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Adherence Slips & Viral Blips
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Excerpted from Resistance Before Therapy, Hidden Mutations, and Blips
46th ICAAC, September 27-30, 2006, San Francisco
Mark Mascolini
Adherence slips and viral blips
Do blips--those fleeting jumps from a sub-50 viral load into detectable territory--open the door to resistance? Three published reports involving a combined 154 people say they do [18-20], and one study of 10 people says they don't [21], although that last study divined a marginal correlation between blips and reported poor adherence (P = 0.08).
An ICAAC study by Abbott investigators also failed to link blips with evolution of resistant virus, even the hair-trigger M184V provoked by 3TC or FTC [22]. And blips did not presage virologic failure in this study, a result confirming most earlier reports. But the Abbott team did confirm the earlier suggestion [21] that adherence slips may cause blips. The findings deserve scrutiny because no one has nailed down what causes blips. Besides iffy adherence, viable explanations include dips in drug levels for other reasons [18], coinfection with another pathogen [20], a viral spill from activated latent reservoirs [18], or random biological or assay variation [21]. (For a review of studies addressing blips and resistance, see reference [23], which is free online. These Johns Hopkins authors maintain that the studies tying blips to resistance [18-20] are "complicated by limited assessment of pre-existing mutations as well as poor sensitivity of the genotyping assay employed.")
To learn whether wobbly adherence precedes blips, Abbott looked at virologic response and adherence records of treatment-naive people starting a first regimen containing either once- or twice-daily lopinavir/ritonavir plus tenofovir and emtricitabine (studies M99-956 and M02-418). Trial clinicians measured viral loads every 4 weeks through week 24, every 8 weeks through week 28, and every 12 weeks through week 96. Pill bottle caps fitted with microchips told researchers whether study participants opened their pill bottles at the right times.
The adherence study focused on 223 people with bottle-cap data, 131 taking once-daily lopinavir and 92 taking twice-daily lopinavir. Defining blips as a viral load spurt to between 50 and 1000 copies followed by a sub-50 load on the next reading, the researchers recorded blips in 60 people (27%), with no significant difference between those taking once-daily lopinavir (30%) and those taking the twice-daily dose (23%) (P = 0.212). The median blip measured 82 copies and ranged from 51 to 858 copies. Neither pretreatment viral load nor pretreatment CD4 count foretold blips. Blips did become more common as the studies proceeded, with a 23.3% blip frequency before week 24, 36.7% between week 24 and week 48, and 40.0% after week 48.
The Abbott team used bottle-opening data to reckon the average number of days a person took the prescribed doses in the week before a blip--and the average number of days with correct adherence during a week when the same person had no blips. The average for the pre-blip period proved significantly lower than the no-blip average (5.55 versus 6.22 days, P = 0.007). Bottle-cap data also recorded a jump in correct adherence just after most blips. The trial design mandated a follow-up viral load reading within 4 weeks of any blip. When people learned their viral load spike was a blip and not a full-fledged rebound, adherence subsided from this higher post-blip level back to the pre-blip plateau.
References
18. Macias J, Palomares JC, Mira JA, et al. Transient rebounds of HIV plasma viremia are associated with the emergence of drug resistance mutations in patients on highly active antiretroviral therapy. J Infect 2005;51:195-200.
19. Cohen Stuart JW, Wensing AM, Kovacs C, et al. Transient relapses ("blips") of plasma HIV RNA levels during HAART are associated with drug resistance. JAIDS 2001;28:105-113.
20. Easterbrook PJ, Ives N, Waters A, et al. The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to <400 copies/ml. AIDS 2002;16:1521-1527.
21. Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. JAMA 2005;293:817-829.
22. Podsadecki TJ, Vrijens B, Tousset E, et al. Lower adherence to HAART observed prior to transient HIV-1 viremia ("blips"). 46th ICAAC. September 27-30, 2006. San Francisco. Abstract H-992.
23. Lee PK, Kieffer TL, Siliciano RF, Nettles RE. HIV-1 viral load blips are of limited clinical significance. J Antimicrob Chemother 2006;57:803-805 (http://jac.oxfordjournals.org/cgi/content/full/57/5/803).
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