Kivexa or Truvada? More evidence
“The most common starting combinations for people new to HIV therapy in the UK are SustivaR (efavirenz) combined with either TruvadaR (tenofovir + FTC) or KivexaR (abacavir + 3TC). With the announcement that AtriplaR, a one-pill, once-a-day treatment combining Truvada and Sustiva, has been licensed in the EU, this combo may become more popular. But is it the best one?”
But is it the best starting combo? The second-most popular is Kivexa® (abacavir + 3TC) plus Sustiva. Does one have the edge over the other?
A study from the English midlands seems to show that if you want a big CD4 boost, take Kivexa; but if you want to minimise your risk of heart problems, take Truvada.
Data on treatment outcomes were analysed for the 110 patients who started on either Truvada or Kivexa, both plus Sustiva, at the HIV clinics in Walsall, Coventry and Northampton during 2006.
Of the 110, 59 started on Kivexa and 51 on Truvada. This was a largely African and heterosexual group of patients; 70% were of African origin and just over half were men.
Pre-treatment average viral loads were slightly lower in the Truvada patients than the Kivexa ones and so were CD4 counts (169 versus 184).
Only two patients had to stop treatment owing to side effects, one on Kivexa and one on Truvada.
When it came to antiviral potency, Kivexa seemed to have some edge over Truvada. Six months after starting, no Kivexa patient still had a viral load over 400, but 12% of the Truvada patients still did, and at this point 80% of Kivexa patients were undetectable (below 40) compared with 73% of Truvada patients. However these differences were not statistically significant and could have been due to chance.
What was significant was that Kivexa patients gained more CD4 cells. The average CD4 rise in the first six months was 169 on Kivexa and 106 on Truvada, and there was a less than one-in-a-hundred probability that this was a chance observation (it has also been seen in other studies).
On the other hand, total cholesterol and ‘bad’ LDL-cholesterol rose in patients on Kivexa but stayed the same on Truvada, even though Sustiva raises cholesterol, and there was a tendency for there to be a better ratio of ‘good’ HDL-cholesterol in the Truvada patients too. There was no evidence of kidney problems in either group.
Start at 350, say new European treatment guidelines
New HIV treatment guidelines released by the European AIDS Clinical Society say that HIV treatment should be started for any patient with a CD4 count of under 350, rather than 200 as in the past. They also say that the goal of any therapy should be to get patients virally undetectable, not matter how treatment-experienced or drug-resistant they are.
They say that a resistance test should be done whenever someone is diagnosed, and removed Combivir (AZT/3TC) from the list of recommended first-line nucleoside drugs, singling out Kivexa or Truvada.
The guidelines were issued at the recent European AIDS Conference alongside new guidelines on the management of hepatitis and of lipodystrophy, cholesterol, diabetes and so on, all packed into a 52-page A6 booklet.
Acknowledging that the new set of guidelines were “much less conservative and more aggressive than the previous sets” in 2003 and 2005, restiring EACS President Dr José Gatell said that the arrival of three to four drugs, some within completely new classes, “will change substantially some aspects of antiretroviral therapy.”
The new European Treatment guidelines are at www.eacs.eu/guide/index.htm
Only half of patients check to see if PEP has worked
A French study has found that although the national system for providing post-exposure prophylaxis (PEP – HIV drugs to prevent infection) after sexual exposure seems to be working quite well, only half of patients given PEP return a month later to be re-tested and see if it has worked.
During 2005 90 patients asked for PEP at the Pitié-Salpetrière Hospital in Paris, one of France’s largest HIV clinics.
Three-quarters of them were men and half of them were gay men, with an average age of 29. Only one in five definitely knew that their partner had HIV, and four of the 90 reported that their contact was ‘HIV-negative’, so it’s not clear why they were seeking PEP. Condoms were not used in just over half the encounters; in 40% of the others, their use was ‘dysfunctional’, i.e. with breakage, slippage and so on. Two people turned up after non-sexual encounters, one from a bite and one after contact with blood.
Although in a lot of cases the HIV risk was pretty low, 80 out of the 90 were given PEP, highlighting, say the researchers, “the issue of the medical decision for these patients in the context of stress and anxiety.”
The average delay between the risk incident and starting PEP was 18 hours and was only more than 48 hours in five patients.
The standard combination prescribed at the hospital was Combivir® (AZT + 3TC) plus Kaletra® (lopinavir/r), and the researchers wonder if tolerability “could be improved with new antiretroviral agents,” because 17.5% of patients had to have their prescription changed due to side effects, usually diarrhoea.
The biggest problem was that too few patients turned up for their follow-up appointments. Only two-thirds turned up after their month of PEP and although their adherence seemed to be almost perfect, it tells us nothing about the other third. And only 50% turned up a month later for a follow-up HIV test, spo although no-one who did turned out to have HIV, oit tells us little about whether PEP worked for everyone.
“Patients’ adherence to follow-up HIV testing should be reinforced to validate the PEP strategy,” say the researchers.
How do we get more Europeans to test for HIV?
Over Europe as a whole, probably 60% of people with HIV don’t know they have it, the 11th European AIDS Conference hard last month (see News). Professor Jens Lundgren of Copenhagen said: “This is the biggest unresolved public health problem in Europe.”
Given that early HIV testing both saves lives and reduces the infection rate, how do we increase the number of tests done? This question was debated at the conference and was also the subject of a special conference in Brussels on 26-27 November.
In the USA, the answer the Centres for Disease Control (CDC) has come up with is to recommend that HIV testing on an opt-out basis – meaning that “an HIV test is performed unless the patient specifically declines” – is performed in the majority of cases that patients seek a health checkup of turn up at hospital A&E departments.
This had run into problems, however, because the laws inn 33 out of 50 states specify that explicit consent, either written or verbal, must be obtained before an HIV test, and 11 states require pretest counselling. State legislatures have proven reluctant to change these laws, and law professor Leslie Wolf, based in the CDC’s home town of Atlanta, said that, given the continued stigma against HIV, a satisfactory standard for patient consent “would require more information about HIV testing than is currently contemplated under the CDC’s recommendations.”
Lundgren told the European Conference that universal testing on the CDC model was “not compatible with European philosophy.
“But,” he added, “We can identify patients with early signs of disease that should prompt testing.”
The European AIDS Clinical Society (EACS), who run the conference, is therefore proposing that the November Conference should hammer out a list of ‘indicator diseases’ the presence of which, in any patient in any healthcare setting, would trigger the offer of an HIV test.
As well as AIDS-defining conditions and other STIs they could include other indicators of risk behaviour or impaired immunity such as digestive diseases, fungal infections and shingles.
There were many questions to be answered, however. As Professor Nathan Clumeck of Belgium observed, ““We don’t want to put GPs into a position where they have to HIV-test almost everyone who has almost every disease.”
The EACS idea received some backing from a Danish study (referenced) that showed that patients who’d previously attended hospital with one or more of a list of non-HIV-related diseases were 37% more likely to subsequently catch HIV, and had a 21% greater death rate.
• Eleventh European AIDS Conference, abstract #P18.4/07.
HIV test vaccine may have harmed volunteers
A new analysis of the STEP ad5 HIV vaccine trial, which was closed when it was found the vaccine was not effective in reducing HIV infections (see ‘Two STEPs Back’, page 38-39), reveals that worse may have happened – the vaccine may have actually made some volunteers more susceptible to HIV.
In a press conference on 7 November, Keith Gottesdiener, the Vice President of Clinical Research for Merck, who made the ad5 vaccine, said that two facts had emerged from the analysis.
One was that HIV infections amongst vaccine recipients were almost exclusively amongst men. Updated data shows that 49 of 914 vaccinated men became infected with HIV – but only one woman. This compares with 33 of the 922 men who got a placebo.
The vaccine trial population consisted largely of gay men and female sex workers, and the reason more men caught HIV may be due to behavioural differences and nothing to do with the vaccine.
What did appear to be vaccine-related was that there was a heightened risk of HIV infection amongst recipients who had high pre-existing immunity to the common cold virus used as the vaccine’s ’wrapping’.
The ad5 vaccine consisted of three segments of HIV wrapped in a ‘vector’ - the shell of an adenovirus, a germ that typically causes mild cold symptoms. It’s so common that many people have pre-existing immunity to it.
Merck found there was a link. In trial volunteers with low immunity to the adenovirus, 28 receiving vaccine caught HIV and 24 receiving placebo. But in those with a high degree of immunity, 21 receiving the vaccine caught HIV and only nine receiving placebo. That’s a highly significant difference.
Why? There might have been chance differences in behaviour between groups of volunteers. But the possibility that alarms the research community is that in volunteers who had pre-existing adenovirus immunity and therefore ‘recognised’ it, an immune reaction may have been set off that made participants more susceptible to HIV.
This is certainly possible: it’s known already that some other viral infections such as herpes make people much more susceptible to HIV.
Gottesdiener said he wanted to emphasise that the vaccine itself could not possibly have caused the HIV infection, “but that the results raise the question of increased susceptibility to infection.”
Margaret Johnston, Director of the US NIAID vaccine programme, said the results gave cause for concern. “We’ll be looking at the scientific justification for moving other vectors forward.”
Lawrence Corey of the HIV Vaccine Trials Network said: “One failed vaccine trial does not mean the whole concept is flawed.”
• Eleventh European AIDS Conference, abstract #P18.4/07.
Women more likely to be non progressors?
A study from Germany has found that women form a higher than average proportion of HIV patients who are so-called Long Term Non-Progressors (LTNPs).
Exactly who is a LTNP varies by definition, but for this study, the researchers defined LTNPs as HIV-positive people who had maintained a viral load below 500 without HIV treatment for at least ten years.
Sixty-one patients from 13 Germany HIV clinics fulfilled this criterion. Nearly half (48%) were women, even though the proportion of people with HIV in Germany who are female is only 15%.
Conversely only 30% of LTNPs were gay men, compared with 60% of the HIV-positive population in Germany.
Over 7.5 years of observation, 87% of the LTNP group had no viral load (VL) over 500 and 50% had no VL over 50.
During this time CD4 counts fell slightly, by 57 cells on average, but this wasn’t a statistically significant decline. Just four (6.5%) of patients had to start HIV treatment, two due to declining CD4 counts and two due to rising viral load.
The 30 patients who maintained viral loads under 50 fall into the group known as ‘elite controllers’ who manage the rare trick of having an effective immune response to HIV. About one in 300 HIV-positive people falls into this category and, needless to say, they are of great interest to researchers who want to know how they do it. An international study is recruiting them (see www.massgeneral.org/aids/hiv_elite_controllers.asp).
It is not known whether other studies have noted a higher than average proportion of women in this category, though women in general do tend to have lower viral loads than men.
• 11th European AIDS Conference, abstract #P6.5/02#P6.5/02
TREATMENT NOTES
Treating chlamydia may help to spread it
A conference at Stockholm University recently has heard that rises in the prevalence of chlamydia in western countries may, paradoxically, be driven by higher rates of screening and treatment. Delegates heard that chlamydia infection tends to have a ‘natural history’: after infection, immunity slowly builds up to the bug until, after about a year, it is strong enough to start purging chlamydia from the body – a process usually over within three years. Treating chlamydia interrupts this development of natural immunity so people are vulnerable to re-infection. This is not an argument against treatment in individual cases, but may explain why national screening programmes haven’t resulted in a fall in cases.
TB is beating us, says Soros
Billionaire George Soros and other public health advocates told the World Conference on Lung Health in Cape Town recently that global programmes to fight TB are ineffective and lead to the development of multi-drug-resistant MDR-TB. “TB is a treatable disease but it has become a death sentence,” said Soros, chair of the Open Society Institute. “Global leaders should move away from empty rhetoric and commit to real programmes.” TB kills 1.6 million people annually, and there are 420,000 cases of MDR-TB a year, most of them caused by failing to ensure people complete their treatment. Only 2% of people with MDR –TB get the pricier drugs needed to beat it, and cases of virtually untreatable XDR-TB continue to be reported, most recently from India.
Rilpivirine on track to beat Sustiva
Results presented at the recent European AIDS Conference show that rilpivirine (TMC278), the second drug in a new group of non-nucleoside HIV drugs (NNRTIs) being developed by Tibotec, was as effective against HIV as efavirenz (Sustiva®) but had fewer of Sustiva’s side effects such as rash, dizziness and abnormal dreams. In the trial 80% of patients new to HIV treatment achieved an undetectable viral load regardless of whether they took efavirenz or one of three doses of rilpivirine. However rilpivirine patients were much less likely to experience rash, dizziness or bad dreams. However the incidence of depression and insomnia were similar between the two drugs.
Black HIV patients get far more kidney disease
People with HIV of African ancestry are far more prone to kidney failure, a US study has found. Rates of End-Stage Renal Disease (ESDR) were eight times more common in African-Americans than in white patients, making this life-threatening condition nearly as common as diabetes. “We can think of few risk factors for ESRD, other than HIV, that are modified to this extent by race,” researcher Andy Choi said. He added, “Our hope is that these results help establish kidney disease as a research priority in the HIV-infected community.”
Roche won’t license needle-free T20 device
Drug companies Roche and Trimeris are withdrawing an application for approval to market the Biojector® 2000 needle-free injection advice for their HIV drug Fuzeon® (T20, enfuvirtide). “While the device has shown potential benefit for some patients, we don’t believe it’s the ideal alternative delivery option for all treatment-experienced patients,” said Michelle Zupancic, Roche’s Vice President for HIV. Roche’s own studies have shown that four our of five patients prefer the Biojector to needles. Roche said that patients who are currently using the Biojector through an existing program or clinical trial may continue to do so, but European advocates pointed out that the device was almost unobtainable in Europe. “People need bio-injector and it should be accessible,” said the French treatment advocacy organisation TRT-5.
Another novel HIV drug makes progress
Modestly promising new results have been published for bevirimat (PA-457), an HIV candidate drug form yet another new class, the maturation inhibitors. These interfere with the making of new viral particles at the last stage of the HIV life cycle. The development of bevirimat has been slow because the original formulation didn’t deliver enough drug to the body. A new study found that a new 300mg tablet produced viral load falls of more than 100-fold in five out of 10 patients with multi-drug-resistant HIV whose regimens were failing, when it was given for 14 days. Manufacturers Panacos are still working on the optimal dose to take onto large trials in 2008.
