Clinical trial NCT00342355: Antiretroviral Therapy for Advanced HIV Disease in South Africa
Official title: Randomized, Open-Label 2x2 Factorial Study to Compare the Safety and Efficacy of Different Combination Antiretroviral Therapy Regimens in Treatment Naive Patients With Advanced HIV Disease and/or CD4+ Cell Counts Less Than 200 Cells/MicroL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: Protease Inhibitors
Reverse Transcriptase Inhibitors
AIDS
Opportunistic Infections
Resource-Poor
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2006-06-21
Enrollment: 1771
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This study will determine how well four different antiretroviral drug therapies work in patients with advanced HIV disease. The trial is part of the South Africa-U.S. Project Phidisa Programme - a collaboration between the South African Military Health Service (SAMHS) of the South African National Defense Force (SANDF), the U.S. Department of Defense, and the U.S. National Institutes of Health - to help prevent HIV transmission among South African military and civilian employees and their families.

Members of the SANDF with HIV infection may be eligible for this study. HIV-infected family members who are 14 years of age and older may also participate. All participants must have a CD4 count of less than 200 or an AIDS-defining illness.

Participants are randomly assigned to one of the following four antiretroviral drug regimens, which require taking 5 pills or more every day:

* AZT (zidovudine) + ddl (didanosine) + EFV (efavirenz)
* AZT (zidovudine) + ddl (didanosine) + r/LPV (lopinavir/ritonavir)
* D4T (stavudine) + 3TC (lamivudine) + EFV (efavirenz)
* D4T (stavudine) + 3TC (lamivudine) + r/LPV (lopinavir/ritonavir)

Patients are followed for up to 6 years. Clinic visits are scheduled once a month for the first 3 months and then once every 3 months for the next five years. Patients undergo a medical history, physical examination, and blood tests at each visit, and complete questionnaires of behavior, quality of life, and force readiness every year.

Detailed description: This is a randomized, open label 2x2 factorial study of four regimens of initial therapy.

I. AZT + ddl + EFV

II. AZT + ddl + r/LPV

III. D4T + 3TC + EFV

IV. D4T + 3TC + r/LPV

Eligible patients will commence their randomly allocated study drugs as soon as possible after randomization. Episodes of treatment limiting toxicity will be managed in keeping with protocol specified guidelines.

Patients who experience treatment failures (as specified in the protocol) will be managed by changing their regimen to that corresponding to one of the other treatment groups.

Eligibility criteria: * INCLUSION CRITERIA:

Uniformed SANDF personnel or family members of SANDF personnel who are registered as eligible for health services from the SAMHS.

HIV positive as diagnosed and/or confirmed in PHIDISA I OR documented HIV infection from an accredited source.

CD4+ cell count less than 200 cells/microL (or less than or equal to 14% for patients post-splenectomy) AND/OR any AIDS defining illness currently or historically. Patients with pulmonary tuberculosis must have a CD4+ cell count less than 200 cells/microL. Patients with KS must have a CD4+ cell count less than 200 cells/microL unless their sarcoma is progressive and/or requires chemotherapy.

Antiretroviral treatment naive (less than 7 days cumulative exposure to any antiretroviral drug) or treated for post-exposure prophylaxis without becoming HIV infected at that time.

Laboratory variables as follows:

1. Haemoglobin greater than or equal to 9.0g/dL for men and greater than or equal to 8.0g/dL for women.
2. Absolute neutrophil count greater than or equal to 500 cells/microL.
3. Platelet count greater than or equal to 25,000/mm(3).
4. Serum transaminase (ALT or AST) less than or equal to 5 times upper limit of normal (ULN).

   14 years or older.

   Likely to be compliant with study procedures and clinical visits in the opinion of the clinical investigator (guidance is provided in the protocol to assist clinicians in making this decision).

   Have completed the PHIDISA treatment adherence counseling session.

   Provision of written informed consent.

   EXCLUSION CRITERIA:

   Any history of pancreatitis or serious pathology indicative of increased risk for pancreatitis.

   Current requirement for use of a medication that is contra-indicated with the PHIDISA II study drugs. Where possible, alternate therapies should be selected in order to facilitate randomization. Patients entering the study with tuberculosis should defer screening and randomization until successful completion of an induction course of anti-mycobacterium therapy including rifampicin. As appropriate this patient could recommence screening when starting the maintenance regimen of anti-tubercular drugs excluding rifampicin.

   Pregnancy (following delivery, such women may be enrolled).

Primary outcomes:
measure: Progression to AIDS or Death in tx naïve Pts With Adv HIV dx in the Four Randomly Assigned Regimens.
timeFrame: January 2004 until March 31 2008
Secondary outcomes:
measure: Serious Adverse Events
timeFrame: January 2004 until March 31, 2008
Other outcomes:
Locations:
city: Centurion
country: South Africa
facility: South African Military Health Services (SAMHS)
city: Eastaern Cape
country: South Africa
facility: Umtata Sickbay
city: Free State
country: South Africa
facility: 3 Military Hospital
city: Gauteng
country: South Africa
facility: 1 Military Hospital
city: Kwazulu-Natal
country: South Africa
facility: Mtubatuba SIckbay
city: Limpopo
country: South Africa
facility: Phalaborwa Sickbay
city: Western Cape
country: South Africa
facility: 2 Military Hospital
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Michael Polis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SAMHS
name: Andrew Ratsela, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rabkin M, El-Sadr W, Katzenstein DA, Mukherjee J, Masur H, Mugyenyi P, Munderi P, Darbyshire J. Antiretroviral treatment in resource-poor settings: clinical research priorities. Lancet. 2002 Nov 9;360(9344):1503-5. doi: 10.1016/S0140-6736(02)11478-4. No abstract available.
citation: Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725-33. doi: 10.1056/NEJM199709113371101.
citation: Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, Sun E, Henry D, Rode R, Potthoff A, Leonard J. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet. 1998 Feb 21;351(9102):543-9. doi: 10.1016/s0140-6736(97)04161-5.
citation: Ledwaba L, Tavel JA, Khabo P, Maja P, Qin J, Sangweni P, Liu X, Follmann D, Metcalf JA, Orsega S, Baseler B, Neaton JD, Lane HC; Project Phidisa Biomarkers Team. Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease. PLoS One. 2012;7(3):e24243. doi: 10.1371/journal.pone.0024243. Epub 2012 Mar 20.
citation: Matthews GV, Manzini P, Hu Z, Khabo P, Maja P, Matchaba G, Sangweni P, Metcalf J, Pool N, Orsega S, Emery S; PHIDISA II study team. Impact of lamivudine on HIV and hepatitis B virus-related outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of antiretroviral therapy in southern Africa. AIDS. 2011 Sep 10;25(14):1727-35. doi: 10.1097/QAD.0b013e328349bbf3.
citation: Phidisa II Writing Team for Project Phidisa; Ratsela A, Polis M, Dhlomo S, Emery S, Grandits G, Khabo P, Khanyile T, Komati S, Neaton JD, Naidoo LC, Magongoa D, Qolohle D. A randomized factorial trial comparing 4 treatment regimens in treatment-naive HIV-infected persons with AIDS and/or a CD4 cell count <200 cells/muL in South Africa. J Infect Dis. 2010 Nov 15;202(10):1529-37. doi: 10.1086/656718. Epub 2010 Oct 13.