St Stephen’s Centre, Chelsea & Westminster Hospital, United Kingdom Kaletra Monotherapy: A Real-Life Experience Laura Waters, Steve Balbeck, Brian Gazzard & Mark Nelson. St Stephen’s Centre, Chelsea & Westminster Hospital, United Kingdom INTRODUCTION Since the introduction of HAART the increasing recognition of drug-related toxicities and the development of more potent antivirals have stimulated exploration of alternative regimens and strategies for experienced patients including protease inhibitor (PI) monotherapy. Limited data supporting the use of boosted lopinavir (LPV/r) as a single agent (unlicensed) has been presented (refs) and larger trials are ongoing. We have a number of patients at our unit who have been prescribed LPV/r therapy outside a trial protocol. METHODS Using our large, prospective database all individuals who have ever received LPV/r monotherapy up until October 2005 were identified; all those taking part in a clinical trial were excluded. Previous treatment history, resistance and reason for switch were defined and CD4, viral load (VL), alanine transaminase (ALT), total cholesterol (TC) and triglygeride (TG) levels were monitored for up to 12 months. Virological Outcomes: log changes Of the 15 individuals with viraemia at the time of switch to LPV/r monotherapy 11/15 (73%) achieved a greater than 1log reduction in viral load. Immunological Outcomes The overall CD4 gain in the 28 individuals with follow-up was 92 cells/mm3 (232 to 324) after a mean of 8.9 months. CD4 changes in the group achieving undetectability are summarised in table 2. Table 2: CD4 change up to 1 year (on treatment; virologically suppressed). Number patients Mean CD4 (cells/mm3) SD(+/-) Change from baseline Month 3 12 353 238 +81 Month 6 9 225 141 +25 Month 9 5 333 218 +57 Month 12 7 318 193 +115 CD4 rises in those who did notreceive a viral load less than 50 copies/ml are demonstrated in table 3 Table 3: CD4 change up to 1 year (on treatment; detectable viraemia). RESULTS 35 individuals, 8 women and 27 men, received LPV/r monotherapy; baseline characteristics are illustrated in table 1. Number patients Mean CD4 (cells/mm3) SD(+/-) Change from baseline Month 3 13 221 188 +36 Month 6 10 293 234 +70 Month 9 9 287 249 +64 Month 12 209 247 +73 Table 1: Baseline Characteristics Age (years); mean (range) CD4 (cells/mm3); mean (range) Viral load (copies/ml); mean (range) Number major PI mutations; median (range) Number minor PI mutations; median (range) No. previous regimens; median (range) Months NRTI exposure; mean (SD) Months NNRTI exposure; mean (SD) Months boosted PI exposure; mean (SD) Months unboosted PI exposure; mean (SD) 43 (29-63) 248 (1-573) 54,866 (<50->500,000) 0 (0-4) 2 (0-5) 5 (1-12) 139 (84) 23 (46) 14 (15) 15 (20) Treatment Failure The 8/28 subjects with follow-up who changed or stopped therapy are described below. Table 4: Subjects switching therapy. Outcome Intensified with TFV/FTC at 1 year (no CD4/VL response) Added TFV/3TC when undetectable, reason unclear Undetectable at 18 months, TFV added for blips ddI added at 2 months, undetectable (reason unclear) Intensified with ABC/3TC at 1 year (no CD4 response) Switched to salvage; later died MAI; VL 150,000 at 1 year Switched TFV/FTC/ATV/r, <50 CD4 662 12/05 VL 69 at 1 year on LPV/r; switched to ABC/TFV/ATV/r <50 after 1 year Subject 1 2 3 4 5 6 7 8 Reasons for switch 19 switched to LPV/r for adherence difficulties, 4 secondary to drug-related toxicity, 1 due to drug interaction and 1 patient request. Reasons were not documented for 10 subjects. 7 individuals had no post-baseline results available for the following reasons: - 2 treatment interruption (prescribed LPV/r to cover NNRTI cessation) - 3 lost to follow-up - 2 for toxicity (1 gastrointestinal, 1 transaminitis ?cause) Virological Outcomes: Undetectability 14/28 (50%) achieved an undetectable viral load within 12 months (mean follow-up 9.2 +/-3.9 months); 10/14 had an undetectable viral load at baseline (and 8/10 of these simplified a LPV-based regimen). 11/14 remain on LPV/r monotherapy and 10/11 have viral load <50 copies/ml at a mean of 12.1 months (range 3-34); 1 subject had a viral load of 129 copies/ml at 20 months. 3/14 changed therapy, 1 added tenofovir for blips, 1 added didanosine and 1 added two nucleosides (reasons unclear). 14/28 did not achieve an undetectable viral load within 12 months, 3 of whom were undetectable at baseline (2 on a LPV-containing regimen). 9/14 remain on LPV/r monotherapy; 7/9 have a viral load less than 400 copies/ml out to 1 year (mean 10 months). 1 has viral load of 1494 copies/ml at 12 months (baseline 57693; 1.5 log drop) and 1 has a viral load at 1878 copies/ml (from >500,000 copies/ml; >2.4log decline) at 3 months. With prolonged follow-up 2 are now undetectable after 16 and 24 months respectively. Of the other 5 subjects, 1 was switched to salvage therapy and subsequently died, 2 were intensified with 2 nucleosides (results pending) and 2 switched to atazanavir-based HAART and achieved viral loads <50 copies/ml. Baseline Resistance 7 patients had a history of major PI mutations (defined as per IAS guidelines); 1 was lost to follow-up and 1 received 3 weeks of LPV/r only, the remaining 5 are described in Table 5. Table 5: Treatment outcomes in subjects with major PI mutations. No. 1 2 3 4 5 Switch From LPV, TFV LPV, TFV, ABC TFV, ddI, NVP AZT, 3TC, ABC, TFV LPV, SQV Major Mutations D30N 32I, 46I, 82A 46I, 50V, 90M 46I, 54L, 84V, 90M 84V VL t0 50 1484 50993 58280 CD4 446 443 103 8 32 change +188 -42 +89 -2 -15 Outcome Continues; VL <400 at 1 year Continues; VL <50 at 6/12 No CD4/VL response 1 year; TFV/FTC added (result awaited) Minimal response 1 year; poor compliance + New Resistance 10 patients with viraemia underwent genotyping on LPV/r monotherapy. 4/10 didn’t amplify, 2/10 had no resistance test recently prior to LPV/r for comparison, 1/10 exhibited no new mutations, 2/10 developed new minor mutations/polymorphisms (63P and 63P/79A/93L respectively) and 1/10 developed 20R/46I/50V. CONCLUSIONS 35 subjects in our cohort were prescribed LPV/r monotherapy and we present outcomes for 28. 2 individuals switched primarily for toxicity however, the impact of adverse events on compliance and subsequent failure could not be elucidated fully from a retrospective note review. The majority of patients were switched to LPV/r for poor compliance and all were treatment experienced. 50% achieved an undetectable viral load (less than 50 copies/ml) and the majority attained a greater than 1log reduction in viral load, an independent prognostic factor. The majority of subjects experienced a CD4 increase. LPV/r therapy provided a safe, effective treatment option in a highly experienced group of poorly compliant individuals.