Antiretroviral Therapy for Advanced HIV Disease in South Africa

NCT ID: NCT00342355

Last Updated: 2013-05-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1771 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-01-31
• Study Completion Date: 2008-08-31

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.

Conditions

HIV

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

AZT+DDI+EFV

Zidovudine,Didanosine,Efavirenz ( Zidovudine 600 mg once daily,Didanosine \<60 kg/125 mg twice daily or \>60kg/200 mg twice daily,Efavirenz 600 mg once daily)

Group Type: ACTIVE_COMPARATOR

Zidovudine

Intervention Type: DRUG

600 mg once daily

Didanosine

Intervention Type: DRUG

\<60 kg/125 mg twice daily or \>60kg/200 mg twice daily

Efavirenz

Intervention Type: DRUG

600 mg once daily

AZT+DDI+r/LPV

Zidovudine,Didanosine,Lopinavir/Ritonavir(AZT 600 mg once daily,DDI 100 mg twice daily,r/LPV 400mg/100mg twice daily)

Group Type: ACTIVE_COMPARATOR

Zidovudine

Intervention Type: DRUG

600 mg once daily

Didanosine

Intervention Type: DRUG

\<60 kg/125 mg twice daily or \>60kg/200 mg twice daily

Lopinavir/Ritonavir

Intervention Type: DRUG

r/LPV 400mg/100mg twice daily

d4T+3TC+EFV

Stavudine,Lamivudine,Efavirenz(d4T 40 mg twice daily,3TC 300 mg once daily,EFV 600 mg once daily)

Group Type: ACTIVE_COMPARATOR

Stavudine

Intervention Type: DRUG

40 mg once daily

Lamivudine

Intervention Type: DRUG

300 mg once daily

Efavirenz

Intervention Type: DRUG

600 mg once daily

d4T+3TC+r/LPV

Stavudine,Lamivudine,Lopinavir/Ritonavir(d4T 40m mg twice daily,3TC 300 mg once daily,r/LPV 400mg/100mg twice daily)

Group Type: ACTIVE_COMPARATOR

Stavudine

Intervention Type: DRUG

40 mg once daily

Lamivudine

Intervention Type: DRUG

300 mg once daily

Lopinavir/Ritonavir

Intervention Type: DRUG

r/LPV 400mg/100mg twice daily

Interventions

Zidovudine

600 mg once daily

Intervention Type: DRUG

Stavudine

40 mg once daily

Intervention Type: DRUG

Didanosine

\<60 kg/125 mg twice daily or \>60kg/200 mg twice daily

Intervention Type: DRUG

Lamivudine

300 mg once daily

Intervention Type: DRUG

Efavirenz

600 mg once daily

Intervention Type: DRUG

Lopinavir/Ritonavir

r/LPV 400mg/100mg twice daily

Intervention Type: DRUG

Other Intervention Names

AZT; D4T; DDI; 3TC; EFV; Kaletra

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).

• Minimum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health Clinical Center (CC)

NIH

Sponsor Role: lead

Responsible Party

Michael Polis, M.D.

Michael Polis

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Polis, MD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Allergy and Infectious Diseases (NIAID)

Andrew Ratsela, MD

Role: PRINCIPAL_INVESTIGATOR

SAMHS

Locations

South African Military Health Services (SAMHS)

Centurion, , South Africa

Umtata Sickbay

Eastaern Cape, , South Africa

3 Military Hospital

Free State, , South Africa

1 Military Hospital

Gauteng, , South Africa

Mtubatuba SIckbay

Kwazulu-Natal, , South Africa

Phalaborwa Sickbay

Limpopo, , South Africa

2 Military Hospital

Western Cape, , South Africa

Countries

South Africa

References

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.

Reference Type: BACKGROUND

PMID: 12433534 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9287227 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9492772 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22448211 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 21716078 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 20942650 (View on PubMed)

Other Identifiers

04-I-N094

Identifier Type: REGISTRY

Identifier Source: secondary_id

999904094

Identifier Type: -

Identifier Source: org_study_id