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Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings

  1. Larry W Chang1,*,
  2. Jamal Harris2,
  3. Eliza H Humphreys3

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 14 APR 2010

Assessed as up-to-date: 30 SEP 2009

DOI: 10.1002/14651858.CD008494


How to Cite

Chang LW, Harris J, Humphreys EH. Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD008494. DOI: 10.1002/14651858.CD008494.

Author Information

  1. 1

    Johns Hopkins School of Medicine, Division of Infectious Diseases, Department of Medicine, Baltimore, MD, USA

  2. 2

    University of California, San Francisco, Department of Pediatrics, San Francisco, California, USA

  3. 3

    University of California, San Francisco, Global Health Sciences, San Francisco, California, USA

*Larry W Chang, Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, 1503 East Jefferson St., Room 116, Baltimore, MD, 21287, USA. larrywillchang@gmail.com. lchang@alum.emory.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 14 APR 2010

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Characteristics of included studies [ordered by study ID]
ART-LINC 2006

MethodsMult-cohort study


ParticipantsAll persons >=16 years of age on ART with no prior history of ART.


InterventionsRoutine virologic monitoring (not defined)


OutcomesMortality


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskN/A, See Table 3.

Allocation concealment?Unclear riskN/A, See Table 3.

Blinding?
All outcomes
Unclear riskN/A, See Table 3.

Incomplete outcome data addressed?
All outcomes
Unclear riskN/A, See Table 3.

Free of selective reporting?Unclear riskN/A, See Table 3.

Free of other bias?Unclear riskN/A, See Table 3.

ART-LINC 2009

MethodsMulti-cohort study


ParticipantsAll persons >=16 years of age on ART with no prior history of ART.


InterventionsRoutine programmatic viral load monitoring (At least one VL measurement between 3 and 9 months after starting ART in at least 50% of patients treated at that site.)


OutcomesTime to switch, CD4 count at switch, rate of switching


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskN/A, See Table 3.

Allocation concealment?Unclear riskN/A, See Table 3.

Blinding?
All outcomes
Unclear riskN/A, See Table 3.

Incomplete outcome data addressed?
All outcomes
Unclear riskN/A, See Table 3.

Free of selective reporting?Unclear riskN/A, See Table 3.

Free of other bias?Unclear riskN/A, See Table 3.

D.A.R.T. 2009

MethodsRandomized Trial


ParticipantsAdults qualifying for ART


InterventionsClinical and Immunologic Monitoring (CD4 q12 weeks) versus Clinical Monitoring


OutcomesEfficacy: Progression to a new WHO stage 4 HIV event or death; Safety: Any serious adverse event which is not HIV related 


NotesAbstract Only


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNot reported.

Allocation concealment?Unclear riskNot reported.

Blinding?
All outcomes
High riskBlinding was not appropriate for this study.

Incomplete outcome data addressed?
All outcomes
Unclear riskLost-to-follow-up analyses not extensively presented but absolute numbers were relatively small.

Free of selective reporting?High riskAbstract only available.

Free of other bias?Low risk

H.B.A.C. 2008

MethodsRandomized Trial


ParticipantsAdults qualifying for ART


InterventionsArm A: Clinical, Immunologic, and Virologic Monitoring (quarterly CD4 counts and viral loads) versus Arm B: Clinical and Immunologic Monitoring (quarterly CD4 counts) versus Arm C: Clinical Monitoring (weekly home visits)


OutcomesDeath; New AIDS-defining illness


NotesAbstract Only


Risk of bias

BiasAuthors' judgementSupport for judgement

Adequate sequence generation?Unclear riskNot reported.

Allocation concealment?Unclear riskNot reported.

Blinding?
All outcomes
High riskBlinding was not appropriate for this study.

Incomplete outcome data addressed?
All outcomes
Unclear riskLost-to follow-up analyses not extensively presented but absolute numbers were relatively small.

Free of selective reporting?High riskAbstract only available.

Free of other bias?Low risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Haubrich 2001Randomized trial evaluating frequent (every two months) viral load testing versus infrequent (twice yearly) viral load testing. We decided to exclude this study because it was comparing effects of different frequencies of one type of monitoring rather than comparing one distinct monitoring strategy to another.

 
Characteristics of ongoing studies [ordered by study ID]
Lallemant

Trial name or titleMonitoring highly active antiretroviral therapy in HIV-infected patients in Thailand.

MethodsTreatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

ParticipantsPatients fulfilling the following criteria are eligible:

  • At least 18 years of age
  • Confirmed HIV infection: two positive serology results from two different blood draws are required for documentation of HIV infection.
  • Antiretroviral drug naive with the exception of short course of antiretroviral drugs received in the context of the prevention of mother-to-child HIV transmission
  • Need for antiretroviral treatment
  • Willingness to receive a long-term treatment for HIV infection, according to the study schedule at the participating sites

Interventions1: Active Comparator VL-S, the standard viral load (VL) based monitoring strategy, where switching is performed when VL is confirmed (within one month) above 400 copies per mL.

2: Experimental CD4-S, the alternative CD4 based monitoring strategy where switching is performed when a confirmed (within one month) relative decline in CD4 count of more than 30% from peak values is observed within 200 cells from baseline.

OutcomesPrimary Outcome Measures: Proportion of "clinical failures" defined as confirmed CD4 count below 50/mm3, first or new AIDS-defining event, or death

Starting dateMay 2005

Contact information

NotesNCT00162682

Laurent

Trial name or titleAntiretroviral treatment simplified follow-up management assessment (ANRS 12110 STRATALL).

MethodsTreatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study

ParticipantsInclusion Criteria:

  • Men or women aged at least 18 years
  • Living in the health district of the hospital attended
  • Confirmed HIV-1 group M infection
  • Meeting one of the following criteria: Stage III or IV (WHO classification), Stage II (WHO classification) and total lymphocytes count < 1,200/mm3
  • Patient agreeing on monthly follow-up and treatment for 24 months
  • Signed informed consent

Interventions1: Experimental Simplify treatment follow-up: Simplified follow-up approach of ART; some clinical consultations will be performed by nurses under the physicians' responsibility; the CD4 cell count and HIV-1 VL will not be available for the management of patients; the biologic assessment for tolerability will be limited

2: No Intervention Standard treatment follow-up: Standard follow-up approach of ART; all clinical consultations will be performed by physicians; the CD4 cell count and HIV-1 VL will be available for the patients management routinely; the biologic assessment for tolerability will be available as needed

OutcomesPrimary Outcome Measures: Increase in the CD4 cell count measured with a FACSCount apparatus after 24 months of ART

Starting dateMay 2006

Contact information

NotesNCT00301561

PENPACT1

Trial name or titleAnti-HIV Drug Regimens and Treatment-Switching Guidelines in HIV Infected Children.

MethodsTreatment, Randomized, Open Label, Active Control, Factorial Assignment, Efficacy Study

ParticipantsInclusion Criteria:

  • Older than 30 days and younger than 18 years of age (may enroll up to the day before their 18th birthday)
  • HIV infected
  • Not previously on highly active ART or received anti-HIV drugs for less than 56 consecutive days after birth to prevent mother-to-infant HIV transmission. Participants who have previously received nevirapine for the prevention of mother-to-infant HIV transmission are not eligible for this study.
  • Willing to use acceptable methods of contraception

Interventions1A: Experimental

Two NRTIs plus a PI with a regimen change recommended at when viral load is 1,000 copies/mL or higher

1B: Experimental

2 NRTIs plus 1 PI with a regimen change recommended when viral load is 30,000 copies/mL or higher

2A: Experimental

2 NRTIs plus a NNRTI with a regimen change recommended when viral load reaches 1,000 copies/mL or higher

2B: Experimental

2 NRTIs plus an NRTI with a regimen change recommended when viral load reaches 30,000 copies/mL or higher

OutcomesPrimary Outcome Measures: Change in VL measured in log10 HIV-1 RNA copies/mL

Starting dateOctober 2005

Contact information

NotesNCT00039741

Sagg

Trial name or titleHIV viral load monitoring in resource-poor settings.

MethodsCluster randomised-trial

ParticipantsInclusion Criteria:

  • Documented HIV-1 infection (according to local standard rapid testing algorithms)
  • Age 18 years or greater
  • Able and willing to provide informed consent to participate
  • Eligible for ART per Zambian national guidelines, which are any of the following:CD4+ cell count less than 200 cells/mm3; WHO Stage IV disease; or WHO Stage III disease and CD4+ cell count less than 350 cells/mm3
  • Residence in the geographical catchment area of the VLS clinic and intent to remain there for the duration of the study
  • Willingness to adhere to the study visit schedule and to be followed-up at home in the event of a missed study visit
  • Initiating ART on the day of VLS enrollment, informed consent, and baseline blood collection

InterventionsRoutine HIV-1 VL testing: Experimental Routine VL testing arm: Routine HIV viral VL at ART initiation (baseline) and at 3, 6, 12, 18, 24, 30 and 36 months thereafter.

Standard of care: No Intervention Standard of care arm: utilizes the current standard of care per Zambian national guidelines to determine treatment failure and eligibility for second-line ART. HIV-1 viral load measurement is performed if the criteria for either immunologic (i.e., CD4+ lymphocyte count-based) or clinical treatment failure are fulfilled. If both immunologic and clinical treatment failure criteria are fulfilled, the ART regimen is changed to second-line without VL testing.

OutcomesPrimary Outcome Measure: Patient survival

Starting dateDecember 2006

Contact information

NotesNCT00929604

 
Comparison 1. Clinical Monitoring vs Immunologic Monitoring and Clinical Monitoring

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality24064Hazard Ratio (Random, 95% CI)1.35 [1.12, 1.63]

2 AIDS-defining illness0 (Fixed, 95% CI)Not estimable

 3 AIDS-defining illness or Mortality24064Hazard Ratio (Random, 95% CI)1.33 [1.16, 1.51]

 4 Serious Adverse Event13316Hazard Ratio (Random, 95% CI)1.12 [0.94, 1.32]

 5 Unnecessary Switch (Switch to Second-line with Undetectable Viral Load)1748Risk Ratio (M-H, Random, 95% CI)30.51 [1.83, 508.01]

 6 Switch to Second-Line24064Risk Ratio (M-H, Random, 95% CI)1.73 [0.37, 8.06]

 
Comparison 2. Clinical Monitoring versus Virologic, Immunologic, and Clinical Monitoring

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality1745Hazard Ratio (Random, 95% CI)1.58 [0.97, 2.60]

2 AIDS-defining illness0Hazard Ratio (Random, 95% CI)Not estimable

 3 AIDS-defining illness or Mortality1745Hazard Ratio (Random, 95% CI)1.88 [1.25, 2.84]

 4 Unnecessary Switch (Switch to Second-line with Undetectable Viral Load)1745Risk Ratio (M-H, Random, 95% CI)30.26 [1.82, 503.91]

 5 Virologic Treatment Failure1745Risk Ratio (M-H, Random, 95% CI)1.16 [0.61, 2.22]

 6 Switch to Second-line1745Risk Ratio (M-H, Random, 95% CI)2.37 [0.99, 5.65]

 
Comparison 3. Immunologic and Clinical Monitoring versus Virologic, Immunologic, and Clinical Monitoring

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality1739Hazard Ratio (Random, 95% CI)1.14 [0.69, 1.89]

2 AIDS-defining illness0Hazard Ratio (Random, 95% CI)Not estimable

 3 AIDS-defining illness or Mortality1739Hazard Ratio (Random, 95% CI)1.28 [0.84, 1.97]

 4 Unnecessary Switch (Switch to Second-line with Detectable Viral Load)1739Risk Ratio (M-H, Random, 95% CI)Not estimable

 5 Virologic Treatment Failure1739Risk Ratio (M-H, Random, 95% CI)1.61 [0.88, 2.95]

 6 Switch to Second-Line1739Risk Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.92]

 
Comparison 4. Immunologic and Clinical Monitoring vs Virologic, Immunologic, and Clinical Monitoring-Observational Studies

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality1Hazard Ratio (Random, 95% CI)2.28 [0.76, 6.79]

 2 Rate of switching1576Rate Ratio (Random, 95% CI)1.60 [1.35, 1.89]

 3 Time to switch (7-18 months f/u)120113Hazard Ratio (Random, 95% CI)1.38 [0.97, 1.98]

 4 Time to switch (19-30 months f/u)19189Hazard Ratio (Random, 95% CI)0.97 [0.59, 1.60]

 5 Time to switch (31-42 months f/u)13725Hazard Ratio (Random, 95% CI)0.29 [0.11, 0.79]

 6 CD4 count at switch1402Mean Difference (IV, Random, 95% CI)Not estimable