The Pharmaceutical Benefits Scheme has recently added three new antiretrovirals, to become available on prescription in December. PAUL KIDD takes a look at the newest weapons in the anti-HIV armoury.
In July this year, the committee which advises the government on listing medicines on the Pharmaceutical Benefits Scheme (PBS) recommended the addition of three new drugs for HIV treatment: enfuvirtide, atazanavir and fosamprenavir. These drugs have been in use in Australia on a limited basis for a while, through clinical trials and Special Access Schemes, but they will now become available for S100 prescription by doctors.
Atazanavir
Developed and marketed by Bristol-Myers Squibb (who also make d4T and ddI), atazanavir is a protease inhibitor. It is sold under the brand name Reyataz and is sometimes referred to by the acronym ATV.
Like other protease inhibitors — such as ritonavir, saquinavir, indinavir, lopinavir, amprenavir and nelfinavir — atazanavir works by interfering with an enzyme called protease, which HIV needs to produce new copies of itself. Atazanavir is different to earlier PIs in that it can be taken once daily and, in clinical trials, it did not lead to the same increases in blood fats.
Atazanavir comes in capsules which each contain either 150 or 200 milligrams of the medicine. The dose is two 200mg capsules once a day, or two 150mg capsules plus 100mg of ritonavir, once a day. It is recommended that atazanavir be taken with a meal, as this increases blood concentrations of the drug by up to 70 percent. Atazanavir should only be prescribed as part of a combination of HIV drugs.
Several clinical studies have demonstrated atazanavir’s effectiveness in comparison to existing drugs.
One large study compared atazanavir to efavirenz in a group of 805 people who had never taken treatment before. Both groups took AZT and 3TC (Combivir) in addition to either 600mg efavirenz or 400mg atazanavir. After 48 weeks of treatment, the numbers of people with viral loads below 400 were about the same (70 percent for the ATV group and 64 percent for the EFV group), leading the researchers to conclude that atazanavir was equivalent to efavirenz. Average increases in CD4 levels were also about the same in both groups.
The group taking atazanavir experienced significantly lower rises in blood cholesterol (an average increase of one percent compared with 18 percent in the EFV arm) and triglycerides (an average fall of nine percent in the ATV arm versus a rise of 23 percent in the EFV arm).
Two other major studies in treatment-na??ve people compared atazanavir with nelfinavir, with similar results.
There hasn’t been as much research into atazanavir’s effectiveness among people who have previously taken other anti-HIV drugs, but what there is is encouraging. One study which compared atazanavir to Kaletra found that Kaletra was superior, but another study which used the ritonavir-boosted dosage of atazanavir (ATV/r) found that ATV/r was as good as Kaletra, and superior to a third arm which took atazanavir plus saquinavir.
There has been no research yet into the use of atazanavir in children or pregnant women.
Like all HIV medicines, atazanavir does lead to side effects in some people. The most significant of these is increases in blood levels of bilirubin, a yellowish waste product of the breakdown of red blood cells in the liver. High bilirubin levels are usually associated with jaundice and can be indicative of liver disease; however there is no evidence that atazanavir causes any clinically significant liver problems. Up to 45 percent of people taking atazanavir in clinical trials have developed increased bilirubin levels, however very few (5–10 percent) become jaundiced.
A number of people taking atazanavir have developed hematuria — small amounts of red blood cells in the urine. We still don’t understand the clinical significance of this, but hematuria can sometimes be a sign of kidney damage. There have also been a small number of reports of people developing abnormal heart rhythms after taking atazanavir, and one case in which a woman developed liver damage.
Other, less serious side effects that have been reported include rash, nausea, vomiting, diarrhoea, headache and abdominal pain. In a study comparing atazanavir to Kaletra, the patients in the atazanavir arm experienced significantly less diarrhoea than those taking Kaletra.
On the upside, perhaps the most important characteristic of this new drug is the side effect it doesn’t cause. Increased blood fat (triglyceride) and cholesterol levels are a troubling side effect of many of the existing HIV drugs, and the protease inhibitors are the worst offenders. Increased triglyceride and cholesterol levels are a major risk factor for heart disease, and the phenomenon is believed to be related to the development of lipodystrophy.
Several clinical studies have found that atazanavir does not raise blood fats and cholesterol to the same degree as other drugs. In a study comparing atazanavir to efavirenz in people who had not previously taken treatments, fasting LDL (‘bad’) cholesterol rose by an average of one percent in the atazanavir group, compared with 18 percent in the group taking efavirenz. Triglyceride levels rose by an average of 23 percent in the efavirenz group, but fell by nine percent in the atazanavir group.
In the studies comparing atazanavir with nelfinavir, the results were similar. After 48 weeks of treatment, people taking atazanavir had typical rises in cholesterol and triglycerides of less than five and 10 percent respectively. Those taking nelfinavir had rises of 30 and 40 percent.
We still don’t fully understand the long-term clinical significance of the rises in blood fats that have occurred with other drugs, and of course it remains to be seen whether the results that have been observed in clinical trials of atazanavir are borne out in clinical experience.
Because there have been reports of abnormal heart rhythms and development or worsening of diabetes among people taking atazanavir, it’s important that people who take this drug are carefully monitored for these conditions, and that you report any side effects to your treating doctor.
Enfuvirtide
Better known as T-20, enfuvirtide is the first drug in a new class called fusion inhibitors. It was originally developed by Trimeris Pharmaceuticals and is manufactured and distributed by Roche under the brand name Fuzeon.
T-20 works against HIV in a different way to existing drugs, by attaching to a protein on the surface of the HIV virus called gp41. Because HIV uses gp41 to bind to and enter human cells (a process called ‘fusion’), this class of drugs can stop the virus from infecting uninfected cells. This is different to the existing reverse transcriptase and protease inhibitors, which work by interrupting the processes by which HIV that has already infected cells multiplies and produces new viruses.
Use of T-20 in Australia to date has been limited to ‘salvage therapy’ in people who have developed resistance to most or all other anti-HIV treatments and, for the foreseeable future, this is not expected to change. The Pharmaceutical Benefits Advisory Committee recommended the inclusion of this drug on the PBS schedule only for people who have developed broad resistance to existing treatments or who have failed treatment with other regimens using drugs from the existing three classes.
Because the T-20 molecule is extremely fragile, this drug must be injected and is not available in an oral form. The drug comes in a powder form in ampoules which must be mixed with sterile water before being injected under the skin, usually on the belly but sometimes on the arm or leg. People who have taken T-20 report that the process of mixing up and injecting this drug takes between 30 and 40 minutes, twice a day. Injection site reactions, which can sometimes be quite painful, are very common.
Clearly this is a drug which poses significant challenges for those who need to use it, but users of T-20 won’t be on their own: comprehensive training and ongoing support are provided.
The good news, however, is that T-20 has proven itself to be a very effective anti-HIV therapy. The two major clinical trials of T-20 were called TORO 1 and TORO 2, both of which examined T-20 in a total of about 1000 heavily pre-treated people who had experienced multiple treatment failure.
These two studies examined the effectiveness of T-20 in combination with an ‘optimised background regimen’ of several other anti-HIV drugs, selected on the basis of resistance testing. The TORO trials were open-label, randomised trials, with about two-thirds of the participants receiving T-20 plus the background drugs, and the remainder taking an optimised regimen without T-20.
In both of the TORO studies, the participants taking T-20 had significantly greater reductions in HIV viral load compared with those who took the optimised background regimen alone. Long-term follow up of people taking T-20 has consistently demonstrated its effectiveness in a good number of patients. The most recent data has shown that T-20 continues to be effective in about a quarter of patients after more than two years.
Some recent research has also suggested that T-20 may be useful and effective even when added to an existing, non-optimised regimen where the patient has developed resistance.
T-20 has been studied in children over six years but not in younger children. There has been one reported case of its use in a pregnant woman with no adverse effects, however further research is needed in this area.
Despite the complexity and inconvenience of the injection process, a study of the health-related quality of life of participants in the TORO trials showed that taking T-20 did not have any adverse effects, and in some cases led to improvements in mental health and general wellbeing. In another survey of people taking this drug, two-thirds said they found the injection process easy or very easy, and only 11 percent reported that it was difficult or very difficult.
The most common side effect reported by people using T-20 is an injection site reaction — pain, redness and swelling at the point where the drug was injected. Around 95 percent of people taking T-20 have experienced injection site reactions. In about nine percent of people the reaction is sometimes severe enough to require pain relief. In the clinical trials of this drug, 50–60 percent of people reported tenderness or soreness at any given time.
Some people have developed an itchy rash after taking T-20. Over time, some people taking this drug report hardening of the skin, and in rare cases, people have developed abscesses.
Apart from these injection site reactions, other side effects of T-20 may include headache, insomnia, peripheral neuropathy and an abnormality in the blood called eosinophilia. There have been two reported cases of hypersensitivity (severe allergic) reactions to T-20.
People taking T-20 are at increased risk of developing bacterial pneumonias and swollen lymph glands; the reasons for this are still not known.
T-20 is an important and useful new addition to the range of drugs available for people with HIV in Australia for people with advanced treatment failure. Research is continuing on other fusion and entry inhibitors which can be taken orally.
Fosamprenavir
The third new drug to be added to the PBS this year is fosamprenavir. As the name suggests, this is related to the existing protease inhibitor amprenavir (Agenerase). Fosamprenavir, which will be sold under the brand name Telzir, is a ‘pro-drug’ of amprenavir — a substance which is converted to amprenavir inside the body. It is manufactured by GlaxoSmithKline. In the US, the drug is marketed under a different name, Lexiva.
The benefits of fosamprenavir against amprenavir are that it requires fewer pills (the usual dose is one 700mg tablet, plus one 100mg capsule of ritonavir, twice a day — versus eight capsules of amprenavir twice a day) and achieves higher blood concentrations than amprenavir. Because of this, GlaxoSmithKline plans to eventually phase out the production of amprenavir.
In a clinical study reported earlier this year, 249 previously untreated people were randomised to receive either fosamprenavir (166 people) or nelfinavir (83 people). The average CD4 counts and viral loads were similar in both groups at the start of the study, and all participants received abacavir and 3TC in addition to the protease inhibitor. After 48 weeks of treatment, 54 percent of the fosamprenavir group, and 40 percent of the nelfinavir group, had viral load levels below 50 copies/ml, and 66 and 51 percent respectively were below 400 copies. The differences between the groups were not statistically significant.
A larger study looked at fosamprenavir boosted with ritonavir, again in comparison to nelfinavir, in untreated people. The participants in this group took either 1400mg fosamprenavir and 200mg ritonavir once a day, or 1250mg nelfinavir twice a day, in combination with abacavir and 3TC. After 48 weeks, 69 percent of the fosamprenavir group, and 68 percent of the nelfinavir group, had a viral load below 400 copies. Among participants who started the trial with very high viral loads or very low CD4 counts, fosamprenavir was superior. It’s important to note that this trial used a once-daily dosing of fosamprenavir.
The CONTEXT study compared the once-daily and twice-daily doses of fosamprenavir, boosted with ritonavir, to Kaletra. The 320 participants in this study had all taken protease inhibitors before, and all received two nucleoside drugs, chosen by resistance testing, in addition to the study drug. The results of this study suggested that Kaletra was superior to fosamprenavir, although the proportion of patients with undetectable viral load after 48 weeks was similar between the Kaletra and twice-daily fosamprenavir arms. The once-daily fosamprenavir arm was slightly less responsive.
Side effects of fosamprenavir are similar to those for amprenavir, including nausea, vomiting, diarrhoea, rash and headache. In rare cases there may be a severe allergic reaction to this drug. Like most other protease inhibitors, fosamprenavir can raise blood triglyceride levels, however it may be less likely to raise cholesterol levels.
