Casper Rokx

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study

Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.

Dolutegravir as maintenance monotherapy: first experiences in HIV-1 patients

BACKGROUND Dolutegravir is recommended as part of combination ART (cART) for HIV-1-infected patients. Toxicities, drug interactions and costs related to cART still warrant the search for improved treatment options. Dolutegravirs high resistance barrier might make it suitable as antiretroviral maintenance monotherapy. The feasibility of this strategy is currently unknown. METHODS This is a prospective case series on five consecutive HIV-1-infected patients on cART without previous virological failure who switched to dolutegravir monotherapy. All were HIV-RNA suppressed <50 copies/mL and had contraindications to current and alternative combinations of antiretroviral drugs. HIV-RNA was measured at baseline, week 4, week 8, week 12 and every 6 weeks thereafter. Patients would be switched back to their original cART upon confirmed HIV-RNA >50 copies/mL. RESULTS The five patients had been HIV-RNA suppressed <50 copies/mL for ≥1.5 years prior to the initiation of dolutegravir monotherapy. All were on NNRTI-containing regimens at the switch. HIV-RNA remained <50 copies/mL at all timepoints in four patients. One patient, with end-stage renal disease and on calcium supplements, had a pre-cART HIV-RNA of 625 000 copies/mL with a CD4 nadir of 120 cells/mm(3) and had HIV-RNA of 8150 copies/mL at week 30. The dolutegravir Ctrough was 0.18 mg/L. This patient did not have acquired resistance or evidence of adherence problems and HIV-RNA was resuppressed after switching to his former cART. CONCLUSIONS This case series indicates that dolutegravir monotherapy might be a valuable maintenance option in selected HIV-infected patients who are well suppressed on cART, if confirmed by future randomized clinical trials.

Increased Virological Failure in Naive HIV-1–Infected Patients Taking Lamivudine Compared With Emtricitabine in Combination With Tenofovir and Efavirenz or Nevirapine in the Dutch Nationwide ATHENA Cohort

BACKGROUND Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART. METHODS This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. RESULTS Therapy-naive HIV-1-infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11-2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25-3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61-3.42) with efavirenz and 2.01 (95% CI, 1.36-2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression. CONCLUSIONS The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available.

Successful switch to rilpivirine/tenofovir/emtricitabine in HIV‐1‐infected patients with an isolated K103N mutation acquired during prior nonnucleoside reverse transcriptase inhibitor therapy

Whether treatment‐experienced HIV‐1‐infected patients with an acquired K103N mutation after failing nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens can be treated with rilpivirine is unknown. The aim of this pilot study was to evaluate the efficacy of rilpivirine/tenofovir/emtricitabine in HIV‐1‐infected patients with an isolated K103N mutation.

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal

Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFis) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFis Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFis reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patients CD4 + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFis constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.

Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naïve HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort

Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable in recommended tenofovir disoproxil‐fumarate (TDF)‐containing combination antiretroviral therapies (cARTs). This statement of equivalence has not been systematically studied. We compared the treatment responses to 3TC and FTC combined with TDF in boosted protease inhibitor (PI)‐based cART for HIV‐1‐infected patients.

The efficacy, pharmacokinetics, and safety of a nevirapine to rilpivirine switch in virologically suppressed HIV-1-infected patients

Abstract:This prospective, open-label nonrandomized controlled trial evaluated the efficacy, safety, and pharmacokinetics of substituting nevirapine/emtricitabine/tenofovir for rilpivirine/emtricitabine/tenofovir in 50 suppressed HIV-1 switchers. One hundred thirty-nine nonswitchers remained on nevirapine as controls. Week 12 HIV-1 RNA was <50 copies per milliliter in 92.0% of switchers and was <50 copies per milliliter at week 24 in 88.0% of switchers and 90.6% of nonswitchers (difference 2.6%, 95% confidence interval: −7.6% to 12.8%). Week 3 geometric mean nevirapine concentration was undetectable and week 1 geometric mean rilpivirine concentration (0.083 mg/L) was comparable with phase 3 trial (P = 0.747). Substituting nevirapine for rilpivirine resulted in ongoing virological suppression and did not have clinically relevant pharmacokinetic effects by cytochrome P450 interactions.

Evidence Gathered From Randomized Clinical Trials and Observational Studies on the Equivalence of Emtricitabine and Lamivudine

TO THE EDITOR—We read the commentary by Ford et al on our study regarding the comparability of results from trials and cohorts regarding the efficacy of lamivudine (3TC) and emtricitabine (FTC) in combination antiretroviral therapy (ART) [1, 2]. Of course, we can only agree with the statement that evidence from randomized clinical trials (RCTs) is of higher quality than observational studies. But we absolutely cannot agree with the conclusion that the results of the RCTs in the 3 studies Ford et al refer to provide sufficient proof of clinical equivalence of 3TC and FTC in first-line human immunodeficiency virus type 1 (HIV-1) treatment. Actually, 3 RCTs do not even address the main question of our study, which concerned the risk of virological failure in treatment-naive patients starting FTC or 3TC, combined with tenofovir (TDF) specifically in a nucleoside reverse transcriptase inhibitor (NRTI) backbone plus a nonnucleoside reverse transcriptase inhibitor (NNRTI). We specifically focused on patients on TDF plus an NNRTI and FTC or 3TC because these are the most frequently used regimens worldwide.

Risk factors in an HIV-infected population for refraining from specialist care

ABSTRACT Background: To obtain maximal benefit of combination antiretroviral therapy (cART), HIV-infected patients should be retained in medical care. Missed clinical visits are independently associated with all-cause mortality among HIV-infected patients. Our objective was to identify risk factors and patient-reported reasons for nonattendance at outpatient clinic appointments. Design and methods: We conducted a cross-sectional case-control study among 447 HIV-infected patients attending the outpatient clinic between March and July 2014. Patients with missed appointments from January 2013 onwards were included as cases and compared to a random selection of same-day controls without missed appointments during the same period. Clinical and socio-demographic characteristics were collected from clinical records and an interviewer-administered questionnaire. Additionally, reasons for nonattendance and possible solutions for future better attendance were addressed in the questionnaire. Multivariable logistic regression analysis was used to determine independent risk factors for nonattendance. Results: A total of 224 cases and 223 controls were included. Independent risk factors for nonattendance were: (i) age <30 years (odds ratio (OR) 7.2; 95% CI: 3.2–16.3 versus ≥50 years); (ii) African region of origin (OR 2.8; 95% CI: 1.5–5.0 versus Western origin); (iii) having children <12 years of age (OR 2.1; 95% CI: 1.1–4.1); (iv) history of drugs- or alcohol abuse (OR 4.4; 95% CI: 1.8–10.8); (v) no cART (OR 2.5; 95% CI: 1.1–5.3) or HIV-RNA >400 copies/ml while receiving cART (OR 3.5; 95% CI: 1.3–9.6). The main reason given for nonattendance was failure to remember the appointments (44%). Most patients would prefer to receive an appointment reminder by SMS (80% of the cases and 55% of the controls). Conclusion: Missing outpatient clinic appointments were associated with available clinical characteristics. Nonattendance may be prevented by sending routine SMS reminders prior to the next appointment.