An interferon-free regimen of sofosbuvir (Sovaldi) plus ribavirin for 24 weeks led
to sustained hepatitis C virological response in 84 to 89% of HIV-positive
people with chronic hepatitis C genotypes 1, 2, 3 or 4, according to results
from the phase 3 PHOTON-2 study presented on Monday at
the 20th International AIDS Conference (AIDS
2014) in Melbourne, Australia. Cure rates were lower, however, for genotype 1a
patients with liver cirrhosis.
People with HIV and hepatitis C virus (HCV)
co-infection experience more rapid liver disease progression than people with
hepatitis C alone and do not respond as well to interferon-based therapy.
Direct-acting antivirals that target different steps of the HCV lifecycle offer
the prospect of shorter treatment, fewer side-effects and higher cure rates for
people with HIV and HCV co-infection as well as for people with HCV mono-infection.
Jean-Michel Molina from University of Paris Diderot presented data from the phase 3 PHOTON-2 trial, which included 274 people with co-infection in Europe and Australia. Most participants (81%) were men and the mean age was 47
years. The most common HCV genotypes were 1 (41%) and 3 (39%), followed by 4
(11%) and 2 (9%). Most people with genotype 1 had harder-to-treat subtype 1a.
Most participants (80%) had not been treated
previously for hepatitis C. Overall, 20% had cirrhosis (13% of previously
untreated, rising to 45% of treatment-experienced). Nearly half had the
favourable IL28B CC gene variant.
Almost all study participants were on stable suppressive
antiretroviral therapy for HIV and the mean CD4 cell count was nearly 600
cells/mm3. The most commonly used antiretrovirals were efavirenz (Sustiva, also in the Atripla co-formulation) at 25%,
raltegravir (Isentress) at 23%,
ritonavir-boosted darunavir (Prezista)
at 21% and boosted atazanavir (Reyataz)
at 17%. All used an NRTI combination of tenofovir and emtricitabine (the drugs
in Truvada). Early studies found no clinically relevant drug-drug interactions between sofosbuvir and these antiretrovirals, and sofosbuvir is already approved in Europe and the U.S. for coinfected patients.
All participants received Gilead Sciences' HCV
polymerase inhibitor sofosbuvir (400mg once daily) plus ribavirin (weight-based
1000-1200 mg/day). A small number of previously untreated participants with HCV
genotype 2 (19 people) were treated for 12 weeks, while all treatment-experienced
people and everyone with harder-to-treat genotype 1 or 4 were treated for 24
Sustained virological response rates at 12 weeks after
completing treatment (SVR12) were 85% for people with genotype 1, 88% for those
with genotype 2, 89% for genotype 3 and 84% for genotype 4. Relapse rates were
13%, 8%, 9% and 16%, respectively. One person with genotype 3 experienced viral
breakthrough during treatment.
Among the participants with HCV genotype 1, response
rates were higher for people who did not have liver cirrhosis (88% overall, 87%
for subtype 1a and 100% for subtype 1b) compared to those with cirrhosis (65%,
62% and 75%, respectively). Presence of cirrhosis was the only significant risk
factor for poorer response in a multivariate analysis.
For people with other genotypes, cirrhosis had less
impact, although the effect was a bit larger for treatment-experienced compared
to treatment-naive participants with genotypes 2 or 3.
Response rates did not differ significantly between HCV
subtypes 1a and 1b, but the number with the latter type was small. Likewise,
there were too few people not taking antiretroviral therapy to permit a
Looking at HIV-related outcomes, four people
experienced intermittent low-level HIV viral load breakthrough, though none
required modification of their antiretroviral regimen. Absolute CD4 cell counts
increased temporarily during hepatitis C treatment, but CD4 percentages
Sofosbuvir plus ribavirin was generally safe and well-tolerated.
Six people experienced serious adverse events and three stopped treatment early
due to adverse events.
The most frequent side-effects among people treated
for 24 weeks were fatigue (20%), insomnia (17%), headache (16%), nausea (15%)
and diarrhoea (11%). One in five developed grade 3-4 laboratory abnormalities,
most commonly elevated bilirubin among people taking atazanavir. While 10% developed
low haemoglobin levels – a known side-effect of ribavirin – only one person had
"Sofosbuvir + ribavirin resulted in high SVR12
rates in HIV patients coinfected with HCV genotype 1, 2, 3 or 4," the
PHOTON-2 researchers concluded. "Sofosbuvir was well tolerated, with a low
rate of treatment discontinuations due to adverse events."
"[this combination] might be attractive in
places where you don't have access to all the new drugs." Jean-Michel Molina
Results from the PHOTON-1 study were published this week in the Journal of the American Medical Association. This study tested the same regimens in people with HIV
and HCV co-infection, but it was conducted in the US and had a different
genotype distribution that allowed for other subgroups comparisons. Just over
half had HCV genotype 1 (79% with 1a), while the remainder were roughly evenly
split between genotype 2 and 3.
As previously reported at this year's Conference on Retroviruses
and Opportunistic Infections (CROI), the overall SVR12 rate for people with genotype
1 was 76%. Among those with genotype 2, response rates were similar for
treatment-naive people treated for 12 weeks and treatment-experienced people treated
for 24 weeks (88% and 92%, respectively). Among those with genotype 3, however,
previously untreated patients taking the shorter duration had a lower response
rate (67% vs 94%).
The response rates in the PHOTON trials are not
particularly impressive compared to the 90-100% SVR12 rates seen in several
other recent interferon-free studies. Sofosbuvir works better when combined
with other direct-acting antivirals such as the NS5A inhibitors ledipasvir or
daclatasvir (Daklinza), which are
expected to be approved soon. A disadvantage of ledipasvir is that it does not
have potent activity against HCV genotypes 2 or 3.
Molina suggested that sofosbuvir plus ribavirin may be
a good option for people who have HIV and HCV co-infection, with genotype 2 or
3 HCV, who do not have liver cirrhosis. "Ribavirin is
generic," he noted, and this combination "might be attractive in
places where you don't have access to all the new drugs."
At a separate session
discussing the hepatitis C treatment revolution and how to make recent advances
available worldwide, Andrew Hill of Liverpool University and others noted that
pangenotypic drugs – those that work against multiple HCV genotypes – could
potentially mean we will not need genotype testing, which would lower the
overall cost of care.