A second-line antiretroviral regimen of lopinavir/ritonavir
(Kaletra/Aluvia) and raltegravir (Isentress) proved just as effective as a
regimen containing lopinavir/ritonavir and two or three nucleoside or nucleotide analogues in large
study conducted in Australia, Africa, Latin America and Asia, researchers from
Sydney’s Kirby Institute reported this week at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
The study was designed to test whether the two-drug regimen
offered a viable alternative to the current World Health Organization recommendation
that second-line antiretroviral therapy in resource-limited settings should consist
of ritonavir-boosted lopinavir or atazanavir, plus two nucleoside or nucleotide
analogues, which may be recycled from the failing first-line regimen.
Another study presented at the conference, conducted in North America, found that people taking a failing protease inhibitor-containing regimen could switch to a regimen that did not contain nucleoside or nucleotide analogues (NRTIs).
The potential weakness of the currently recommended approach
is that patients may already have high-level resistance to one or more of the
recycled agents, leaving the success of the second-line regimen vulnerable to
poor adherence or unforeseen drug interactions that lead to low drug levels and
failure of viral suppression.
The Second-Line study was designed to evaluate an
alternative regimen that could overcome the risks of resistance, using one of
the currently recommended agents.
Lopinavir/ritonavir is becoming widely available in
resource-limited settings both as a branded product (Aluvia) manufactured by AbbVie (formerly Abbott) and in various
generic formulations. Merck, the
manufacturer of raltegravir, has issued voluntary licences to two Indian
companies, and six South African manufacturers, but the drug is not licensed to
the Medicines Patent Pool, which might allow more rapid and extensive adoption
by a range of generic manufacturers, in turn leading to potential price
reductions. Merck has
stated that it does not “think that the Medicines Patent Pool presents the
most appropriate tool to increase access to raltegravir in the developing world
at this point in time”.
The Medicines Patent Pool currently considers raltegravir to
be a medium-priority medicine for use in third-line therapy due to WHO’s
tentative recommendation of the drug for use in third-line regimens in
The Second-Line study randomised 558 adults who were
receiving first line NNRTI-based antiretroviral therapy and who had two
consecutive viral load measurements above 500 copies/ml, at least seven days apart. The study excluded
participants with active hepatitis B infection or any opportunistic infection,
as well as pregnant women and current drug users.
Nucleoside drugs in the second-line regimen were selected after
resistance testing where available, or else by reference to an algorithm.
The primary endpoint of the study was the proportion of
patients with viral load below 200 copies/ml at week 48.
Participants had been receiving first-line treatment for a
median of three and half years at the time of study entry. The median baseline
viral load of participants was 4.3 log10 copies, more than half of
participants had viral load above 10,000 copies/ml at baseline, and 20% of
participants had viral load above 100,000 copies/ml. A substantial proportion
of patients had very advanced HIV disease: 25% had CD4 cell counts below 100
cells/mm3 and a further 25% had CD4 cell counts between 100 and 200
Final analysis showed no significant difference in virologic
outcomes at week 48, whether by intent-to-treat or missing equals failure
analysis. By non-completer-equals-failure analysis, 77.8% of the raltegravir
group and 76.8% of the NRTI group had viral load below 200 copies/ml and 66.2%
and 66.4% respectively had viral load below 50 copies/ml.
below 200 copies was more frequent in those with baseline viral load below
100,000 copies/ml (87.6 vs 85.8%), but there was no significant difference in
outcomes by regimen in the higher viral load stratum (65 vs 59.6%).
Participants receiving lopinavir/ritonavir and raltegravir had significantly greater
CD4 cell gains during the study (+167 cells vs + 132 cells, P<0.01), and
also experienced greater improvements in haemoglobin and neutrophil counts.
There was no significant difference in adverse events
between the two groups, although the raltegravir group experienced significantly
greater increases in total, HDL and LDL cholesterol. There was no significant
difference in deaths or AIDS-defining events.
The study authors conclude that the new regimen offers
simplicity, efficacy and tolerability, and should be considered as a robust
alternative strategy to the currently recommended second-line ART regimens. The
advantage of the raltegravir regimen is that both drugs can be dosed twice a
day, so the two products have the potential to be co-formulated in one pill,
which would assist in adherence and supply chain management.