Scaling up: what to do first?
Polly Clayden, HIV i-Base
The revised 2009 WHO guidelines have four major changes since the 2006 edition:
- Routine CD4 countsEarlier ART initiation CD4 threshold of 350 cells/mm3 from 200 cells/mm3
- Changing d4T to tenofovir in first-line regimens
- Increased number of sequential lines of treatment
In an oral session, Rochelle Walensky from Harvard presented findings from a study using a mathematical model simulated to project the clinical and economic outcomes from implementing each of these changes and combinations of these changes.
This study was designed to assist policy makers with their prioritisation process in recognition that implementing all of the guideline changes immediately poses major challenges in most resource limited settings.
The study used input data from a South African cohort with a mean age 32 years and a mean CD4 count of 375 cells/mm3 (ie healthier patients with the potential to benefit from starting earlier). Other input parameters included 24-week ART suppression rates of 75% and 78% rate of suppression at 24-weeks for first and second line ART respectively; annual costs of $36 and $135 for d4T and tenofovir respectively and 1.7-2.6% and 0.4-1.6% incidence of d4T and tenofovir related toxicity were also used.
The investigators ranked, in terms of survival and cost effectiveness, all 13 possible combinations of: (1) ART initiation at CD4 <200 cells/mL or CD4 <350 cells/mm3; (2) Replacing d4T with tenofovir; and (3) Number of available treatment regimens (1 or 2).
They examined 5-year survival, projected life expectancy and incremental cost effectiveness of different treatment scenarios. They used the WHO definition of less than 1x per capita GDP as the threshold for very cost effective. For South Africa this is <$5,400 per year of life saved.
The baseline assumption was that patients received a single, d4T-based ART regimen, initiated at WHO Stage III/IV.
Dr Walensky reported that the projected baseline survival was 99 months, with a 65% 5-year survival rate. Switching from d4T to tenofovir gave a modest improvement, with a 110-month life expectancy and 67% 5-year survival. Adding ART at <200 cells/mm3 to baseline gave a 116 month life expectancy and 80% 5-year survival. Adding a second line regimen increased life expectancy to 121 months but added little to 5-year survival (66%) compared to baseline. Adding ART started at <350 cells/mm3 increased life expectancy to 124 months and 5-year survival to 87%.
Stepwise additions of switching to tenofovir or adding a second-line regimen to a one line d4T-containing regimen initiated at 350cells/mm3, gave increased life expectancy of 140 and 178 months and 91% five year survival (for both changes) respectively.
Switching to tenofovir from d4T in addition to initiating at 350 cells/mm3 and adding a second-line, ie following the complete WHO revisions, increased life expectancy to 192 months with 91% 5-year survival.
Dr Walensky summarised the above results noting that the incremental life expectancy gains are maximised with the following stepwise programmatic additions: first the expansion of ART eligibility to CD4 <350 cells/mm3 one-line (124 months); followed by the addition of second line therapy (178 months); finally followed by the replacement of d4T with and tenofovir (192 months).
When examining the incremental cost-effectiveness of alternative programmes, three were found to be economically effective: d4T 350 cells/mm3/one-line (cost-effectiveness ratio $610/year of life saved [YLS]), tenofovir/< 350 cells/mm3/one-line ($1,410/YLS), and tenofovir/<350 cells/mm3/two-lines ($2,230/YLS). The investigators noted that these results persisted despite plausible variation in efficacy and cost assumptions.
The results of this study are extremely sensitive to the price of tenofovir. A sensitivity analysis revealed a decrease in the price of tenofovir from $135 to $51 per person year would make tenofovir more effective and less costly than d4T.
Dr Walensky suggested that the limitations to this study were that it only shows results for people initiating ART and did not address people in ongoing care. Also that while the analysis looks at value for money it does not project the implications of each component of the WHO recommendations on programme budgets.
To the question What to do first she concluded that the decision is dependent on a countrys current policy and capacity. In countries without laboratory capacity, CD4 monitoring and ART at <350 cells/mm3 is the most crucial priority to start with. Where this is already available, replacing d4T with tenofovir are both cost effective and give survival benefits. The addition of second-line ART offers greater survival benefit but with substantial increases in total costs.
Ref: Walensky R et al. Scaling up WHO recommendations for HIV therapy in resource-limited settings: what to do first? Oral abstract WEAE0205.