February’s Conference on Retroviruses and Opportunistic Infections (CROI), held this year in Los Angeles, provided a wealth of information regarding some very promising new drugs; increased our knowledge of how to use current drugs better; and explained more about the causes, of and treatment for lipodystrophy and other drug side-effects. For more details of all these studies – and more – visit NAM’s website, www.aidsmap.com.

Four new drugs show promise for treatment-experienced

Data on three new drugs aimed at people with drug-resistant HIV were presented at this year’s CROI, and details of a fourth were released just as ATU went to press.

Of the two integrase inhibitors currently in clinical trials, Merck’s raltegravir (formerly known as MK-0518) is furthest along. This drug is taken twice a day and cannot be boosted by a ‘mini’ dose of ritonavir.

Interim results (some from 16 weeks and some from 24 weeks) from the 48-week BENCHMRK 1 and 2 studies showed that twice as many participants who were randomised to receive treatment with raltegravir plus optimised background therapy achieved a viral load below 50 copies/ml compared to those who received a placebo plus optimised background therapy. Participants taking raltegravir also gained between two and three times more CD4 cells than those on placebo.

Considering that the participants were highly treatment-experienced (all had extensive resistance to drugs from the main three classes of antiretrovirals, about 90% had received an AIDS diagnosis, and they had taking antiretroviral therapy for an average of ten years) these data are very promising indeed. Results from the study also showed that the drug was well tolerated, with very people leaving the study early. Particularly good results were seen for the participants who were able to combine raltegravir with T-20 (Fuzeon) and the newest protease inhibitor, darunavir (Prezista) – 98% achieved a viral load below 400 copies/ml. However, even 61% of those participants who were taking no other active drugs achieved a viral load below 400 copies/ml.

The conference also heard interim results from a smaller, less advanced study of a second integrase inhibitor, Gilead’s elvitegravir (formerly GS-9137 or JTK-303) that can be taken once daily because it is ritonavir-boosted. This study suggests elvitegravir is potent, but only when used in higher doses (three doses were tested and the lowest dose arm of the study was stopped early due to too many people ‘failing’ treatment) and durable, but only when it is combined with at least one other active drug.

"The story here [is that] we have a potent drug, but it is only good if there are other companion drugs available to use with it,” the study’s lead author, Andrew Zolopa, told the conference.

One of the problems seen with elvitegravir was the emergence of resistance if other drugs weren’t used to back it up, similar to what is seen with NNRTIs like efavirenz (Sustiva) or nevirapine (Viramune). In fact, test tube studies hint that there may be some cross resistance with raltegravir, suggesting that resistance to one drug may mean the whole class will not work, just like NNRTIs.

Interim, 24-week results were also presented on the only chemokine antagonist (also known as CCR5 inhibitors) to reach advanced clinical trials. In these studies, Pfizer’s maraviroc was dosed either once daily or twice daily, depending on the other drugs that participants took in the Motivate-1 and –2 studies.

Up to 48% highly treatment-experienced patients who received maraviroc achieved a viral load below 50 copies/ml when the drug was added to an optimised background regimen (compared with 25% or fewer taking a placebo). Participants taking maraviroc also gained almost twice as many CD4 cells as patients taking the placebo. Data so far suggest that maraviroc appears to be safe, since treatment discontinuation and disease progression rates were broadly similar between the placebo and treatment arms of both studies.

Finally, promising early results were announced in March by Australian biotechnology company, Avexa. A 21-day study of their new nucleoside backbone drug (NRTI), apricitabine (formerly AVX754), suggests that even in people with high level 3TC- or FTC- resistance, significant viral load reductions are possible. The drug, which is taken twice a day, also appeared to be well tolerated. More details will be presented later this year at the next major HIV conference, the fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Australia.

New NNRTI may compete with efavirenz

Tibotec’s investigational NNRTI, TMC278, appears to have the potency of efavirenz (Sustiva), but with significantly fewer side-effects, according to 48-week results of a 96-week study of the drug in people new to anti-HIV treatment.

In this study, participants were randomised to receive efavirenz or one of three doses of TMC278, all taken once daily. These were taken alongside AZT/3TC (Combivir) or tenofovir/FTC (Truvada).

After 48 weeks, there was no significant difference between any of three doses of TMC278 or efavirenz in the proportion of participants whose viral load fell to below 50 copies/ml (between 77 - 81% on TMC278 and 81% on efavirenz). Increases in CD4 cell counts were also broadly similar.

Although there was no difference in the frequency of serious side-effects between the two drugs, participants taking TMC278 were less likely to experience central nervous system or psychiatric side-effects than those taking efavirenz, and the incidence of rash was also lower amongst the TMC278-treated participants. Blood fats (total cholesterol and triglycerides) were also lower in the participants on TMC278.

Slightly higher discontinuation rates for the highest dose (150mg) of TMC278 resulted in the investigators selecting the 75mg dose for further phase III study. If successful, Tibotec is likely to market TMC278 as a direct competitor to efavirenz for first-line anti-HIV treatment.

Caution over once-daily Kaletra or nevirapine

In the UK, it is not recommended to take lopinavir/ritonavir (Kaletra) or nevirapine (Viramune) once daily, even though some people do take these drugs this way in clinical practice. Two studies at CROI suggest that some people are more likely to have their treatment fail them using these drugs in this way.

A large open-label study sponsored by the US government (rather than Abbott, Kaletra’s manufacturer) found that taking Kaletra (using the old, soft-gel formulation) once daily appeared to be less effective than taking the drug twice a day in participants with viral loads above 100,000 copies/ml when they started anti-HIV therapy for the first time.

And a small study from France that compared once-daily nevirapine with once-daily tenofovir (Viread) and once-daily 3TC (Epivir) to twice-daily nevirapine with twice-daily Combivir (AZT/3TC) was stopped early due to high rates of early virological failure in people taking the once-daily treatments. It’s not clear why this was the case, but the study’s authors suggest that once-daily nevirapine should not be taken with the combination of tenofovir and 3TC.

Treatment interruptions slightly increase risk of heart disease

Further analysis of the SMART treatment interruption study has found that the participants who were randomised to take CD4-guided treatment interruptions had a slightly increased risk of cardiovascular disease compared with those who remained on anti-HIV treatment.

The SMART study was the largest HIV clinical trial ever, involving close to 6,000 participants in several countries. The study was stopped early after it was found that participants who interrupted their treatment not only had a higher risk of progression to AIDS, but also of serious illnesses including liver, kidney and heart disease.

Researchers from the study have now compared the risk of heart disease between the two arms of the study. A total of 79 cardiovascular events, such as fatal and non-fatal heart attacks, coronary artery disease, and stroke, occurred. There were 48 events in the treatment interruption arm and 31 amongst participants who took anti-HIV treatment continuously. The investigators calculated that the participants who interrupted treatment had a risk of cardiovascular events that was 50% higher than those did not interrupt. The analysis also found that, of the participants who were on anti-HIV therapy at the start of the study, those taking a regimen that included an NNRTI were over twice as likely as those taking a protease inhibitor to experience a cardiovascular event. But the researchers also found that each addition year of treatment with a protease inhibitor also increased the risk of a cardiovascular event slightly.

Because the number of cardiovascular events in the study was small, the difference between the two arms was of only slight statistical significance. The study’s authors noted that while there was “no evidence that interruption immediately increases risk of cardiovascular disease,” longer-term consequences remain to be determined. In the meantime, they said, the data suggest that anti-HIV therapy should not be stopped or avoided due to concerns about perceived cardiovascular risk.

Efavirenz twice as likely to lead to fat loss than Kaletra

The most surprising data to be presented at CROI came from the (non-drug company-funded) ACTG 5142 study, which last year suggested that efavirenz was more durable than lopinavir/ritonavir (Kaletra) over two years. This time, it was Kaletra’s chance to shine: people taking Kaletra with two nucleoside backbone drugs were significantly less likely to experience fat loss (lipoatrophy) than those taking efavirenz with two nucleoside backbone drugs. In fact, participants who took efavirenz were almost twice as likely to experience fat loss in the face or limbs compared to those who took Kaletra. Until now, it was thought that fat loss was primarily caused by the thymidine nucleoside analogues (primarily d4T and, to a lesser extent, AZT).

ACTG 5142 was a large, randomised study that compared a nucleoside-sparing regimen of Kaletra and efavirenz against Kaletra or efavirenz paired with 3TC plus either d4T, AZT or tenofovir. The study was designed to test whether avoidance of nucleoside analogue drugs was effective and safe.

Lipoatrophy (defined as a 20% loss of limb fat at week 96), was experienced by 32% of the efavirenz + two nucleoside group, 17% of the Kaletra + two nucleoside group, and 9% of the Kaletra/efavirenz group.

Even though participants who received tenofovir were less likely to experience lipoatrophy compared to those receiving d4T or AZT, when lipoatrophy incidence was analysed according to pairings of drugs, participants on tenofovir who also took efavirenz were twice as likely to develop lipoatrophy (12%) than those who received Kaletra (6%).

Similarly, AZT recipients who took efavirenz were also at greater risk of lipoatrophy (40% versus 16% for Kaletra recipients). The difference was less pronounced for d4T recipients (51% for efavirenz, 33% for Kaletra).

The study’s authors concluded that efavirenz recipients had, on average, a 2.7-fold higher risk of lipoatrophy compared to Kaletra recipients when both were taken with two nucleoside backbone drugs.

Lead author, Richard Haubrich of the University of California, San Diego, told the conference that treatment guidelines would now need to take into account the effects of different regimens on body fat distribution.

However, Judith Aberg, of the ACTG told US HIV information website, ‘The Body’, that it was too early to come to any firm conclusions regarding efavirenz’s link with lipoatrophy. “I don't want people to think because they see this that they shouldn't be using efavirenz,” she said. “That's the wrong message. People need to take a step back. We need to figure out what's going on...before we make any further comments about it.”

New treatment safe and effective for bone loss

Bone problems, such as osteopenia, osteoporosis and osteonecrosis, are increasingly being recognised as potential side-effects of anti-HIV therapy. New research presented at CROI suggests that alendronate (Fosamax) is a safe and effective treatment for HIV-positive individuals with loss of bone mineral density. This drug is already approved for the treatment of osteoporosis in HIV-negative people in the United States and Europe. No-one taking alendronate reported any significant side-effects,and the drug appeared to work equally well in men and women.