Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase.
OBJECTIVE
Raltegravir (MK-0518) belongs to the new class of HIV integrase inhibitors. To date, there have been no reports investigating the potential for differential effects on viral dynamics with integrase inhibitors relative to current antiretroviral drugs.


METHODS
Patients in this phase II study (P004) were antiretroviral treatment naive. Part 1 of this study compared monotherapy with raltegravir (100 mg, 200 mg, 400 mg, or 600 mg twice daily) with placebo over 10 days. In part 2, patients were enrolled for 48 weeks of combination therapy, with randomization to one of the four dosages of raltegravir or to efavirenz, in addition to tenofovir and lamivudine. Mathematical models were used to investigate processes underlying viral dynamics.


RESULTS
From day 15 through to day 57, individuals in the raltegravir arm were significantly more likely to have HIV RNA < 50 copies/ml (P < or = 0.047). Plasma viral loads were 70% lower at initiation of second-phase decay for individuals taking raltegravir than for those taking efavirenz (P < 0.0001). This challenges the current hypothesis that second-phase virus originates from infected long-lived cells, as an integrase inhibitor should not impact on viral production from this cell population. Mathematical modeling supported two hypotheses as consistent with these observations: (i) that second-phase virus arises from cells newly infected by long-lived infected cells and (2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA.


CONCLUSIONS
These observations challenge the current understanding of HIV-1 turnover and compartmentalization. They also indicate the promise of this new integrase inhibitor raltegravir.
Murray
John M
JM
National Centre in HIV Epidemiology and Clinical Research, Sydney, NSW 2052, Australia. J.Murray@unsw.edu.au
Emery
Sean
S
Kelleher
Anthony D
AD
Law
Matthew
M
Chen
Joshua
J
Hazuda
Daria J
DJ
Nguyen
Bach-Yen T
BY
Teppler
Hedy
H
Cooper
David A
DA
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000627:therapeutic use; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D016014:Linear Models; D009930:Organic Chemicals / Q000627:therapeutic use*; D063065:Organophosphonates / Q000627:therapeutic use; D011760:Pyrrolidinones; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D018709:Statistics, Nonparametric; D000068698:Tenofovir; D013997:Time Factors; D019562:Viral Load; D016662:Virus Integration / Q000187:drug effects; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019428:HIV Integrase Inhibitors; D009930:Organic Chemicals; D063065:Organophosphonates; D011760:Pyrrolidinones; D012367:RNA, Viral; D019259:Lamivudine; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D000225:Adenine; C098320:efavirenz