Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy

ABSTRACTProtease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n= 18 subjects)-, lopinavir/ritonavir (n= 4)-, or indinavir and then lopinavir/ritonavir (n= 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region ofpol. We then quantified the susceptibilities of the mutants to the HIV-2 “active” PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective.

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HIV-1 viral load and resistance in genital secretions in patients taking protease-inhibitor-based second-line therapy in Africa

Antiviral Therapy ◽

10.3851/imp3200 ◽

2017 ◽

Vol 23 (2) ◽

pp. 191-195 ◽

Cited By ~ 1

Author(s):

Anne Hoppe ◽

◽

Marina Giuliano ◽

Abbas Lugemwa ◽

Jennifer A Thompson ◽

...

Keyword(s):

Viral Load ◽

Protease Inhibitor ◽

Second Line ◽

Second Line Therapy ◽

Line Therapy ◽

Hiv 1

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The Effectiveness of Intravitreal Ranibizumab in Patients with Diabetic Macular Edema Who Have Failed to Respond to Intravitreal Bevacizumab

Ophthalmologica ◽

10.1159/000444103 ◽

2016 ◽

Vol 235 (3) ◽

pp. 133-136 ◽

Cited By ~ 7

Author(s):

Rita Ehrlich ◽

Idit Dan ◽

Iris Deitch ◽

Ruth Axer-Siegel ◽

Karin Mimouni

Keyword(s):

Macular Edema ◽

Diabetic Macular Edema ◽

Intravitreal Bevacizumab ◽

Tertiary Hospital ◽

Second Line ◽

Intravitreal Ranibizumab ◽

Second Line Therapy ◽

Line Therapy ◽

Intravitreal Treatment ◽

The Mean

Purpose: To investigate the response to intravitreal ranibizumab after failure of intravitreal bevacizumab in patients with diabetic macular edema (DME). Methods: Demographics, visual acuity (VA), central macular thickness (CMT), and HbA1C were retrospectively collected from DME patients treated with second-line intravitreal ranibizumab at a tertiary hospital in 2012-2013 and followed for at least 3 months. Results: Twenty-two patients (26 eyes) were included in the study, with a mean (±SD) age of 66 ± 8.1 years and followed for an average of 28.36 months. The mean number of intravitreal bevacizumab injections was 7.3 ± 2.8, and of intravitreal ranibizumab injections 5.11 ± 2.4. After 3 ranibizumab injections, 57% of eyes showed improvement in VA. The change in VA was statistically significant (p = 0.044) in those eyes where the pretreatment acuity for the second-line therapy was <20/40 (logMAR 0.3). CMT decreased from 435.95 ± 83.28 to 373.69 ± 44.39 µm (p = 0.01). The number of ranibizumab injections was significantly correlated with the change in CMT (p = 0.037). Conclusion: Intravitreal treatment with ranibizumab can be efficacious in eyes with DME that have failed to respond to bevacizumab.

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The Epidemiology Of Immune Thrombocytopenia and Clinical Features Of Patients At a Single Center In Northwestern Turkey

Blood ◽

10.1182/blood.v122.21.4750.4750 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4750-4750

Author(s):

Gulsum Emel Pamuk ◽

Ahmet Koylu , Internist ◽

Mehmet Sevki Uyanik ◽

Hematology Fellow ◽

Muzaffer Demir ◽

...

Keyword(s):

Clinical Features ◽

Immune Thrombocytopenia ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Northwestern Turkey ◽

The Mean

Introduction There is only a few data about the epidemiology of immune thrombocytopenia (ITP). Until now, no data about the frequency of ITP in Turkey has been reported. It is quite difficult to perform an epidemiologic study because there are multiple pathogenic mechanisms in ITP and no laboratory or clinical data is characteristic for the diagnosis. We determined the epidemiology of ITP in northwestern region of Turkey and we evaluated the clinical features in our ITP patients. Methods Twohundred-and-sixteen patients diagnosed with ITP between 2000-2012 at our center were retrospectively evaluated. Our hospital has been the only tertiary referral center for hematological diseases (benign and malignant) for a mixed rural and urban population of 616000 people (316000 males, 300000 females) for longer than 16 years. The incidence rates and prevalence per 100000 poulation aged ≥16 years were calculated. Results Of 216 ITP patients, 159 (73.6%) were females and 57 (26.4%) were males (female/male: 2.8). The mean annual incidence of ITP was 2.92/100000 (95%CI: 1.57-4.27) and the overall prevalence was 35.1/100000 (95%CI: 30.3-39.8). The prevalence in women (53/100000, 95%CI: 44.8-61.2) was higher than the prevalence in men (18/100000, 95%CI: 15.4-20.6). The mean age at the time of diagnosis was 42.3 years (median age: 40, range:8-87). Of 162 ITP patients who were given first-line therapy, there was complete response (CR) in 124 (76.5%) and partial response (PR) in 22 (13.6%) (Table 1). Seventythree (50%) of the 146 patients who obtained response (CR+PR) with first-line therapy relapsed at a median of 6 months (range: 2-98 months). The median follow-up in patients who did not relapse was 11 months (range: 2-108 months). The frequency of relapse-free remission in patients responsive to first-line therapy was 61% at one year and 52% at 5 years. Thirtynine patients (48.1%) who were responsive to second-line therapy (CR+PR) relapsed at a median of 5.5 months (range: 2-83 months). Twentyfive patients (53.2%) who were steroid-responders relapsed at a median of 6 months (range: 2-83 months). Ten patients (34.5%) who were responsive to splenectomy relapsed at a median of 6.5 months (range: 2-54 months). Splenectomy was performed in 49 ITP patients. In 30 patients, it was the second-line treatment modality; in 13 patients, it was third-line; and in 6, it was fourth-line. Splenectomized patients were followed up for a median of 35.5 months (range: 2-187 months). The median duration from diagnosis until splenectomy was 7 months (range: 2-102). Of 49 patients who underwent splenectomy, 43 (87.8%) had CR and one (2%) had PR. Nine of the 44 patients (20.5%) relapsed at a median of 24 months (range: 5.5-141). The median duration of remission in 35 patients (79.5%) who did not relapse was 30.5 months (range: 2-84 months). When splenectomy and steroids were compared as second-line treatment options, CR rate was higher with splenectomy (p=0.002) and total response (CR+PR) tended to be better (96.7% vs. 82.5%, p=0.09). Patients responsive to steroids as second-line therapy tended to relapse more than patients treated with splenectomy (53.2% vs. 33.3%, p=0.088). When relapse-free remission durations with splenectomy and steroids were compared, it was seen that it was longer with splenectomy (p<0.001). The relapse-free remission rates after splenectomy were 90% at 1 year and 62% at 5 years. These rates were lower with steroid therapy (45% at 1 year, 36% at 5 years). Conclusions The annual incidence and prevalence of ITP in northwestern Turkey was similar to data from western countries –at the lower limit for some countries. Effective treatment strategies seem to be steroids as first-line therapy and splenectomy in refractory cases. Disclosures: No relevant conflicts of interest to declare.

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