Abstract
Objectives
To evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy.
Methods
...Dynamics of resistance to one, two and three or more antiretroviral classes were evaluated from 1999–2018. Virological success (VS) after the latest therapy switch was evaluated according to cumulative class resistance and cumulative genotypic susceptibility score (Stanford HIV_DB algorithm).
Results
Among 13 663 isolates (from 6739 patients), resistance to at least one drug class decreased sharply from 1999 to 2010 (≤2001, 84.6%; 2010, 43.6%; P < 0.001), then remained relatively constant at ∼40% during 2010–18, with the proportion of resistance to three or more classes also stable (∼5%). After 2008, integrase inhibitor resistance slightly increased from 5.6% to 9.7% in 2018 and contributed to resistance, particularly in isolates with resistance to three or more classes (one class, 8.4%; two classes, 15.3%; three or more classes, 34.7%, P < 0.001). Among 1827 failing patients with an available follow-up, by 1 year after genotype-guided therapy start the probability of VS was 87.6%. Patients with cumulative resistance to three or more classes and receiving a poorly active regimen showed the lowest probability (62.6%) of VS (P < 0.001) compared with all other patients (≥81.8%). By Cox regression analysis, cumulative MDR and receiving poorly active antiretroviral regimens were associated with a lower hazard of VS compared with those without resistance.
Conclusions
A dramatic drop of HIV-1 drug resistance at failure has been achieved over the last two decades in Italy; resistance to three or more classes is low but present among currently failing patients. Its management still requires a rational and careful diagnostic and therapeutic approach.
Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients.
This study aimed at ...evaluating the prevalence at failure of INSTI-resistant variants and the impact of baseline minority resistant variants (MiRVs) on the virological response to an INSTI-based regimen.
Samples at failure of 134 patients failing a raltegravir-containing (n = 65), an elvitegravir-containing (n = 20) or a dolutegravir-containing (n = 49) regimen were sequenced by Sanger sequencing and ultra-deep sequencing (UDS). Baseline samples of patients with virological failure (VF) (n = 34) and of those with virological success (VS) (n = 31) under INSTI treatment were sequenced by UDS. Data were analysed using the SmartGene platform, and resistance was interpreted according to the ANRS algorithm version 27.
At failure, the prevalence of at least one INSTI-resistant variant was 39.6% by Sanger sequencing and 57.5% by UDS, changing the interpretation of resistance in 17/134 (13%) patients. Among 53 patients harbouring at least one resistance mutation detected by both techniques, the most dominant INSTI resistance mutations were N155H (45%), Q148H/K/R (23%), T97A (19%) and Y143C (11%). There was no difference in prevalence of baseline MiRVs between patients with VF and those with VS. MiRVs found at baseline in patients with VF were not detected at failure either in majority or minority mutations.
UDS is more sensitive than Sanger sequencing at detecting INSTI MiRVs at treatment failure. The presence of MiRVs at failure could be important to the decision to switch to other INSTIs. However, there was no association between the presence of baseline MiRVs and the response to INSTI-based therapies in our study.
In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an ...alternative to plasma HIV RNA for resistance genotyping.
Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success viral load (VL) <50 copies/mL were compared with those identified in the last plasma RNA genotype available. Rilpivirine/emtricitabine/tenofovir disoproxil fumarate RAMs studied were K65R, L100I, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C and M230I/L in the RT. We studied patients without virological failure (VF) and with at least 1 VF (two consecutive VLs >50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes.
In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA.
Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate.
Objectives
To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)‐sparing regimens with tenofovir alafenamide (TAF)‐based combinations in HIV‐1‐infected adults, we performed a ...network meta‐analysis (NMA) to provide estimates of relative efficacy for these two regimens.
Methods
A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI‐sparing regimens. A Bayesian random‐effect model was used to compare virological suppression rates at 48 weeks for NRTI‐sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF).
Results
Twenty‐three studies in treatment‐naïve patients identified by the SLR were included in the NMA, including four studies assessing NRTI‐sparing regimens. In treatment‐naïve patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI‐sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naïve patients with viral load < 100 000 HIV‐1 RNA copies/mL, a credible difference was found between NRTI‐sparing treatments and E/C/F/TAF. Studies in treatment‐experienced patients were too heterogeneous to allow for an NMA.
Conclusions
The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI‐sparing regimens in terms of 48‐week efficacy in treatment‐naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI‐sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI‐sparing regimens for initiation of antiretroviral therapy in treatment‐naïve HIV‐infected patients.
The prevalence of rilpivirine, emtricitabine and tenofovir resistance-associated mutations (RAMs), described in vitro and in vivo, was determined in antiretroviral-naive patients.
From 2008 to 2011, ...1729 treatment-naive patients were tested for resistance by bulk sequencing. We studied the primary rilpivirine RAMs (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C and M230I/L) and other potential rilpivirine-associated mutations (V90I, L100I, K101T, E138S, V179D/I, Y188L, V189I, G190A/E/S and M230V). We also studied the M184V/I and K65R mutations for emtricitabine and tenofovir, respectively.
Among 1729 sequences, half of patients had B-subtype viruses and the other half non-B (with 26.7% CRF02, n=461). Primary rilpivirine RAMs were infrequent (4.6%, n=79) and the most prevalent were E138A (3%, n=52), E138K, (0.3%, n=5), H221Y (0.3%, n=5), E138G (0.2%, n=4) and Y181C (0.2%, n=4). The frequency of the primary rilpivirine RAMs was similar between B and non-B subtypes. The other potential rilpivirine-associated mutations that were most prevalent were V179I (8.4%, n=145), V90I (3.8%, n=65) and V189I (2.3%, n=40). The common V179I, V189I and V90I polymorphisms have not been associated with virological failure in Phase 3 clinical studies. By the ANRS algorithm, 4.9% (n=84) of samples were resistant to rilpivirine, 3.7% (n=32) of B-subtype viruses versus 6% (n=52) of non-B-subtype viruses (P=0.02, χ(2) test). The prevalence of K65R and M184I/V was 0.06% (1/1729) and 1% (18/1729), respectively. The prevalence of K103N was 2% (35/1729).
The prevalence of rilpivirine, emtricitabine and tenofovir resistance mutations was very low in antiretroviral-naive patients. The prevalence of resistance to rilpivirine (4.9%, n=84) was not statistically different from the prevalence of efavirenz and nevirapine resistance in our population.
Objectives
Long-term results at week 96 are needed to evaluate the capacity of the darunavir/ritonavir monotherapy strategy to maintain a sustained control of the HIV-1 viral load.
Methods
MONOI is a ...prospective, open-label, non-inferiority, randomized, 96 week trial comparing darunavir/ritonavir monotherapy versus a darunavir/ritonavir triple-therapy strategy to maintain HIV-1 viral load suppression in HIV-1-infected patients. Clinical trial registration: NCT00412551.
Results
From 225 randomized patients, 219 patients reached the 48 week follow-up and 211 reached the 96 week follow-up (106 patients in the darunavir monotherapy arm and 105 in the darunavir triple-therapy arm). Baseline characteristics were well balanced between the two treatment groups. At week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81-94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75-90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral load <50 copies/mL, with no statistical difference between the two groups. Throughout the 96 week follow-up, 66/112 patients (59%, 95% CI 49-68) and 79/113 patients (70%, 95% CI 61-78) consistently had HIV-1 RNA <50 copies/mL with darunavir/ritonavir monotherapy and darunavir/ritonavir triple therapy, respectively.
Conclusions
The MONOI study establishes darunavir/ritonavir monotherapy as durable and efficacious for maintaining virological suppression in HIV-1 patients. Darunavir/ritonavir monotherapy should be considered as a (tailored) treatment option for standard triple-therapy patients who have had a substantial period of viral suppression.
Objectives
In the context of simplification strategies, it is essential to know the feasibility of a switch to a rilpivirine-based therapy. The aim of this study was to describe rilpivirine, ...tenofovir and emtricitabine resistance in HIV-1-infected patients who experienced virological failure during their previous antiretroviral treatment.
Patients and methods
The studied population included two groups of patients, all rilpivirine naive, tested for resistance by bulk sequencing from 2008 to 2011: the first group (n = 998) failing a nucleoside reverse transcriptase inhibitor (NRTI) plus boosted protease inhibitor (PI)-based regimen and the second group (n = 3733) failing an NRTI plus non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen.
Results
In the first group, the frequency of rilpivirine mutations and resistance to rilpivirine (5.1%) was similar to that in antiretroviral-naive HIV-1-infected patients. Among the 1605 patients from the second group with at least one NNRTI mutation in their HIV, the prevalence of viruses ‘resistant’ or ‘possibly resistant’ to efavirenz, nevirapine and etravirine was 78%, 79% and 74%, respectively, while 59% were resistant to rilpivirine. Resistance to rilpivirine was significantly more frequent in non-B subtype versus B subtype viruses. Among pretreated patients with viruses with at least one NNRTI mutation (other than for rilpivirine), 22% of sequences were susceptible to the combination rilpivirine/emtricitabine/tenofovir disoproxil fumarate.
Conclusions
In patients failing an NRTI plus NNRTI-based regimen, to know the feasibility of a switch to rilpivirine/emtricitabine/tenofovir disoproxil fumarate, reliable resistance information should be available at the time of use of concurrent NNRTI therapy.
Abstract Antiretroviral therapy has decreased the rate of HIV-related mortality and extended the life span of HIV patients. Current guidelines recommend the use of a 3-drug regimen, such as two ...nucleoside reverse transcriptase inhibitors and a protease inhibitor, boosted by ritonavir. Osteoporosis can be associated with the HIV disease itself or with antiretroviral therapy. Many trials have been conducted employing a single drug regimen to simplify antiretroviral therapy but few studies assessed the effect of the single drug regimen on bone mineral density (BMD). The objectives of the study were to assess and compare the relative (%) changes in lumbar spine and hip BMD over 48 weeks in HIV patients treated with mono or triple antiretroviral regimens The study was conducted using data from a randomized trial (MONARK) conducted in 136 antiretroviral-naïve HIV patients (89 men and 47 women) comparing the antiviral efficacy of a single-drug protease inhibitor regimen of lopinavir/ritonavir (LPV/r) versus LPV/r in combination with zidovudine (ZDV) and lamivudine (3TC). Lumbar spine and total hip BMD were assessed in 100 patients by dual-energy X-ray absorptiometry at baseline and 48 weeks. 48 week-BMD data were available for 43 patients (mean age 37 years) with a mean baseline lumbar spine Z-score of −0.1 in the LPV/r monotherapy group and for 25 patients (mean age 35.8 years) with a mean baseline lumbar spine Z-score of −0.2 in the LPV/r + ZDV + 3TC group. After 48 weeks, lumbar spine BMD significantly decreased by 4.4% (− 5.1% to −2.1%, P ≤ 0.001) in the LPV/r group and by 4.0% (− 5.0% to −1.7%, P ≤ 0.0001) in the LPV/r + ZDV + 3TC group. There was no significant difference in BMD changes between the two groups. These results suggest that bone loss is observed 48 weeks after the initiation of antiretroviral therapy, whether the patients receive a single- or triple-drug antiretroviral regimen.
Virological failure (VF) in patients on maraviroc-based treatment has been associated with altered HIV tropism and resistance to maraviroc. This multicentre study aimed to characterize VF in patients ...treated with maraviroc.
We analysed 27 patients whose treatment failed between 2008 and 2011. They had been screened for HIV tropism before maraviroc initiation using population-based V3 genotyping. HIV-1 tropism and resistance of R5 viruses to maraviroc at VF and at baseline were determined retrospectively using an ultrasensitive recombinant virus assay (RVA).
Viruses from 27 patients given maraviroc on the basis of the R5 genotype were characterized at the time of treatment failure. The RVA indicated that 12 patients harboured CXCR4-using viruses and 15 (56%) had pure R5 viruses at failure. One-third of those harbouring CXCR4-using viruses (4/12) were infected with R5X4/X4 viruses according to the RVA before maraviroc initiation. We analysed the phenotypic resistance to maraviroc of four patients harbouring R5 viruses at failure; two harboured viruses whose maximum percentage inhibition was reduced by 65%-90%, while the other two were infected with susceptible viruses. All patients had effective concentrations of drugs.
Half of the maraviroc-treated patients who experienced VF harboured CXCR4-using viruses at failure, one-third of them were detected by a phenotypic method before maraviroc initiation. Phenotypic assessment of R5 virus resistance to CCR5 antagonists at failure could help optimize antiretroviral therapy.
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