Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype-C-infected patients.
BACKGROUND
Virological monitoring is essential to identify antiretroviral treatment (ART) failure, but not widely available. Here, accumulation of resistance and consequences for second-line therapy were investigated in African HIV-1 subtype-C-infected patients.


METHODS
A total of 836 patients initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART and received biannual HIV RNA monitoring. When first-line ART was continued despite virological failure (HIV RNA>1,000 copies/ml), genotypic resistance analysis was performed at baseline, first failure (t1), and 6 or 12 months later (t2). Major resistance mutations (IAS), Stanford genotypic sensitivity scores (GSSs) and proportions of patients meeting WHO-defined failure criteria were compared between time points.


RESULTS
Most patients (642/836, 77%) reached viral suppression and 145/642 patients (23%) experienced subsequent failure after a median of 18 months. Counselling resulted in virological re-suppression in 27% (39/145) and 40% (58/145) continued first-line ART despite virological failure; 26 patients were included for genotypic analysis.The mean number of major drug resistance mutations per person increased from 2.8 (t1) to 4.3 (t2). Initially, NNRTI-associated mutations (n=47) predominated; only 25 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations (mainly M184V) were detected. During prolonged viraemia, NRTI resistance increased (n=44, +76%), in particular thymidine analogue mutations (from 4 to 14) and K65R (from 3 to 6). Consequently, GSSs declined from baseline to t1 and t2: from 3.8 to 1.0 to 0.7 (NNRTIs) and from 6.8 to 5.1 to 4.0 (NRTIs). Despite broad resistance, immunological failure was limited at t2.


CONCLUSIONS
Rapid accumulation of drug resistance occurred when ART was continued despite virological failure. Treatment options were lost, even when WHO-defined failure criteria were not met. This study calls for wider access to virological monitoring.
Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
Roos E
RE
Barth
Susan C
SC
Aitken
Hugo
H
Tempelman
Sibyl P
SP
Geelen
Erik M
EM
van Bussel
Andy I M
AI
Hoepelman
Rob
R
Schuurman
Annemarie M J
AM
Wensing
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000821:virology
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors