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  5th IAS Conference on HIV Pathogenesis, Treatment and Prevention
July 19th-22nd 2009
Capetown, South Africa
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Earlier HAART at 350 CD4 Instead of Current 200
in Developing World Recommended

  Compared with the 250-cell threshold, starting at 350 had an incremental cost-effectiveness ratio of $1,200 per year of life saved, the researchers said.
"It is probably both effective and cost-effective" to allow therapy to start at the higher level, the researchers said.
presented them in a poster here at the fifth International AIDS Society conference on pathogenesis, treatment, and prevention of HIV
The current standard for starting HIV treatment in South Africa followed World Health Organization guidelines for the developing world -- a patient is eligible for treatment when his or her CD4-positive T cell count falls below 200 per cubic millimeter of plasma or when there is an AIDS-defining illness.
But guidelines in the developed world now suggest starting at a higher level -- 350 cells per cubic millimeter -- and some recent studies have suggested that clinical outcomes would be even better if the threshold were set to 500 cells or more.
Clinical trials are under way in Africa to settle the issue, but they won't report for another five years. In the meantime, Dr. Walensky and colleagues said, their model may provide guidance to clinicians.
The bottom line, they said, is that in all cases, starting therapy at the 350-cell threshold saved more lives, prevented more disease, and cost more, compared with a threshold of 250 cells.
The researchers estimated that such a threshold would mean 4.7 million people would be eligible for therapy in South Africa over the next five years.
Under the assumption that 10% of those patients would be identified and given care, Dr. Walensky and colleagues said, using the 350-cell threshold would result in 1,599,900 deaths compared with 1,622,000 for the lower level.
There would also be 1,664,500 opportunistic infections, compared with 1,689,700 using the lower threshold.
On the other hand, costs would increase by $141,977,100 (U.S.), they found.
At the other extreme, if all eligible patients were identified and linked to care, the higher threshold would avert 221,000 opportunistic diseases and 253,000 deaths.
The additional costs in that scenario would rise to $1.4 billion, the researchers said.
Either scenario would increase long-term survival by at least 7.9 years, with an average per-person life expectancy of 3.8 years with no therapy and 12.5 years at the 350-cell threshold.

Annals of Internal Medicine
Source reference:
Walensky RP et al. "When to Start Antiretroviral Therapy in Resource-Limited Settings" Ann Intern Med 2009; 151.
When to Start Antiretroviral Therapy in Resource-Limited Settings
Rochelle P. Walensky, MD, MPH; Lindsey L. Wolf, SB; Robin Wood, FCP, MMed, DTM&H; Mariam O. Fofana, AB;Kenneth A. Freedberg, MD, MSc; Neil A. Martinson, MBBCh, MPH; A. David Paltiel, PhD; Xavier Anglaret, MD, PhD;Milton C. Weinstein, PhD; and Elena Losina, PhD, for the CEPAC-International Investigators*
Annals of Internal Medicine 4 August 2009 | Volume 151 Issue 3
Background: The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years.
Objective: To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa whileawaiting the results of these trials. Design: Cost-effectiveness analysis by using a computer simulation model of HIV disease.
Data Sources: Published data from randomized trials and observational cohorts in South Africa.
Target Population: HIV-infected patients in South Africa. Time Horizon: 5-year and lifetime. Perspective: Modified societal.
Intervention: No treatment, ART initiated at a CD4 count less than 0.250 x 109 cells/L, and ART initiated at a CD4 count less than 0.350 x 109 cells/L. Outcome Measures: Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness.
Results of Base-Case Analysis: If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count thresholdfor ART initiation of 0.350 x 109 cells/L would reduce severe opportunistic diseases by 22 000 to 221 000 and deaths by 25 000 to 253 000 during the next 5 years compared with ART initiation at 0.250 x 109 cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 109 cells/L. Compared with an initiation threshold of 0.250 x 109 cells/L, a threshold of 0.350 x 109 cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved.
Results of Sensitivity Analysis: Initiating ART at a CD4 count less than 0.350 x 109 cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%.
Limitation: This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 x 109 cells/L or of reduced HIV transmission. Conclusion: Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 109 cells/L, earlier than is currently recommended.
Primary Funding Source: National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.
Recent data from cohort studies and mathematical models in the developed world suggest that treatment outcomes of HIV-infected patients improve when antiretroviral therapy (ART) is initiated at CD4 counts less than 0.350 x 109 cells/L or even 0.500 x 109 cells/L (1-4). The question of when to start ART in HIV-infected patients is even more critical in resource-limited settings, in the context of higher rates of mortality and opportunistic diseases-including tuberculosis and other severe bacterial infections-at CD4 counts greater than 0.200 x 109 cells/L (5). At CD4 counts between 0.200 and 0.350 x 109 cells/L, the rates of such opportunistic diseases in South Africa may be 10-fold higher than those seen in the United States (5, 6). Several international clinical trials, including one in South Africa, are currently enrolling patients. These trials will explicitly address the clinical benefits of earlier ART initiation (at CD4 counts <0.350 x 109 cells/L or <0.500 x 109 cells/L) compared with the current World Health Organization (WHO) standard of care (stage 3 or 4 disease or when CD4 counts decrease to <0.200 x 109 cells/L) (7-9).
Although clinical trials may provide insight into the optimal timing of ART in resource-limited settings, they can only address short-term outcomes and will not be available to inform practice for several years (8, 9). Our objective is to inform crucial decisions now, until these trials are reported, by using a model-based analysis to examine treatment strategies with different ART initiation thresholds in South Africa.
Although the forthcoming trials in South Africa and other resource-limited settings should yield important information in the next 5 to 10 years, our analysis suggests that, until trial data are available, a CD4 count threshold of 0.350 x 109 cells/L for initiating ART would probably yield better clinical outcomes than a lower threshold. The magnitude of such benefits multiply with increased rates of HIV identification and linkage to care. A threshold of 0.350 x 109 cells/L is also expected to be highly cost-effective in the interim. Many of the clinical benefits of starting earlier occur beyond the 5-year time horizon of the trial (manifested in increased life expectancy). Even so,our results suggest that a threshold of 0.350 x 109 cells/L remains cost-effective if the probability is 17% or greater that the forthcoming trials will demonstrate improved clinical outcomes with starting ART earlier.
When ART is initiated according to current treatment guidelines, we found that an ART initiation threshold of 0.250 x 109 cells/L is very cost-effective in the long term for HIV infection in South Africa, with a ratio of $1100/YLS (7); for a threshold of 0.350 x 109 cells/L, the cost-effectiveness ratio is $1200/YLS. That these ratios are similar suggests that if HIV treatment is worth initiating, early initiation provides similar value to later treatment. We specifically designed sensitivity analyses to see how these results might change and found that very high rates of drug resistance and pill fatigue would be required to make earlier therapy not cost-effective. Because our results depend heavily on the frequency of opportunistic diseases at higher CD4 counts, morbidity rates should be assessed carefully at high CD4 counts; initiation of therapy at a greater CD4 count threshold than 0.350 x 109 cells/L may be justified in South Africa.
Conducting the current trials remains critically important in informing the question of when to start ART. Evidence-based guidelines continue to maintain that randomized, controlled trials are the gold standard for developing policy; modeling analyses are still considered lower levels of evidence (40, 41). As such, randomized trials will probably be used as the benchmark evidence for HIV treatment throughout the world. Meanwhile, our model-based analysis suggests that opening up the option to start ART earlier in the disease course would probably improve clinical outcomes, at least until trial results are available. Our results suggest that 25 000 lives may be at stake; waiting 5 years for trial results could be costly in human terms.
Despite findings that a CD4 count threshold for ART initiation of 0.350 x 109 cells/L may be beneficial, a study on patient characteristics at presentation to care in South Africa suggests that a discussion of earlier versus deferred ART initiation may not be germane at present; in that study, the mean CD4 count of patients who started ART was only 0.096 x 109 cells/L (42). However, wider implementation of the WHO guidelines for using HIV testing technologies (43) and improved HIV screening and linkage to care should result in the identification of more patients who are eligible for earlier therapy initiation (7). Decisions need to be made on how best to optimize their care, and efforts to identify them must continue if a policy of earlier therapy is to have a meaningful effect. Our analysis demonstrates that a CD4 count threshold of 0.350 x 109 cells/L is highly effective and confers similar value to a threshold of 0.250 x 109 cells/L.
However, an ART initiation threshold of 0.350 x 109 cells/L may not be optimal in some cases, such as when treatment capacity is limited-as is currently the case in many places (16). In such settings, prioritization-whether ART should be provided on a first-come, first-served basis or on a CD4 count-based policy-is already problematic (44). With inadequate treatment capacity, increasing the treatment initiation threshold for all patients to a CD4 count of 0.350 x 109 cells/L, without prioritization for the sickest patients, could result in more deaths in the near term, even if earlier therapy is associated with long-term benefits. Thus, guidelines thatmove toward ART initiation at higher CD4 counts should be implemented only in settings with adequate capacity to treat all of those who are eligible and at highest risk.
Our study has limitations. First, this analysis does not represent an assessment of the estimated value of perfect information, which would examine whether the trial is worth doing. Because trials are already enrolling, we address the question of the optimal clinical strategy while awaiting the results of those trials. Second, we incorporated input data from multiple sources. Although they were uniformly derived, not all data are from similar cohorts in South Africa. Sensitivity analyses demonstrate that within reasonable reported ranges, our major conclusions are robust to these data estimates. Third, implementation of ART strategies by CD4 threshold in international settings-where CD4 testing is not universally available-may require investments in infrastructure. Fourth, our model does not account for the potential benefits of ART, unrelated to opportunistic diseases, that might be attributable to treatment at CD4 thresholds higher than the current standard of care (45). We also do not capture any additional benefits in preventing HIV transmission that earlier ART may confer because of viral load reduction (46). To the extent that these benefits occur, earlier therapy would be even more advantageous. Finally, earlier therapy may have other additional benefits in African countries that have higher rates of malaria and bacterial diseases than those documented in South Africa (5, 31). Ongoing randomized trials are studying the question of when to initiate ART in resource-limited settings. As these trials continue to enroll and accrue follow-up toward the primary outcomes, decisions must be made now regarding the optimal ART initiation policy in these settings. While we await trial results in settings of adequate treatment capacity, this study demonstrates that it is probably both effective and cost-effective to liberalize the opportunity for ART to be initiated at a CD4 count threshold of 0.350 x 109 cells/L in South Africa.