detail and assess how they might impact on other HIV vaccine candidates in development.”
Simon Collins of HIV i-Base in London said: “It’s deeply disappointing, but it should strengthen rather than discourage research into HIV prevention alternatives, whether that is use of treatment, alternative vaccine approaches, microbicides, pre-exposure prophylaxis or, indeed, helping people use condoms.”
The Ad5 Vaccine was designed to stimulate cellular immunity. This means that in theory it should have been able to strengthen the response of CD8 cells, ‘priming’ them to recognise HIV so that when the real thing came along, an infection would have been contained. At the very least, it was hoped that it would mitigate the course of HIV infection and reduce viral load.
However viral loads in HIV-infected volunteers were virtually the same - 40,000 in the vaccine group and 37,000 in the placebo group.
Peter Kim, the president of Merck Research Laboratories, said: “We share in the disappointment of the research and HIV communities today. Sadly, developing an AIDS vaccine remains one of the most challenging tasks facing modern medicine.”
Prezista works better than Kaletra
The new ‘third generation’ protease inhibitor drug darunavir (Prezista) works better than lopinavir (Kaletra) when given to patients new to therapy, the 47th ICAAC Conference heard last month.
Prezista is currently only licensed for use in treatment-experienced patients. But the fact that it achieved somewhat better viral loads with considerably fewer side effects than Kaletra, still the market leader amongst protease inhibitors, has led manufacturers Tibotec to file an application to the US Food and Drug Administration to license it for patients new to HIV therapy. If this is granted Tibotec could take a slice of the lucrative first-drug market away from the non-nucleoside drugs efavirenz and nevirapine – and it has NNRTI drugs of its own coming along too (see The Second Treatment Revolution).
In the ARTEMIS trial, patients received either two 400mg pills of darunavir plus a ‘booster’ capsule of ritonavir twice a day, or two 400mg pills of Kaletra (which is a lopinavir/ritonavir combined pill). This is two-thirds of the darunavir dose prescribed for experienced patients.
After 48 weeks’ treatment, 84% of those taking darunavir had viral loads under 50 versus 78% taking Kaletra.
This 6% difference was not statistically significant, i.e. could have been due to chance. But in patients who started with viral loads over 100,000, 79% on darunavir versus 67% on Kaletra reached viral undetectability, and this was statistically significant.
Side effects were generally better on darunavir too, with one exception. Fourteen per cent of patients on darunavir got diarrhoea versus 34% on Kaletra, and the levels of blood fats such as cholesterol and triglycerides did not rise as much on darunavir.
The exception was that three patients on darunavir (9%) got a rash graded as ‘serious’, as opposed to one patient (4%) on Kaletra. The most serious case, however, was regarded as due to the anti-PCP medicine dapsone rather than darunavir.
• 47th ICAAC Conference, abstract H-718b.
Fake microbicide man fined
The Australian corporate regulator is taking proceedings against a businessman for falsely claiming that his product, a lubricant called Citrofresh, acts as an “invisible condom” against HIV. Ravi Narain could face a fine of up to A$400,000 (£175,000) for misleading his investors. He claimed that Citrofresh could “offer a global solution to reduce and eventually stop the spread” of HIV.
Meanwhile, microbicide campaigners have written to the UK Medical and Healthcare Regulatory Authority demanding it takes similar action against a British company called Kirklees Medical Ltd. for making similar claims about its lubricant, K-Lube.
Kirklees claims that K-Lube “is less than 50% effective against HIV in actual use between partners though it performed exceptionally well against other STIs” and that it has “anti-viral and antibacterial properties.”
Kirklees has placed adverts on gay and straight websites for people interested in anal sex saying its products make it safer.
Although over two dozen candidate products are currently being tested as possible microbicides against HIV and STIs, none has as yet been shown to work, and the so-called ‘active ingredient’ in K-lube, chlorhexidine gluconate, has been ruled out as a possible microbicide.
HIV hurts heart, guts, brain and immunity – even on treatment
A number of studies recently have shown that, even in people on successful treatment, HIV continues to cause subtle, long-term damage in the body.
A new analysis of the SMART study, in which half the participants stopped their HIV treatment if they had CD4 counts over 350, shows that there was more risk of heart attacks in people off HIV treatment than on it, even though HIV drugs can raise cholesterol.
The reason for this is that HIV reduces cholesterol levels in the body. Shouldn’t this be a good thing? No, because it cuts the levels of the ‘good’ high-density or HDL cholesterol, which protects against heart attacks, even more.
A second study has confirmed that one in five people with HIV, even on treatment, have persistent deficits in concentration, memory and the ability to perform fine movements. The North Carolina study found that only 44% of the deficits improved with HIV treatment. HIV is thought to cause persistent mild inflammation of brain cells which may continue despite treatment.
A similar situation has been found in the gut. A third study found that nine out of 19 patients who had been on HIV therapy for over four years and had blood viral loads under 50 still had detectable HIV in immune cells lining the small intestine. One theory of the causation of AIDS is that long-term gut damage exhausts the immune system.
Finally a fourth study found that patients with HIV were 60% more likely to develop non-AIDS defining cancers, despite treatment, than a matched group of negative patients, probably because of subtle deficits in the part of the immune system that detects cancers.
Altogether these studies suggest that even in the era of potent anti-AIDS treatment, HIV infection still damages the health - and is best avoided.
• 47th ICAAC Conference, abstract H-378
• AIDS 21(14): 1915-21.
• AIDS 21 (15): 2106-08.
• 47th ICAAC, abstract H-1721.
Integrase inhibitor still working well
The new HIV drug raltegravir (Isentress) continues to show potent anti-HIV activity and a remarkably low level of side effects, the ICAAC Conference heard last month.
Raltegravir is the first integrase inhibitor, a new class of HIV drug. Although the CCR5 inhibitors, in the guise of maraviroc (see separate story) have beaten the integrase inhibitors to being licensed as the first new class of HIV drugs for four years, doctors are more excited about the latter, which appear potent and easy to take.
In a study in which 178 highly treatment-experienced patients were given three different doses of raltegravir and another 45 an inactive placebo, 54% achieved a viral load under 50 and maintained it for a year, compared with 13% on placebo. Although patients also took the best mix of currently licensed drugs doctors could devise, the vast majority were resistant to all drugs licensed when the study began, or all but Fuzeon, making raltegravir’s performance even more impressive.
Raltegravir appeared to cause virtually no side effects in addition to the ones caused by other drugs: there were similar rates of symptoms such as diarrhoea regardless of whether people were taking the drug or the placebo.
It’s not a perfect drug. HIV can become resistant to raltegravir reasonably fast, and 35 out of 38 patients who failed their treatment due to drug resistance had resistance to raltegravir. More than two-thirds of these had no other active drug in their combination, showing the importance of supporting the new drugs with other active ones.
Raltegravir is expected to be licensed in the USA this month, and in the EU soon.
New type of HIV drug approved in Europe
Maraviroc, the first of a new class of HIV drugs, the CCR5 inhibitors, was licensed for prescription in Europe on 24 September.
The licensing of maraviroc (ma-RA’-vi-roc), which will be sold under the brand name Celsentri, means the approval of the first new class of HIV pills in Europe for over a decade, since the first NNRTI, nevirapine, was licensed in February 1998.
Maraviroc is the first CCR5 inhibitor, a type of entry inhibitor, meaning that it stops HIV getting into the cell. It is the first HIV treatment that targets not the HIV virus but human cells. It attaches to CCR5, a cell-surface molecule that is one of the two attachment points that HIV needs to hook on to in order to infect a cell, the other being the CD4 molecule.
In MOTIVATE, a trial of maraviroc in highly-treatment-experienced patients, 46.8% of those receiving maraviroc twice daily, plus the best mix of other drugs doctors could devise (an ‘optimised background regimen’ or OBR), achieved viral loads under 50 and maintained them for a year, compared with 16% taking an inactive placebo plus OBR.
Maraviroc only works against one type of HIV and not against another kind that attaches to a different cell-surface molecule, CXCR4. A pre-treatment test is needed to find out what kind of virus you have, which doesn’t pick up on all CXCR4- using virus.
HIV can and does change spontaneously from CCR5to CXCR4 virus, or ‘dual tropic’ virus that can use both molecules. In the MOTIVATE trial, there was a 13% rate of treatment failure due to reappearance of HIV viral load. Two-thirds of these failures were accompanied by the appearance of CXCR4 virus.
There are concerns that the latter kid of virus is more damaging to the immune system; in another study presented at ICAAC, patients with CXCR4 or dual-tropic virus were more than twice as likely to develop AIDS over a four-year period than patients with CCR5 virus, and had viral loads on average ten times higher.
On the other hand, CCR5 inhibitors seem to do something mysterious that keeps CD4 counts higher; in the MOTIVATE trial, patients failing on maraviroc still had CD4 count rises of 71 cells on average, compared with 14 cells for patients taking placebo.
See The Second Treatment Revolution for more.
• 47th ICAAC Conference, abstract nos. H-718a, H-715 and H-1027.
Pillboxes could cut drug failure
The simple measure of giving pillboxes to everyone starting HIV therapy could raise the success rate by 15% and cut patients’ average viral load by 56%, a study from San Francisco has found.
Pillboxes make more difference to the chance of therapies succeeding than changing from a twice-a-day treatment to a once-a-day one, the researchers conclude.
The study gave 245 HIV positive patients recruited from homeless shelters pillboxes holding a week’s worth of drugs when they started their therapy.
Two-thirds of patients used their pillboxes at least some of the time.
Adherence improved modestly in patients using pillboxes – from an average of 73% of doses correctly taken to 77.5%. However adherence amongst pillbox users improved as time went on, and not in those who didn’t use them.
