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German medicines watchdog rejects ‘new tenofovir’ pill
Gus Cairns, 2016-08-22 09:30:00
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
of TAF for both HIV and
hepatitis B have found little or no decline in kidney function or bone density
in patients taking TAF, compared with declines in patients 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.
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 say 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 patients taking Descovy
versus ones taking Truvada, especially
in patients also taking protease inhibitors - though meta-analyses are subject
to magnifying confounders, factors unanticipated by researchers
and not counted in the data.
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.