Research Topic #1
Optimization of long-term ART in the Latin America and Caribbean context.
Research Topic 1, aim 1: Catalog ART usage and effects
We believe that differences in co-morbid conditions, and perhaps source of antiretroviral therapy (ART -- generic versus branded), may be associated with differences in toxicity/tolerability and/or antiviral effect of ART. Aim 1 will catalog co-morbid conditions, source of ART (generic versus branded), drug toxicities, and antiviral effect across sites; compare each of these across our sites; and determine associations between co-morbid conditions / source of ART on one hand and toxicities / antiviral effect on the other.
One additional question of interest is whether the same regimen exhibits varying toxicities and effectiveness based on different patterns of co-morbidities across sites. The use of generic ART medication may also be associated with differences in toxicity profiles compared to the same branded drug, and will be examined separately; association with anti-HIV effect differences will also be assessed.
Research Topic 1, aim 2: To analyze the aggregate effectiveness of sequential ART regimens on long-term outcomes and to determine predictors of long-term success.
A model will be developed to determine predictors of success using both surrogate and clinical endpoints. The rationale for this is that most currently available data are derived from clinical trials that assess response to therapy on the basis of surrogate markers and over one to two years. However, patients in “real-world” care settings receive multiple sequential ART combinations, with regimen changes dictated by failure, allergy, toxicity, concurrent illness, or drug availability (e.g. stable patients may switch regimens based on change in drugs available in the country). We hypothesize that predictors of long term aggregate success of multiple sequential regimens will be identified by modeling based on aggregate treatment effect over time, using clinical endpoints or CD4 cell counts as the outcome measures. Order of use of PI versus NNRTI will be studied to see whether it predicts long-term outcome.
Earlier work by CCASAnet team members suggests that starting with NNRTIs might be more effective than starting with PIs, and provides evidence of feasibility. Single dose nevirapine during pregnancy is hypothesized to negatively impact long term effectiveness of sequential regimens that include an NNRTI at any point in the sequence.
Research Topic 1, aim 3: To develop and evaluate additional measures of HIV care outcomes, including preventable causes of death despite the availability of ART and simpler/less-expensive markers of ART effectiveness.
We will investigate preventable causes of death despite the availability of ART. Since ascertainment of deaths is essential for this aim, common methods for ascertaining deaths will be defined. At each site, variables such as types of therapy offered, gender, age group, risk category, opportunistic infections (OIs), malignancies, and other co-infections will be correlated with causes of death. The rationale for this is that there are limited data on causes of death in HAART-treated individuals, particularly in developing countries. There are data to indicate that primary prophylaxis for certain infections, such as tuberculosis are associated with increased survival, even in settings where HAART is available. There are also data from developed countries suggest that a considerable proportion of deaths are due to potentially preventable causes or to late diagnosis of HIV-infection.
We hypothesize that potentially preventable causes of death are even more common in developing countries, which, in turn, might allow for the development of strategies that may lead to earlier diagnosis of HIV infection or to wider use of available prophylactic measures.
We will also examine on a regional basis whether simpler and less expensive surrogate markers are independent predictors of response to antiretroviral therapy compared with the accepted standard of CD4 monitoring. Hemoglobin levels, body mass index (BMI), and total lymphocyte counts will be assessed longitudinally and comparisons made with changes in CD4 levels and mortality endpoints. Comparisons will also be made with plasma HIV viral RNA levels in subsets with available HIV RNA data. The rationale for this is that the recently increased availability of ART in resource-poor settings has heightened the need for less expensive methods of monitoring response to HIV therapy. Although anemia, weight loss, and total lymphocyte counts have been shown to independently predict levels of immunosuppression and mortality, their clinical utility in monitoring response to ART has not been documented consistently across subgroups and populations.
We hypothesize that these indicators will be independently associated with response to ART, even after controlling for background incidence of malnourishment and other conditions. Comparisons will also be made across our region.
As one example, the WHO criterion for the cut-off point for starting therapy based on total lymphocyte count (TLC), as a surrogate for CD4 counts, is 1,200. Recent work presented at the IAS meeting in July 2005 by the ART-LINC collaboration (which includes one of this proposal's leaders) confirmed that TLC is a strong marker of probability of survival one year after starting ART, but suggested that the WHO TLC cut-off for HAART may need to be increased. Further work to study whether the TLC cut-off may vary by site or co-morbid conditions is important. Combinations of these simpler, less expensive markers will also be studied.
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