Lopinavir/ritonavir (Kaletra) Monotherapy or plus Zidovudine and Lamivudine in Treatment-naive HIV Patients

Current HIV treatment guidelines recommend 3-drug regimens containing a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

Use of single NRTIs early in the AIDS epidemic led to drug resistance and treatment failure, but the development of potent second-generation PIs led investigators to explore boosted PI monotherapy in an effort to reduce drug side effects, treatment complexity, and cost.

Two studies looking at lopinavir/ritonavir (Kaletra) monotherapy – as initial therapy or for treatment simplification – were described in recent journal articles.

MONARK

French researchers reported data from the MONARK study in the January 30 2008 issue of AIDS.

In this 96-week, prospective, open label trial, 83 previously untreated patients were randomly assigned to receive lopinavir/ritonavir soft-gel monotherapy, using the older soft-gel capsule formulation, while 53 received a standard 3-drug regimen containing lopinavir/ritonavir plus ATZ/3TC (Combivir). (The small boosting dose of ritonavir in the Kaletra pill is not counted as a separate drug.) Participants had relatively low baseline viral load, below 100,000 copies/mL.

The primary endpoint of the study was the proportion of patients achieving an HIV RNA level below 400 copies/mL at week 24 and below 50 copies/mL at week 48.

As previously reported, interim data showed that virological efficacy was similar in both groups at 48 weeks, although those in the monotherapy arm had more episodes of low-level viremia. Further, patients reported fewer side effects and improved quality of life in the monotherapy arm compared with the 3-drug arm.

But the latest data looking at participants who actually remained on their assigned treatment (on-treatment or as-treated analysis) -- as opposed to all who were originally allocated to the 2 study arms (intent-to-treat analysis) -- indicate that lopinavir/ritonavir monotherapy is inferior to standard combination therapy in terms of viral suppression.

Results

• At week 48, in an intent-to-treat analysis, 64% of participants in the monotherapy arm achieved a viral load below 50 copies/mL compared with 75% in the 3-drug arm, which was not a statistically significant difference (P = 0.19).

• However, in an on-treatment analysis, 80% and 95%, respectively, achieved this endpoint, which was a significant difference (P = 0.02).

• In the monotherapy arm, PI-associated resistance mutations were observed in 3 of the 21 patients (14%) who qualified for genotypic resistance testing.

• These mutations were associated with a modest impact on lopinavir susceptibility.

• The frequency of serious adverse events was similar in the monotherapy and 3-drug arms (12% vs 8%), though none were considered to be related to study treatment.

Based on these findings, the study authors concluded, “Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.”

In addition, those who stayed on lopinavir/ritonavir monotherapy did not experience fewer side effects, which is one of the main rationales for trying monotherapy.

Despite these results, the authors suggested in their discussion that lopinavir/ritonavir monotherapy might still be useful under certain circumstances.

“Taking into account the long-term rates of lipoatrophy, viral resistance, patient satisfaction, and the cost of therapy are also critical to identify clinical scenarios in which lopinavir/ritonavir monotherapy might yet play a significant role in the treatment of HIV infection,” they wrote.

“We conclude that first-line monotherapy with lopinavir/ritonavir soft gel capsules is virologically less effective than the current standard-of-care triple combination with two NRTIs and lopinavir/ritonavir soft gel capsules,” they continued. “Given the requirement for chronic therapy with current antiretroviral treatments, however, and the long-term toxicities associated with all antiretroviral therapies, long-term strategies that limit exposure while providing adequate virological efficacy deserve further study.”

They recommended that future monotherapy studies should use the more convenient new lopinavir/ritonavir tablet formulation and focus on select patient populations.

In the second report, in the January 11, 2008 issue of the same journal, Spanish researchers presented results from the OK4 study, the latest in a series of clinical trials testing “Only Kaletra.”

Unlike MONARK, OK4 used an induction-maintenance strategy. Rather than starting on lopinavir/ritonavir monotherapy, 205 HIV patients who had already achieved virological suppression on a standard regimen of lopinavir/ritonavir plus 2 NRTIs were randomly assigned to either continue the triple regimen or drop the NRTIs and continue on lopinavir-ritonavir alone. NRTIs were resumed if virological rebound occurred during monotherapy.

The primary endpoint was the proportion of patients without therapeutic failure, defined as confirmed HIV RNA higher than 500 copies/mL (excluding subjects receiving monotherapy who experienced re-suppression to < 50 copies/mL after resuming baseline NRTIs), loss to follow-up, or change of randomized therapy other than reintroduction of NRTIs.

Results

• At week 48, the percentage of patients without therapeutic failure was 94% in the monotherapy arm compared with versus 90% in the continued triple therapy arm (difference, -4%; upper limit of 95% CI 3.4%).

• The percentage of patients with viral load below 50 copies/mL at 48 weeks by intent-to-treat (missing data or NRTI resumption considered as failure), were 85% and 90%, respectively (P = 0.31).

This research team concluded, “In this trial, 48 weeks of lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was non-inferior to continuation of 2 nucleosides and lopinavir/ritonavir in patients with prior stable [HIV] suppression.”

However, they added, “episodes of low level viremia were more common in patients receiving monotherapy.”