It’s the ‘holy grail’ of HIV treatment research — an effective, tolerable antiviral regimen that can be taken just once a day. And it’s getting close. Some HIV treatments are already available which are taken once a day, and several others should soon join the list.
In the early days of HIV treatment, AZT, then the only antiviral available, was prescribed in what are today considered extreme doses, requiring people to take the drug every four hours, day and night. The level of commitment required to take the drug six times a day, including waking up twice a night, the high dosage and the resultant side effects, meant that for many people the treatment seemed worse than the disease.
Treatments, and our understanding of how to make them work, have come a long way since those early days. The prospect that once-daily HIV treatment might soon be a reality is the realisation of a longstanding goal of drug manufacturers and a longstanding dream of people with HIV.
Drug companies are looking for once-daily treatments for several reasons. The most important is the belief that, with fewer doses to take each day, the likelihood of missing a dose, and potentially promoting resistance to the drug, is reduced.
There is strong evidence to suggest that people taking twice-daily HIV treatment regimens tend to miss fewer doses than people taking their drugs three or more times a day.
While the development of once-daily treatments would enhance adherence rates a bit, there’s a law of diminishing returns at work here. Regimens requiring more than two doses a day can be especially inconvenient, while the difference between twice-daily and once-daily dosing is likely to be somewhat less.
But while the effect on adherence levels of once-daily regimes is likely to be limited, the improvement in convenience for the people who have to take the drugs could be quite large. And this is a major incentive to drug companies who, after all, want to sell their product.
Drug manufacturers are well aware that, even in countries which don’t have US-style direct-to-consumer advertising, people with HIV/AIDS tend to be highly knowledgeable and assertive consumers. In a market with almost 20 drugs already available, manufacturers are now looking for that extra ‘something’ that might make us ask our doctors to consider using a specific drug in our treatment program, and in this regard ‘once-daily dosing’ is right up there with ‘no side effects’.
Speaking of side effects, one of the difficulties in developing once-daily antivirals is balancing dosing convenience with the risk of toxicities. Virtually any drug can be given in large enough doses to last for a 24-hour period, but it’s not always a good idea.
As the amount of drug in each dose increases, the risk of developing toxic side effects also increases.
An alternative to this approach is to slow down the physical processes that remove it from the body. The protease inhibitor Kaletra (which is taken twice a day) uses this technique. Kaletra capsules contain the active ingredient (lopinavir) along with a small amount of another protease inhibitor, ritonavir, which slows down the liver‘s elimination of the lopinavir. Ritonavir is also being used in other treatment combinations in a similar way, and is being investigated in other combinations.
Existing drugs
Only three of the 16 antiretrovirals currently available in Australia are approved for once a day dosing.
The non-nucleoside analogue drug efavirenz (Stocrin) was the first once-daily antiviral approved in Australia. Efavirenz’s long half-life means it is usually taken as one 600mg tablet at night. Tenofovir (Viread) is a relative newcomer, also taken once a day. It is a nucleotide analogue, and it’s only available in Australia on a restricted basis.
The newer formulation of the nucleoside analogue drug ddI (didanosine, Videx EC) has a special enteric coating which enables it to be dosed once a day, instead of the twice-daily dosing that the original (big white) ddI tablets required. Both the old and new formulations of ddI must be taken on an empty stomach.
New ways with old medicines
Several other already-approved HIV medicines are being studied to determine their potential for once-daily dosing.
It’s important to stress here that none of these drugs are currently routinely dosed once daily in Australia, and people taking these drugs should not change their dosing schedule except on their doctor’s advice. In many cases the research supporting once-daily dosing for the antivirals listed below is not yet conclusive, and if further studies do support once daily dosing, the drug manufacturers will have to seek approval for the new dosing protocols with government authorities before they can be prescribed this way.
3TC (lamivudine) is one of the most commonly prescribed antivirals in Australia. It’s usually taken as one 150mg tablet, twice a day. Several studies have shown that 300mg once daily is as effective as twice-daily, and it is now approved for use this way in the US and Europe, where a 300mg tablet is now available..
The manufacturer of d4T (stavudine, Zerit) has developed a new once-daily formulation of the drug. Called Zerit XR (‘extended release’) in the US and Zerit PRC in Europe, it is not yet available in Australia. The new formulation has been plagued by production problems and was the subject of a warning issued in the US after several people developed lactic acidosis when Zerit XR was combined with ddI.
The usual dosing for saquinavir (Invirase/Fortovase) is three times a day, making it an unlikely inclusion in this list. But several studies have suggested that, when combined with low-dose ritonavir, once-daily saquinavir might be a possibility.
A 2002 trial conducted in Thailand by an Australian-Dutch-Thai consortium looked at a once-daily regimen of 1600mg saquinavir (soft gel capsule — Fortovase) in combination with 100mg of ritonavir. The regimen was effective in reducing viral load to undetectable levels in 93 percent of the 69 participants in the trial. A follow-up sub-study suggested that the hard-gel capsule (Invirase) formulation of saquinavir was even more effective when combined with low-dose ritonavir, and would probably have fewer side effects.
The granddaddy of all antiretrovirals, AZT (zidovudine, Retrovir) is also a candidate for future once daily dosing. At the Barcelona AIDS conference, researchers reported on a small study comparing AZT 300mg twice daily with 600mg once daily. Although this study showed that the twice-daily formulation of AZT was superior, it did suggest that a regimen which began with a short period (perhaps two weeks) of twice-daily dosing, followed by a switch to once-daily dosing, might work. The manufacturer is doing more research.
The 2NN study, presented at the 2003 Retrovirus conference in Boston, compared the two leading non-nucleoside drugs, nevirapine (Viramune) and efavirenz, and also compared once and twice-daily dosages for nevirapine. The results of this study showed that there was no significant difference between the 400mg once-daily and 200mg twice-daily options. Once daily dosing has not been approved for nevirapine anywhere yet, but research is continuing.
The ZODIAC study, reported at the ICAAC conference in Chicago in September, looked at once daily dosing for the nucleoside analogue abacavir (Ziagen). This study compared the standard 300mg twice-daily dose with 600mg once daily in 385 treatment-naive people with HIV, who also received once-daily doses of efavirenz and 3TC. The results were similar in both groups, however the once-daily group reported a slightly higher number of hypersensitivity reactions.
Several studies have shown that the protease inhibitor amprenavir (Agenerase) can be taken once daily when combined with low-dose ritonavir (1200mg + 200mg). As with other combinations containing ritonavir, the addition of ritonavir caused increases in cholesterol and triglyceride levels.
In the pipeline
There are three other once-daily antivirals already in the approval pipeline.
The nucleoside analogue emtricitabine (FTC, Emtriva) has already been approved in the US and Europe. FTC is a chemical cousin of 3TC and is dosed as one 200mg capsule once daily.
The company making FTC will make it available in Australia in some circumstances to people who need it.
Atazanavir (Zrivada/Reyataz), an experimental protease inhibitor which has been approved in the US and (with some restrictions on its use) in Europe, is dosed as either two 200mg tablets once daily, or as two 150mg tablets, plus one 100mg ritonavir capsule, also once a day. As well as its once-daily dosing, atazanavir has also generated interest because it does not appear to raise blood fat levels to the same degree as other protease inhibitors.
Fos-amprenavir (Lexiva) is licensed in the US, but not yet Europe or Australia. It is a pro-drug (a substance that is converted into the active drug inside the body) of the protease inhibitor amprenavir (Agenerase) and, like amprenavir, can be dosed either twice a day or (in combination with ritonavir) once a day.
The future
Developing once-daily HIV antivirals is a major focus of current drug research, and it’s likely there will be other drugs on the once-daily menu soon.
The experimental entry inhibitor PRO-542, which is given by intravenous infusion, has one of the longest half-lives of any HIV drug. Current research suggest that it could be given just once a week or even less often.
Another important trend that we will see in the future is co-formulation of multiple drugs in a single pill. Glaxo’s Combivir and Trizivir, already approved in Australia (but taken twice a day and in combination with other drugs) are just the first. The ultimate goal for the drug manufacturers is to have the right drugs in the right HAART).”>drug classes to enable them to eventually market one or more single pill, once a day HIV treatments.
The science
The key to making drugs that can be taken once a day is in the science of pharmacokinetics — the study of how drugs are absorbed into, and removed from, the body.
Pharmacokinetic studies are usually incorporated in phase 1 and 2 clinical trials, as well as preclinical studies in animals. Scientists measure the amount of drug in the bloodstream over a period of time after administering the drug to determine what dose is needed to achieve the desired effect and to see how long that effect lasts.
The drug’s a class=“glossary-term” href=”/glossary/term/412”>bioavailability — the amount of the drug that makes it from the stomach into the bloodstream — and half-life — the time it takes before only half the original blood concentration is left — are measured, along with the minimum and maximum concentrations in the blood (*Cmin* and Cmax).
The objective is to not have too much drug (which could be toxic) or too little (which might not work) in the bloodstream at any time.
From all of these measurements, scientists can calculate the area under the curve (AUC) which indicates the total effect of a specific dose of the drug — and how often the drug must be taken to maintain a effective concentration.
