Outcomes no better with single-pill regimens

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One pill a day HIV treatments such as atripla, stribild and eviplera have the same rates of virological failure, drug resistance and side-effects as multiple tablet regimens, according to a meta-analysis. Single tablets cost the UK’s National Health Service (NHS) five times more but have unproven clinical benefits, Andrew Hill of the Chelsea & Westminster Hospital said.

Typically, new drugs stay on patent for 20 years. This means that the pharmaceutical company which originally developed the drug has the exclusive right to sell it. Following this, other manufacturers can produce generic versions of the drug, which are equivalent to the branded product, but are typically 80% cheaper. The NHS has been encouraging the increased use of generic equivalents wherever possible across a wide variety of health conditions.

With the NHS currently spending £411m a year on antiretroviral drugs alone and the number of patients expected to keep on growing, there is a particular need to control this spending. Generic versions of efavirenz, lamivudine, ritonavir, zidovudine and nevirapine are already available in the UK. Within the next three years, tenofovir, abacavir, lopinavir, atazanavir and darunavir will also come off patent.

However pharmaceutical companies often use a strategy known as “evergreening” in order to extend the period of time in which they have patented products in the market. One form this can take is the development of fixed dose combinations and single tablet regimens. For example, lamivudine (epivir) was first produced in 1990. Although the patent on this expired in 2010, GlaxoSmithKline had by then produced a pill that combined lamivudine with zidovudine(combivir) which remained under patent until 2013. They also combined lamivudine with abacavir inKivexa, which they will have the exclusive right to manufacture until 2019. Furthermore, the company has recently launched a one-pill-a-day HIV treatment, triumeq, which puts lamivudine, abacavir and dolutegravir into a single tablet regimen. Another example of “evergreening” is Gilead’s tenofovir alafenamide fumarate (TAF), an alternative formulation of tenofovir that is safer for the kidneys and bones. While TAF was discovered in 2001 it will probably only be launched a few months before the original drug’s patent expires in 2017.

The development of single tablet regimens may meet a demand from patients and clinicians for treatments that are more convenient and easier to take, but can the high price tags be justified by better patient outcomes? Antiretroviral regimens made up of generic drugs in three separate tablets typically cost less than £1,000 per person per year. Branded single tablet regimens cost between £4,500 and £7,400 per person per year.

In order to find out whether there are any differences in clinical outcomes that could justify the increased costs, Hill and colleagues conducted a systematic review and meta-analysis, pooling the results of randomised trials which compared co-formulated antiretrovirals with individual components. Included are five older trials in which, for example, the fixed dose combination kivexa was compared with its individual components, abacavir and lamivudine. Participants needed to take an additional drug (a protease inhibitor or non nucleoside reverse transcriptase inhibitor) separately and some trials involved twice-a-day regimens and four more recent trials in which single tablet regimens such as atripla, stribild and eviplera were compared with the use of regimens of three or four tablets.

A total of 2,568 patients took part. All the single tablet regimen trials involved people who were already stable on antiretroviral therapy and virally suppressed switching to a new regimen. The lack of randomised studies in patients beginning HIV treatment for the first time is a limitation. But Hill said that if pharmaceutical companies believe that single tablet regimens really are better for new patients, it’s up to them to run the randomised controlled trials to demonstrate this. Observational cohorts – which provide a lower standard of evidence and are subject to biases in patient selection – were not included.

The primary outcome of interest was virological failure (viral load above 400 copies/ml on two consecutive occasions). This happened as infrequently with individual drugs as with co-formulated pills, in both groups of trials. (The very slight reduction in risk of virological failure with combined pills was not statistically significant: 1.3%, 95% confidence interval -2.8% to +0.2%). Similarly, there was no significant difference in cases of drug resistance or of patients changing treatment because of side-effects.

However a slightly larger number of people joining trials of single tablet regimens but randomised to receive individual tablets changed their treatment despite having an undetectable viral load. Hill speculated that this might be explained by people wanting to join a trial in order to access single tablet regimens and then dropping out when randomised the “wrong” arm. (4.8% more switches, 95% confidence interval 1.6% to 7.9%).

Data on patient preferences did show that co-formulated pills are the more popular option, even if they weren’t associated with any benefits as measured in Quality of Life scores. The early trials found 5% better adherence with fixed dose combinations whereas the more recent trials’ adherence data are less clear. Moreover any adherence benefits didn’t translate into actual differences in clinical outcomes. Hill concluded that the benefit of fixed dose combinations over individual generic pills has not been proven in randomised trials, despite the large differences in costs.

Hill said that the high price of branded drugs cannot be justified by the cost of the raw materials and of production – investigation of the prices charged by Indian and Chinese generic factories suggest very low costs.

Larger savings might be achieved if competition between generic suppliers leads to lower prices. In contrast, a lack of competition between suppliers or slow uptake by patients and clinicians would minimise the savings.

Hill concluded that companies which have invested in research and development should be rewarded with appropriate value-based prices for their new medicines, after evaluation by the UK’s National Institute for Health and Care Excellence (NICE).

Patents for new medicines should be respected. But evergreen patenting should be closely monitored, he said. When patents expire, medicines should be provided at generic prices close to the cost of production. When a generic drug becomes available, cost-effectiveness analyses and the prescribing decisions they inform must be re-evaluated for other drugs that treat the same condition. Existing prices may no longer be justified.

Patients should be systematically asked to switch to generic drugs when they become available.

There are real-life issues involved in encouraging greater use of generics. Royal Liverpool University Hospital has reported that although local guidance recommended generic efavirenz and kivexa as the standard first-line therapy, only 8% of prescriptions complied with this. Doctors only occasionally recorded their justification for giving atripla instead. Clinicians in Middlesborough persuaded around half those taking atripla to switch to generic efavirenz and truvada. While most patients were satisfied with the change, up to a third were not.

Finally, when 96% of patients in Copenhagen were switched from atripla the drug company responded by dramatically lowering their prices – which meant that a year later most patients could switch back. In all these settings, clinical outcomes after switching were excellent.

Aidsmap material
BHIVA abstract
BHIVA abstract

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