In this cohort of 611 ART-naïve, treatment-eligible Kenyan adults, almost half had elevated pre-ART D-dimer levels (>500 ng/mL) indicating increased risk for morbidity and mortality. Women, PLHIV with higher viral load and those with TB at ART initiation were most likely to have elevated pre-treatment D-dimer. At six month visit after starting ART, D-dimer levels decreased, with the median falling to below the threshold indicative of elevated coagulation. The most significant declines were observed among those with highest pre-treatment levels, including participants with high pre-treatment viral load and those with co-existing TB. To our knowledge, this is largest cohort report of changes in this critical coagulation marker after ART initiation from a sub-Saharan African country and our findings provide important information about the benefits of treatment initiation, particularly for PLHIV with advanced disease.
At study enrollment, among all treatment eligible PLHIV in Kenya with median viral load of roughly 100,000 copies/mL, we observed a median D-dimer of 516 ng/mL which is above the clinical cutoff of 500 ng/mL. Our findings showed somewhat lower baseline levels than previous studies of untreated African cohorts, including a study of women living with HIV in Rwanda (21) and another of South African PLHIV with advanced disease.(3) In our cohort, women, PLHIV with high viral load and those with TB had higher pre-treatment D-dimer levels. Sex differences in coagulation makers have been previously documented in HIV-negative populations and in PLHIV enrolled in clinical trials conducted in high resource settings.(22-24) Similar to our results, a study conducted in South Africa and Uganda also found higher pre-treatment D-dimer levels in women compared to men.(25) Previous studies in PLHIV have shown an association between advanced disease and coagulation markers (1, 3, 22, 25), including D-dimer, however we believe this to be one of the largest African cohorts in which pre-treatment findings have been described. There are few previous reports of the relationship between TB and D-dimer in PLHIV however TB disease has been shown to induce a hypercoagulable state (26, 27) and a study of 98 PLHIV in Gabon also reported higher pre-ART D-dimer levels among those with concurrent TB infection compared to those without (28).
We report significant reduction in D-dimer levels over the first six month after ART initiation in Kenyan PLHIV, particularly among those with higher viral load and TB at enrollment. Overall, median D-dimer level at six months on treatment was 390 ng/mL which is below the clinical cutoff of 500 ng/mL and there was a 31% decline overall in D-dimer levels after treatment start. PLHIV starting ART with higher viral load and those with TB saw the largest declines in D-dimer. Our results are unique as few studies have evaluated change in coagulation markers after ART initiation among PLHIV coinfected with TB. While we had only a small number of participants with TB at enrollment (N=31), in this cohort, PLHIV with TB had significantly higher pre-ART D-dimer levels compared to those without TB and there was a 172% decline and median D-dimer levels at six months were within clinically normal values. Our findings are consistent with the previously cited study from Gabon which also found significant decreases in D-dimer among 19 PLHIV with TB after ART initiation (28). These findings demonstrate the important benefits of treatment initiation for PLHIV particularly those with advanced disease and comorbidities. While the impact of treatment with antiretroviral medications on levels of coagulation markers in PLHIV has been shown in clinical trials, there are limited findings from real world cohorts, particularly from African settings.
The SMART trial found that among participants who achieved viral load <400 copies/mL, at six months on ART median decline in D-dimer level was -0.10 ug/mL (IQR: -0.31 – 0.00) or a 51% reduction (15). The Monitoring of Early Adherence (META) cohort study, conducted in South Africa and Uganda, also showed significant reductions in D-dimer at 12 months after ART initiation among 438 PLHIV.(25) While we examined D-dimer change over the first six months on ART in a cohort of PLHIV with more advanced disease than these previous studies, our results are consistent. Our estimate of mean change in the first six months after treatment initiation is also similar to a study of 100 PLHIV from South Africa with advanced disease which reported significant reductions in D-dimer at six months after ART initiation (-0.12, p<0.0001).(3) In a cohort of Rwandan women living with HIV, significant reductions in D-dimer levels were observed at two years on ART demonstrating the continued salutary effect of treatment initiation.(21) The decrease in D-dimer levels as a result of treatment can be anticipated to result in favorable outcomes in terms of thrombotic complications and survival.
There are several important strengths of this analysis. As noted, our findings are unique based on the size and setting of the cohort, as well as the measurement of D-dimer and viral load over the first six months of treatment. The large size of this African cohort is important given that the majority of PLHIV receive care in similar settings and the fact that few prior studies have focused on coagulation markers in this population. Our findings demonstrating the effect of ART initiation on D-dimer levels are highly relevant for this population and underscore the importance of treatment initiation to improve long term health outcomes for PLHIV. Our study is also novel with regard to our description of D-Dimer in PLIHV with TB disease; as noted, very few previous studies have examined D-dimer in PLHIV with TB despite it being the leading cause of death among PLHIV (29). There are also limitations to our analysis including the relatively short duration of follow-up which did not allow us to examine the durability of the reductions we observed in D-dimer. The sample size also limited our ability to examine associations between baseline and change in D-dimer levels with morbidity and mortality outcomes over time. We did not have a comparison group with which to compare our data such as PLHIV starting ART with higher CD4 counts or persons not living with HIV. Our study was conducted prior to the introduction of ‘treat all’ guidelines in Kenya and during a time when majority of patients initiated NNRTI-based regimens. This cohort is thus representative of the patient population eligible for treatment during that period and reflect outcomes for patients starting the ART regimens recommended at that time.