Overview of MRC studies in 2008
Simon Collins, HIV i-Base
The first session at the conference included an overview of new Medical Research Council (MRC) adult studies that will start in 2008.
Boosted-PI monotherapy as maintenance therapy
The PIVOT study, due to start enrolment in May 2008, is the largest UK trial to be planned since the Delta trial fifteen years ago, The study will include over 40 sites across the UK and Ireland.
PIVOT stands for “Protease Inhibitor monotherapy Versus Ongoing Triple-therapy in the long term management of HIV infection”. The trial proposes randomising 400 patients with CD4 >100 cells/mm3, who have been suppressed <50 copies/mL for > 6 months on PI- or NNRTI-based triple therapy, to either continue this treatment or switch to boosted-PI monotherapy, with follow-up out to five years.
Patients who have previously had virological failure on a PI-containing regimen are excluded, but patients who have failed on an NNRTI-based regimen will be eligible if there is a resistance test available from the time of failure. Additional exclusion criteria include patients with a history of encephalopathy, who have >30% cardiovascular risk, or uncontrolled hyperlipidaemia. Choice of boosted PI is at the discretion of the individual doctor/patient but currently this would be expected to be lopinavir/r, darunavir/r or possibly atazanavir/r, although none is currently approved for this indication. Switching to alternative boosted-PIs is allowed within the study, as is therapeutic drug monitoring (TDM) to confirm trough levels are adequate in individual patients.
Viral rebound in patients on the monotherapy arm (>50 copies/mL on 2 consecutive tests 4 weeks apart) prompts a return to triple therapy for the rest of the study.
The primary endpoint is the preservation of future treatment options defined by any change in a patients resistance profile. Secondary endpoints include serious drug or disease-related complications, tolerability, and changes in viral load, CD4, quality of life, neurocognitive function, cardiovascular risk, cost of healthcare. Sub-studies include drug exposure and viral suppression in compartments including genital tract and CSF.
Several studies have already looked at options for boosted-PI monotherapy, generally showing better results when used as a switch treatment after suppression to <50 copies/mL on a triple combination regimen. These studies, mainly using lopinavir/r monotherapy, have shown 25% of patients may fluctuate with low-level viraemia (50-500 copies/mL) but that did not result in PI-resistance and is suppressed if RTIs are added back to the combination.
Recruitment starts in May 2008, with 60 months follow-up.
For further details please contact: PIVOT@ctu.mrc.ac.uk
Can hydroxychloroquine decrease immune activation in asymptomatic patients?
Nick Paton from the MRC Clinical Trials Unit (CTU) outlined a Wellcome-sponsored MRC study (HCQ01) looking at whether an intervention in early asymptomatic infection that may be able to reduce immune activation. Early immune activation directly impacts on CD4 loss and may also independently contribute to disease progression. Hydroxychloroquine (HCQ) is anti-malarial treatment first synthesised in 1955 that has other indications including systemic lupus erythematosus, cutaneous manifestations of dermatomyositis, hyperlipidaemias, thromboembolic prophylaxis in antiphospholipid antibody syndrome and rheumatoid arthritis.
Although the exact mechanism of action is unclear, by increasing endosomal pH, immune modulation is thought to interfere with steps in T-cell activation pathway, including MHC class II antigen presentation and T-cell receptor mediated calcium signalling. Several studies have also indicated modest antiretroviral activity.
The tolerability profile was reported as being generally good, especially at low doses and when not used for chronic treatment, but grade 3/4 side effects include diarrhoea (<10% patients) rash and headache (both <5% patients), proximal muscle weakness (reversible) and retinopathy have been reported in <1% and <0.01% patients respectively.
This 48-week Phase II study proposes randomising 100 asymptomatic treatment-naive patients (CD4>400 cells/mm3) to either 400mg HCQ (2 x 200mg tablets, once daily) or matched placebo. In addition to standard monitoring a wide panel of immunological markers will be analysed.
The primary endpoint is change in activation of CD8+ T cells. Activation is estimated as 46% in untreated HIV, which drops to 11% in patients on HAART. This study is powered to detect reduction to 35% with HCQ which modelling suggests could decrease hazard of disease progression by over 50%.
Recruitment starts in April 2008, aiming for enrolment by October, and including 18 months follow-up.
For further details please contact: HCQ01@ctu.mrc.ac.uk
START (Strategic Timing of AntiRetroviral Treatment)
Professor Margaret Johnson from the Royal Free and outgoing chair of BHIVA, presented an overview for the much discussed and anticipated START trial. Based on the international network responsible for the SMART treatment interruption study, START plans to randomise 900 treatment-naive patients with CD4 counts > 500 cells/mm3 to either early (immediate) or deferred (when CD4 <350 cells/mm3) treatment. If this 70-site pilot phase is successful the study will roll out to include 4000 patients at 150 sites, with 4.5 years follow-up planned for all patients.
The rationale for earlier treatment is based on greater efficacy and tolerability of first-line treatment options in 2008 together with compelling data from SMART and several large cohort studies, showing an increased risk of generally rare but life threatening diseases in patients with CD4 counts above 350 cells/mm3 who are not on treatment compared to those suppressed on HAART. The SMART study notable found a protective effect of HAART against serious non-AIDS defining morbidity (and mortality) including cardiovascular, renal and hepatic events.
As with SMART, the study is planned to include a broad range of important sub-studies and will be powered to inform other aspects of clinical care.
If this benefit is found from earlier treatment it has the potential to narrow the gap in life expectancy that still exist between HIV-negative people and HV-positive people suppressed to <50 copies/mL. This will be balanced against tolerability, resistance and impact on quality of life, In the context of the prospect of long-term treatment.
Many patients may think there is little difference between being on treatment for 30 years, or 32 years (starting slightly earlier), for the chance of higher and more durable CD4 responses and a reduced risk of complications that are currently rare but which may increase as we age.
START is expected to enroll in the UK in Autumn 2008, with 4.5 years follow-up.
For further details please contact: START@ctu.mrc.ac.uk