Antiretroviral Therapy for Advanced HIV Disease in South Africa

National Institutes of Health Clinical Center (CC)

Status and phase: Completed; Phase 4

Conditions: HIV

Treatments: Drug: Stavudine; Drug: Lamivudine; Drug: Didanosine; Drug: Zidovudine; Drug: Efavirenz; Drug: Lopinavir/Ritonavir

Study type: Interventional

Funder types: NIH

Identifiers

NCT00342355

04-I-N094 (Registry Identifier)

999904094

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,771 patients

Sex: All

Ages: 14+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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1,771 participants in 4 patient groups

AZT+DDI+EFV

Active Comparator group

Description:

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)

Treatment:

Drug: Didanosine

Drug: Efavirenz

Drug: Zidovudine

AZT+DDI+r/LPV

Active Comparator group

Description:

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

Treatment:

Drug: Didanosine

Drug: Lopinavir/Ritonavir

Drug: Zidovudine

d4T+3TC+EFV

Active Comparator group

Description:

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

Treatment:

Drug: Efavirenz

Drug: Lamivudine

Drug: Stavudine

d4T+3TC+r/LPV

Active Comparator group

Description:

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

Treatment:

Drug: Lopinavir/Ritonavir

Drug: Lamivudine

Drug: Stavudine