Role of HIV and human herpesvirus-8 infection in pulmonary arterial hypertension
Hsue, Priscilla Ya; Deeks, Steven Gb; Farah, Husam Ha; Palav, Swapnaa; Ahmed, Samira Ya; Schnell, Amandaa; Ellman, Allison Bc; Huang, Laurenceb; Dollard, Sheila Cd; Martin, Jeffrey Nb,c
From the aDivisions of Cardiology, USA
bPositive Health Program of the Department of Medicine, San Francisco General Hospital, USA
cDepartment of Epidemiology and Biostatistics, all at the University of California, San Francisco, USA
dCenter for Infectious Diseases at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Correspondence to Priscilla Y. Hsue, MD, Room 5G1, Division of Cardiology, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110, USA. Tel: +1 415 206 8257; fax: +1 415 206 5447; e-mail: email@example.com
Background: Previous work has found a high prevalence of pulmonary arterial hypertension in HIV-infected persons, but establishment of a causal relationship has been limited by the lack of well characterized contemporaneous HIV-uninfected comparator groups. Among HIV-uninfected persons, human herpesvirus-8 (HHV-8) has also been linked to pulmonary arterial hypertension (PAH), but whether this relationship occurs among HIV-infected persons – who have among the highest prevalence of HHV-8 infection – has not been examined.
Methods and results: We echocardiographically calculated pulmonary artery systolic pressure and measured HHV-8 antibodies in HIV-infected and HIV-uninfected adults. Among the 196 HIV-infected participants, the median pulmonary artery systolic pressure (PASP) was 27.5 mmHg and 35.2% had PASP greater than 30 mmHg. This compared to a median of 22 mmHg among 52 HIV-uninfected participants in whom 7.7% had a PASP greater than 30 mmHg (P < 0.001). After adjustment for injecting drug and stimulant use, smoking, age, and gender, HIV-infected participants had 5.1 mmHg higher mean PASP and seven fold greater odds of having a PASP greater than 30 mmHg (P < 0.001). Although we found no association between HHV-8 and PAH among all HIV-infected participants, a borderline relationship was present when restricting to those without risk factors for PAH.
Conclusion: HIV-infected persons have a high prevalence of elevated PASP, which is independent of other risk factors for PAH. This suggests a causal role of HIV in PAH and emphasizes the need to understand the natural history of PAH in this setting. A role for HHV-8 infection in PAH remains much less definitive.
With the advent of antiretroviral therapy, HIV-infected individuals are living longer and comorbid conditions are becoming increasingly more important in influencing their survival. Among the less well characterized comorbidities is pulmonary arterial hypertension (PAH), a potentially life threatening disorder featuring increased pulmonary vascular resistance and progressive right ventricular failure [1,2]. In the general population, the majority of PAH is idiopathic, with a minority attributed to factors such as lung disease, valvular disease, and injecting drug use (IDU) . For persons with HIV infection, the frequent presence of IDU is of obvious concern for increasing the prevalence of PAH, but HIV infection per se has also been purported as being causal [4–8]. Recently, an etiologic role for another virus, human herpesvirus 8 (HHV-8, also known as Kaposi's sarcoma-associated herpesvirus) has been proposed , which is relevant to persons with HIV infection, given their substantial prevalence of HHV-8 infection .
Although classification systems  and clinical practice guidelines [11,12] list HIV infection among the known causes of PAH, whether HIV infection is truly causal or can be explained by known risk factors such as IDU has not been established. For example, among case series reports of PAH among HIV-infected patients, several had a substantial percentage of individuals with a documented history of IDU [5,13] and none had a concurrent comparator group of HIV-uninfected individuals. Whether HHV-8 is a cause of PAH is also not clear. Following the initial report describing an association , other studies have refuted this finding [14–19].
To overcome prior limitations in the investigation of HIV in PAH, we studied the prevalence of PAH as assessed by echocardiography in an unselected sample of HIV-infected adults along with a well characterized contemporaneous HIV-uninfected comparator group. We sought to evaluate if HIV infection is associated with the occurrence of PAH independent of other known risks – especially IDU – and, if so, what are the determinants of PAH among HIV-infected persons. In particular, we took advantage of the high prevalence of HHV-8 infection in HIV-infected persons to evaluate the role of HHV-8 in PAH.
HIV-infected participants were recruited from a clinic-based cohort, the Study of the Consequences of the Protease inhibitor Era (SCOPE), based at San Francisco General Hospital. Participants in our echocardiographic substudy were consecutive volunteers from SCOPE; there were no exclusion criteria. HIV-uninfected participants were persons who answered advertisements (e.g., flyers in the medical center) directed toward persons believed to be HIV uninfected. All persons in this group were tested and documented as HIV-antibody-negative; there were no other eligibility criteria. All participants provided informed consent.
Clinical and sociodemographic characteristics
All participants underwent a structured interview addressing sociodemographic characteristics, prior diagnoses of PAH, behavioral factors associated with PAH, and activity tolerance using the New York Heart Association classification. Questions concerning IDU and the use of stimulants, specifically cocaine and amphetamine/methamphetamine, were asked with confidential self-administered instruments. HIV-infected participants had assessment of their HIV disease as part of the parent SCOPE cohort.
Participants were examined in the supine position by a sonographer blinded to HIV-infection status. Using a Vivid Seven Imaging System (GE, Milwaukee, Wisconsin, USA), tricuspid regurgitation was assessed in three different views, and three sequential complexes were recorded. Continuous-wave Doppler measurement of peak regurgitant jet velocity was used to estimate the pressure gradient between the right ventricle and the right atrium using the modified Bernoulli equation . Pulmonary artery systolic pressure (PASP) was quantified by adding the calculated pressure gradient to the mean right atrial pressure, which was estimated using standard echocardiographic methods . In participants who had trace or no tricuspid regurgitation, we assumed that PASP was normal, as most persons who have clinically significant pulmonary hypertension have measurable tricuspid regurgitation . To assess for elevated left-sided heart filling pressures as a cause of elevated PASP, we determined the presence of diastolic dysfunction according to guidelines from the American Society of Echocardiography [23–25]. Mitral regurgitation was assessed using standard criteria .
Antibodies to HHV-8
Two enzyme-linked immunoassays (EIA) and one immunofluorescence assay (IFA) were used to determine HHV-8 antibody status. In the EIA, peptides from the HHV-8 open reading frame (ORF) 65-encoded protein  and the ORF K8.1-encoded protein  are used as the target antigens in separate assays. In the IFA, HHV-8 containing BCBL-1 cells, in which HHV-8 is induced to lytic replication , are used as antigen substrate. Specimens reactive in the IFA (regardless of reactivity in the EIA) or in both of the EIA were deemed seropositive for HHV-8 . Testing was limited to the HIV-infected participants.
Other laboratory assays
Plasma HIV RNA levels were determined by the branched DNA (bDNA) amplification technique (Quantiplex HIV RNA, version 3.0, Chiron Corporation, Emeryville, California, USA). Hepatitis C virus (HCV) serostatus was determined by the HCV EIA version 2.0 (Abbott Laboratories, Abbott Park, Illinois, USA). CD4+ T cell counts were measured at the San Francisco General Hospital clinical laboratory.
In both the analysis investigating the role of HIV in PAH and the analysis of HHV-8 in determining PAH among the HIV-infected participants, we used a two-stage approach to subject selection. In the first approach, all relevant participants were included and multivariable regression was used to assess independent contribution of variables. In the second approach, as another method to minimize confounding, we restricted the sample by excluding those who ever used injection drugs, were HCV antibody-positive (as a further method to exclude IDU), ever smoked (as a surrogate for lung disease), or had grade II or higher diastolic dysfunction, or 3+ or greater mitral regurgitation (to exclude those with high-filling pressures of the left ventricle that could cause PAH). This restriction approach is particularly useful for factors, such as IDU, where the never-used state is easily defined, but the degree of exposure among users is difficult to quantitate. A further restricted sample excluded participants who ever used cocaine or amphetamine/methamphetamine by any route, as use of stimulant agents has been linked to PAH . In all analyses, PASP was evaluated both in continuous form and dichotomized at less than 30 versus greater than 30 mmHg. The value of 30 mmHg was chosen because a similar cutoff point was used to define PAH in an unselected group of patients with sickle cell disease, in which values above this cutoff point were determined to confer substantial mortality risk . Linear regression was used to evaluate factors associated with the continuous measure of PASP and logistic regression was used for the dichotomized variable. In the multivariable analyses evaluating the role of HIV in PAH, all potential confounding variables were included in the final model in addition to HIV (the primary predictor variable). The same approach was used in the multivariable linear regression of the role of HHV-8 in PAH among the HIV-infected participants. In the multivariable logistic regression of HHV-8 among the HIV-infected participants, because the number of potential confounding factors was large relative to the number of events, we limited inclusion to variables that were associated with PASP at a P value of <0.20 in unadjusted analyses.
A total of 196 HIV-infected and 52 HIV-uninfected participants were evaluated (Table 1). The median age was 47 years in the HIV-infected group and 45 years in the HIV-uninfected group; over 80% of participants in both groups were men. Caucasian race was most common in both groups, and the HIV-infected group had a higher percentage of African–Americans. Among the HIV-infected participants, 62% had never used injection drugs, 32% had used in the past, and 6.1% were current users; one (1.9%) of the HIV-uninfected participants had used injection drugs in the past. Smoking was common in both groups. Among the HIV-infected participants, the median duration of HIV infection was 15 years, and the majority (82%) was currently using antiretroviral medication. The median CD4+ T cell count was 420 cells/μl, and the median plasma HIV RNA level was less than 75 copies/ml. Over half (58%) of the HIV-infected group was HHV-8 antibody positive.
Distribution of PASP
The median PASP among the HIV-infected participants was 27.5 mmHg [interquartile range (IQR) 22–32.5] compared with 22 mmHg (IQR 18–25) among the HIV-uninfected participants (P < 0.001, Wilcoxon rank sum) (Fig. 1). Among the HIV-infected group, 35.2% [95% confidence interval (CI) 28.5–42.3%] had PASP greater than 30 mmHg, 15.8% greater than 35 mmHg, and 6.6% greater than 40 mmHg. In contrast, only 7.7% of the HIV-uninfected participants had a PASP greater than 30 mmHg (P < 0.001 compared with the HIV-infected group) and only one subject (1.9%) had a value above 35 mmHg (P = 0.005). To assess the prevalence of elevated PASP among those HIV-infected persons without known predilection for PAH, we excluded those who ever used injection drugs or stimulants, were HCV antibody-positive, ever smoked, had evidence of grade II or higher diastolic dysfunction (only two participants), or had severe (three or more) mitral regurgitation (no participants). In the 49 HIV-infected participants who remained, the prevalence of elevated PASP was still high. The median PASP was 28 mmHg (IQR 19–33); 36.1% had PASP greater than 30 mmHg, 14.8% greater than 35 mmHg, and 6.7% greater than 40 mmHg. Despite the high prevalence of elevated PASP among the HIV-infected participants, only seven (3.6%) experienced class II or higher New York Heart Association activity tolerance (all were class II), and there was no evidence of an association with PASP (P = 0.61).
Association between HIV infection and elevated pulmonary artery systolic pressure
After adjusting for age, gender, race, smoking, IDU, and stimulant use, HIV-infected participants had 5.1 mmHg higher mean PASP (95% CI 3.1–7.0, P < 0.001) and seven-fold greater odds of having PASP more than 30 mmHg (95% CI 2.3–21, P < 0.001) (Tables 2 and 3). Among the other variables examined, only age had a significant association with PASP. After restricting to the subset of participants without history of IDU, HCV antibody-positivity, smoking, or grade II or higher diastolic dysfunction, the magnitude of the associations somewhat increased. In this subset of 65 individuals, HIV-infected participants had an age and gender-adjusted 6.1 mmHg higher mean PASP than HIV-uninfected participants (95% CI 2.6–9.6, P = 0.001) and had a 15-fold greater odds of having PASP greater than 30 (95% CI 1.5–141, P = 0.021). Further exclusion of all participants with a history of stimulant use resulted in essentially unchanged significant associations between HIV and PASP (data not shown).
Association between HHV-8 infection and elevated PASP among HIV-infected persons
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).
Other factors associated with elevated PASP among HIV-infected persons
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).
Disclosures: Dr Hsue reports that she has received a grant award from Actelion.
There are no conflicts of interest.
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