We evaluated the relative merits of different HIV monitoring strategies in resource-limited settings based on data from southern Africa. We found that CD4 monitoring could substantially increase length of life and reduce total costs relative to the symptom-based approaches currently practiced in many regions, especially outside of major urban areas. Monitoring CD4 increased length of life through earlier initiation of HAART and prevention of severe opportunistic diseases. Compared with the most effective symptom-based strategy, initiation of HAART at a CD4 count of 200 cells/μl or 350 cells/μl increased life expectancy by nearly 7 and 12 months, respectively.
These gains in life expectancy are substantial. Previous studies suggest that use of HAART compared to no HAART increases life expectancy by approximately 20 months.12
Thus, addition of CD4 monitoring and initiation of treatment when CD4 counts reach 350 cells/μl provides a 60% additional gain in longevity compared with introduction of antiretroviral therapy. For the population eligible for HAART in southern Africa, the achievable gains in length of life is large: initiating antiretroviral therapy for one million people at a CD4 count of 200 cells/μl would provide 542,000 life years over providing HAART without CD4 monitoring, and initiating HAART at 350 cells/μl would provide additional 440,000 life years.
In South Africa, and perhaps in several other countries, much of this gain in longevity could be obtained while reducing total expenditures for HIV care by avoiding expensive hospitalizations for opportunistic diseases, which outweighed the higher costs of CD4 testing and HAART. The reduction in total costs is large in South Africa in part because of the relatively high cost of inpatient care, and our analysis suggests that monitoring CD4 may reduce costs of HIV care also in Namibia, Botswana, and Swaziland, where the quality of the epidemic is similar and inpatient care costs are relatively high.38
However, even in Malawi, where the healthcare infrastructure is very basic, healthcare costs are low, and use of inpatient care is inconsistent, the incremental cost-effectiveness ratio of monitoring CD4 every 6 months and starting HAART at 200 cells/μl was $670 per life-year gained.38
A threshold of twice the per capita GDP is often cited as an acceptable incremental cost-effectiveness ratio for developing countries.39, 40
By that standard, monitoring CD4 is cost-effective in all parts of southern Africa. Our analysis also suggests that even in the most resource-limited settings, starting HAART at 350 cells/μl is an effective and cost-effective intervention.
Our analysis highlights that the sizeable worldwide investments to make HAART available could be strongly leveraged by using CD4 monitoring to initiate treatment prior to onset of serious opportunistic diseases and severe immunocompromise. Recent evidence shows that, in resource-limited settings, where HAART is commonly started at low CD4 counts or with opportunistic diseases, rates of death after treatment initiation are much higher than in Europe and North America, especially in the first few months of treatment.41, 42
Addition of viral load monitoring resulted in an additional increase in life expectancy of 2 months relative to use of only CD4 monitoring. Two months is an important additional benefit. However, this gain in effectiveness came at a less favorable incremental cost-effectiveness ratio than did CD4 monitoring because viral load testing is substantially more expensive and provides about one quarter of the benefit of CD4 testing. If the price of viral load testing were significantly reduced, the cost effectiveness would improve markedly. In developed countries, where cost-effectiveness acceptability thresholds are substantially higher, viral load monitoring is considered a cost-effective intervention. Viral load monitoring has other benefits, such as reduced transmission by limiting the number of people with non-suppressed HIV replication, and fewer accumulated resistance mutations. Because we did not include these potential benefits, we may have underestimated the overall benefits of viral load testing.
Why has CD4 monitoring not been universally adopted in resource-limited settings? The initial investment in CD4 technology and infrastructure is expensive. The cost of CD4 flow cytometers, which require highly trained personnel and laboratories with refrigeration, is high, and ministries of health and public health programs may not be able or willing to make the investment. In addition, the cost of an individual CD4 test, while modest in comparison to the cost of HAART or viral load monitoring, may limit access to testing and treatment. Finally, the WHO guidelines encourage using a CD4 threshold of 200 cells/μl for HAART initiation, but they acknowledge the limited capability to expand monitoring capacity.
These challenges are increasingly surmountable. Recent advances in CD4 enumeration technology allow for lower per-test cost, as well as smaller machines that require relatively little infrastructure, maintenance, and technical expertise.43
Alternative financing mechanisms may allow health care systems to minimize the initial investment in equipment through reagent rental agreements and amortization. Both the reductions in technical challenges, and our finding that CD4 monitoring is cost effective or cost saving, support expanding CD4 monitoring as a valuable tool in scaling-up treatment in southern Africa. Use of CD4 monitoring to determine treatment initiation, and initiating HAART early, will benefit a substantial proportion of those individuals for whom treatment would be otherwise delayed until life-threatening symptoms develop.
Our analysis has several limitations. Although the phase and prevalence of the epidemic in South Africa is similar to other countries in the region, most of the data for our model comes from a single region. Some opportunistic diseases, most notably tuberculosis, place a unique burden in that region and may limit the generalizability of our results. In addition, although our estimates of the health benefits of alternative management strategies are likely applicable more broadly in Africa, the study cohorts in Cape Town received care in a setting with potential access to clinics and hospitals. In settings in which individuals with opportunistic diseases have no access to hospitals, their mortality will be higher, and their cost of care will be lower than we projected. In those settings, more efforts to prevent severe opportunistic diseases may have additional mortality benefits.
We also used some data from clinical trials. While clinical trials may provide the best or only source of data, events such as treatment failure and response to HAART may differ from other settings. In addition, we used a societal perspective for this analysis, where all costs and benefits are included. However, additional perspectives may be relevant to parts of southern Africa where costs and benefits are accrued by different parts of the healthcare system. For example, the perspective of a donor organization which bears costs but sees no direct benefits may be important where donors play an important role in the healthcare system. Finally, our model is not intended to restrict the use of viral load monitoring in southern Africa. Rather, we highlight the importance of CD4 monitoring and early treatment initiation as the priority in improving the care of individuals in southern Africa.
The rapid increase in access to treatment in resource-limited regions represents a major progress towards reducing HIV morbidity and mortality. Our analysis shows that, where HAART is available, CD4 monitoring with earlier treatment initiation provides a substantial increase in length of life which, in some settings, may be achievable while reducing total expenditures for HIV. As the number of people receiving HAART increases, the potential health benefit and cost savings from use of CD4 monitoring will also increase.