HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Once-Daily
Lopinavir/ritonavir (Kaletra) and Nevirapine (Viramune) Demonstrate Suboptimal
Efficacy in Some Patients
In
an effort improve the convenience of antiretroviral therapy, researchers have
tested once-daily dosing regimens for several drugs. While once-daily dosing is
adequate for some agents (e.g., efavirenz
[Sustiva], boosted fosamprenavir
[Lexiva], boosted atazanavir
[Reyataz]), others should be taken twice daily.
At
the 14th Conference on Retroviruses and Opportunistic Infections last month in
Los Angeles, researchers presented data from studies testing once-daily lopinavir/ritonavir
(Kaletra) and once-daily nevirapine (Viramune).
Once-daily
Lopinavir/ritonavir
In the first study (ACTG A5073), investigators
looked at both once-daily dosing of lopinavir/ritonavir and directly-observed
therapy (DOT). In this 48-week open-label trial, 402 antiretroviral-naive patients
with HIV viral loads ? 2000 copies/mL were randomly assigned to receive 400/100
mg lopinavir/ritonavir self-administered twice daily, 800/200 mg lopinavir/ritonavir
self-administered once daily; or 800/200 mg lopinavir/ritonavir once daily administered
as DOT for 24 weeks, then self-administered for the remaining 24 weeks. Participants
also received once-daily emtricitabine (Emtriva) plus d4T (Zerit XR) or tenofovir
(Viread).
Results
•
82% of patients
completed the study, and 71% remained on their original lopinavir/ritonavir dose
schedule.
•
Overall, the probability of
virological response through week 48 did not differ significantly between twice-daily
and once-daily self-administered lopinavir/ritonavir.
•
However, among patients with
baseline HIV RNA levels above 100,000 copies/mL, the virological response rate
was significantly higher in the twice-daily arm.
•
The virological response rate
through week 24 was higher for patients receiving DOT compared with self-administration,
but the difference did not reach statistical significance.
"Although
overall there was no difference in sustained virologic response between twice
daily and once-daily lopinavir/ritonavir, twice-daily may have an advantage for
ART-naive patients with high viral loads," the investigators concluded. "DOT
may have a treatment role while maintained, but there is no evidence of sustained
virologic benefit once stopped."
Beth Israel Med Ctr, New York,
NY; Harvard School of Public Hlth, Boston, MA; Univ of Pennsylvania School of
Medicine, Philadelphia, PA; Johns Hopkins Univ Med Inst, Baltimore, MD; Miriam
Hosp, Providence, RI; Univ of Puerto Rico School of Medicine, San Juan; Div of
AIDS, NIAID, NIH, Bethesda, MD.
In the second study, conducted in France, 71 antiretroviral-naive
patients with CD4 cell counts below 350 cells/mm3 (for men) or 250 cells/mm3 (for
women) were randomly assigned to receive either 400 mg nevirapine plus 3TC plus
tenofovir once daily or else 200 mg nevirapine plus AZT (Retrovir) plus 3TC twice
daily for 96 weeks.
Results
•
8 patients (22%), all in the
once-daily arm, experienced early non-response or virological breakthrough by
week 12.
•
2 additional subjects (1 in
each arm) experienced later virological breakthrough.
•
Genotypic testing showed that
these patients harboured resistant HIV, including virus with the M184M/V/I (n
= 4), K65R/K (n = 4), and various NNRTI-resistance mutations (Y181Y/C, G190A/G,
K101E, K103N).
•
Drug monitoring showed that
trough nevirapine plasma concentrations were at or above the expected level in
all patients.
•
The non-responders/relapsers
in the once-daily arm had higher baseline median plasma viral loads (approximately
262,000 vs 51,000 copies/mL) and lower baseline median CD4 cell counts (approximately
100 vs 200 cells/mm3) compared with sustained responders in the same arm.
The
researchers concluded that, "In antiretroviral-naive HIV-infected patients,
the once-daily 3TC, tenofovir, and nevirapine regimen resulted in an unexpectedly
high rate of early non-response with a high incidence of K65R and M184V. The reasons
for these failures are unclear."
In light of these results, the trial
steering committee discontinued the study and recommended that all patients in
the once-daily arm switch to other regimens.
D
Mildvan, C Tierney, Robert Gross, and others. Randomized Comparison in Treatment-naive
Patients of Once-daily vs Twice-daily Lopinavir/ritonavir-based ART and Comparison
of Once-daily Self-administered vs Directly Observed Therapy. 14th Conference
on Retroviruses and Opportunistic Infections (CROI). Los Angeles, February 25-28,
2007. Abstract 138 (oral).
D
Rey, MP Schmitt, G Hoizey, and others. Early Virologic Non-response to Once Daily
Combination of Lamivudine, Tenofovir, and Nevirapine in ART-naive HIV-infected
Patients: Preliminary Results of the DAUFIN Study. 14th CROI. Abstract 503 (poster).
