Five published model-based cost-effectiveness analyses have examined the value of laboratory monitoring in resource-limited settings [6
]. The data used as model input parameters for each of these studies vary by country, each with differences in the natural history of HIV disease progression as well as incidence of tuberculosis and other opportunistic diseases. In Tables and , we provide an overview of some of the differences in methods, assumptions, costs, and time horizons utilized across these studies. What follows is a brief examination of each study. We included only strategies relevant to the question of laboratory monitoring for the purpose of ART initiation and switching. A composite summary of results from all studies is provided in , where we have repeated the calculations in each study using conventional cost-effectiveness methodology, including elimination of dominated strategies that may have been reported in the individual studies. A more detailed version of these calculations is provided in of the Technical Appendix
. To allow for appropriate comparison across studies, we have expressed all cost-effectiveness results in per-person costs and benefits and have updated all ratios to 2007 US dollars.
Details on modeling assumptions and design for cost-effectiveness studiesof laboratory monitoring in sub-Saharan Africa
Table 2b Monitoring cost input parameters for cost-effectiveness studies of laboratory monitoring in resource-limited settings a 
Cost-effectiveness of laboratory monitoring strategies in studies from sub-Saharan Africaa
Goldie et al., New England Journal of Medicine 2006 [6
In this Côte d’Ivoire analysis, Goldie et al. examine multiple strategies: no ART, ART with clinical monitoring alone where alternative numbers of opportunistic diseases are used for ART initiation (and discontinuation), as well as ART initiation and discontinuation guided by CD4 monitoring. This was one of the earliest analyses of laboratory monitoring; HIV RNA was scarcely used in resource-limited settings at the time and is not examined in this analysis. Only a single antiretroviral therapy regimen is assumed to be available (51% virologic suppression at 52 weeks).
Compared to no ART, ART initiation with development of two opportunistic diseases and discontinuation upon one results in a cost-effectiveness ratio of $660/YLS, very cost-effective by WHO standards for Côte d’Ivoire (Tables and ). The description of the wide range of clinical strategies examined in this analysis is excluded here for simplicity. When CD4 monitoring is available and ART is initiated at CD4<200/μl (or <350/μl with a severe opportunistic disease), there is a resultant increase in life expectancy of more than 2 years, from 41.37 months to 69.63 months. Compared to the clinical monitoring described above, the incremental cost-effectiveness ratio for the CD4-based strategy is $1,140/YLS. Thus, CD4 monitoring would be considered cost-effective for Côte d’Ivoire.
Bishai et al., AIDS 2007 [7
Using data from Kenya, Zimbabwe, and Botswana, the authors examine four strategies over a 10-year time horizon: no ART, ART with no laboratory monitoring, ART with CD4, and ART with CD4 and HIV RNA monitoring. All strategies are evaluated under scenarios of either one or two lines of ART. For comparison with other studies, we have eliminated discussion of the total lymphocyte strategy, which is no longer recommended for routine monitoring by the WHO [23
After elimination of dominated and total lymphocyte count strategies, the results reveal that CD4 monitoring has a cost-effectiveness ratio ranging from $640/QALY when only first-line ART is available, to $5,960/QALY when a second-line is also available (). The latter ratio is considered very cost-effective for Botswana but exceeds the one-times-the-GDP threshold for both Kenya and Zimbabwe (). An important assumption in this paper is that when CD4 counts are utilized, clinical criteria alone are insufficient to start or switch ART (). The authors note, “The costs of the CD4 cell count tests are offset significantly by eliminating costly drug treatment for patients who meet criteria on clinical grounds, but whose CD4 cell counts remain adequate.” This modeling assumption conflicts with current WHO recommendations, which are to initiate ART with the development of any stage 3 or 4 opportunistic disease regardless of CD4 count [2
]. Compared to CD4 monitoring, viral load monitoring was less economically attractive, with incremental cost-effectiveness ratios ranging from $16,860/QALY (first-line only) to $15,250/QALY (second-line available) compared to CD4 monitoring alone.
Vijayaraghavan et al., JAIDS 2007 [8
In this study from South Africa, the authors examine the cost-effectiveness of a developed-world approach to ART, including laboratory monitoring, in a resource-limited setting. Two strategies, with two lines of ART available, are examined. The first is ART initiation and monitoring according to “WHO criteria,” where CD4 monitoring occurs every 6 months, ART is initiated at a threshold of CD4<200/μl, and ART is switched based on CD4 or clinical criteria. The second is a “developed world strategy,” where CD4 and HIV RNA monitoring occur every 3 months; ART is initiated at a threshold of CD4<350/μl or HIV RNA>100,000 copies/ml; and ART is switched for CD4 decrease (to <200/μl or to 50% of its peak on-treatment value), HIV RNA increase to >400 copies/ml, or clinical criteria.
When applied to South Africa, the developed world strategy increases both costs and life expectancy compared to the WHO strategy. The incremental cost-effectiveness ratio of the developed world strategy, with quarterly CD4 and HIV RNA monitoring, is $5,780/LYS, very cost-effective by South African criteria (Tables and ).
Phillips et al., Lancet 2008 [9
In this analysis, which uses data from several lower income countries, the authors consider strategies for switching and stopping ART over a 20-year horizon. The benefits of laboratory monitoring for ART initiation are not addressed; all patients in this analysis are assumed to be ART-eligible (). Switching strategies examined include clinical observation alone, CD4 monitoring, or CD4 and HIV RNA monitoring. The results – amended in to show only the undominated strategies – suggest that CD4 monitoring without HIV RNA testing is incrementally less cost-effective than the more expensive strategy of switching with a new stage 3 or 4 event. These results define CD4 monitoring in ART switching decisions as a “weakly dominated” strategy. HIV RNA monitoring, compared to switching based on a new stage 3 or 4 event (with the CD4-dominated strategy eliminated), has a cost-effectiveness ratio of $3,610/QALY. This incremental cost-effectiveness ratio is higher than that originally reported by Phillips et al. (Technical appendix
, ) but is below the one-times-the-GDP very cost-effective threshold for some countries in sub-Saharan Africa ().
Bendavid et al., Archives of Internal Medicine 2009 [10
This analysis, set in southern Africa, examines alternative strategies for starting, switching, and stopping ART according to symptom-based monitoring, CD4 monitoring alone, and CD4 with HIV RNA monitoring. Two lines of ART are available, and the authors consider alternative thresholds for ART initiation, based on first opportunistic disease and/or a CD4 count threshold <200/μl or <350/μl. ART switching criteria are based on second or third opportunistic disease, 50% CD4 count decline, and/or an increase in HIV RNA, when such monitoring is available.
Among all of the strategies considered, the authors find the following four undominated strategies and their associated incremental cost-effectiveness ratios: 1) biannual CD4 monitoring with ART initiation at <200/μL (comparator, no ratio calculated), 2) biannual CD4 monitoring with ART initiation at <350/μl ($90/YLS), 3) biannual CD4 and HIV RNA monitoring with ART initiation at <350/μl ($4,140/YLS), and 4) quarterly CD4 and HIV RNA monitoring with ART initiation at <350/μl ($124,000/YLS) (). The authors highlight that, for any given ART initiation strategy, symptom-based monitoring approaches are more expensive but less effective than CD4-based strategies. This finding that CD4 monitoring alone is cost-saving compared to symptom-based approaches may be due to the previously described averted high cost of opportunistic diseases when ART is initiated based on CD4 cell counts.
A Comparison across Studies
While the discussion above describes the results from each of the individual studies, it is important to recognize that the incremental cost-effectiveness ratios in each of these studies depend not only on the costs of the laboratory monitoring interventions but also on the costs of ART and clinical care. Additionally, such costs vary depending not only on the year and the country in which the analysis takes place but also on how the cost is estimated. summarizes the CD4 and HIV RNA costs per test in each of these studies; they range from $5-$31 per CD4 test and $26-$92 per HIV RNA test. Annual costs for ART regimens vary even more widely, ranging from $130-$429 for first-line and from $640-$1,432 for second-line regimens. Laboratory monitoring in each of these studies generally results in an expedited and timelier switch to a more expensive second-line ART regimen, on which patients often remain for many years. Thus, ART regimen costs, rather than the laboratory test costs themselves, are the primary determinant of the total costs in these analyses. As price negotiations render 2nd-line ART regimens less expensive worldwide [24
], laboratory monitoring strategies may become more cost-effective. Sensitivity analyses may be helpful to allow one country’s policy makers to apply cost-effectiveness results of monitoring strategies conducted in another country. Generally, most studies report that results were sensitive to both ART and laboratory test costs.
This review has several limitations. First, we were bound by the strategies selected and information provided in the reviewed analyses. The decision regarding which monitoring strategies to examine is not uniform across studies. Furthermore, not all studies reported how their costs were derived, and, as a result, costs for this review could not be normalized across studies occurring in different settings and times. Additionally, the high cost of initial investment in the implementation of laboratory monitoring, including the costs of modifying existing infrastructure and of purchasing and maintaining laboratory information management systems, warrants careful consideration and is generally not commented on in these studies.
Finally, the recently reported DART study is among the most widely cited studies on laboratory monitoring in resource-limited settings [25
]. While results from DART suggest that quarterly CD4 monitoring bundled with other laboratory tests (hematology and biochemistry panels) provided only modest survival benefits compared to clinical monitoring alone, it did not address CD4 monitoring alone, CD4 monitoring at longer intervals, or CD4 monitoring for the purpose of ART initiation [25
]. Because cost-effectiveness results from DART remain unpublished, they were not available for this review. However, preliminary cost-effectiveness analyses from the DART study suggest that CD4 monitoring alone (in the absence of other laboratory monitoring) may be cost-effective in some settings (cost-effectiveness ratio of $2,146/QALY (2008 USD)) [26
Increasingly the WHO and other health-governing agencies are relying on cost-effectiveness analyses among their guiding principles [4
]. Current published studies on the cost-effectiveness of CD4 count and HIV RNA laboratory monitoring differ in design, setting, test cost, and specific strategies compared. While it may be desirable for cost-effectiveness analyses to be individualized to specific settings, relying on this approach may not be practical; some results may be generalizable across countries. Future cost-effectiveness analyses would be more comparable and generalizable if they clearly state the time horizon and year of currency, include critical components of test costs (personnel training, lab infrastructure, specimen transport, and quality assurance programs), and analyze strategies that are most reflective of current in-country clinical practice. We find that many, though not all studies, suggest that CD4 monitoring is cost-effective – and maybe cost-saving – in at least some resource-limited settings. The cost-effectiveness of HIV RNA monitoring, however, ranges widely. The lowest published values ($3,610-$4,140/YLS) suggest that biannual HIV RNA monitoring may be considered cost-effective, but generally in resource-limited countries with the highest per capita
GDPs. Further studies are needed to evaluate newer algorithms of targeted HIV RNA monitoring upon meeting other clinical and/or immunologic criteria [28