1.
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

2.
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

3.
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)

4.
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

5.
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.