The Association between Detected drug Resistance Mutations and CD4 + T-Cell Decline in HIV-Positive Individuals Maintained on a Failing Treatment Regimen
Free accessResearch articleFirst published online February, 2018
The Association between Detected drug Resistance Mutations and CD4 + T-Cell Decline in HIV-Positive Individuals Maintained on a Failing Treatment Regimen
To analyse the effect of drug resistance mutations (DRM) on CD4+ T-cell (CD4) trends in HIV-positive people maintained on virologically failing anti-retroviral therapy (ART).
Methods
Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline.
Results
5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/ nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline.
Conclusions
Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.
References
1.
ImazA., FalcóV., RiberaE.Antiretroviral salvage therapy for multiclass drug-resistant HIV-1-infected patients: from clinical trials to daily clinical practice.AIDS Rev2011; 13: 180–193.
2.
WHO.Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. (Accessed 10 July 2014.) Available from http://www.who.int/hiv/pub/guidelines/arv2013/en/.
3.
PhillipsA.N., CohenC., LundgrenJ.D.Issues in the design of trials comparing management strategies for heavily pretreated patients.Curr Opin HIV AIDS2006; 1: 476–481.
4.
DeeksS.G.Durable HIV treatment benefit despite low-level viremia: reassessing definitions of success or failure.JAMA2001; 286: 224–226.
5.
LedergerberB.Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes.Lancet2004; 364: 51–62.
6.
CastagnaA., DaniseA., MenzoS.Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study).AIDS2006; 20: 795–803.
7.
CampbellT.B., ShulmanN.S., JohnsonS.C.Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection.Clin Infect Dis2005; 41: 236–242.
8.
DeeksS.G., HohR., GrantR.M.CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy.J Infect Dis2002; 185: 315–323.
9.
SloandE.M., KumarP.N., KimS., ChaudhuriA., WeicholdF.F., YoungN.S.Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo.Blood1999; 94: 1021–1027.
10.
StoddartC.A., LieglerT.J., MammanoF.Impaired replication of protease inhibitor-resistant HIV-1 in human thymus.Nat Med2001; 7: 712–718.
Cozzi-LepriA., ParedesR., PhillipsA.The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI*.HIV Med2012; 13: 62–72.
13.
DionisioD., VivarelliA., ZazziM.Long-term CD4+ T-cell response in HIV-1-infected patients continuing combination antiretroviral therapy despite high-level viremia and drug resistance.Eur J Clin Microbiol Infect Dis2003; 22: 69–71.
14.
BarbourJ.D., WrinT., GrantR.M.Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults.J Virol2002; 76: 11104–11112.
15.
VaidyaN.K., RongL., MarconiV.C., KuritzkesD.R., DeeksS.G., PerelsonA.S.Treatment-mediated alterations in HIV fitness preserve CD4+ T cell counts but have minimal effects on viral load.PLOS Comput Biol2010; 6: e1001012.
16.
RenaudM., KatlamaC., MalletA.Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen.AIDS1999; 13: 669–676.
17.
RodesB., GarciaF., GutierrezC.Impact of drug resistance genotypes on CD4+ counts and plasma viremia in heavily antiretroviral-experienced HIV-infected patients.J Med Virol2005; 77: 23–28.
18.
de MendozaC., Martin-CarboneroL., GallegoO., CorralA., Gonzalez-LahozJ., SorianoV.Relationship between drug resistance mutations, plasma viremia, and CD4+ T-cell counts in patients with chronic HIV infection.J Med Virol2005; 76: 1–6.
19.
GianottiN., GalliL., ZazziM.No pol mutation is associated independently with the lack of immune recovery in patients infected with HIV and failing antiretroviral therapy.J Med Virol2011; 83: 391–398.
20.
AntinoriA., LiuzziG., CingolaniA.Drug-resistant mutants of HIV-1 in patients exhibiting increasing CD4 cell count despite virological failure of highly active antiretroviral therapy.AIDS2001; 15: 2325–2327.
UKHIV Drug Resistance Database. (Accessed 16 November 2015.) Available from http://www.hivrdb.org.uk/.
24.
WittkopL., CommengesD., PellegrinI.Alternative methods to analyse the impact of HIV mutations on virological response to antiviral therapy.BMC Med Res Methodol2008; 8: 68.
25.
ThiébautR., WalkerS.When it is better to estimate a slope with only one point.QJM2008; 101: 821–824.
26.
SingerJ.D.Using SAS PROC MIXED to fit multilevel models, hierarchical models, and individual growth models.J Educ Behav Stat1998; 23: 323–355.
27.
GlymourM.M., WeuveJ., BerkmanL.F., KawachiI., RobinsJ.M.When is baseline adjustment useful in analyses of change? An example with education and cognitive change.Am J Epidemiol2005; 162: 267–278.
28.
CalmyA., BalestreE., BonnetF.Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings.BMC Infect Dis2012; 12: 147.
29.
StoreyJ.D., TibshiraniR.Statistical significance for genomewide studies.Proc Natl Acad Sci U S A2003; 100: 9440–9445.
30.
FoxZ., DragstedU.B., GerstoftJ.A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial.Antivir Ther2006; 11: 761–770.
31.
De LucaA.The impact of resistance on viral fitness and its clinical implications. In: GerettiA.M., ed. Antiretroviral Resistance in Clinical Practice. London: Mediscript; 2006. (Accessed 13 August 2013.) Available from: http://www.ncbi.nlm.nih.gov/books/NBK2244/.
32.
MillerM.D., WhiteK., PetropoulosC., ParkinN.T.Decreased replication capacity of HIV-1 clinical isolates containing K65R or M184V RT mutations.10th Conference on Retroviruses and Opportunistic Infections (CROI). 10–14 February 2003, Boston, MA, USA. Poster 616.
33.
WainbergM.A.The impact of the M184V substitution on drug resistance and viral fitness.Expert Rev Anti Infect Ther2004; 2: 147–151.
34.
BackN.K., NijhuisM., KeulenW.Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme.EMBO J1996; 15: 4040–4049.
35.
DevereuxH.L., EmeryV.C., JohnsonM.A., LovedayC.Replicative fitness in vivo of HIV-1 variants with multiple drug resistance-associated mutations.J Med Virol2001; 65: 218–224.
36.
PradoJ.G., FrancoS., MatamorosT.Relative replication fitness of multi-nucleoside analogue-resistant HIV-1 strains bearing a dipeptide insertion in the fingers subdomain of the reverse transcriptase and mutations at codons 67 and 215.Virology2004; 326: 103–112.
37.
MenzoS., MonachettiA., BalottaC.Processivity and drug-dependence of HIV-1 protease: determinants of viral fitness in variants resistant to protease inhibitors.AIDS2003; 17: 663–671.
38.
RobinsJ.M., GreenlandS.Identifiability and exchangeability for direct and indirect effects.Epidemiology1992; 3: 143–155.
39.
KaufmanJ.S., MacLehoseR.F., KaufmanS.A further critique of the analytic strategy of adjusting for covariates to identify biologic mediation.Epidemiol Perspect Innov2004; 1: 4.
40.
ColeS.R., HernánM.A.Fallibility in estimating direct effects.Int J Epidemiol2002; 31: 163–165.
41.
CongM.E., HeneineW., García-LermaJ.G.The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions.J Virol2007; 81: 3037–3041.
42.
CiaffL., Koulla-ShiroS., SawadogoA.Dual therapy with a boosted protease inhibitor plus lamivudine is an effective maintenance strategy in patients on second-line antiretroviral therapy in Africa: the ANRS 12286/MOBIDIP trial.J Int AIDS Soc2016; 19Suppl 2: 5.
43.
HoffmannC.J., MaritzJ., van ZylG.U.CD4 count-based failure criteria combined with viral load monitoring may trigger worse switch decisions than viral load monitoring alone.Trop Med Int Health2016; 21: 219–223.
44.
LucasG.M.Antiretroviral adherence, drug resistance, viral fitness and HIV disease progression: a tangled web is woven.J Antimicrob Chemother2005; 55: 413–416.
