Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis

doi:10.1016/S2352-3018(14)00061-7

The Lancet HIV

Volume 2, Issue 2, February 2015, Pages e42-e51

https://doi.org/10.1016/S2352-3018(14)00061-7 Get rights and content

Summary

Background

WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study.

Methods

As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance.

Findings

From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3·0 (1·3–4·3) in the NtRTI group and 3·0 (1·0–4·3) in the raltegravir group. The median sGSS in the NtRTI group was 1·0 (0·5–1·8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2·18, 95%CI 1·07–4·47; p=0·03) and week 48 (2·49, 1·09–5·69; p=0·03), baseline plasma viral load greater than 100 000 copies per mL (3·43, 1·70–6·94; p=0·0006), baseline gGSS >4·25 (4·73, 1·94–11·6; p=0·0007), and being Hispanic (3·13, 1·21–8·13; p=0·02) or African (3·49, 1·68–7·28; p=0·0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2·47, 95% CI 1·02–5·99; p=0·05), baseline log₁₀ viral load (1·83, 1·12–2·97; p=0·02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3·18, 1·12–9·02; p=0·03).

Interpretation

Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable.

Funding

University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research.

Introduction

Resistance to antiretroviral therapy (ART) is a major challenge in the management of HIV. Management of virological failure in people with virus resistance to multiple drug classes is well understood;1, 2, 3, 4, 5, 6 however, little evidence from prospective clinical trials is available on how best to manage virological failure of a first-line ART regimen. Until very recently, no well powered randomised controlled trials in this population had been done.7, 8 Experience generated from multiple late salvage studies has informed the standard advice in this situation: perform a resistance test (in practice, most commonly a genotypic ART resistance test) and use two or preferably three drugs to which the virus is demonstrably sensitive.¹

In low-income and middle-income countries (LMICs) plasma viral load monitoring is not routinely available in public health systems, and genotypic ART resistance testing less so. At virological failure, WHO recommends a switch to a pharmacologically enhanced (boosted) protease inhibitor (ie, a new drug from a class with a high genetic barrier to resistance) combined with two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs—ie, recycling of drugs from a previously used class); advice based mainly on expert opinion informed by cohort studies.⁹

Concern exists about the efficacy and durability of regimens anchored by boosted protease inhibitors and supported by NtRTIs because ART regimen efficacy may be compromised by NtRTI-resistance selected during first-line therapy. This concern is particularly important in LMICs in which viral load measurement is generally not available for routine monitoring, which limits the possibility for early detection of virological failure and restricts the capacity to prevent selection of ART drug resistance. As a practical substitute WHO recommends the use of clinical or immunological (CD4 T-cell count) monitoring.¹⁰ NtRTI resistance is common in patients identified by clinical or immunological methods as having failure of first-line ART.11, 12 As a result, most patients switched to a ritonavir-boosted protease inhibitor plus two NtRTIs will not be receiving fully active regimens. The extent to which this baseline NtRTI resistance compromises the outcomes of second-line ART is unknown.

In the SECOND-LINE study⁷ we randomly assigned 558 participants to a WHO-recommended ART regimen of ritonavir-boosted lopinavir plus two or three NtRTIs (NtRTI group) or to a new, two-drug NtRTI-sparing regimen of ritonavir-boosted lopinavir plus raltegravir (raltegravir group). Of the 558 assigned, 541 participants formed the primary modified intention-to-treat population (mITT; defined as all participants who received at least one dose of study drug and attended at least one study visit after enrolment).⁷ After 48 weeks, response to treatment in the raltegravir group was non-inferior to that in the NtRTI group (difference 1·8%, 95% CI −4·7 to 8·3), which was maintained to 96 weeks (4·4%, −2·6 to 11·3).7, 13 Here we report the relation between baseline virological resistance and virological failure and emergent resistance during the study.

Section snippets

Study design and participants

SECOND-LINE was an international, multicentre, open-label, randomised controlled trial that enrolled HIV-1 infected participants with confirmed virological failure after standard non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NtRTI first-line combination ART. Eligible patients were randomly assigned to receive ritonavir-boosted lopinavir given with either two or three NtRTIs (NtRTI group) or with raltegravir (raltegravir group). The main study methods are described in full in

Results

Between April 19, 2010, and July 22, 2013, in the mITT study population, 271 participants were assigned to the NtRTI group and 270 to the raltegravir group (figure 1): 89% and 94% had plasma viral load recorded at 96 weeks, and 79% and 87% had both successfully amplified baseline reverse transcriptase sequences for analysis and viral loads recorded at 96 weeks.

We previously reported baseline resistance in the SECOND-LINE cohort.⁷ In brief, at baseline we observed at least one major NNRTI or

Discussion

A relation exists between genotypic sensitivity to NtRTIs after virological failure of first-line ART and virological outcome after 96 weeks of the SECOND-LINE study. Contrary to our hypothesis, however, participants with few active NtRTI options did as well as, if not better, than those with a greater degree of sensitivity to the NtRTIs. This association was true not only in the NtRTI group but also in the NtRTI-sparing raltegravir group. After adjusting for other predictors, we found that

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HIV drug resistance is a major global hurdle to successful and sustained antiretroviral therapy. Global guidelines recommend testing for antiretroviral drug resistance and results are used to inform treatment regimen design for patients at different stages of therapy. Several clinical trials investigated optimal regimens after failure of first-line antiretroviral therapy, yielding data that advanced knowledge and informed care. However, further interpretation of data from these studies questioned the benefit of antiretroviral drug resistance testing for cases in which first-line treatment is not effective and, furthermore, that relying on the results of antiretroviral drug resistance testing could be misleading and unnecessary. In this Viewpoint, which is largely focused on high-income settings, we review these data, reflect on the potential problems with their interpretation, and call for caution in their extrapolation. Without negating the importance of the data, and recognising the varied circumstances related to HIV drug resistance testing in different global settings, we advise caution before changing current practice and recommendations. We believe that we should not universally stop considering HIV drug resistance testing at failure of first-line antiretroviral therapy.
Switching to coformulated bictegravir, emtricitabine, and tenofovir alafenamide maintained viral suppression in adults with historical virological failures and K65N/R mutation
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In this retrospective study, PLWH aged ≥20 years who had previous virologic failures with emergent K65N/R were included for switching to BIC/FTC/TAF after having achieved plasma HIV RNA load (PVL) <200 copies/ml for ≥3 months. PLWH were excluded if integrase inhibitor resistance-associated mutations were detected. The primary end point was losing virologic control (PVL >50 copies/ml) at week 48 using a modified US Food and Drug Administration snapshot algorithm.
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Despite the emergence of K65N/R +/- M184V/I after virologic failures, BIC/FTC/TAF could be an option for simplification after viral suppression.
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Citation Excerpt :
Our meta-analysis also shows that TAM mutations are present at a moderate level among people failing a NNRTI-based first-line regimen. Interestingly, in several studies, the detection of NRTI resistance and particularly of TAMs before starting second-line ART was associated with better virological suppression, possibly because patients who developed resistance may, on average, have better adherence [42,43]. The large-scale switch to DTG-based ART should be accompanied by longitudinal, real-world studies of virological failure and drug resistance monitoring.
To estimate the prevalence of NRTI and NNRTI drug resistance mutations in patients failing NNRTI-based ART in Southern Africa.
We conducted a systematic review to identify studies reporting drug resistance mutations among adult people living with HIV (PLWH) who experienced virological failure on first-line NNRTI-based ART in Southern Africa. We used a Bayesian hierarchical meta-regression model to synthesize the evidence on the frequency of eight NRTI- and seven NNRTI-DRMs across different ART regimens, accounting for ART duration and study characteristics.
We included 19 study populations, including 2,690 PLWH. Patients failing first-line ART including emtricitabine or lamivudine showed high levels of the M184V/I mutation after 2 years: 75.7% (95% Credibility Interval [CrI] 61.9%-88.9%) if combined with tenofovir, and 72.1% (95% CrI 56.8%-85.9%) with zidovudine. With tenofovir disoproxil fumarate, the prevalence of the K65R mutation was 52.0% (95% CrI 32.5%-76.8%) at 2 years. On efavirenz, K103 was the most prevalent NNRTI resistance mutation (57.2%, 95% CrI 40.9%-80.1%), followed by V106 (46.8%, 95% CrI 31.3%-70.4%).
NRTI/NNRTI drug resistance mutations are common in patients failing first-line ART in Southern Africa. These patients might switch to dolutegravir-based regimen with compromised NRTIs, which could impair the long-term efficacy of ART.
Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial
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WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.
In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI −3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3–4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.
Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.
Janssen.
Retrospective study on the outcome of two-drug regimens based on dolutegravir plus one reverse transcriptase inhibitor in virologically-suppressed HIV-infected patients
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Citation Excerpt :
In that analysis, patients receiving 3TC plus a PI were also evaluated; however, previous selection of M184V did not appear to increase the risk of VF. The results of the current study are also consistent with those from two large RCTs on second-line regimens performed in low-income countries: in these studies, the presence at baseline of NRTI resistance was paradoxically associated with a better virological outcome of regimens based on lopinavir/ritonavir with either NRTIs or raltegravir (RAL) [30,31]. An interesting in vitro study investigated the effects of the HIV mutations K65R, M184I and M184V on the emergence of resistance against RAL, elvitegravir (EVG) and DTG in tissue cultures [32].
This was a retrospective study on the efficacy and drug resistance mutations selected at virological failure (VF) in prospectively-followed HIV-infected patients switched to dolutegravir plus rilpivirine (DTG+RPV) or lamivudine (DTG+3TC) while virologically suppressed (HIV-RNA <50 copies/mL). VF was defined as HIV-RNA >50 copies/mL in two consecutive determinations or in a single determination if followed by treatment modification, or >1000 copies/mL in a single determination. Totally, 374 patients were analysed (307 switched to DTG+3TC and 67 to DTG+RPV); 220 had documented historical resistance. The median (IQR) time with HIV-RNA <50 copies/mL before switch was 4.52 (1.93–8.14) years. VF occurred in 17 patients after a median of 1.74 (0.90–2.46) years of follow-up in the 3TC group [incidence rate (95% CI) 3.34 (2.08–5.37) per 100-PYFU] and in 2 patients after a median of 1.78 (1.10–2.99) years of follow-up in the RPV group [incidence rate (95% CI) 1.57 (0.4–6.28) per 100-PYFU]. The 48-week estimated probabilities to maintain virological suppression during treatment with a two-drug regimen were 97.8% (95% CI 95.1–99.0%) vs. 98.3% (95% CI 88.6–99.8%) in the 3TC versus RPV group (P = 0.311). At switch, patients with VF had undetectable HIV-RNA since 0.71 (0.23–1.07) years versus 1.49 (0.64–2.2) years in those without VF (P = 0.001). In the 3TC group, VF was not associated with the presence of historical resistance to nucleoside analogues, and DTG-resistant variants were not selected at VF. One VF to DTG+RPV occurred because of historical resistance to RPV, accompanied by newly selected G140A and Q148R mutations. VF was infrequent with these regimens and was negatively associated with duration of viral undetectability. Drug resistance mutations selected at failure of these regimens were those expected in case of failure of any regimen including DTG, 3TC or RPV, but the impact of resistance to NRTIs on efficacy of DTG+3TC seems lower than expected.
Protease Inhibitors
2020, Encyclopedia of Virology: Volume 1-5, Fourth Edition
Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV infection. In the 1990s, the introduction of PIs in combination with other antiretrovirals, led to a decrease in mortality by stopping HIV progression. PIs, which prevent HIV from replicating by blocking the HIV-protease, represent an important antiretroviral class due to their low potential to select resistance. However, due to their liver metabolism via the cytochrome P450, PIs are often associated with undesirable side effects, interaction with concomitant drugs and poor bioavailability. To overcome the reduced bioavailability and maintain plasma concentrations high enough to inhibit HIV viral replication, PIs are co-administered with a boosting drug, such as ritonavir-darunavir or ritonavir-atazanavir in combination with a nucleoside reverse transcriptase inhibitor. (NRTI). In special specific populations, including those with anticipated adherence issues, confirmed or suspected HIV antiretroviral resistance or intolerance to other classes of antiretroviral therapy, boosted PIs remain widely used.

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ArticlesBaseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet

Lancet

Lancet Infect Dis

Lancet Infect Dis

Lancet Infect Dis

Lancet

Lancet

Guidelines for the use of antiretroviral agents in adults and adolescents

Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia

N Engl J Med

Raltegravir with optimized background therapy for resistant HIV-1 infection

N Engl J Med

Maraviroc for previously treated patients with R5 HIV-1 infection

N Engl J Med

Lancet

A pragmatic randomised controlled strategy trial of three second-line treatment options for use in public health rollout programme settings: the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial

N Engl J Med

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach

Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings

J Infect Dis

Articles
Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis