ACTG 5273: Second-line Lopinavir/Ritonavir Plus Raltegravir Noninferior to

Lopinavir/Ritonavir Plus NRTIs in Resource-Limited Settings

Source: 2016 Conference on Retroviruses and Opportunistic Infections

ACTG 5273 (SELECT): multicenter, open-label, noninferiority, randomized phase III trial[1]

Summary of Key Conclusions

Following failure of NNRTI-based ART in patients in resource-limited settings, second-line treatment with lopinavir/ritonavir plus raltegravir noninferior to treatment with lopinavir/ritonavir plus NRTIs

o Virologic efficacy of both strategies > 90% at Week 48 o Immunologic response similar between arms

Patients with more NRTI resistance mutations at entry less likely to experience virologic failure o Similar counterintuitive relationship observed in EARNEST and SECOND-LINE trials[2,3] o Higher levels of resistance at entry may predict higher adherence to second-line

treatment or may be a marker of impaired virus

Time to grade ≥ 3 toxicity shorter in NRTI-containing arm

Patients in raltegravir arm experienced higher increases in total cholesterol and triglycerides

27% of the 96 patients who experienced virologic failure developed new resistance mutations on second-line ART

Findings support World Health Organization (WHO) guidelines on choice of second-line ART in resource-limited settings[4]

Background

WHO ART guidelines recommend NNRTI plus NRTIs as first-line ART followed by boosted PI plus NRTIs for second-line ART[4]

NRTI-sparing regimens under investigation as means of avoiding NRTI toxicity

Previous studies compared lopinavir/ritonavir plus raltegravir with lopinavir/ritonavir plus NRTIs as second-line ART in resource-limited settings

o EARNEST trial and SECOND-LINE trial each demonstrated similar virologic efficacy between lopinavir/ritonavir plus raltegravir and lopinavir/ritonavir plus NRTIs at Week 96[2,3]

Current study evaluated safety, efficacy of lopinavir/ritonavir plus raltegravir vs lopinavir/ritonavir plus NRTIs as second-line ART in resource-limited settings

Schematic of Study Design

Eligibility

Main inclusion criteria o HIV-1 RNA ≥ 1000 copies/mL after 24 weeks of treatment with NNRTI-based ART

Baseline Characteristics

Treatment arms well matched at baseline

Characteristic Lopinavir/Ritonavir + Raltegravir

(n = 258)

Lopinavir/Ritonavir + NRTIs (n = 254)

Female, % 52 50

Median age, yrs (range) 39 (34-44) 38 (33-43)

Country of residence, %

India 31 31

Malawi 22 22

South Africa 20 20

HIV-1 subtype C, % 83 79

Median duration of first-line ART, yrs (range)

4.1 (2.2-6.3) 4.0 (2.2-6.0)

Median HIV-1 RNA, log10 copies/mL (range)

4.6 (4.0-5.2) 4.5 (3.9-5.1)

Median CD4+ cell count, cells/mm3 (range)

138 (49-268) 133 (56-274)

Resistance test before entry, % 4 4

ARTs in last regimen, %

TDF 39 35

ZDV 36 35

d4T 25 30

3TC 100 100

EFV 46 38

NVP 54 62

NRTIs in second-line ART, %

FTC, TDF -- 68

3TC, ZDV -- 19

3TC, ABC -- 8

FTC, ZDV, TDF -- 3

3TC, ZDV, ABC -- 2

3TC, lamivudine; ABC, abacavir; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; NVP, nevirapine; TDF, tenofovir DF; ZDV, zidovudine.

Description of Current Analysis

Study objective: to determine noninferiority of raltegravir arm vs NRTI arm at Week 48 o Study powered to detect noninferiority at 10% margin

Primary endpoint: time to virologic failure, defined as confirmed HIV-1 RNA > 400 copies/mL after ≥ 24 weeks of first-line ART

Secondary endpoints o Safety o Immunologic response o AIDS, serious non-AIDS events o Resistance at failure

Patients followed for median 87 weeks (range: 71-96) o 2.4% of patients lost to follow-up o 6 patients discontinued (4 in raltegravir arm vs 2 in NRTI arm) o 8% of patients switched NRTIs on study

Main Findings

No difference in time to virologic failure between arms at Week 48 o Difference in likelihood of failure between arms: -3.4% (95% CI: -8.4% to 2.5%) o Raltegravir arm met criteria for noninferiority to NRTI arm, but did not meet criteria for

superiority

No difference in proportion of patients with HIV-1 RNA ≤ 400 copies/mL, < 200 copies/mL, or < 40 copies/mL between arms through Week 96

No difference between arms in mean change in CD4+ cell count through Week 96

No differences in number of AIDS events, serious non-AIDS events, or deaths between arms

Clinical Outcomes, n Lopinavir/Ritonavir + Raltegravir

(n = 258)

Lopinavir/Ritonavir + NRTIs

(n = 254)

AIDS events

Pulmonary tuberculosis 10 7

Extrapulmonary tuberculosis

0 3

Other 3 3

Serious non-AIDS events

Myocardial infarction 1 0

Stroke 0 1

Renal disease 0 2

Other 5 2

Death 3 3

Time to grade ≥ 3 toxicity shorter in NRTI arm (P = .04) o Risk not associated with specific toxicity

Patients receiving raltegravir experienced higher increases in total cholesterol (P < .05) and triglycerides (P < .05)

o No difference between arms in total cholesterol–to–high density lipoprotein ratio, high density lipoprotein level, or glucose level

Resistance Analysis

More than 90% of patients had NNRTI and NRTI resistance at study entry o 89% to 90% had M184V/I o 21% to 23% had K65R o Approximately 50% had at least 1 thymidine analogue mutation (TAM)

Resistance Mutations at Study Entry, %

Lopinavir/Ritonavir + Raltegravir

(n = 258)

Lopinavir/Ritonavir + NRTIs

(n = 254)

Samples tested 95 97

Mutations by class

NRTI + NNRTI 92 96

NNRTI only 3 1

NRTI only 1 1

NRTI + NNRTI + PI 2 0

No major IAS* mutations 2 2

M184V/I 89 90

TAMs

0 54 50

1-2 22 26

3-4 22 20

≥ 5 2 4

K65R 23 21

≥ 3 IAS* NRTI mutations 52 53

IAS, International AIDS Society. *As defined by IAS-USA.[5]

Median NRTI genotypic sensitivity score (GSS) in NRTI arm: 1 (range: 0.25-1.00) o 48% had NRTI GSS < 1, indicating reduced susceptibility

In NRTI arm, likelihood of failure higher in patients with NRTI GSS ≥ 1 vs those with NRTI GSS < 1 (difference: -8.4% at Week 48; 95% CI: -16.6% to -0.3%; P = .04)

In overall study population, risk of virologic failure was decreased with higher levels of resistance

96 patients (19%) experienced virologic failure: 46 (18%) in raltegravir arm, 50 (20%) in NRTI arm o 84 patients (88% of those with virologic failure) had samples available for analysis o 23 patients (27% of those with virologic failure) had new resistance mutations

NRTI arm: TAMs in 4 patients, major PI mutations in 7 patients

Raltegravir arm: integrase mutations in 12 patients

References

1. La Rosa AM, Harrison LJ, Taiwo B, et al. ACTG 5273 randomized trial of second-line ART supports WHO guidance. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 30.

2. Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371:234-247.

3. Amin J, Boyd MA, Kumarasamy N, et al. Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection. PLoS One. 2015;10:e0118228.

4. World Health Organization.Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/. Accessed February 25, 2016.

5. Wensing AM, Calvez V, Günthard HF, et al. 2014 update of the drug resistance mutations in HIV-1. Top

Antivir Med. 2014;22:642-650.