Going Solo
Is it safe to switch to a single boosted protease inhibitor, and can this
strategy offer hope to people in the developing world searching for second-line
therapy? Robert Fieldhouse investigates
Illustration Antonio Maggi
The
world fell out of love with ‘one-drug’ HIV therapy back in 1994
when the results of the DELTA trial showed two nukes were better than one.
Two years later, triple therapy became the ‘gold standard’ and
since then three has remained the magic number.
But three years ago, Dr Joe Gathe from Texas impressed attendees at the 43rd
Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago
with results of his small pilot study in 30 of his own patients who started
therapy with lopinavir/ritonavir (Kaletra) alone. Over 24 weeks, 21 of the
30 trial participants achieved an undetectable viral load below 400 copies,
whilst CD4 gains over the same time averaged an impressive 214 cells. Lopinavir/ritonavir
is an attractive candidate for this treatment approach as it is regarded as
potent with a high genetic barrier to the development of drug resistance.
At the time, many hoped this might lead to greater access to simple, potent
therapies across the globe. Simply, taking one drug should be cheaper than
taking three.
Many researchers have further explored the idea of ‘Kaletra monotherapy.’
Some have looked at its potential as first-line therapy, others as a means
of simplifying treatment, allowing patients to drop often toxic nucleoside
analogues from their combo, while others have explored it as a concept for
treating people with limited options while they wait for new drugs to come
along. At this year’s British HIV Association meeting, Dr Laura Waters
from the Chelsea and Westminster hospital (C&W), London presented the
findings of a study where treatment-experienced patients were switched from
triple therapy to Kaletra monotherapy in the clinical setting for at least
12 months. She recruited 35 patients with CD4 cell counts averaging 248 cells
and viral loads of around 55,000 copies. On average, people had used five
prior antiretroviral regimens. Half of the patients included in the analysis
(14/28) achieved an undetectable viral load below 50 copies. These people
had taken an average of five previous antiretroviral regimens before switching
to Kaletra monotherapy, but still gained an average of 155 CD4 cells after
switching. Even patients with resistance to protease inhibitors (PIs) did
fairly well. Five switched to Kaletra monotherapy despite having major PI
drug resistance mutations and three of them still achieved a viral load below
400 copies.
After an average of 14 months, 12 of the 20 remaining patients still had undetectable
viral load.
At this year’s World Aids Conference, four separate studies further
explored the idea of Kaletra monotherapy.
Simplification
Dr Nunes took 60 patients (who were a lot less treatment-experienced than
those included in the C&W hospital study) who had been on triple therapy
for at least six months. He switched half over to Kaletra monotherapy. None
of the participants in this study had experienced treatment failure in the
past. At week 48, 26/30 (86.7 per cent) in the Kaletra monotherapy group and
25/30 (83.3 per cent) in the control group had a viral load below 80 copies.
One patient in each group experienced treatment failure and one patient on
Kaletra monotherapy stopped due to diarrhoea, while another needed to intensify
with tenofovir (Viread) and 3TC (Epivir). Participants are due to be followed
for another 48 weeks.
Kaletra mono vs efavirenz triple
Dr William Cameron has followed his Kaletra monotherapy switch patients for
up to two years. In total, 155 patients were recruited from clinics in the
US, Canada and Spain. Patients had taken AZT/3TC lopinavir/ritonavir for at
least 24 weeks when they were either switched to Kaletra monotherapy or to
AZT/3TC, efavirenz (Sustiva).
Half (50 per cent) of those treated with Kaletra monotherapy compared to 61
per cent of the patients treated with efavirenz achieved and maintained a
viral load below 50 copies through 96 weeks.
Viral load blipped between 50 and 500 copies in 12 patients taking Kaletra
monotherapy, but 11 re-suppressed their virus below 50 copies by sticking
with the one-drug regimen. Two out of four who needed to add nucleoside analogues
back in also got their virus to undetectable again.
New PI drug resistance mutations were detected in 2/15 (13 per cent) of the
patients treated with Kaletra monotherapy, while NNRTI resistance mutations
were detected in 1/5 (20 per cent) of the patients experiencing treatment
failure on efavirenz. The researchers concluded that Kaletra monotherapy may
be “effective in selected patients".
Kaletra monotherapy first-line
MONARK is another pilot, randomised, 96-week trial comparing the safety and
efficacy of Kaletra monotherapy with a standard AZT/3TC Kaletra regimen.
This study, similar to the work undertaken by Dr Gathe, recruited 136 people
living with HIV who had never taken antiretroviral therapy before. Patients
were given drug resistance testing before starting the trial to ensure they
were sensitive to the drugs with which they were being treated. Over 48 weeks,
approxiamately one fifth of the patients receiving Kaletra monotherapy discontinued
therapy while approxiamately one third of those on AZT/3TC lopinavir/ritonavir
stopped their treatment. CD4 gains over 48 weeks were similar between the
two groups (+ 152 cells, Kaletra monotherapy compared with + 159 cells among
people receiving AZT/3TC lopinavir/ritonavir).
Through 48 weeks of therapy 2/83 (2 per cent) of patients receiving Kaletra
monotherapy developed resistance mutations (both in protease), versus 1/53
(2 per cent) on AZT/3TC lopinavir/ritonavir who developed the 3TC-associated
mutation M184V. Similar proportions of patients experienced virologic failure
(11 per cent taking Kaletra monotherapy vs 13 per cent taking triple therapy).
The authors concluded: “Initiating antiretroviral therapy with LPV/r
monotherapy showed a sustained virological efficacy. However, LPV/r monotherapy
was associated with more episodes of viremia compared with three-drug therapy."
Kaletra triple vs Kaletra mono
The fourth study presented at Toronto compared a triple combo of two nukes
and lopinavir/ritonavir with lopinavir/ritonavir alone. Patients who simplified
to Kaletra monotherapy could re-introduce the nukes if their viral load rebounded
to detectable. Typically, patients had been treated with lopinavir/ritonavir
and two nukes for more than six months before entering the study and had viral
loads below 50 copies.
In total, 198 patients were enrolled. After 48 weeks, 85 per cent of the patients
receiving Kaletra monotherapy had maintained a viral load below 50 copies
compared to 90 per cent of the patients receiving triple therapy including
lopinavir/ritonavir.
Six of the 100 patients receiving Kaletra monotherapy experienced treatment
failure; two developed protease inhibitor-associated drug resistance mutations,
compared with ten of 98 people treated with triple therapy. One of these developed
protease inhibitor resistance.
What price for the new tablet?
During the World Aids conference, Abbott Laboratories, the maker of lopinavir/ritonavir,
announced it will sell the new heat stable tablet form of the drug, under
the name Aluvia, at a price of $2,200 a year in developing and middle-income
countries outside sub-Saharan Africa. In Africa and other developing countries,
Aluvia will continue to be sold at $500 a year.
Abbott has been criticised over the past year for the pricing of lopinavir/ritonavir
in low and middle income countries, and also for failing to register the product
in all countries eligible for the ‘access’ price of $500 a year.
Second line potential?
At Toronto this year, activists from around the world called for the greater
availability of potent, tolerable second-line therapy options for the hundreds
of thousands of people who have started therapy in resource-limited settings.
Last year during PN’s visit to the Hannan Crusaid clinic in Gugulethu,
South Africa, Dr Linda-Gail Bekker told us Kaletra was often the key drug
used to treat drug-experienced patients, but that the refrigerating of the
old version was a problem for many.
Hopefully, wider availability of the new tablet, which can be stored without
a fridge, will go some way to providing a solution. But first line ARVs still
costs upwards of $135 a year, whereas the least expensive second-line regimen
costs upwards of $500. In July this year, 25 activists from around the world
met in London with representatives from both Abbott and Gilead Sciences (the
manufacturer of tenofovir and FTC), as both these companies drugs are seen
as crucial components of second-line therapy. Highlighting the disparity in
cost between first- and second-line therapy, activists called for the companies
to grant voluntary licenses to generic companies to manufacture these key
drugs. Gilead has subsequently agreed to grant voluntary licenses to three
generic suppliers in India to produce tenofovir and distribute it to resource-limited
settings.
Compelling
The studies presented at the World Aids Conference provide compelling evidence
that treatment with a boosted protease inhibitor alone may be potent enough
for some; at least for one year of therapy. Further analysis and larger studies
may help us to identify exactly who stands to benefit most from this approach.
