German medicines watchdog rejects ‘new tenofovir’ pill

The German health technology assessment agency IQWiG has announced that it finds no advantage in Descovy, a combination pill containing a new version of the HIV drug tenofovir, over its alternative, Truvada, which is the most widely-used HIV medicine. A press release say that it will not be recommending the provision of Descovy free to patients by the German federal health service as part of antiretroviral therapy (ART) .

The new version of tenofovir in Descovy  is called tenofovir alafenamide or TAF and is combined in the pill with another drug, emtricitabine. TAF is a chemically altered version of the original version, tenofovir disoproxil fumarate or TDF, which is combined with emtricitabine in Truvada. TAF has greater affinity for being absorbed into cells than TDF. This means that it can be given in doses only one-tenth as large as TDF, and also that the levels it reaches in the bloodstream are much lower. This should mean that TAF will cause lower rates of the two side-effects most strongly associated with tenofovir, kidney damage and bone mineral loss, and several different studies of TAF for both HIV and hepatitis B have found little or no decline in kidney function or bone density in people taking TAF, compared with declines in people taking tenofovir.  

TAF is not marketed as a single drug by its makers Gilead Sciences but is incorporated into three fixed-dose combinations, Descovy, Genvoya (Descovy + elvitegravir + cobicistat) and Odefsey (Descovy + rilpivirine). These replicate, respectively, Truvada, Stribild and Eviplera (Complera in the US) which are the same combinations using TDF.

Glossary

European Medicines Agency (EMA)

Regulatory agency that evaluates medicines for safety and efficacy in Europe, performing a similar role to the Food and Drug Administration (FDA) in the United States. The EMA recommends to the European Commission that a medicine can be marketed in the European Union and European Economic Area.

equivalence trial

A clinical trial which aims to demonstrate that a new treatment is no better or worse than an existing treatment. While the two drugs may have similar results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

morbidity

Illness.

non-inferiority trial

A clinical trial which aims to demonstrate that a new treatment is not worse than another. While the two drugs may have comparable results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

Descovy, which is the subject of the IQWiG Benefits Assessment, was given marketing authorisation in the EU by the European Medicines Agency (EMA) on 21 April this year. However, the negative opinion of IQWiG (equivalent to NICE in the UK) is a reminder that EMA authorisation simply allows marketing of a drug in the EU: it is up to individual countries to decide whether to incorporate it into their pharmacopoeia (standard drugs) and pay for it through national health systems.

IQWiG say that there are no data on the benefits or otherwise of Descovy over Truvada in some groups. These include adolescents. Gilead Sciences say that German HIV treatment guidelines do not distinguish between adults and adolescents but IQWiG says they are a distinct population and Descovy needs to be studied in them.

IQWiG also say that the data Gilead Sciences agreed to supply to the body that ultimately sanctions medicines in Germany, the Federal Joint Committee of physicians, dentists, hospitals and health insurers (G-BA), was not adhered to. Gilead had agreed to compare the performance of the two two-drug pills directly, using them with the same third drug – either rilpivirine, efavirenz, or dolutegravir.

In the event Gilead supplied different data, IQWiG say. They supplied data comparing the performance of Descovy when combined with the drugs elvitegravir and cobicistat and compared that with the single-formulation pill Stribild, which combines Truvada with the other two drugs; studies of Descovy did not all use Genvoya but sometimes Descovy plus the two separate drugs. Gilead says that essentially the third and fourth drugs used are the same, but IQWiG is concerned that the data cannot rule out specific interactions between TAF and elvitegravir or cobicistat.

They also do not like the fact that, just because the G-BA has already said that “there is no proof of an added benefit or lesser benefit” of elvitegravir/cobicistat compared with efavirenz, this must imply that Genvoya would be also be non-inferior to Truvada when efavirenz was the third drug used rather than the other two. The agency say that absence of proof that Genvoya plus efavirenz would be inferior to Truvada/efavirenz (usually given as the combination pill Atripla) is not the same as proving that it is equivalent. No data even suggesting equivalence have been submitted for rilpivirine or dolutegravir, they add.

The German agency is also unhappy about the quality of the data supplied for treatment-experienced people. Gilead supplied data on patients who switched from previous therapies. G-BA, however, wanted data that distinguished patients who actually needed to switch due to viral failure or side-effects, and patients who did not need to but were switched as part of studies. The data supplied appears to mix both groups. This makes it more difficult to establish a clear advantage for Genvoya over the previous therapies, IQWiG says.

Finally, although the comparison studies certainly show fewer tenofovir-related side-effects, the biggest one showed no difference in overall effectiveness, IQWiG say. They remark that “the analyses provided no hints of an added benefit of the new combination in comparison of continuation of ongoing treatment for mortality, morbidity and health-related quality of life.”

IQWiG also did their own meta-analysis of studies that included TAF and found that there was evidence of an increased rate of 'nervous system disorders' in people taking Descovy versus people taking Truvada, which was significant in people taking every class of third drug except protease inhibitors. This sounds worrying, though a high proportion of these side-effects were headaches, which are already one of the most common side-effects of TDF. In addition, meta-analyses are subject to magnifying confounders, factors unanticipated by researchers and not counted in the data. However, if this increased rate with TAF is real, it remains unexplained.

This is not the end for Descovy provision in Germany. The G-BA will now conduct a consultation exercise, which may turn up new evidence, or Gilead may supply that requested; they then make a final decision. If they uphold IQWiG’s opinion, German doctors will still be free to prescribe Descovy, because of the EMA authorisation; however the drug will not be refundable through Germany’s public health insurance schemes, and so if it is more expensive than Truvada, patients will have to pay the difference out of their own pockets. This is likely to be a considerable sum if, as expected, cheap generic versions of Truvada start becoming available next year.