Viread

For example, patients may have drug resistance that can reduce the antiviral activity of 1 or more of the drugs in a 3-drug regimen. Therefore, there is a rationale for considering regimens that contain fewer than 3 drugs.

A virologically suppressive 2-drug regimen that does not carry an increased risk of drug resistance, that lowers the economic cost of requiring a third drug for HIV treatment, and that eliminates any toxicities associated with a third drug would be attractive for some patients with HIV infection.

Kalead-1 is the first trial to study the combination of lopinavir/ritonavir (Kaletra) soft gel capsules (SGC) and tenofovir DF (Viread) as first-line therapy in antiretroviral-naive, HIV-1 infected adults.

Study Design

The multicenter, open-label Phase III study was designed to compare the antiviral activity and safety of lopinavir/ritonavir SGC plus tenofovir as a first-line 2-drug regimen, versus a standard-of-care 3-drug regimen of lopinavir/ritonavir SGC plus 2 nucleoside reverse transcriptase inhibitors (NRTIs).

Methods

The 72-week study consists of 2 phases. The first phase of 24-26 weeks was built into the study design to gauge the initial virological safety of a 2-drug regimen. If virological suppression was successful during the first phase (HIV RNA < 50 copies/mL), then subjects continued in the trial for the further 48 weeks of the second phase.

Figure 1. Kalead1 Study Design
LPV/r = lopinavir/ritonavir; TDF = tenofovir DF

Antiretroviral-naive male and female subjects older than 18 years of age with plasma HIV RNA > 400 copies/mL and any CD4 count were eligible for the study.

Participants were randomly assigned to 1 of the following regimens:

• lopinavir/ritonavir SGC 400/100 mg twice daily + tenofovir 300 mg once daily (dual therapy);
• lopinavir/ritonavir SGC 400/100 mg twice daily + 2 NRTIs chosen by the study investigators (triple therapy).

The subjects were monitored for plasma HIV RNA, CD4 cell counts, adverse events, and routine clinical laboratory parameters. All randomized subjects who received at least 1 dose of the study drugs were included in this interim 48-week efficacy analysis for non-inferiority. No drug resistance testing was performed.

Baseline characteristics are shown in Table 1.

The 2 treatment arms were comparable at baseline for all criteria except CD4 cell count, which was significantly lower (P=0.019) in the triple-therapy arm. However, the difference was no longer evident when the subjects were stratified by CD4 cell counts < 200 cells/mm3 vs > 200 cells/mm3 (P = non-significant).

• 72 subjects were randomized to lopinavir/ritonavir + tenofovir (dual therapy) and 80 to lopinavir/ritonavir + 2 NRTIs (triple therapy).

• 62 of 72 (86.1%) in the dual therapy arm and 63 of 80 (78.8%) in the triple therapy arm reached the end of the first phase of the study.

• 51 (82.3%) and 56 (88.9%) of the subjects in the 2 arms who reached the end of the first phase 1 did so with 2 consecutive HIV RNA measurements below 50 copies/mL, and thus qualified to enter the second phase.

• Of the 51 subjects in the dual therapy arm and 56 subjects in the triple therapy arm, 7 (13.7%) and 6 (10.7%) subjects, respectively, discontinued before week 48 (see Figure 2 for details).

Figure 2

The distribution of the investigator-prescribed NRTIs in the triple therapy arm is presented in Figure 3.

Figure 3. Investigator-prescribed NRTI combinations in the 3-drug-arm

Results

Efficacy

• The reduction in HIV RNA from baseline to week 48 was comparable between the 2 treatment arms.

• 5 subjects (6.94%) in the dual therapy arm had viral load blips at week 48, with values ranging from 51 to 91 copies/mL.

• In the triple therapy arm, there were 3 viral load blips (3.75%; P=ns), ranging from 72 to 1000 copies/mL.

• CD4 cell count increases were significantly greater in the dual therapy arm at week 48 (see Figure 4).

Figure 4: Evolution of CD4 cell count from screening through week 48

Safety

• The number of discontinuations due to various reasons was comparable in the 2 treatment arms through week 48

• The overall incidence of adverse events through week 48 was comparable in the 2 groups (see Table 2).

• Investigator-reported lipid elevations (dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia) occurred less frequently in the dual therapy arm (P=0.086).

• However, when laboratory fasting serum lipid values were compared, the differences between Grade II-III-IV (moderate to severe) elevations of triglycerides and total cholesterol were not significant in the 2 arms.

Conclusion and Discussion

Based on these findings, the study investigators concluded, "48-week results demonstrated comparable virologic efficacy and tolerability when a dual regimen of lopinavir/ritonavir + tenofovir was compared to lopinavir/ritonavir + 2 NRTIs in antiretroviral-naive patients. CD4 increases were significantly greater in the dual therapy arm at week 48."

"Finally, while not reaching statistical significance," they added, "there was a trend for lower incidence of lipid elevations in the dual therapy arm."

Kalead-1 is the first study to compare dual antiretroviral regimens with standard-of-care triple-combination therapy in HIV-infected adults naive to antiretroviral therapy. The results of the study suggest that a dual therapy with lopinavir/ritonavir + tenofovir may be equally effective and tolerable when compared to 3-drug HAART.

A monotherapy strategy using lopinavir/ritonavir has been compared to triple therapy with lopinavir/ritonavir + 2 NRTIs employing various approaches (antiretroviral naive, induction-maintenance, simplification to lopinavir/ritonavir monotherapy among virologically suppressed patients). Lopinavir/ritonavir monotherapy, while effective, does carry an increased risk of selecting protease resistance mutations, a greater incidence of viral load blips, and virological failure when compared to triple therapy with lopinavir/ritonavir as the anchor.

In the Kalead-1 study, through 48 weeks, the researchers noted, there was no difference between the dual and the triple therapy arms with regard to the incidence of viral load blips, emergence of protease inhibitor resistance, or virological failure.

The limitations of the Kalead-1 study include the choice to use investigator-selected NRTIs in the triple therapy arm instead of a standard comparative arm. Also, the dosing of lopinavir/ritonavir was not once-daily in neither of the treatment arms, due to the lack of once-daily labeling in Italy. Obviously, the attractiveness of dual therapy would be enhanced if lopinavir/ritonavir were to be taken once daily, thereby making the entire regimen once daily. Furthermore, the new tablet formulation of lopinavir/ritonavir -- which allows for fewer pills per dose with no food requirements -- was only used in the Kalead-1 study by a few subjects near the end of the trial (none prior to week 48).

In conclusion, the investigators noted, "Further study of dual therapy HAART with lopinavir/ritonavir employing [once daily] dosing, with the tablet formulation, and with other NRTI partners (3TC, FTC [emtricitabine], abacavir) is warranted."

08/07/07

Reference
M Pinola, G Carosi, G Di Perri, and others (for the Kilead 1 study group). LPV/r-based 2-drug HAART vs LPV/r-based 3-drug HAART: Comparable virological efficacy and tolerability in HIV-1-infected naive subjects (Kalead-1 study) - 48-week results. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, July 22-25, 2007. Sydney, Australia. Abstract (poster) WEPEB035.