A Trial of 2 Options for Second Line Combination Antiretroviral Therapy Following Virological Failure of a Standard Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)+2N(t)RTI First Line Regimen (SECOND-LINE)

The investigators hypothesize that following virological failure of a standard NNRTI+2N(T)RTI regimen second-line antiretroviral therapy consisting of ritonavir-boosted lopinavir and 2N(T)RTIs will offer comparable efficacy to that provided by ritonavir-boosted lopinavir and raltegravir.

The study will be conducted for 96-weeks with the primary endpoint analyzed after 48-weeks.

The primary endpoint is virological: a comparison of virological suppression in plasma < 200 copies/mL between the randomized arms after 48 weeks.

Secondary and exploratory endpoints include virological, immunological, safety, clinical, metabolic, drug adherence, drug resistance and quality of life.

In HIV-infected subjects who have virologically failed first-line antiretroviral therapy comprising 2N(t)RTI + NNRTI a regimen of second-line therapy incorporating ritonavir-boosted lopinavir and raltegravir provides comparable (i.e., non-inferior) antiretroviral efficacy over 48 weeks to a regimen containing ritonavir-boosted lopinavir and 2-3N(t)RTIs.

Eligible patients will be randomised to one of two arms:

I. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3N(t)RTIs

II. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400 mg twice daily

The primary objective of this study is to compare the virological efficacy of the two strategies as measured by the proportion of participants with HIV RNA < 200 copies/mL 48 weeks after randomisation.

Secondary objectives include virological, immunological, safety and antiretroviral therapy endpoints.

Exploratory endpoints include clinical, metabolic, drug resistance, medication adherence and quality of life endpoints.

• Drug: Ritonavir-boosted lopinavir and raltegravir
  Two heat-stable ritonavir-boosted lopinavir tablets and one 400 mg raltegravir tablet taken every 12 hours
  Other Name: Kaletra, Aluvia, Isentress
• Drug: Ritonavir-boosted lopinavir and 2N(t)RTI
  Ritonavir-boosted lopinavir 2 heat-stable tablets taken every 12 hours and 2N(t)RTIs as prescribed
  Other Name: nucleosides, nucleotides, nuncleoside backbone

• Active Comparator: Ritonavir-boosted lopinavir and 2N(t)RTI
  This is the current standard of care for second line therapy following failure of standard first-line NNRTI+2N(t)RTIs according to WHO guidelines.
  Intervention: Drug: Ritonavir-boosted lopinavir and 2N(t)RTI
• Experimental: Ritonavir-boosted lopinavir and raltegravir
  This is an experimental arm which is likely to be fully active in the presence of N(t)RTI mutations and which preliminary evidence suggests should be potent and durable.
  Intervention: Drug: Ritonavir-boosted lopinavir and raltegravir

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 at least 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 (at least 7 days apart) HIV RNA results of greater then 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/microlitres
   • hemoglobin < 7.0 g/decilitres
   • platelet count < 50,000 cells/microlitres
   • ALT great than 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 hospitalization
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

• Merck
• Abbott
• amfAR, The Foundation for AIDS Research