Immunological and virological features of HIV-infected patients with increasing CD4 cell numbers despite virological failure during protease inhibitor-based therapy

Abstract Background Ritonavir-boosted darunavir (DRV/r) is a protease inhibitor (PI) indicated for the treatment of naïve and pretreated HIV-infected patients since 2007. Our study aims to describe DRV/r-treated patients experiencing virological failure (VF) documented with HIV resistance testing. Methods Data from patients belonging to the ANRS CO3 Aquitaine Cohort treated with a regimen including DRV/r between February 2007 and December 2015 were analyzed. Baseline characteristics of patients experiencing VF (defined by 2 consecutive plasma viral loads >50 copies/mL) were compared with those without VF. We then described factors associated with VF as emergence of IAS DRV resistance–associated mutations (RAMs). Results Among the 1458 patients treated at least once with a DRV/r-based regimen, 270 (18.5%) patients experienced VF during follow-up, including 240 with at least 1 genotype resistance test (GRT). DRV RAMs were detected in 29 patients (12%). Among them, 25/29 patients had ≥2 DRV RAMs before DRV/r initiation, all of whom had experienced VF during previous PI treatments. For 18/29, DRV/r was maintained after VF, and controlled viremia was restored after modification of DRV-associated antiretroviral molecules or increased DRV dose. Finally, only 6/29 patients selected new DRV RAMs after DRV/r initiation. All of these experienced previous VFs while on other PIs. Conclusions These results highlight the efficacy and robustness of DRV/r, as the emergence of DRV RAMs appeared in <0.4% of patients receiving a DRV/r-based regimen in our large cohort.

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Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01643-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2934-2939 ◽

Cited By ~ 43

Author(s):

Constance Delaugerre ◽

Philippe Flandre ◽

Marie Laure Chaix ◽

Jade Ghosn ◽

François Raffi ◽

...

Keyword(s):

Protease Inhibitor ◽

Triple Therapy ◽

Virological Failure ◽

Therapy Group ◽

Resistance Mutation ◽

Resistance Testing ◽

Initial Screening ◽

Resistance Mutations ◽

Cd4 Cell Count ◽

Hiv 1

ABSTRACT The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society—USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.

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HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China

BMJ Open ◽

10.1136/bmjopen-2014-005886 ◽

2014 ◽

Vol 4 (10) ◽

pp. e005886 ◽

Cited By ~ 16

Author(s):

Xuebing Leng ◽

Shujia Liang ◽

Yanling Ma ◽

Yonghui Dong ◽

Wei Kan ◽

...

Keyword(s):

Drug Resistance ◽

Virological Failure ◽

Nucleoside Reverse Transcriptase Inhibitor ◽

Drug Users ◽

Monitoring Network ◽

Transcriptase Inhibitor ◽

First Line ◽

Cd4 Cell Count ◽

Reverse Transcriptase Inhibitor ◽

Cd4 Cell

ObjectiveTo explore HIV virological failure and drug resistance among injecting drug users (IDUs) receiving first-line antiretroviral treatment (ART) in China.DesignA series of cross-sectional surveys from 2003 to 2012 from the Chinese National HIV Drug Resistance (HIVDR) Surveillance and Monitoring Network.SettingChina.ParticipantsData were analysed by the Chinese National (HIVDR) Surveillance and Monitoring Network from 2003 to 2012. Demographic, ART and laboratory data (CD4+ cell count, viral load and drug resistance) were included. Factors associated with virological failure were identified by logistic regression analysis.Results929 of the 8556 individuals in the Chinese HIVDR database were IDUs receiving first-line ART. For these 929 IDUs, the median duration of treatment was 14 months (IQR 6.0–17.8). 193 of the 929 IDUs (20.8%) experienced virological failure (HIV viral load ≥1000 copies/mL). The prevalence of HIVDR among patients with virological failure was 38.9% (68/175). The proportion of patients with drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs), nucleoside reverse transcriptase inhibitor (NRTIs) and protease inhibitors (PIs) was 52.9%, 76.5% and 4.4%, respectively. Factors independently associated with virological failure include: ethnic minorities, junior high school education or less, farmers, self-reported missing doses in the past month, CD4 cell count at survey from 200 to 349 cells/mm3 or from 0 to 199 cells/mm3, and residence of Guangxi and Yunnan provinces.ConclusionsThe proportion of virological failure was high among IDUs receiving first-line ART in China. However, better treatment outcomes were observed in Guangxi and Yunnan, which indicates the importance of ART education and adherence to intervention, especially for patients who are farmers, minorities or have a poor educational background.

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Switch from protease inhibitor- to efavirenz-based antiretroviral therapy improves quality of life, treatment satisfaction and adherence with low rates of virological failure in virologically suppressed patients

International Journal of STD & AIDS ◽

10.1258/ijsa.2009.008487 ◽

2010 ◽

Vol 21 (3) ◽

pp. 166-171 ◽

Cited By ~ 21

Author(s):

R E Campo ◽

C Cohen ◽

K Grimm ◽

T Shangguan ◽

J Maa ◽

...

Keyword(s):

Quality Of Life ◽

Antiretroviral Therapy ◽

Protease Inhibitor ◽

Virological Failure ◽

Treatment Satisfaction

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HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy

AIDS ◽

10.1097/00002030-199904160-00001 ◽

1999 ◽

Vol 13 (6) ◽

pp. F35-F43 ◽

Cited By ~ 297

Author(s):

Steven G. Deeks ◽

Frederick M. Hecht ◽

Melinda Swanson ◽

Tarek Elbeik ◽

Richard Loftus ◽

...

Keyword(s):

Protease Inhibitor ◽

Cell Count ◽

Salvage Therapy ◽

Inhibitor Therapy ◽

Protease Inhibitor Therapy ◽

Cd4 Cell Count ◽

Hiv Rna ◽

Count Response ◽

Cd4 Cell

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Dual-protease inhibitor (PI) therapy was associated with an increased rate of virological failure,

Inpharma Weekly ◽

10.2165/00128413-200816250-00013 ◽

2008 ◽

Vol &NA; (1625) ◽

pp. 8

Author(s):

&NA;

Keyword(s):

Protease Inhibitor ◽

Virological Failure

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Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01136-06 ◽

2007 ◽

Vol 51 (6) ◽

pp. 2035-2042 ◽

Cited By ~ 7

Author(s):

Ana Marin-Niebla ◽

Luis Fernando Lopez-Cortes ◽

Rosa Ruiz-Valderas ◽

Pompeyo Viciana ◽

Rosario Mata ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitor ◽

Virological Failure ◽

Low Dose ◽

Pharmacokinetic Data ◽

Time Curve ◽

Once Daily ◽

Intention To Treat ◽

Immunodeficiency Virus ◽

Treatment Naïve

ABSTRACT We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median C max, area under the concentration-time curve from 0 to 24 h, and C min plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C min levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

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Characterization of HIV-1 from patients with virological failure to a boosted protease inhibitor regimen

Journal of Medical Virology ◽

10.1002/jmv.21997 ◽

2011 ◽

Vol 83 (3) ◽

pp. 377-383 ◽

Cited By ~ 4

Author(s):

Marie Rathcke Lillemark ◽

Jan Gerstoft ◽

Niels Obel ◽

Gitte Kronborg ◽

Court Pedersen ◽

...

Keyword(s):

Protease Inhibitor ◽

Virological Failure ◽

Protease Inhibitor Regimen ◽

Inhibitor Regimen ◽

Hiv 1

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Mathematical Modeling of the Interrelationship of CD4 Lymphocyte Count and Viral Load Changes Induced by the Protease Inhibitor Indinavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.2.358 ◽

1998 ◽

Vol 42 (2) ◽

pp. 358-361 ◽

Cited By ~ 7

Author(s):

George L. Drusano ◽

Daniel S. Stein

Keyword(s):

Viral Load ◽

Protease Inhibitor ◽

Disease Progression ◽

Antiviral Effect ◽

Hiv Protease ◽

Cd4 Cells ◽

Viral Inhibition ◽

Hiv Rna ◽

Cell Counts ◽

Cd4 Cell

ABSTRACT While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (r 2 = 0.86, P < 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (r 2 = 0.60, P < 0.01). Simultaneously modeling both influences in a linked nonlinear model (r 2 = 0.93, P < 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.

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