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Cost effectiveness of alternative strategies for initiating and monitoring highly active antiretroviral therapy in the developing world
Global Health Sciences Literature Digest
Published January 07, 2008
Journal Article

Vijayaraghavan A, Efrusy MB, Mazonson PD, Ebrahim O, Sanne IM, Santas CC. Cost effectiveness of alternative strategies for initiating and monitoring highly active antiretroviral therapy in the developing world. J Acquir Immune Defic Syndr. 2007 Sep 1;46(1):91-100.


To evaluate the cost-effectiveness of initiating and monitoring highly active antiretroviral therapy (HAART) of HIV-infected persons in the developing world according to the US Department of Health and Human Services (US) versus World Health Organization (WHO) guidelines.

Study Design

A lifetime Markov Monte Carlo simulation model of direct and indirect costs, quality of life, survival, and transmission to sexual contacts associated with treating patients with HIV according to US DHHS versus WHO guidelines. The authors adhered to the recommendations of the Panel on Cost-Effectiveness in Health and Medicine for conducting cost-effectiveness analyses.(1)


The setting was hypothetical, but data on the age at which patients entered the model and the initial distribution of CD4 cell count and HIV viral load came from a treatment-naive population of HIV-positive patients in South Africa, which is an upper middle-income country, and has a larger total number of HIV-positive individuals than any other country.(2)


Hypothetical: An estimated population of 5.1 million(2) HIV-positive adults in South Africa, 15-49 years of age, with age 26 the base case value.


The authors used a Monte Carlo analysis of the Markov decision model, basing it on a simulation cohort of 10,000 patients for each intervention. Patients in the WHO group who entered the model with a CD4 count ≤200 cells/mm3 or WHO stage III or IV disease began HAART immediately. The remaining patients initiated HAART once their CD4 count dropped to ≤200 cells/mm3 or they developed AIDS. Patients in the US group who entered the model with a CD4 count ≤350 cells/mm3, a viral load >100,000 copies/mL, or WHO stage III or IV disease began HAART immediately. The remaining patients initiated HAART once their CD4 count dropped to ≤350 cells/mm3, their viral load increased to >100,000 copies/mL, or they developed AIDS.

Patients not on HAART

Risk of disease progression was based on viral load and CD4 cell counts and natural history data was used to estimate rates of disease progression without therapy. As recommended in the WHO guidelines, first-line HAART consisted of stavudine, lamivudine, and nevirapine (for women) or efavirenz (for men). Second-line HAART consisted of tenofovir, didanosine, and ritonavir-boosted lopinavir. Patients in the WHO and US arms of the model received the same drug regimens. After starting a HAART regimen, patients in whom virologic replication was suppressed had an increase in their CD4 cell count. Each month, patients with virologic suppression could have continued virologic suppression, treatment-related toxicity, or virologic rebound. CD4 cell counts declined in patients experiencing virologic rebound. Patients who had drug-related toxicity switched to an alternate WHO-recommended antiretroviral regimen. Patients in the WHO group with incompletely suppressed viral loads could be identified when their CD4 cell counts were tested every 6 months. Based on WHO guidelines, these patients were switched to a second-line regimen if their CD4 count fell to lower than 50% of its peak value or to <200 cells/mm3. In the US group, treatment failure was identified when patients' viral load was tested every 3 months. These patients were switched to a second-line regimen if their viral load was >400 copies/mL. Patients in both groups also changed HAART regimens if they developed AIDS. The authors assumed that the probability of achieving a successful virologic response decreased after virologic failure, but not after changing antiretrovirals because of toxicity.(3,4,5)

Primary Outcomes

Direct and indirect costs, adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) of implementing US versus WHO HIV treatment guidelines in developing countries.


Treating and monitoring according to US vs. WHO guidelines: When the authors considered only the benefit to index patients, they found that initiating HAART at a CD4 count of 350 cells/mm3 or a viral load >100,000 copies/mL as opposed to 200 cells/mm3, incorporating viral load testing, and testing more frequently, increased life expectancy by 1.89 years, or 1.83 QALYs, at an incremental lifetime cost of $9725, for an ICER of $5314 per QALY. This is less than 1 GDP per capita for South Africa ($4900 in 2005). Impact of US guidelines on reduced HIV transmission: The authors then determined that treating all HIV-infected adults (5.1 million) according to US versus WHO guidelines would reduce the number of HIV transmissions to sexual partners by 137,000 over the lifetime of the currently infected patients. Of this overall decrease, 35% of the reduction in transmission is attributable to initiating treatment at a higher CD4 count (CD4 count ≤350 cells/mm3 vs. CD4 count ≤200 cells/mm3), 60% is attributable to inclusion of viral load testing (treating patients with viral load of >100,000 copies/mL), and 5% is attributable to more frequent testing (every 3 months vs. every 6 months). Incorporating the impact of transmission to partners, cost $11,867 more and increased life expectancy by 2.58 years, or 3.00 QALYs, for an ICER of $3956 per QALY. Seventy percent of the differential increase in life expectancy was attributable to initiating treatment at a higher CD4 count, 28% to inclusion of viral load testing, and 2% to more frequent testing. Looked at separately, the ICERs of each of these 3 strategies were $1168, $7860, and $41,286, respectively.

In a separate analysis of the indirect costs from early HIV/AIDS mortality among the index patients and their sexual partners, the incremental indirect cost per patient was $16,778 for the index patient and $101,265 for their sexual partners. The indirect cost for the sexual partners is considerably higher because of the expectation that the GDP net of inflation is predicted to rise rapidly over the next 50 years in South Africa.(6) For South Africa, based on these modeling assumptions, treating all HIV-positive patients according to US vs. WHO guidelines would result in cost savings of $39.4 billion over the lifetime (approximately 38 years) of all currently infected adult patients and the partners to whom they transmit HIV. Increased direct medical costs of $60.5 billion would be more than offset by indirect cost savings of $99.9 billion across the index patients and their sexual partners. Over a 5-year period, treating and monitoring all adult HIV-positive patients in South Africa according to US vs. WHO guidelines would increase direct costs by $14 billion but result in approximately 370,000 fewer deaths, 1 million fewer new AIDS cases, and 290,000 fewer new cases of HIV.

Sensitivity analyses: The authors conducted 1-way sensitivity analyses to determine the effect of individual parameters in the model on the stability of the cost-effectiveness results. Results were most sensitive to clinical variables, such as the effect of changes in CD4 cell count on the risk of progression to AIDS and the probability of virologic rebound, as well as to the quality-of-life variables. The major cost variables to which the model was sensitive were the cost of viral load testing and the cost of second-line and alternate second-line HAART regimens. Results were also sensitive to the discount rate. The transmission variables to which the model was most sensitive included changes in viral load and viral load at baseline.


The authors conclude that treating patients in the developing world according to developed world (US Department of Health and Human Services) guidelines is more effective than treating patients according to developing world (WHO) guidelines. Including the impact of HIV/AIDS on direct and indirect costs, this approach is cost-saving for the economy as a whole. Even without the inclusion of indirect costs, the cost-effectiveness of this approach for direct costs is well within the range of an ICER 1 to 3 times GDP per capita, judged cost-effective as outlined by the Commission on Macroeconomics and Health.(7) These findings suggest that in many upper- to middle-income countries in the developing world, treating patients according to developed world guidelines can provide important health benefits for a reasonable investment in health care resources.

Quality Rating

There is no system for rating the quality of cost-effectiveness studies. The authors point out several limitations. 1. Data were combined from multiple sources with varied study designs. The authors obtained data from the best available published literature, however, and where such data were not available, they based any assumptions on the advice of clinical experts and varied all estimates widely in sensitivity analyses. 2. There were a few parameters for which data from the developing world were not available, and the authors had to rely on data from the developed world or make simplifying assumptions. They limited the use of developed world data to natural history or clinical parameters that are thought to be similar across countries. 3. With regard to indirect costs, it is possible that AIDS patients receiving HAART are sicker than the average adult (working or nonworking and HIV-positive or HIV-negative) and that, as a result, GDP per capita may not be an entirely accurate reflection of incremental productivity in this group. 4. It is possible that the real GDP in South Africa may grow more slowly than predicted. 5. The analysis was limited to sexual transmission of HIV and did not incorporate the impact of mother-to-child transmission (MTCT). While MTCT is an important problem, the guidelines for treating pregnant women and their infants are quite different than the overall WHO "3 by 5" guidelines and warrant a separate analysis. 6. The authors have assumed that the infrastructure to conduct CD4 cell count and viral load testing exists in South Africa. 7. Regardless of the finding that treating patients according to developed world guidelines is highly cost-effective in the short-term and cost-saving in the long-term, some governments may not be able to afford to follow these guidelines without outside financial assistance.

In Context

The results of this study are similar to those of recently published studies that evaluated the cost effectiveness of early versus late initiation of antiretrovirals in South Africa.(8,9) Bachmann(8) found that initiating HAART at a CD4 count of 350 versus 200 cells/mm3 increased life expectancy by 2.3 years compared with 1.9 years in the present model. Bachmann's incremental costs were significantly higher than this study ($8936 vs. $2350), resulting in a somewhat higher ICER ($3885 per life-year gained versus $1270 [calculated using Bachmann's assumptions]). Badri et alix found a similar increase in life expectancy (2.2 years) but had a somewhat lower incremental cost ($1650) and ICER ($766 per life year saved). The difference in cost between the present study and Bachmann's is most likely attributable to the inclusion of overhead in his cost estimates (because this study was conducted from the perspective of a tax funded health service) and higher drug prices. This study's finding that treating patients with a high viral load (>100,000 copies/mL) increased life expectancy compared with treating patients based on CD4 cell counts alone is consistent with a recent analysis by Bogaards et al.(10) In a community-based setting in sub-Saharan Africa, selecting patients for treatment based on plasma viral load in addition to CD4 cell counts was the most efficient treatment initiation strategy and resulted in a larger reduction in the 1-year AIDS incidence rate than selecting based on CD4 cell counts alone.

Programmatic Implications

Despite the significant progress made by WHO's "3 by 5" program, there are a number of potentially significant benefits to treating patients in the developing world according to developed world (e.g., US) guidelines. First, by initiating treatment at a higher CD4 cell count, people can begin lifesaving HAART before severe immunologic damage occurs. Patients initiating HAART at lower CD4 cell counts are less likely to respond to treatment, more likely to progress to AIDS and die,(11,12,13) and more likely to experience immune reconstitution inflammatory syndrome (IRIS).xvii Second, by initiating treatment for patients with viral loads >100,000 copies/mL regardless of CD4 cell count, patients who are likely to progress most quickly to AIDS and die instead initiate HAART before their CD4 cell counts decline significantly.(14) Third, using viral load to monitor patients on HAART allows clinicians to identify treatment failure more quickly and to switch antiretroviral therapy, slowing disease progression, improving treatment outcomes, and reducing transmission of HIV. Finally, patients with viral loads >100,000 copies/mL are much more likely to transmit HIV than patients with lower viral loads.(15) Implementation of WHO guidelines does not specifically target this group of highly efficient transmitters of HIV. whose treatment reduces HIV transmission rates by decreasing viral load.(16) Other techniques that have been proven to decrease HIV transmission (e.g., education, voluntary counseling and testing programs) are also critically important. All these approaches improve the chances of gaining control of this epidemic.


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