When assessing all HIV-infected participants, we found no evidence of an association between HHV-8 infection and PASP. In unadjusted analyses, HHV-8 infected participants had 0.39 mmHg lower mean PASP than HHV-8 uninfected participants (95% CI −3.2–2.4, P = 0.78) and had only a 1.2-fold greater odds of PASP greater than 30 mmHg (95% CI 0.67–2.3, P = 0.51). After adjusting for age, gender, HCV infection, and a variety of HIV-related parameters, inferences were unchanged, still indicating no association between HHV-8 infection and PASP (data not shown). We then restricted the sample to persons without prior IDU, HCV antibody positivity, smoking, or grade II or higher diastolic dysfunction. Among the 47 individuals who remained, those with HHV-8 infection had an age- and gender-adjusted 4.6 mmHg higher mean PASP than HHV-8 uninfected participants (95% CI −0.11 to 9.2, P = 0.056). The much greater difference in mean PASP between HHV-8 infected and HHV-8 uninfected participants in this subgroup compared with the entire group of 196 HIV-infected individuals suggested that the presence of IDU, HCV infection, or smoking was modifying the effect of HHV-8 infection on PASP. Indeed, the P value for the interaction term testing for this was 0.028 (Table 4). To assess the robustness of the association between HHV-8 and PASP that we observed in these 47 individuals, we created other restricted subgroups among the HIV-infected participants. We found that any group that excluded HCV-infected persons resulted in the same statistically borderline association between HHV-8 infection and PASP. Performing the same restriction and assessing PASP as a dichotomous variable again revealed a qualitatively different role of HHV-8, but this did not reach statistical significance (2.8-fold greater odds of PASP greater than 30 mmHg among HHV-8 infected participants; 95% CI 0.69–11, P = 0.15).
When evaluating PASP as either a continuous or dichotomous variable, there was no strong evidence for a role of age, gender, race, stimulant use, smoking, duration of HIV infection, duration of use of any class of antiretroviral drugs, current or nadir CD4+ T cell count, or current plasma HIV RNA level. Among the strongest associations was that for HCV infection (a surrogate of IDU), but this did not reach levels of conventional statistical significance (P = 0.093).
Although HIV infection is listed amongst the causes of PAH in widely used classification systems  and testing for HIV has been incorporated into practice guidelines for persons with PAH [11,12], a closer look at the prior evidence for a causal role of HIV reveals deficiencies. The foremost deficiency relates to the fact that persons with HIV infection commonly have a history of IDU, which is associated with PAH . Hence, simply finding a high frequency of PAH among HIV-infected persons, without accounting for IDU or having a comparator group of HIV-uninfected persons, is insufficient evidence. The two case series most widely cited as establishing high frequency of PAH in HIV disease indeed had many patients with concomitant history of IDU [5,13]. Even examining the most recent comprehensive review finds that among the 76 HIV-infected persons with PAH and no other apparent known cause, 51.3% had a history of IDU, leaving only 37 cases without IDU . In the only comparative study we are aware of that contained both HIV-infected and HIV-uninfected individuals , HIV infection was found in three persons with PAH and not found among controls, but it was unclear if this difference held true after adjustment for IDU.
To overcome limitations in the prior evidence to establish a role of HIV in PAH, we first included well characterized contemporaneous HIV-uninfected persons to serve as a direct comparator group. Second, we assessed the critical confounding factor of IDU by confidential self-administered questionnaire, and we used a biological proxy, presence of antibodies to HCV, to enhance sensitivity. Furthermore, we probed for the use of stimulants (i.e., cocaine or amphetamine/methamphetamine) via non-parenteral routes, thereby providing comprehensive measurement of the main recreational agents that have been associated with PAH. Third, to overcome limitations in finding sufficient numbers of patients with clinically manifest PAH, we focused on measuring PASP in an unselected group of HIV-infected patients. What we observed is a substantially higher than expected prevalence of elevated PASP among HIV-infected persons that was many times greater than among HIV-uninfected individuals and independent of IDU and stimulant use. Taking our design features into account, we believe that these data are among the strongest to date for a causal role of HIV in PAH.
Because our participants were not selected on the basis of symptoms, it is best to describe the elevated PASP we have identified as ‘preclinical’ PAH and note that it is different from previous reports in HIV-infected persons that have studied clinically manifest PAH. The high prevalence of elevated PASP that we have found is substantiated by an earlier echocardiographic study among HIV-infected patients which found a high and unexplained prevalence of isolated right ventricular enlargement . More recently, other echocardiographic work in unselected HIV-infected individuals has also preliminarily found high prevalence of elevated PASP [36,37].
Because what we have identified is ‘preclinical’ PAH, it is not known if most affected individuals will develop symptomatic disease. Because the prevalence of clinically manifest PAH among HIV-infected patients is substantially lower than what we have observed for ‘preclinical’ PAH, we do not believe that most individuals will develop symptoms. What is of concern, however, is whether these individuals will experience sudden death. This is relevant because in the investigation of PAH among an unselected group of patients with sickle cell anemia, of the 32% who had PASP of at least 30 mmHg, mortality was 17.5% at 17 months of follow-up . Approximately 50% of those persons who died did so of sudden death, some of them not having developed classic symptoms of PAH (Mark Gladwin, personal communication). Therefore, it is possible that undiagnosed PAH is currently an important cause of death among HIV-infected persons. Some evidence for this was seen in a recently completed large treatment strategy trial in HIV-infected adults, in which the number of unexplained deaths was similar in magnitude to the number of deaths due to cardiovascular disease .
If HIV is causally related to PAH, by what biologic mechanism does this operate? Attempts to locate direct evidence of HIV infection in diseased lung tissue of patients with PAH have been unsuccessful . More recently, investigation has been focused on a potential indirect role of HIV that may be mediated through vascular endothelial growth factor-A, platelet derived growth factor, endothelin-1, transforming growth factor beta, interleukin-6, and HIV Nef [40–44]. Our inability to relate specific HIV-related parameters (e.g., plasma HIV RNA level, CD4+ T cell count, or antiretroviral therapy) to PAH unfortunately does not add to the understanding of pathogenesis.
We evaluated the role of HHV-8 infection in PAH to confirm prior work in which HIV-uninfected patients with primary pulmonary hypertension were found to have evidence of HHV-8 in their lungs by immunohistochemistry and nucleic acid amplification . This study has been followed by six others refuting the finding [14–19], and one report that detected HHV-8 by immunohistochemistry but not by nucleic acid amplification . Importantly, our study design differed from others in that by concentrating on HIV-infected participants, we were assured to study a large number of HHV-8 infected persons. This avoids criticisms of prior work in which even if HHV-8 was truly a sufficient (but not necessary) cause of PAH, an association which could be very difficult to detect in a population with very low overall HHV-8 prevalence. In addition, by focusing on HIV-infected persons, in whom other overt HHV-8 related disease manifestations such as Kaposi's sarcoma occur, we theorized that we would optimize our ability to observe PAH. With one of the largest sample sizes to date to study HHV-8 in PAH, we did not detect an association when evaluating all HIV-infected participants but did find some evidence when restricting to persons without HCV infection. Although the association we found occurred in a prespecified subgroup, the effect is of borderline statistical significance, and we cannot readily provide a biologic explanation as to why the effect of HHV-8 would be stronger in HCV-uninfected persons. Furthermore, the epidemiology of HHV-8 infection would not predict that it is a culprit in PAH. Specifically, there is no evidence of increased incidence of PAH in homosexual men in the United States or persons residing in the Mediterranean, two groups with the highest prevalence of HHV-8 who live in developed settings in which PAH would be expected to be diagnosed if it occurred. Therefore, considering the entirety of the literature to date, we believe that the evidence for a role of HHV-8 in PAH is far less definitive than that of HIV and still must be considered suspect. Yet, before the idea is discarded, it would seem necessary for others to repeat our approach of evaluating large numbers of HHV-8 infected persons (with and without HCV infection).
There are potential limitations to our work. Without performing right heart catheterization to confirm elevated PASP, our estimate of the absolute prevalence of elevated PAH could be biased. Yet, even if the absolute estimates are biased in either direction, because our measurement of PASP was blinded to HIV infection status, any misclassification is non-differential. Therefore, the relative difference in PAH between HIV-infected and HIV-uninfected groups should be unaffected. In terms of ruling out confounding, we recognize that we did not have a sensitive measurement of chronic liver disease and portal hypertension, which are believed to cause to PAH . We did, however, observe a relationship between HIV and PAH even after excluding persons with HCV infection, by far the most common cause of liver disease in this population. What is potentially more significant is unknown confounding factors. That primary (or idiopathic) PAH remains such an important diagnostic entity among persons with PAH indicates that the etiologic factors responsible are largely unknown. It is conceivable that some of these factors – especially if behaviorally acquired – could be more prevalent among HIV-infected persons.
Because the clinical implications of ‘preclinical’ PAH amongst HIV-infected persons are unknown, it is premature to suggest that routine screening should be performed to detect this condition. However, because of the importance of asymptomatic elevated PASP in other patient groups (e.g., sickle cell anemia) there is urgency in both confirming our estimates of the high prevalence of this condition in HIV-infected persons and determining the subsequent clinical outcomes. A better understanding of the pathogenesis of HIV-related PAH is also needed, in that this may both help shape future paradigms in HIV care and unlock many of the longstanding uncertainties about the pathogenesis of primary PAH.
We thank Henry Masur, MD and Mark T. Gladwin, MD for their helpful suggestions. This paper was presented in part at the 78th Scientific Sessions of the American Heart Association, Dallas, Texas, USA, November 12–15, 2005 and at the 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado, USA, February 5–8, 2006. The work was supported by grants from the Doris Duke Charitable Foundation (Clinical Scientist Development Award to PYH), the American Heart Association (Beginning Grant-in-Aid to PYH), the NIH (R01 AI052745, R01 CA119903, P30 AI27763 and MO1 RR000083) and the University of California AIDS Research Program California AIDS Research Center (CC99-SF-001).
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