MRC HIV Trials

COTOX is an open randomised trial in individuals with HIV infection and with either a history of, or a current, mild to moderate skin and/or febrile reactions to co-trimoxazole. The trial compares a 10 day desensitisation with rechallenge to full doses when restarting co-trimoxazole as prophylaxis against Pneumocystis carinii pneunomia (PCP). It it planned to recruit 388 individuals and follow them for at least 6 months.

Evaluation of Resistance Assays (ERA) Trial

ERA is a randomised trial to assess the clinical utility of HIV drug resistance testing, which is divided into two parts. In Part A, for patients who are not heavily treatment experienced, randomisation is to (a) no resistance assay, or (b) a centralised genotypic assay. In Part B, for patients who are heavily treatment experienced, randomisation is to (a) a centralised genotypic assay or (b) a centralised genotypic assay plus a centralised phenotypic assay.

By the end of May 2001, 54 subjects had been enrolled in Part A and 302 in Part B. Recruitment to the trial will close on 31 July 2001 and all subjects will be followed-up for another 12 months. Main results from the trial are expected to be available in late 2002. Although Part A is under-powered due to low recruitment, it is hoped to combine the results with those of the PERA trial in a meta-analysis.

ESPRIT

The ESPRIT study is a large randomised, open-label, phase III, international study of subcutaneous recombinant IL-2 (Proleukin®) in patients with HIV-1 infection and CD4+ cell counts of 300/mm3 or greater: “ESPRIT” stands for Evaluation of Subcutaneous Proleukin® in a Randomised International Trial. The purpose of the trial is to compare the effects of IL-2 or no IL-2 on progression of HIV disease and mortality over a 5-year period in patients taking combination anti-retroviral therapy.

The trial is being run in 24 sites in the UK and in 22 other countries world-wide. The trial has a web-site for people interested in the study. The web-site has the trial protocol and information about the trial drug IL-2, as well as listing all the hospitals and clinics offering this trial.

FORTE

This is a phase II, UK-based trial to evaluate the activity and tolerability of three different anti-retroviral regimens including using more potent therapy continuously or as induction therapy. Participants with HIV infection who have never had anti-retroviral drugs but who need to initiate therapy. Eligible participants will be allocated to receive open therapy with either:

1. a 4-drug combination of Didanosine (ddI), Stavudine (d4T), Nevirapine plus Nelfinavir throughout or
2. a 3-drug combination of ddI, d4T plus Nevirapine throughout or
3. a 4-drug combination of ddI, d4T, Nevirapine plus Nelfinavir for 24 weeks (“induction”) followed by a 3-drug combination of ddI, d4T and Nevirapine (“maintenance”).

The aim is to recruit 150 participants and to follow them for at least 48 weeks.

Patients are seen monthly and obtain monthly viral load results. Pharmacological monitoring for Nelfinavir & Nevirapine are included at weeks 4 and 8.

12 sites in the UK submitted Forte to their LRECs and a total of 11 sites have received full approval. Eight sites, (Birmingham Heartlands, Brighton, Sheffield, Kings, Chelsea & Westminster, the Central Middlesex Hospital, St Mary’s and St Thomas’) have been set up and are ready to screen participants. Another 4 sites will be visited and ready to screen in the next month. As of 20/12/99 eleven patients have been recruited into Forte.

INITIO

This is an international trial involving 17 countries comparing different strategic approaches to combination anti-retroviral therapy that includes both the first and subsequent regimens (if a change is necessary for therapeutic failure or intolerance) in individuals with HIV infection who wish to start treatment.

The participants will be randomised to open treatment with either:

1. Didanosine (ddI) + Stavudine (d4T) + Efavirenz (EFV), followed by Zidovudine (ZDV) + Lamivudine (3TC) + Abacavir (ABC) + Nelfinavir (NFV) for therapeutic failure,
2. ddI + d4T + NFV, followed by ZDV + 3TC + ABC + EFV for therapeutic failure, or
3. ddI + d4T + NFV + EFV, followed by ZDV + 3TC + ABC + Ritonavir (RTV) + Saquinavir (SQV) for therapeutic failure.

Thus, one arm starts with triple therapy including a non-nucleoside RT inhibitor, another arm starts with triple therapy including a protease inhibitor, and the third arm starts with quadruple therapy including both a NNRTI and PI.

Participants will be seen monthly for the first 3 months and then every 3 months until the end of the trial and may choose to enter one or more of the substudies that will run in conjunction with the main trial.

The aim is to recruit over 1,000 participants worldwide, with at least 80 from the UK. Switzerland has recruited well and enrolled 51 participants within 10 months of starting the trial. In the UK, 20 sites have/are submitting to their LRECs and a total of 10 sites have already received full approval. Within the last month six sites, Brighton, St Mary’s Hospital, London, Sheffield, Chelsea and Westminster, Kings and Wycombe General Hospital have been set up and 9 patients have been randomised. Another 4 sites will be ready to screen in the next month and we look forward to some rapid recruiting. For more information and up-to-date recruitment figures on a UK and an

OPTIMA – Options in Management with Antiretrovirals

The purpose of the OPTIMA trial, is to compare the effect of different management strategies on both clinical outcomes (survival, time to AIDS defining event, time to serious adverse event), virologic and immunologic response, and other healthcare outcomes (quality of life measures, resource utilisation, cost-effectiveness) in patients who have failed several regimens of conventional HAART.

OPTIMA is a tri-national trial (Canada, the USA and the UK). The trial will have a range of one to three and a half years follow-up in patients with advanced HIV disease. This trial will help delineate the most effective therapeutic strategies in the management of such patients.

The strategies to be compared in this open randomised study are:

• An HIV drug free period of 3 months followed by HIV treatment with up to 4 drugs (“standard ART”)
• An HIV drug free period of 3 months followed by HIV treatment with 5 or more drugs (“mega-ART”)
• Immediate start of an HIV treatment with up to 4 drugs (“standard ART”)
• Immediate start of an HIV treatment with 5 or more drugs (“mega-ART”)

The OPTIMA trial is the first large-scale, multicenter, randomised controlled trial with clinical endpoints to compare the relative efficacy of these different strategies. The use of multiple settings in different ‘therapeutic cultures’ will allow for generalisability of the findings and provide evidence that will facilitate management of HIV disease in this group.

A total of 1700 patients – including 400 from the UK – will be randomised over period of 2.5 years at 75 medical centres in the three countries. Patients will be followed at regular intervals during the 3.5 year study, until the last patient randomised has been followed for at least one year.

The trial funding will be tripartite: the Department of Veterans Affairs (VA) Cooperative Studies Program will provide funding for the 30 VA sites. The UK Medical Research Council (MRC) and the Canadian Institutes for Health Research (CIHR) will provide funding for 25 and 22 clinical sites respectively in their country.

Inclusion Criteria:

1. Age 18 years or more
2. Confirmed HIV infection
3. Failure of at least two different multi-drug regimens, which included drugs of all classes that the patient could tolerate
4. A history of at least 3 months continuous HAART and still on treatment
5. Two most recent (which can include screening) results (on current ART) of either: CD4+ T-cell count below 100 cells/mm3 and pVL more than 5,000 copies/ml; or 100-199 cells/mm3 and pVL more than 10,000 copies/ml

Exclusion Criteria:

1. Pregnancy, or intention of becoming pregnant, or breast-feeding
2. In the opinion of the investigator, Mega-ART is contraindicated e.g. by intolerance to multiple drugs
3. Current (within 3 months) ART regimen containing more than 5 drugs
4. Serious, uncontrolled opportunistic infection (OI) within 14 days of screening
5. Presence of other significant, underlying disease (non HIV-related) likely to cause early death
6. Likelihood of poor compliance

This trial will be recruiting at clinical sites across the UK from July.

Details of clinical sites will be coming soon. If you are interested in entering this trial please discuss this with your HIV Clinic or if you are interested in offering this trial at your site contact the MRC CTU.

PENTA 7

There is some evidence from research in the US that early, aggressive treatment of HIV infected babies may cause marked reductions in HIV RNA viral load, despite the very high levels seen in babies. PENTA 7 is an open study of early intervention of antiretroviral therapy with three drugs (Nelfinavir, ddI and d4T) for vertically infected HIV infants (aged less than 12 weeks of age). Twenty children were enrolled in PENTA 7 and will be followed until summer 2002. Informed by the results of the pharmacokinetic study (see Durban abstract), the dose of Nelfinavir within the study has been increased to 150 mg/kg/day for neonates.

PENTA 8: PERA (Paediatric Evaluation of Resistance Assays)

A parallel paediatric trial to ERA is recruiting across Europe and in Brazil. In children, there have been no clinical trials evaluating the usefulness of resistance testing, although a much more limited choice of drugs is available for children and, it is possible that genotypic resistance evolves more slowly in children than in adults despite higher RNA viral load.

Children allocated to Arm 1 have access to resistance testing at trial entry and at any time during follow-up when clinically indicated. The primary analyses will compare HIV-1 RNA viral load in the genotypic testing versus no testing arms at 12 months. To guide health purchasers, a decision-analytic model will be developed to estimate the incremental cost per life-year gained associated with the resistance testing versus no testing.)

180 children will be recruited to this trial. Eligible children or adolescents (up to 18 years of age) must have had at least 2 classes of drugs (or had at least 3 NRTIs or 2 NRTIs for more than 2 years). Amprenavir is made available for all children (aged 4 years or over) through the trial.

For an update and trial documents visit the PENTA website.

TB-1

TB-1 is a randomised trial that compares two alternative policies currently recommended by the British Thoracic Society (BTS); chemoprophylaxis plus regular monitoring and regular monitoring alone, in HIV infected individuals who are considered to be at increased risk of developing tuberculosis (TB). The trial will evaluate the benefits and risks of chemoprophylaxis with isoniazid in terms of preventing the development of active TB.

The aim is to recruit 750 participants and to follow them for a minimum of two years.

SHIELD

SHIELD is a randomised, double-blind trial of dextrin sulphate (DS) vaginal gel versus placebo in sexually active females at low risk of HIV infection. The study is funded by the MRC and complements the European Community programme to investigate vaginal microbicides with the long-term aim of identifying the best product(s) to take forward into an efficacy trial in Africa.

The clinical centre conducting this phase II study is Professor Jonathan Weber’s department at St Mary’s Hospital, where previous phase I studies of DS and PRO2000 have been carried out. 50 women have completed SHIELD and so far no significant side-effects have been seen in the women participating in the study (blinded data). The unblinded data are being prepared for a Data and Safety Monitoring Committee (DSMC) to review in October.

The next step is to investigate higher concentrations of DS to see if it remains well-tolerated at these larger doses. A dose escalation study is under development and this would be a dual centre study conducted at St Mary’s and at the Institute of Tropical Medicine in Antwerp, Belgium in Professor Marie Laga’s department.

The African phase II study which is to be conducted in Uganda and Cote-d’Ivoire will follow these preliminary studies, hopefully starting in the middle of next year.