[Viva] Fwd: CATIE News - Exploring possible treatment options after virological failure with raltegravir

Tue Jan 20 00:08:28 PST 2015

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From: CATIE <mailer at catie.ca>
Date: Mon, Jan 19, 2015 at 4:58 PM
Subject: CATIE News - Exploring possible treatment options after
virological failure with raltegravir
To: dbecker106 at gmail.com

     CATIE News - Bite-sized HIV and hepatitis C news bulletins
       CATIE News - Exploring possible treatment options after virological
failure with raltegravir

There are several classes of anti-HIV drugs, the newest of which is
integrase inhibitors.

The first licensed integrase inhibitor was raltegravir (Isentress) and the
second was elvitegravir (in Stribild). These two drugs represent the first
generation of integrase inhibitors. HIV that is resistant to raltegravir
can often also be resistant to elvitegravir and vice versa. When HIV is
resistant to more than one drug in a class, this type of resistance is
called cross-resistance.

The next integrase inhibitor that was licensed was dolutegravir (Tivicay
and in Triumeq). This drug belongs to the second generation of integrase
inhibitors.

In general, integrase inhibitors are well tolerated, have potent anti-HIV
activity and, in the case of raltegravir and dolutegravir, have relatively
few interactions with other drugs.
 Results from some trials

In clinical trials with heavily treatment-experienced people who received
raltegravir, strains of HIV that can resist raltegravir (and in some cases
also elvitegravir) have emerged in up to 60% of participants. In contrast,
in clinical trials of raltegravir with participants who had never
previously been exposed to anti-HIV therapy, up to 8% of participants have
developed strains of HIV that are resistant to this drug.
 In the clinic

The world of clinical trials is akin to a carefully controlled environment,
with only highly selected participants who do not usually represent the
full range of people seen at hospitals and clinics. It is therefore
important that observational studies are conducted with clinic populations
after a drug is licensed.
 In France

Physician-researchers at leading infectious disease clinics in France have
conducted an observational study of their patients whose regimens were
based on raltegravir (that is, raltegravir was likely the most potent drug
in their combinations). The doctors were particularly interested in how HIV
might have changed or mutated to resist the effect of raltegravir and
perhaps other integrase inhibitors and what this might mean for future
therapeutic options. All participants were experiencing virological
failure, defined by researchers as the results of two consecutive viral
load test results that were greater than 50 copies/ml.

In an analysis of blood samples from just over 500 participants,
technicians found that 61% had HIV that was still susceptible to *all
*integrase
inhibitors. In cases where HIV was resistant to raltegravir, 14% were also
resistant to dolutegravir. Other findings appear later in this *CATIE News*
bulletin.
 Study details

Researchers recruited 502 participants from 17 clinics across France. All
participants were using raltegravir-based regimens that were failing. Their
average profile was as follows:

   - age – 48 years
   - gender – 74% men, 26% women
   - viral load – between 200 and 6,310 copies/ml
   - CD4+ count – 218 cells/mm3
   - average number of previously used anti-HIV drugs – 8
   - most common strain (or subtype) of HIV – subtype B (the most common
   strain in North America, Western Europe and Australia)

 Researchers defined virological failure as two consecutive viral load test
results that were greater than 50 copies/ml. Virological failure occurred
on average 11 months after raltegravir-based regimens were initiated.

Commonly used drug combinations at the time of virological failure were as
follows:

   - raltegravir + two nucleoside analogues (also called “nukes”)
   - raltegravir + nukes + protease inhibitors
   - raltegravir + protease inhibitors

 Results

The good news is that technicians found that in 61% (306) of participants
HIV was susceptible to *all* integrase inhibitors, including raltegravir.
 Cross-resistance associated with raltegravir resistance

The researchers presented data on 194 participants who had HIV that was
resistant to raltegravir. Among these 194 people, there was only a small
proportion—11% (21 of 194 participants)—in whom elvitegravir could be used
because of lack of cross-resistance. In contrast, among those with HIV that
was resistant to raltegravir, 64% (124 of 194 participants) had HIV that
was susceptible to dolutegravir.
 Linked to resistance

The development of HIV that was resistant to raltegravir was associated
with the following:

   - having a viral load greater than 1,000 copies/ml
   - having HIV that was only modestly susceptible to the non-raltegravir
   component in regimens

 The researchers said that doctors treating raltegravir-using patients
should take this information into account. They also stated that minimizing
the time patients spend on a failing regimen containing raltegravir or
elvitegravir is very important. The longer HIV is exposed to a failing
regimen of either of those integrase inhibitors, the more likely it is to
develop and accumulate mutations that can help it to also resist
dolutegravir.

*—Sean R. Hosein*

REFERENCES:

   1. Fourati S, Charpentier C, Amiel C, et al. Cross-resistance to
   elvitegravir and dolutegravir in 502 patients failing on raltegravir: a
   French national study of raltegravir-experienced HIV-1-infected
patients. *Journal
   of Antimicrobial Chemotherapy*. 2015; *in press*.
   2. Hu Z, Kuritzkes DR. Altered viral fitness and drug susceptibility in
   HIV-1 carrying mutations that confer resistance to nonnucleoside reverse
   transcriptase and integrase strand transfer inhibitors. *Journal of
   Virology*. 2014 Aug;88(16):9268-76.
   3. Quashie PK, Oliviera M, Veres T, et al. Differential effects of the
   G118R, H51Y and E138K resistance substitutions in HIV integrase of
   different subtypes. *Journal of Virology*. 2015; *in press.*
   4. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of
   dolutegravir in treatment-experienced subjects with raltegravir-resistant
   HIV type 1 infection: 24-week results of the VIKING Study. *Journal of
   Infectious Diseases*. 2013 Mar 1;207(5):740-8.
   5. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in
   antiretroviral-experienced patients with raltegravir- and/or
   elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3
   study. *Journal of Infectious Diseases*. 2014 Aug 1;210(3):354-62.
   6. Malet I, Gimferrer Arriaga L, Artese A, et al. New raltegravir
   resistance pathways induce broad cross-resistance to all currently used
   integrase inhibitors. *Journal of Antimicrobial Chemotherapy.*  2014
   Aug;69(8):2118-22.
   7. Llibre JM, Schapiro JM, Clotet B. Clinical implications of genotypic
   resistance to the newer antiretroviral drugs in HIV-1-infected patients
   with virological failure. *Clinical Infectious Diseases*. 2010 Mar
   15;50(6):872-81.

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