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) -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

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 % ( ) HbCAg +, 5.5% ( %) HbSAg +, 0.5% (0-2.8%) HCV + (Rebenau et al Sex Transm Dis 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 -Goal: evaluate real life application of WHO guidelines -Design: Retrospective cohort outcomes study -Setting: RN run rural clinic -Participants: Adults starting HAART from Jan to Dec , follow up until Dec 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) 1 st toxicity driven switch

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 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)

Results

-Mortality: 6.5 per 100 patient-years ( ) -Non significant trend for higher mortality on non-TDF regimens: TDF CI ( ), AZT CI ( ), and d4T CI ( ) -Trend was sustained on multivariate analysis -Difference of loss for follow up non statistically significant

Results Switch rates TDF ( ) “renal toxicity” AZT ( ) “severe anemia” d4T ( ) “severe neuropathy” “lipodystrophy” -This was sustained in the multivariate analysis

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 -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?

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?

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?