Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch.
BACKGROUND
High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification.


METHODS
Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression.


RESULTS
One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥ 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL.


CONCLUSIONS
Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.
Department of Clinical Research, London School of Hygiene and Tropical Medicine, United Kingdom.
Victoria
V
Johnston
Karen
K
Cohen
Lubbe
L
Wiesner
Lynn
L
Morris
Johanna
J
Ledwaba
Katherine L
KL
Fielding
Salome
S
Charalambous
Gavin
G
Churchyard
Andrew
A
Phillips
Alison D
AD
Grant
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D011446:Prospective Studies; D012367:RNA, Viral / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013019:South Africa; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects* / Q000235:genetics
D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors
adherence; resistance; second-line antiretroviral therapy; virological failure