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BHIVA 2015: HIV Treatment Outcomes No Better with Single-tablet Regimens than Individual Pills

One-pill-a-day HIV treatments such as Atripla, Stribild, Complera, and Triumeq and Triumeq have the same rates of virological failure, drug resistance, and side effects as multiple tablet regimens, according to a meta-analysis presented to the British HIV Association (BHIVA) conference this week in Brighton. Single tablets cost the UK National Health Service (NHS) 5 five times more but have unproven clinical benefits, said Andrew Hill of Chelsea and Westminster Hospital.

[Produced in collaboration with Aidsmap.com]

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

With the NHS currently spending £411 million (more than US $6 million) a year on antiretroviral drugs alone and the number of patients expected to keep 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 3 years, tenofovir, abacavir, lopinavir/ritonavir, 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 during which they have patented products on 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 drug expired in 2010, GlaxoSmithKline had by then produced a pill that combined lamivudine with zidovudine or AZT (Combivir), which remained under patent until 2013. The company also combined lamivudine with abacavir in the Epzicom or Kivexa coformulation, which they will have the exclusive right to manufacture until 2019. Furthermore, GSK has recently launched a one-pill-a-day HIV treatment, Triumeq, that puts lamivudine, abacavir, and dolutegravir into a single-tablet regimen.

Another example of "evergreening" is Gilead Sciences’ tenofovir alafenamide (TAF), an alternative formulation of tenofovir disoproxil fumarate that works equally well but 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? Overall, antiretroviral regimens made up of generic drugs taken as 3 separate pills typically cost less than £1000 ($1500) per person per year, while branded single-tablet regimens cost between £4500 and £7400 ($6800 and $11,000) per person per year.

No Clear Benefit to Coformulated Tablets

In order to find out whether there are any differences in clinical outcomes that could justify the increased costs, Andrew Hill and colleagues conducted a systematic review and meta-analysis, pooling the results of randomized trials that compared coformulated antiretrovirals against their individual components. Included are:

5 older trials in which, for example, the fixed-dose combination Epzicom was compared to 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.

4 more recent trials in which single tablet regimens such as Atripla, Stribild, and Complera were compared to the use of regimens of 3 or 4 tablets.

A total of 2568 patients were included in the analysis. All the single-tablet regimen trials involved people who were already stable on antiretroviral therapy (ART) and virally suppressed who switched to a new regimen. The lack of randomized studies of 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 randomized 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 2 consecutive occasions). This happened as infrequently with individual pills as with coformulated tablets, 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 randomized 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 randomized the "wrong" arm (4.8% more switches; 95% confidence interval 1.6% to 7.9%).

Data on patient preferences did show that coformulated pills are a more popular option, even if they were not 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 did not 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 randomized trials, despite the large differences in costs.

Rising Antiretroviral Costs

In a plenary talk at the meeting 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.

For example, a year’s supply of the hepatitis B drug entecavir costs around £24 ($36) to produce, and a generic version is available in India for around £285. Bristol Myers-Squibb sells branded versions in India for £875 ($430), in the UK and some other European markets for £4,600 ($6,900), and in the US for around £10,000 ($15,000).

Similarly, the new hepatitis C drug sofosbuvir costs £70 ($40) to produce, Hill's team found. Prices are far higher in Western countries, but with substantial variations that cannot easily be explained -- £18,000 ($27,000) in Spain, £35,000 ($53,000) in the UK, and £57,000 ($86,000) in the US, for example.

While antiretrovirals are not as expensive as this, their prices rise every year by about 8%. Moreover, the number of people receiving HIV treatment in the UK rises every year at a similar rate.

This year 78,000 people are receiving antiretrovirals, with a cost to the NHS of £411 million (more than US $6 million). By 2019 we can expect 106,000 people to be on antiretrovirals, with the bill rising to £559 million ($845 million). These numbers do not include people taking Truvada (tenofovir/emtricitabine) for pre-exposure prophylaxis (PrEP) or hepatitis C treatment, although both need to be financed by the same specialized services budget of NHS England.

Over 5 years, the antiretroviral drug bill could reach £2.41 billion ($3.6 billion) if branded drugs, included some coformulations, continue to be used. Switching whenever possible to generic versions of the same drugs would reduce the bill to £1.16 billion ($1.75 billion).

Daily pill counts would not be substantially different, as appropriate single-tablet regimens are not always available. They would rise from an average of 2.3 pills in the first scenario to 3.5 pills with the use of generics (or fewer if generic coformulations became available).

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 minimize the savings.

Hill concluded that companies that have invested in research and development should be rewarded with appropriate value-based prices for their new medicines, after evaluation by the 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 -- such a strategy could save the NHS £1.25 billion ($1.8 billion).

Switching Strategies

The real-life issues involved in encouraging greater use of generics were reflected in several presentations at the BHIVA conference.

Royal Liverpool University Hospital reported that although local guidance recommends generic efavirenz and Epzicomas the standard first-line therapy, only 8% of prescriptions complied with this. Doctors only occasionally recorded their justification for giving the Atripla single-tablet regimen 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.

4/24/15

References

A Hill, et al. No difference in risk of virological failure between antiretroviral treatments using co-formulated versus individual drugs: meta-analysis of 9 randomised trials in 2,568 patients. 21st Annual Conference of the British HIV Association (BHIVA). Brighton, April 21-24, 2015. Abstract O10.

A Hill. Generics: the facts. 21st Annual Conference of the British HIV Association (BHIVA). Brighton, April 21-24, 2015.