Safety and Immunovirologic Outcomes with Maraviroc Combination Regimens in Patients with a History of Past Treatment Failures and Virologic Resistance in Brazil: An Open-Label, Multicenter Phase 3b Study

Abstract

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/μl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

“…Additional safety and immunovirologic ativity data of Maraviroc in regimens were obtained after newer agents such as darunavir, raltegravir, and etravirine were clinically available [41]. It was found that Maraviroc was well tolerated over 96 weeks as a combination with different agents, and treatment with Maraviroc in combination with OBT was associated with significantly greater immunovirologic activity versus placebo plus OBT [40, 41]. …”

Young adults HIV-1 infected by vertical transmission in southern Brazil – Clinical, demographic, and virological features

“…29–33 In Brazil, in the adult population failing first- and second-line therapy, maraviroc susceptibility ranges from 42% to 70%s in different cities. 34,35 A pediatric study in São Paulo city found 45% in use of maraviroc. 36 A lack of virological suppression associated with improper cART adherence is related to viral resistance.…”

“…38,39 The association of subtype C and R5 tropism, considering all patients have been infected for an extensive period of time, is also previously reported that indicates the occurrence of X4 or dual tropic virus appears to be rare in this clade. 17–43 A conserved nature of HIV-1 C subtype V3 sequence may reduce the possibility of coreceptor switch in these viruses, which may explain the low prevalence of X4-tropic in this population. 44 Nevertheless, a study conducted in India, which included only HIV-1 subtype C perinatally-infected patients, showed a higher prevalence of X4 tropic strains in an older population.…”

The evolution of clinical study design in heavily treatment-experienced persons with HIV: A critical review

“…26 BRIGHTE required that participants had eliminated all ARV options from ≥4 classes for resistance, previous side effects, contraindications, or unwillingness to use enfuvirtide (a twice-daily injectable). 27,28 All five studies in Periods 2 and 3 required that participants had ≥1 fully active ARV that could be used in the background regimen, but only BRIGHTE limited inclusion to those who had active 35,40,43,45,47,50,51,53,56,62,63,66,76,81,83,93,94,103,104 --Phase 3 or 3b 24/89 (27) 12,14,[16][17][18][19][20][21][22]28,32,34,39,41,46,52,55,57,65,75,105 3 23-25 2 26,27 Randomized (fully or partially) 59/89 (66) 13,14,[16][17][18...…”

“…Blinded (fully or partially) 21/89 (24) 12,14,17,19,20,[39][40][41]43,45,[51][52][53]62,66,67,103,106 1 24 1 27 Non-inferiority 9/89 (10) 19,34,41,42,46,50,57,105,111 14,[20][21][22][30][31][32]35,37,[40][41][42][43][45][46][47][48]50,53,[56][57][58]61,65,75,…”