Second-Line Protease Inhibitor-Based Antiretroviral Therapy after Non-Nucleoside Reverse Transcriptase Inhibitor Failure: The Effect of a Nucleoside Backbone
Free accessResearch articleFirst published online February, 2013
Second-Line Protease Inhibitor-Based Antiretroviral Therapy after Non-Nucleoside Reverse Transcriptase Inhibitor Failure: The Effect of a Nucleoside Backbone
Virological failures on combined anti-retroviral therapy still occur. Boosted protease inhibitor (PI/r)-based therapy is a commonly used option after non-nucleoside reverse transcriptase inhibitor (NNRTI) failure, but whether two fully active nucleoside reverse transcriptase inhibitors (NRTIs) are required is unknown. We investigated the effect of an NRTI backbone in individuals receiving PI/r after failing NNRTI-based combined antiretroviral therapy.
Methods
A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) and UK HIV Drug Resistance Database to identify individuals who failed first-line NNRTI and two NRTIs, and switched to PI/r-based therapy between January 1999 and December 2008 was conducted. We investigated the effect of NRTI on suppression.
Results
In total, 470 individuals met study criteria: 19.6%, 34.5% and 46.0% started 0, 1 or ≥2 NRTIs, respectively. Median CD4+ T-cell count was 223 cells/mm3 and HIV-RNA was 4.3 log10 copies/ml; 246 (52.3%) underwent genotyping before switch. Virological failure occurred in 10.9% and 13% after 48 and 96 weeks, respectively. In multivariable analysis, heterosexual risk group and HIV RNA were independently associated with virological failure; higher CD4+ T-cell count was protective (HR=0.92). Number of new NRTIs or genotypic sensitivity score of backbone had no effect on treatment success rates when modelled as categorical or continuous variables.
Conclusions
Successful treatment with a second-line PI/r may not require two active NRTIs. If replicated in clinical trials, these findings could guide future recommendations.
References
1.
GazzardB.G., AndersonJ., BabikerA.British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med2008; 9: 563–608.
2.
d'Arminio MonforteaA., LepriA.C., RezzaG.Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. AIDS2000; 14: 499–507.
3.
DielemanJ.P., JambroesM., GyssensI.C.Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. AIDS2002; 16: 737–745.
4.
LennoxJ.L., DejesusE., BergerD.S.Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr2010; 55: 39–48.
5.
MillsA.M., NelsonM., JayaweeraD.Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS2009; 23: 1679–1688.
6.
DaarE.S., TierneyC., FischlM.A.Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med2011; 154: 445–456.
7.
World Health Organization.Antiretroviral therapy for HIV infection in adults and adolescents. Recommendations for a public health approach. 2010 revision. (Updated 2010. Accessed 27 May 2011.) Available from http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf.
8.
ArribasJ.R., DelgadoR., ArranzA.Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr2009; 51: 147–152.
9.
CameronD.W., da SilvaB.A., ArribasJ.R.A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis2008; 198: 234–240.
10.
ArribasJ.R., HorbanA., GerstoftJ.The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS2010; 24: 223–230.
11.
NunesE.P., Santini de OliveiraM., MerçonM.Monotherapy with lopinavir/ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMo Study). HIV Clin Trials2009; 10: 368–374.
12.
BiermanW.F.W.HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS2009; 23: 279–291.
13.
Pujades-RodríguezM., O'BrienD., HumbletP., CalmyA.Second-line antiretroviral therapy in resource-limited settings: the experience of Médecins Sans Frontières. AIDS2008; 22: 1305–1312.
14.
CaneP., ChrystieI., DunnD.Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ2005; 331: 1368–1371.
MurphyR.A., SunpathH., CastillaC.Second-line antiretroviral therapy: long-term outcomes in South Africa. J Acquir Immune Defic Syndr. 2012; 61: 158–163.
17.
MadrugaJ.V., BergerD., McMurchieM.Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet2007; 370: 49–58.
18.
HullM., MooreD., HarrisM.A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations.49th Interscience Conference on Antimicrobial Agents and Chemotherapy. 12–15 September 2009, San Francisco, CA, USA. Abstract H-916.
19.
BartlettJ.A., RibaudoH.J., WallisC.L.Lopinavir/ ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS2012; 26: 1345–1354.
20.
BunupuradahT., ChetchotisakdP., AnanworanichJ.A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ ritonavir in patients failing NNRTI regimens: the HIV STAR study. Antivir Ther2012; 17: 1389–1390.
21.
GilksC.F., WalkerA.S., DunnD.T.Lopinavir/ritonavir monotherapy after 24 weeks of second-line anti-retroviral therapy in Africa: a randomised, controlled trial (SARA). Antivir Ther2012; 17: 1363–1373.
BarberT.J., GerettiA.M., AndersonJ.Outcomes in the first year after initiation of first-line HAART among heterosexual men and women in the UK CHIC Study. Antivir Ther2011; 16: 805–814.
24.
IsraelskiD., Gore-FeltonC., PowerR.Sociodemographic characteristics associated with medical appointment adherence among HIV-seropositive patients seeking treatment in a county outpatient facility. Prev Med2001; 33: 470–475.
