15th HIV Resistance Workshop: resistance to Kaletra monotherapy

Monotherapy and induction and maintenance strategies have a frustrating history in HIV research. Poorly designed studies resulted inexorably in the failure of single-agent arms. The Abbott studies MONARK and M03-613 appear to be an exception to that rule. Learning from history that the induction phase needs to be robust, all patients in M03-613 were treated with a triple therapy regimen containing lopinavir/ritonavir (LPV/r) plus AZT and 3TC for at least 24 weeks followed by LPV/r monotherapy if viral load was below 50 copies/ml for 3 consecutive visits for the rest of the study. A control arm consisting of efavirenz (EFV) plus AZT and 3TC for the complete 96 weeks; this arm did not simplify to LPV/r monotherapy but represented standard of care control.

In this open-label study, 92 patients were ‘de-intensified’ to receive LPV/r monotherapy for median 56 weeks. At baseline, patients were treatment naïve with no resistance reported to study drugs. 9 of the 92 patients experienced a viral rebound >500 copies/ml. Results were available for 8 of these patients of whom 2 showed significant protease (PR) resistance.

Patient 1 - viral rebound >500 copies/ml at week 40

Baseline mutations: RT K219Q, PR M36I/L63P

Genotype at week 40: RT K103N, K219Q, PR L10F, M46L, L63P, V82A, I54V (at week 48)

Patient 2 - viral rebound >500 copies/ml at week 44

Baseline: RT Y181C, L210W, T215Y, K219N, PR L63P

GT at week 48: RT M41L, D67N, V118I, Y188L, L21W, T215Y, PR M36I, L63P, A71V, G73S, L90M, I54V (at week 56), V82A (at week 76)

Of note, in patient 2, many of the PR mutations reported were detected during the induction phase whilst treated on a triple regimen.

In the second MONARK study, Abbott compared monotherapy alone from initiation of therapy in treatment-naïve patients to a control 3 drug regimen containing LPV/r 400/100mg BID plus AZT and 3TC. 136 patients were assessed in an open-label randomised study with 53 patients maintained on the 3 drug arm while 83 were started on LPV/r monotherapy. These treatment naïve patients had a baseline profile of 100 cells/mm3 and no resistance to study drugs detected. Resistance testing were performed when patients blipped with a viral load >500 copies after having achieved

Patient 1

Protease mutation at M46I at week 40, added AZT and 3TC to the regimen re-achieving viral suppression below 50 copies for the remaining 48 weeks.

Patient 2

Protease mutations at L10F/L and V82A at week 72

There are two frustrating conclusions to be drawn from these studies. The first provocatively expressed by John Mellors from Pittsburgh University that the ‘jury is still out on induction-maintenance’. The problem is that neither study proves unequivocally that LPV/r monotherapy is either exceptionally good or bad. However, it does demonstrate that with potent treatment such as LPV/r even a single agent can suppress viremia for prolonged periods (at week 72 in MONARK monotherapy patient 2) – at least 50 but

Secondly, and infuriatingly, more precise techniques for resistance testing were not deployed. With a company that has both the capacity and expertise to understand resistance, a more sophisticated analysis would have been enlightening and expected. K103N for example was observed at week 40 in the M03-613 study (LPV/r plus AZT and 3TC versus LPV/r monotherapy) in treatment naïve patients with no prior exposure to EFV. This strongly suggests that this mutation was transmitted at infection and present – but not detected at baseline. Similarly, low level mutations including PR mutations may have been present at baseline but not detected due to the lack of sensitive genotyping performed. It is possible, but unknown whether these ‘silent’ mutations could have contributed to resistance evolution on treatment in those patients who did develop resistance.

Following the scientific meeting, Abbott was keen to meet and share these data with the patient advocate community to assess their response. Advocates present at the consultation were impressed with the results but unable to wholeheartedly support LPV/r monotherapy with such equivocal results. Community representatives raised more issues such as the potential impact of baseline NNRTI mutations on subsequent virologic response and whether patients on LPV/r are predisposed to ‘blip’ more often. Finally, for those patients who did fail with PR resistance, it is concerning that a number of mutations reported confer cross-resistance to other PIs such as V82A or L90M. This may limit possibilities for sequencing with other PIs following LPV/r failure.

Overall though, Abbott is to be commended for its courage in pursuing monotherapy and for demonstrating that LPV/r monotherapy may still have utility in some clinic situations. With more detailed analysis and a higher level of confidence, such strategies may prove to be useful for patients embarking on first-line therapy and in countries where resources ultimately determine the treatment of choice. Abbott confirmed that it intends to present fully efficacy data at 96 weeks for both studies very soon.