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Journal Club. “Implementing a Tenofovir -Base First-Line Regimen in Rural Lesotho: Clinical Outcomes and Toxicities After Two Years” JAIDS 2011 Bygrave et al. Background. - Stavudine (d4T) was the most commonly used backbone drug in resource limited settings (RLS)

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Journal club
Journal Club

“Implementing a Tenofovir-Base First-Line Regimen in Rural Lesotho: Clinical Outcomes and Toxicities After Two Years”

JAIDS 2011

Bygrave et al


Background
Background

-Stavudine (d4T) was the most commonly used backbone drug in resource limited settings (RLS)

-Based on RCT’s by Gallant et al in JAMA 2004 (TDF vs d4T) and in NEJM 2006 (TDF/FTC + EFZ vs AZT/3TC + EFZ) the WHO guidelines of 2009 recommended TDF or AZT in favor of d4T

-Lesotho adopted these recommendations before the release of these guidelines


Background1
Background

-Pop. ~ 2 million, 40% below poverty line, GDP around 6 bi $ (wiki)

-Almost ¼ of the population is HIV + (UNAIDS)

-HIV co-infections: 35.5 % (28.9-42.6) HbCAg +, 5.5% (2.8-9.6%) HbSAg +, 0.5% (0-2.8%) HCV + (Rebenau et al Sex TransmDis 2010)

-In US: MMWR 2011 survey on Armed Forces>

HIV/HBV: 1.6% HIV/HCV: 1.4%

-MSF established a RN run clinic at the Scott Health Service Area in rural Lesotho in 2006


Study outline
Study Outline

-Goal: evaluate real life application of WHO guidelines

-Design: Retrospective cohort outcomes study

-Setting: RN run rural clinic

-Participants: Adults starting HAART from Jan 1 2008 to Dec 31 2008, follow up until Dec 31 2009. Exclusion criteria: GFR < 30 ml/min or no Cr or CD4 at baseline

-Data collection: extraction from files by a team of 3 clinicians

-End points: (1) death (2) loss for follow up {defined by missing an appointment for > 90 days} (3) 1st toxicity driven switch


Study outline1
Study Outline

-TDF prescribed to all non pregnant adults with GFR> 50ml/mim

-AZT is pregnant or GFR < 50 ml/min

-d4T: excluded from d4T and Hb < 8 g/dl

-All on triple Rx with 3TC + nevirapine or efavirenz

-HAART started when CD4 < 350 or WHO stage 3 or 4


Study outline2
Study Outline

-Nelson Aalen cumulative hazards estimative method to calculate cumulative hazards for regimen change using Cox regression for the following confounders: Age, gender, TB at HAART initiation, pregnancy at HAART initiation, CD4 baseline, and GFR

-Nelson Aalen is used to estimate cumulative hazards (vs survival Kaplan-Meier) (wikipedia)



Results1
Results

-Mortality: 6.5 per 100 patient-years (5.3-7.9)

-Non significant trend for higher mortality on non-TDF regimens: TDF CI (3.8-7.0), AZT CI (5.0-11.1), and d4T CI (5.8-11.7)

-Trend was sustained on multivariate analysis

-Difference of loss for follow up non statistically significant


Results2
Results

Switch rates

  • TDF (2.0-4.5)

    “renal toxicity”

  • AZT (5.4-12.1)

    “severe anemia”

  • d4T (14.8-24.1)

    “severe neuropathy”

    “lipodystrophy”

    -This was sustained in the multivariate analysis


Strengths
Strengths

-Feasible study design in a setting the is very different from where RCT’s were done

-No blinding: switches are not protocol driven. Allows us to understand why providers or patients elect to switch between regimens when they are aware of the medication used.

-Nurse managed: realistic to RSL settings


Weaknesses
Weaknesses

-Retrospective

-No validation system for data collection mentioned

-Death in Lesotho

-Side effects vs loss for follow up

-Anemia not included in multivariate analysis: bias against d4T?


Weaknesses1
Weaknesses

-HBV status? This data is not included in the pivotal TDF trial, but given HBV as much more prevalent in Lesotho than in US, this could have introduced bias.

-Definition of toxicity?


Weaknesses2
Weaknesses

-How often can they measure Cr? Can they check proteinuria? What about phosphate?

-Is Lesotho ready to deal with CKD?

-LDL? To they care about dyslipidemia as much as we care?


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