Using a database of HIV patients undergoing genotypic resistance test after HAART failure to understand the dynamics of M184V mutation.
OBJECTIVE
M184V/I mutation is associated with high-level phenotypic resistance to lamivudine (3TC). The aim of the present analysis was to correlate the time of appearance/disappearance of M184V/I with duration of 3TC treatment.


METHODS
Overall, 211 patients were selected from a database of HIV patients undergoing genotypic resistance test after virological failure of HAART regimens in two major reference centres in Rome between 1999 and 2001. At the time of genotyping, 120 of them (56.9%) were failing a 3TC-including HAART, while 91 (43.1%) received 3TC only in previous HAART. Duration of the current 3TC-containing regimen and the time from the end of last 3TC treatment to genotypic resistance test (GRT) were analysed.


RESULTS
Among patients currently undergoing 3TC-containing HAART, the prevalence of M184V/I was 82.5% (78.3/4.2%, respectively) and significantly associated to current 3TC use at GRT. Prevalence of M184V/I was associated to longer history of 3TC (from 47.1% in patients treated with 3TC for <6 months, to 84.0% among those treated for 7-12 months; 100.0% of patients with >42 months of current 3TC carried M184V. At logistic regression analysis, the rate of increase of M184V/I in 3TC-failing patients was statistically significant (OR: 1.066 per month of current 3TC therapy, 95% CI: 1.020-1.114, P<0.01), suggesting a 6.6% monthly increase of probability of M184V/I. Among patients who interrupted 3TC, overall prevalence of M184V/I was 23.1%: proportion of patients carrying the M184V/I dropped from 83.3% among those who interrupted 3TC from < or = 3 months, to 56.3, 20, 10.5 and 0% for those interrupting 3TC from 6, 12, 24 and > or = 24 months, respectively. At logistic regression, the rate of disappearance of M184V/I was also statistically significant (OR: 0.883 per month, 95% CI: 0.804-0.970, P=0.01), indicating a 11.7% monthly decrease of probability of M184V/I after 3TC interruption.


CONCLUSIONS
Dynamics of appearance/disappearance of M184V/I mutation is rapid after 3TC failure/interruption, suggesting ease of development of such a mutation, but also suggesting a remarkable growth disadvantage for HIV. From the clinical perspective, recycling of drugs whose antiviral activity is affected by M184V mutation can be successful after appropriate drug wash-out, also in heavily pretreated patients.
Zaccarelli
Mauro
M
National Institute for Infectious Diseases 'Lazzaro Spallanzani', Rome, Italy. maurozac@inwind.it
Perno
Carlo Federico
CF
Forbici
Federica
F
Cingolani
Antonella
A
Liuzzi
Guiseppina
G
Bertoli
Ada
A
Trotta
Maria Paola
MP
Bellocchi
Maria Concetta
MC
Di Giambenedetto
Simona
S
Tozzi
Valerio
V
Gori
Caterina
C
D'Arrigo
Roberta
R
De Longis
Patrizio
P
Noto
Pasquale
P
Girardi
Enrico
E
De Luca
Andrea
A
Antinori
Andrea
A
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D016208:Databases, Factual; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D054303:HIV Reverse Transcriptase