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Early Clues From Raltegravir Failure in Clinical Practice; Diverse Patterns of Resistance Mutations
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Although integrase inhibitors have proved highly potent in rescue regimens for people with multidrug-resistant HIV, these novel agents may fail when not bolstered by other active drugs. Clinical experience with raltegravir has lasted long enough for four groups to analyze failure of this agent in practice--and thus to begin mapping the variables of failure. A few consistent findings emerged, but no consistent mutation pattern.
Steven Deeks and colleagues at the University of California, San Francisco (UCSF), made two interesting observations in 22 people whose raltegravir or elvitegravir regimen failed virologically: Patients continued to derive a CD4 benefit after viral rebound, and resistant virus appeared to have reduced replication capacity ("fitness").
The 22 patients had a median CD4 count of 46.5 and a median viral load of 4.92 log (about 80,000 copies) before starting an integrase inhibitor salvage regimen, 17 with raltegravir and 5 with elvitegravir. They had taken a median of 14.5 antiretrovirals from a median of 4 antiretroviral classes. Deeks monitored them for a median 10.8 months of integrase inhibitor therapy. CD4 gains persisted long after virologic failure, standing a median 42 cells higher than pretreatment counts 3 months after virologic failure and 50 cells higher 6 months after failure.
The UCSF team documented integrase mutations and decreased susceptibility to raltegravir or elvitegravir at virologic failure in 18 of 22 people, but 4 people with partial adherence to their regimen had no genotypic or phenotypic evidence of resistance to the integrase inhibitor. G140S or mutations at position Q148 turned up in 11 people, usually together. N155H evolved in 4 people and caused a smaller loss of susceptibility to the integrase drug than the other mutations. Y143R/C emerged in 3 people--never with mutations at positions 140, 148, or 155--and caused the greatest loss of susceptibility to integrase inhibitors. Mutations continued to accumulate when people kept taking a failing integrase inhibitor.
One person whose virus carried only the N155H mutation had a 41-fold drop in susceptibility to raltegravir. When that patient stopped raltegravir and continued the other salvage antiretrovirals at a CD4 count of 509, viral load initially remained unchanged for 1 week, a finding suggesting that raltegravir had little residual antiviral activity after failure, at least in this person. When evidence of genotypic and phenotypic resistance began to wane over the next month, the patient's viral load climbed 10-fold, a finding suggesting that N155H mutant virus has a substantial fitness defect. Deeks cited a monkey study also showing a stable viral load after raltegravir was stopped upon emergence of N155H, then a rapid viral rebound as the mutation faded.
Studying 16 people in whom raltegravir salvage failed, Christine Katlama and colleagues at Pitie-Salpetriere Hospital in Paris recorded persistent low-level viremia with failing regimens [2]. This Paris team tracked 50 people starting a raltegravir regimen after a median 14 years of treatment including darunavir in 68%, enfuvirtide in 57%, and etravirine in 37%. The raltegravir regimen included darunavir in 84%, enfuvirtide in 35%, etravirine in 74%, and atazanavir in 29%. Median CD4 count before raltegravir stood at 169 (range 1 to 833) and median viral load at 15,136 copies (range 339 to 724,436 copies). These people had a median of 13 protease inhibitor mutations (range 8 to 20) before starting raltegravir and a median of 1 nonnucleoside mutation (range 0 to 4).
Thirty-five people (70%) reached a viral load below 40 copies within 24 weeks of starting raltegravir, while viral loads languished between 40 and 400 copies in 10 (20%) through a median follow-up of 11 months. Viral loads never fell below 400 copies in 5 people (10%). Among 19 people genotyped during raltegravir failure, only 4 had detectable resistance mutations, including G140S plus Q148H in 2 and a solitary N155H in 2. Two of these people, 1 with N155H and 1 with G140S/148H, had no active drugs in their background regimen. G140S plus Q148H replaced N155H in the viral populations of 1 person. Merck investigators also documented evolution of viral populations from N155H to Q148H in a phase 2 trial [3].
Data on 51 people starting raltegravir salvage in Bordeaux confirmed the diverse mutation patterns seen with raltegravir failure as well as replacement of N155H by other mutations [4]. Bernard Masquelier and coworkers monitored people starting raltegravir salvage with a median CD4 count of 245 and a median viral load of 4.2 log (about 18,000 copies). After 3 months of raltegravir-based salvage, most people had a viral load below 400 copies/mL, and after 6 months 23 of 35 people in follow-up at that point (66%) had a viral load under 50 copies.
The Bordeaux clinicians recorded four mutation patterns in 11 people with raltegravir failure:
· In 5 people Q148H/R plus one or more secondary mutations: V72I, L74M, G140A/S, E138A, K156N, K160N, V201I, T206S
· In 3 people N155S/H replaced by patterns including L74M, T97A, Y143C/H/R, G163R, V151I, S230R
· In 1 person S230N
· In 2 people no new mutations but maintenance of pretreatment substitutions L74M in 1 and V201I, E157Q, and T206S in the other
Masquelier's group was the third at this workshop to report replacement of N155H with other mutations [2-4] and one of three to report resistance centered on mutations at position 143 [1,4,5]. Like an Italian team [5], Masquelier correlated pretreatment integrase substitutions with raltegravir failure.
With colleagues in Rome and Milan, Francesca Ceccherini-Silberstein found evidence suggesting that naturally occurring integrase substitutions (polymorphisms) in a patient's viral population before raltegravir salvage may influence emergence of primary mutations during virologic failure [5]. The 51 people studied began raltegravir with a median viral load of 50,000 copies and a median CD4 count of 131. After only 7 to 19 days of raltegravir, the median load plunged by 2.2 log (over 100-fold) and after 4 weeks by 2.43 log. At that point half of the patients had a load under 50 copies/mL and the overall median CD4 count climbed by 76 cells, a significant gain (P = 0.007).
Ceccherini-Silberstein recorded an array of mutations in patients who did not respond to raltegravir, including N155H in 2, Q148H/R + G140S in 2, Y143R + T97A in 1, and G163R + T97A in 1. Five people who never reached a viral load below 50 copies had a K156N substitution before raltegravir that persisted during failure. Patients with the polymorphisms T97A, G163R, or V165I before raltegravir never attained an undetectable viral load and added mutations during raltegravir treatment--Y143R with T97A, T97A with G163R, and N155H with V165I. Ceccherini-Silberstein suggested that "different patterns of mutations conferring resistance to raltegravir can be related to selected polymorphisms present at baseline."
References
1. Hatano H, Lampiris H, Huang W, et al. Virological and immunological outcomes in a cohort of patients failing integrase inhibitors. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 10.
2. Katlama C, Caby F, Andrade RM, et al. Virological evolution in HIV-treatment-experienced patients with raltegravir-based salvage regimens. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 11.
3. Miller MD, Danovich RM, Ke Y, et al. Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from P005, a phase II study in treatment- experienced patients. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 6.
4. Da Silva D, Pellegrin I, Anies G, et al. Mutations patterns in the HIV-1 integrase related to virological failure on raltegravir-containing regimens. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 12.
5. Ceccherini-Silberstein F, Armenia D, D'Arrigo R, et al. Virological response and resistance in multi-experienced patients treated with raltegravir. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 18.
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