Bone and Body Comp: A Sub Study of the SECOND-LINE Study

The use of anti HIV drugs (ART), and in particular a class of drugs known as nucleoside reverse transcriptase inhibitors (N(t)RTI), has been associated with changes in body fat and in particular loss of peripheral fat in the limbs. Low bone mineral density and osteoporosis are also common in HIV-infected patients. There appears to be some association between ART and bone loss, but this is poorly understood and requires further research. The SECOND-LINE study provides an opportunity to examine if a new anti-HIV drug (raltegravir) can result in greater increase in limb fat than a drug regimen containing N(t)RTI, which is currently standard of care. This study also provides an opportunity to examine if additional bone loss occurs with the second regimen of anti-HIV drugs and whether non-N(t)RTI regimens of ART used in second line therapy result in more or less bone loss than use of other classes of anti-HIV drugs such as protease inhibitors or N(t)RTI combinations.

It is hypothesized that subjects randomised into Raltegravir arm will demonstrate greater increases in limb fat and smaller reductions in bone density at the proximal femur over 48 weeks than those randomised into the control arm (LPV/r + 2-3N(t)RTIs).

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Lopinavir / ritonavir; Drug: 2-3N(t)RTI; Drug: raltegravir

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • CEADI
• India
  • Chennai, India, 600113
    • YRGCare Medical Centre
• Malaysia
  • Kuala Lumpur, Malaysia, 50603
    • University of Malaya Medical Centre
• South Africa
  • Bloemfontein, South Africa
    • Josha Research
  • Cape Town, South Africa, 7925
    • Desmond Tutu HIV Foundation
  • Soweto, South Africa
    • Chris Hani Baragwanath Hospital
• Thailand
  • Bangkok, Thailand, 10330
    • HIV-NAT Program on AIDS - Thai Red Cross

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Second-Line main study identifier: NCT00931463

Inclusion Criteria:

1. HIV-1 positive by licensed diagnostic test
2. Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate)
3. Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for ≥ 24 weeks
4. No change in antiretroviral therapy within 12 weeks prior to screening
5. Failed first-line NNRTI + 2N(t)RTI combination therapy according to virological criteria defined by two consecutive (≥7 days apart) HIV RNA results of > 500 copies/mL
6. No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors
7. Able to provide written informed consent

Exclusion Criteria:

1. The following laboratory variables:

   • absolute neutrophil count (ANC) < 500 cells/µL
   • hemoglobin < 7.0 g/dL
   • platelet count < 50,000 cells/µL
   • ALT > 5 x ULN
2. Pregnant or nursing mothers
3. Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B surface antigen
4. Use of immunomodulators within 30 days prior to screening
5. Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, amiodarone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, astemizole, terfenadine, vardenafil, and St. John's wort)
6. Intercurrent illness requiring hospitalisation
7. Active opportunistic disease not under adequate control in the opinion of the site Principal Investigator
8. Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal Investigator might adversely affect participation in the study
9. Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for the protocol-defined period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1. Lopinavir / ritonavir + 2-3N(t)RTI; LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3N(t)RTI	Drug: Lopinavir / ritonavir; LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily; Drug: 2-3N(t)RTI
Active Comparator: Arm 2. Lopinavir /ritonavir + raltegravir	Drug: Lopinavir / ritonavir; LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily; Drug: raltegravir; raltegravir 400mg 1 tablet twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean Bone Mineral Density Changes From Baseline to 48 Weeks as Measured by DXA Scan	48 weeks
Mean Limbs Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan	48 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean Total Body Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan	48 weeks
Mean Triglycerides Changes From Baseline to 48 Weeks	48 weeks
Mean Total Cholesterol Changes From Baseline to 48 Weeks	48 weeks
Mean Glucose Changes From Baseline to 48 Weeks	48 weeks

Collaborators and Investigators

• Sponsor: Kirby Institute
• Investigators: Principal Investigator: Paddy Mallon, Mater Misericordiae University Hospital, Dublin; Principal Investigator: Waldo Belloso, Hospital Italiano, Argentina; Principal Investigator: Samuel Ferret, Hopital Saint-Louis, France; Principal Investigator: Praphan Phanuphak, HIV-NAT Program on AIDS - Thai Red Cross, Bangkok; Principal Investigator: Jennifer Hoy, The Alfred

Publications and helpful links

General Publications

• Martin A, Moore C, Mallon PW, Hoy J, Emery S, Belloso W, Phanuphak P, Ferret S, Cooper DA, Boyd MA; Second Line study team. Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. AIDS. 2013 Sep 24;27(15):2403-11. doi: 10.1097/01.aids.0000432534.47217.b4.
• Martin A, Moore CL, Mallon PW, Hoy JF, Emery S, Belloso WH, Phanuphak P, Ferret S, Cooper DA, Boyd MA; Second-Line Study Team. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line antiretroviral therapy. PLoS One. 2013 Oct 30;8(10):e77138. doi: 10.1371/journal.pone.0077138. eCollection 2013.
• Boyd MA, Amin J, Mallon PW, Kumarasamy N, Lombaard J, Wood R, Chetchotisakd P, Phanuphak P, Mohapi L, Azwa I, Belloso WH, Molina JM, Hoy J, Moore CL, Emery S, Cooper DA; SECOND-LINE Study Group. Body composition and metabolic outcomes after 96 weeks of treatment with ritonavir-boosted lopinavir plus either nucleoside or nucleotide reverse transcriptase inhibitors or raltegravir in patients with HIV with virological failure of a standard first-line antiretroviral therapy regimen: a substudy of the randomised, open-label, non-inferiority SECOND-LINE study. Lancet HIV. 2017 Jan;4(1):e13-e20. doi: 10.1016/S2352-3018(16)30189-8. Epub 2016 Nov 1.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 19, 2012
• First Posted (Estimated): January 20, 2012

Study Record Updates

• Last Update Posted (Actual): June 26, 2025
• Last Update Submitted That Met QC Criteria: June 25, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Viral Protease Inhibitors; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Antiviral Agents; Cytochrome P-450 Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Raltegravir Potassium; Ritonavir; Lopinavir
• Other Study ID Numbers: 2L body comp sub-study