Second-line NRTI-sparing regimen proves equally effective for resource-limited settings

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 20^th 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 resource-limited settings.

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 cells/mm³.

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.

Viral suppression 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.