Efficacy and Safety Study of Darunavir for the Treatment of HIV/AIDS

Monotherapy in Africa: Evaluation of New Therapy

The aim of this pilot study is to assess the feasibility, efficacy and safety of Darunavir/ritonavir 800/100 mg once daily (DRV/r) monotherapy as a switch-maintenance strategy for patients receiving second-line ART at Yaoundé Central Hospital in Cameroon. HIV-infected adults receiving second-line antiretroviral therapy (ART) for ≥3 months with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) will undergo plasma HIV-1 RNA ("viral") load testing. Those with a viral load below 50 copies/ml (<50 cps/ml) will undergo a repeat test ideally 4-6 weeks later (allowed up to 12 weeks); if the viral load is confirmed as <50 cps/ml the patient will be invited to join the randomised phase of the study. Patients (n=150) will be randomised 1:2 to either continue the current triple ART regimen (n=50) or switch to DRV/r monotherapy (n=100). The primary end-point will be viral load suppression <400 cps/ml at week 24; secondary end-points will be viral load suppression <50 cps/ml at week 12 and week 24, safety, tolerability, and emergence of protease inhibitor (PI) drug-resistance. Patients will continue observational follow-up depending on the treatment arm they are randomized to. After week 48, patients will return to local standard of care. Pharmacokinetics (PK) and pharmacogenomics sub-study to correlate plasma concentrations of DRV to outcomes, HIV-1 drug resistance testing sub study to detect mutants archived at the time of first-line ART failure and measuring HIV DNA load will be performed, as well as a cost-effectiveness analysis will test the hypothesis that savings can be achieved by switching to DRV/r monotherapy without affecting quality of care. The primary virological objective is to evaluate efficacy in terms of the percentage of subjects who have plasma HIV-1 RNA levels <400 cps/ml after 24 weeks of follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing 2 NRTIs + LPV/r (or ATV/r) (FDA Snapshot method).

Study hypothesis:

we propose that maintenance therapy with DRV/r monotherapy is a feasible, effective and safe treatment option for patients receiving second-line ART in Yaoundé.

Inclusion Criteria:

1. Subjects with documented HIV-1 infection.
2. Male or female aged > 21 years old.
3. Subjects receiving ART with 2 NRTIs + LPV/r (or ATV/r) for at least 3 months at the time of Screening 1.
4. Nadir T lymphocyte cluster of differentiation 4 (CD4) >100 cells/mm3
5. Plasma HIV-1 RNA <50 copies/ml at Screening 1 confirmed ideally 4-6 weeks later at Screening 2 (two results must be documented; a first result obtained up to 12 weeks earlier will be accepted).
6. Subjects can comply with the protocol requirements. In particular, subjects should be willing to be followed up at least until week 24 (discontinuation prior to week 24) and for the DRV/r arm up to week 48 (discontinuation after week 24) even if they discontinue randomized treatment.
7. Subjects who have voluntarily signed and dated the consent form.

Exclusion Criteria:

1. Clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insufficiency).

2. Co-infection with hepatitis B (HBsAg positive).

3. Grade 3 or 4 laboratory abnormality as defined by AIDS, including haemoglobin ≤8mg/dL; platelets ≤50 000/mm3; estimated creatinine clearance ≤60ml/ minute, aspartate aminotransferase; alanine aminotransferase and alkaline phosphatase >3 times the upper limit of normal; and total bilirubin >2.5 times the upper limit of normal; with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:

   • Pre-existing diabetes or asymptomatic glucose grade 3 or 4 elevations.
   • Asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.

4. Presence of any currently active AIDS defining illness (Category C conditions according to the Centers for Disease Control Classification System for HIV Infection 1993) with the following exceptions:

   • Stable cutaneous Kaposi's Sarcoma (i.e., no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study.
   • Wasting syndrome due to HIV infection. Note: An AIDS defining illness that is not clinically stabilized for at least 30 days will be considered as currently active.

5. Pregnant or breastfeeding women.

6. Active substance abuse, including alcohol or recreational drugs.

7. Any clinically significant disease (e.g., tuberculosis, cardiac dysfunction, pancreatitis, acute viral infections) or life threatening disease in the previous 14 days, or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.

8. Any medical or psychiatric condition which, in the opinion of the investigator, could compromise the subject's safety or adherence to the trial protocol.

9. Previously demonstrated clinically allergy or hypersensitivity to any of the excipients of the investigational medication (DRV).

   Note: DRV is a sulfonamide. Subjects who have previously experienced a sulfonamide allergy will be allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the sulfonamide class and DRV has been identified in subjects participating in phase II trials.

10. Participation in any other clinical trials that involve administration of antiretrovirals or other drugs within the last 4 weeks and during the participation in this trial.