By Liz Highleyman

In an effort to simplify antiretroviral therapy and reduce the occurrence of side effects, researchers have explored monotherapy using a single ritonavir-boosted protease inhibitor (PI) with no nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

Two series of pilot and follow-on studies of lopinavir/ritonavir (Kaletra) monotherapy -- IMANI in the U.S. and OK (Only Kaletra) in Spain -- have been underway for a number of years, and have reported interim results at several previous conferences. At the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in Washington, DC, both research groups presented longer-term data.

IMANI-2: 96 weeks

Joseph Gathe and colleagues presented final results from the IMANI-2 study through 96 weeks, or nearly 2 years.

IMANI-2 was a prospective, Phase 2, single-arm, open-label pilot trial of lopinavir/ritonavir single-agent therapy in 39 antiretroviral-naive patients. Participants had a viral load of at least 2000 copies/mL (mean 4.4 log copies/mL) and a CD4 cell count < 400 cells/mm3. They had no active opportunistic infections, did not require treatment for hepatitis B or C, and had no detectable lopinavir/ritonavir resistance mutations.

About two-thirds of participants were men, half were white, 44% were black, and the average age was 41 years. At baseline, the median CD4 count was 258 cells/mm3, though 26% had 51-200 cells/mm3 and 8% had < 50 cells/mm3.

As previously reported, 79% of study participants had HIV RNA < 75 copies/mL at week 48 in an intent-to-treat (ITT) analysis. Patients who did not maintain HIV suppression intensified therapy by adding more drugs.

Results

• At week 96, 29 of 39 patients (74%) had HIV RNA < 75 copies/mL in an intent-to-treat "missing = failure" analysis.

• Using an as-treated analysis, the proportion was 29 out of 33 (88%).

• Instances of transient viral load rebound ("blips") were generally attributed to poor adherence.

• 4 out of 6 patients who experienced HIV rebound during the first 48 weeks re-suppressed viral load after adherence counselling or intensification of therapy.

• 5 of 39 patients (13%) experienced low-level viremia after viral suppression.

• During 48-96 weeks, 8 patients had detectable low-level viremia, 6 of whom re-suppressed after adherence counselling.

• 1 participant had a viral load of more than 14,000 copies/mL, and 1 had nearly 25,000 copies/mL.

• The mean CD4 cell increase from baseline to week 96 was 310 cells/mm3 (range approximately 100-600 cells/mm3).

• No primary protease inhibitor resistance mutations were observed.

• Lopinavir/ritonavir tablets were generally well tolerated, with no serious adverse events noted between weeks 48 and 96.

• Total cholesterol and triglyceride levels increased after starting lopinavir/ritonavir; while cholesterol stabilized after week 24, triglyceride levels continued to rise through week 96.

• Framingham cardiovascular scores, however, did not increase significantly, though 1 patient started lipid-lowering therapy.

Based on these findings, the researchers concluded, "Lopinavir/ritonavir single-agent therapy in antiretroviral naive subjects demonstrated durable virologic control through 96 weeks in 74% of subjects (ITT M=F)."

"Transient viremia or virologic failure was associated with non-adherence or concurrent illness," they continued. "These data speak to the efficacy, safety, and durability of virologic control for lopinavir/ritonavir single-agent therapy in naive patients and should encourage ongoing clinical study of this strategy."

Finally, they added that the success of IMANI-2 suggests that lopinavir/ritonavir monotherapy "may be an option for clinicians/patients." Specifically, "a desire to avoid NRTI toxicity, reduce the cost of HAART, or simply patient preference are situations where this strategy could be applied."

OK04: 144 weeks

In the OK04 trial, eligible participants had no history of virological failure while taking a protease inhibitor and achieved HIV suppression < 50 copies/mL for more than 6 months on a standard HAART regimen consisting of lopinavir/ritonavir plus 2 NRTIs. Some patients then stopped the NRTIs, but re-added them if they experienced viral rebound > 50 copies/mL.

At 96 weeks, lopinavir/ritonavir monotherapy with reintroduction of NRTIs as needed was non-inferior to triple therapy for maintenance of HIV suppression. After the initial 96-week comparative phase, patients originally randomized to triple therapy switched to monotherapy. Final 144 week data from the patients originally randomized to the monotherapy arm were reported at ICAAC.

Results

• Of the 100 patients originally randomized to lopinavir/ritonavir monotherapy, 70 (70%) maintained viral load < 50 copies/mL on monotherapy in an intent-to-treat analysis with missing data or NRTI reinduction considered as failure.

• Of the 18 patients (18%) who experienced virological failure during follow-up, 15 restarted NRTIs (2 were lost to follow-up).

• 1 patient with virological failure did not restart NRTIs due to detection of PI resistance mutations.

• After NRTI reinduction:

• 11 patients achieved sustained virological suppression;

• 3 attained HIV suppression but subsequently experienced viral rebound (1 with PI resistance mutations);

• 1 did not achieve viral suppression (with no PI mutations found).

• 9 patients on lopinavir/ritonavir monotherapy were lost to follow-up.

• 2 died while virologically suppressed.

• 1 patient on monotherapy switched to triple therapy even though viral load was < 50 copies/mL.

• From week 48 through week 144, resistance genotyping did not identify any new isolates with major PI mutations.

These findings led the investigators to conclude, "After 3 years most patients on lopinavir/ritonavir monotherapy remain virologically suppressed."

"Incidence of PI resistance was very low," they added. "In patients with virological failure, reinduction with [NRTIs] was generally successful."

Finally, they noted, 3-year results from the OK04 trial support "long term efficacy and a minimal risk of resistance of the strategy lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed."

While the IMANI-2 and OK04 research teams both concluded that lopinavir/ritonavir monotherapy is a viable strategy for maintaining viral suppression without development of resistance, another study (MONARK) did detect PI resistance mutations in patients who experienced viral rebound while on lopinavir/ritonavir monotherapy. Many experts believe that, wherever possible, standard 3-drug HAART remains the preferred option.

Hosp. 12 Octubre, Madrid, Spain; Hosp. Príncipe de Asturias, Alcalá de Henares, Spain; Hosp. V Nieves, Granada, Spain; Hosp. Xeral Cíes,Vigo, Spain; Hosp. Alicante, Alicante, Spain; Hosp. La Paz, Madrid, Spain.

11/4/08

References

J Gathe, R Yeh, C Mayberry, and others. Single Agent Therapy with Lopinavir/Ritonavir Durably Suppresses Viral Replication in ARV Naive Patients: IMANI II: 96Week Final Results. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1241.

F Pulido, R Delgado, A Arranz, and others (OK04 Study Group). Three-Year Efficacy of Lopinavir/ritonavir Monotherapy in the OK04 Trial. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1240.