Antiretroviral combination therapy consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) is the most frequent choice for initial treatment of HIV positive individuals in high, middle and low-income countries. Such combination therapy has been shown to be effective in preventing or reversing the decline in immune function and dramatically decreasing the risk of opportunistic infections and thereby morbidity and mortality from HIV; however, even when using the most potent and best tolerated combination therapy available, HIV may become resistant to the antiretroviral drugs administered and virological failure may occur, thereby making it necessary to switch antiretroviral therapy.
In the event of virological failure, most guidelines in high-income countries recommend that therapy with a boosted protease inhibitor (bPI) should be initiated, and the nucleoside backbone should be modified to 2 NRTIs predicted to be active on the basis of resistance testing.
The current WHO guidelines are similar to high income country guidelines, in that they recommend starting a bPI in combination with two “new” NRTIs and preliminary data suggesting that response to bPI-based second-line regimens are relatively good in Africa ; however, there are two additional challenges in Africa that may influence the optimal drug combination for second-line therapy:
2.1 Late detection of failure
Failure can be regarded as early or late, depending on the duration of ongoing viral replication. In high-income countries it is now usual to check viral load (VL) periodically throughout treatment, so that virological failure can be detected early. The earlier a treatment switch is initiated, the less likelihood there is of further resistance mutations developing prior to treatment switch. Without intensive VL monitoring, the switch to second-line therapy is based on immunological or clinical failure rather than virological failure. Therefore at the time of failure many patients in Africa are likely to have extensive cross-class resistance to NRTIs and NNRTIs.
2.2. Limited ability to individualise second-line therapy
There is a clear relationship between the number of active drugs in the “optimised background regimen” and virological success. A contribution to the success of second-line therapy in high-income countries is therefore likely to come from optimal use of individualised NRTIs in conjunction with the bPI. However, resistance testing is not routinely performed in Africa, and it is unrealistic to expect it to become part of the standard of care for the foreseeable future. A further limitation on second-line treatment is the restricted availability of second-line drugs. Therefore, individually optimised therapy is simply not realistic for most patients failing first-line therapy in Africa and a standardised approach to sequencing regimens is needed, as has been recognised and advocated by WHO. 
There is sparse clinical trial evidence on which to base a rational treatment decision in high-income countries and there is even more uncertainty when it comes to Africa. There is general agreement that an effective second-line regimen should contain a bPI as a backbone. There are a number of possible choices for the bPI, but lopinavir/ritonavir (distributed as “Aluvia” in Africa and “Kaletra” in Europe) is almost always used in Africa due to the availability of a fixed dose combination that is heat stable. The uncertainty arises with what to combine with that bPI backbone. The possible treatment options include:
3.1 bPI plus two new NRTIs
The current WHO-recommended standard of care is to combine the bPI with two new NRTIs. However, there may be limited activity of NRTIs in a second-line regimen used in Africa (as discussed above) and hence there may be room to improve the outcome from second-line therapy using a different approach.
3.2. bPI plus raltegravir
Raltegravir belongs to a novel class of drugs called integrase inhibitors. These act by blocking integration of proviral DNA into host cell DNA, thereby effectively preventing infection of the cell. This action is independent of the reverse transcriptase and protease enzymes. Raltegravir has therefore no cross resistance with the first-line drugs which obviates the need for resistance testing at the time of first-line failure in order to optimise second-line therapy. Furthermore, raltegravir is an oral drug, which is very well tolerated, has high potency, has few drug interactions and is heat-stable. The drug therefore represents a particularly attractive candidate for use in Africa.
3.3 bPI monotherapy
There is increasing evidence from randomised controlled trials that lopinavir/ritonavir can achieve excellent results when used alone, without other drugs. Three of the four large randomised controlled trials of lopinavir/ritonavir that have been published to date investigated switching to lopinavir monotherapy after patients had gained full virological suppression using triple-therapy. In all of these studies, bPI monotherapy was found to be non-inferior to triple-therapy [5-9].
In contrast, the fourth study compared lopinavir/ritonavir monotherapy with triple-therapy in treatment naïve patients starting therapy for the first time (MONARK trial). In this study the monotherapy arm was found to be inferior to triple-therapy.  Adherence was a key factor in achieving good virological response to bPI monotherapy in this naïve patient population. 
Taken together, these trials indicate that PI monotherapy can be a viable treatment option, particularly when used after patients have achieved virological suppression on combination therapy and when patients maintain high levels of adherence. Following an initial period of induction with effective combination therapy, bPI monotherapy may be sufficient to ensure clinical and immunological stability and to maintain VL suppression for many years in a roll-out programme setting.
Following the massive rollout of ART in Africa, large numbers of people are receiving first-line ART, and over the coming few years an increasing number will be developing treatment failure and requiring second-line therapy. There is an urgent need to develop the evidence base for second-line therapy in Africa and other low-income countries where there is extensive NRTI and NNRTI resistance at the time of failure and where program and resource limitations mean that a single uniform second-line treatment (rather than individualised patient treatment) is likely to be the only feasible management approach. The considerably higher costs of second-line therapy present a further imperative for optimising the use of the drugs in this setting and why a robust evidence base for second-line therapy is urgently needed.
 Gazzard, B., British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med, 2005. 6 Suppl 2: p. 1-61.
 Chimbetete, C., et al., Immunological response to boosted PI-containing second-line ART after switching for clinical/immunological criteria is comparable to response to first-line in patients with low CD4 counts in Africa. 15th Conference on Retroviruses and Opportunistic Infections; Boston, USA. Abstract 832, 2008.
 WHO, Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach. World Health Organisation, Geneva, 2006.
 Grinsztejn, B., et al., Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet, 2007. 369(9569): p. 1261-9.
 Pulido, F., et al., Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. Aids, 2008. 22(2): p. F1-9.
 Arribas, J.R., Pulido, F., Delgado, R., González-García, J., Pérez-Elías, M.J. A.A., Portilla, J., Pasquau, J., Iribarren, J.A., Rubio, R., Ocampo, A., Miralles, P., Knobel, H., Gaya, F., Muñoz, R.M., Clotet, B., Podzamcer, D., OK04 Study Group, Lopinavir-ritonavir Monotherapy vs Lopinavir-ritonavir and Two Nucleosides for Maintenance Therapy of HIV. Ninety-six Week Results of a Randomized, Controlled, Open Label, Clinical Trial (OK04 Study). 11th European AIDS Conference; Madrid, Spain. 2007, 2007.
 Arribas, J.R. and F. Pulido, Early virologic rebound in a pilot trial of ritonavir-boosted atanazavir as maintenance monotherapy. J Acquir Immune Defic Syndr, 2007. 46(1): p. 118; author reply 118-9.
 Cameron, W., B. da Silva, and J. Arribas, A two-year randomised controlled trial in antiretroviral naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (study M03-613). 17th International AIDS conference; Toronto, Canada; Abstract THLB0201, 2006.
 Nunes, E.P., Oliveira, M.S., Almeida, M.M.T.B., et al. , 48-week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/mL on HAART - the KalMo study. . 16th International AIDS Conference; Toronto, Canada, 2006.
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