Version May 2024
INTRODUCTION — Human immunodeficiency virus (HIV) infection can be complicated by pulmonary hypertension (PH). The World Health Organization (WHO) classifies patients with PH into five groups based upon etiology (table 1) [1]. Patients in the first group are considered to have pulmonary arterial hypertension (group 1 PAH), while patients in the remaining four groups are considered to have PH (group 2, 3, 4, and 5 PH). When all five groups are discussed collectively, the term PH is used. HIV-related PAH (HIV-PAH) belongs to group 1.
In this topic review, the prevalence, pathogenesis, clinical diagnostic evaluation, and treatment of HIV-PAH are discussed. PH that is unrelated to HIV infection is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
PREVALENCE — HIV-PAH is a rare complication of HIV infection, occurring in approximately 1 out of every 200 HIV-infected patients (0.5 percent) [2-11]. This is 100 to 1000-times greater than the prevalence of PAH in individuals without HIV infection. However, studies likely underestimate the true prevalence of HIV-PAH because patients with asymptomatic PAH are not included. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Epidemiology'.)
●Best supporting this prevalence is a prospective study of 7648 patients with HIV, which found a prevalence of right-heart catheterization-confirmed HIV-PAH of 0.5 percent [6]. This study, which was performed from 2004 to 2005 (after the introduction of potent antiretroviral therapy [ART]), reported a similar prevalence to that which was reported in studies performed prior to the use of effective ART, suggesting that ART has not altered the prevalence of HIV-PAH [6,10]. (See 'Antiretroviral therapy' below.)
●Smaller cohort studies have demonstrated prevalence rates of HIV-PAH as high as 2.6 to 14 percent using echocardiography [9,12-14]. However, the observational design of many of these studies and the limitations of echocardiography in the diagnosis of PAH make such assessments of prevalence unreliable [15].
●Patients with high viral loads and low CD-4 count have a higher prevalence of increased pulmonary artery systolic pressures ≥40 mmHg and mortality than uninfected patients [16]. However, patients with HIV who did not have pulmonary hypertension were not included in this analysis.
Reflective of our practice, PAH (ie, group 1 PAH) is probably no longer the predominant form of pulmonary hypertension (PH) in patients with HIV. With the advent of ART, HIV-infected patients are living longer allowing for common chronic cardiac [17] and respiratory diseases to manifest. As a result, PH due to left-heart disease (group 2 PH) and/or lung disease (group 3 PH) is expected to increase. PH due to pulmonary venoocclusive disease (also group 1) is rare in general but has also been reported. (See "Cardiac and vascular disease in patients with HIV" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Miscellaneous'.)
PATHOGENESIS — The pathology of HIV-PAH is indistinguishable from that seen in patients who have idiopathic PAH (IPAH), and thus, similar pathogenetic mechanisms are likely involved [18,19]. Additional viral and host factors likely play important roles in patients with HIV (figure 1). However, the relative contributions of each are difficult to discern because many patients with HIV infection have coexisting conditions that are independently associated with PAH (eg, intravenous drug use, chronic liver disease, cocaine, and stimulants) [2,20,21]. Mechanisms specific to HIV infection are discussed here, while general pathology and pathogenetic mechanisms in IPAH are discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Pathogenetic mechanisms'.)
HIV-related factors — While HIV is not known to infect endothelial cells, the following HIV-associated proteins may contribute to the development of HIV-PAH:
●gp120 – gp120 is an HIV surface glycoprotein that stimulates secretion of endothelin-1, a molecule known to contribute to IPAH [22]. A similar contribution to HIV-PAH, is supported by the observation that circulating monocytes from patients with HIV have increased endothelin-1 gene expression [22]. Oxidative stress induced by gp120 (and tat) may lead to endothelial dysfunction and vascular injury in HIV-infected rats [23].
●Tat – Tat is an HIV transactivator that downregulates the expression of bone morphogenetic protein receptor type II (BMPR2), a molecule that plays a role in the development of IPAH [24]. In support, BMPR2 protein expression was found to be downregulated in HIV-infected drug users compared with HIV-infected or uninfected drug users [21]. Tat has also been implicated in the proliferation of pulmonary artery smooth muscle cells [25]. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.)
●Nef – Nef is an HIV adaptor protein that exists in alveolar mononuclear cells and endothelial cells of patients who have HIV-PAH [26]. In animals, infection with a Nef-positive virus induces plexiform lesions typical of PAH, whereas infection with a Nef-negative virus does not. In another study patients with HIV-PAH had an increased number of HIV-nef gene polymorphisms when compared with patients who had HIV without PAH [27].
While coinfection with human herpes virus 8 (HHV-8) has been suggested to play a role in HIV-PAH, it is not involved in the development of IPAH suggesting that this hypothesis is unlikely [28-31].
Host factors — Individuals who have a specific human leukocyte antigen (HLA) may be predisposed to HIV-PAH. In a case-control study, the frequency of HLA class II DR52 and DR6 was increased among patients with HIV-PAH, compared with both healthy patients and patients with HIV without PAH [32].
Numerous host inflammatory cytokines are increased in patients with HIV infection. Examples include interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and platelet-derived growth factor, which together can induce a procoagulant state, increase the expression of endothelial adhesion molecules, and increase the accumulation of inflammatory cells in the pulmonary arteries [33-35]. However, these cytokines are unlikely to be the sole cause of HIV-PAH because they are elevated in all patients with HIV infection, only a fraction of whom develop PAH.
DIAGNOSTIC EVALUATION
Suspecting PAH — In most patients, the diagnosis of HIV infection is already present. Thus, PAH should be suspected in patients with HIV who present with new symptoms and signs suggestive of PAH. Rarely, HIV is discovered during the routine evaluation of pulmonary hypertension (PH). The clinical presentation is identical to that associated with other types of PAH, the details of which are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
The average duration from the detection of HIV infection until the onset of PAH-related symptoms is roughly two years, occasionally longer [2,36]. However, PAH can occur in the early and late stages of HIV infection [7].
Accurate predictors for PAH development in HIV-infected patients are lacking:
●One study reported that plasma HIV-RNA, chronic hepatitis C, previous drug addiction, or female sex increased the risk of developing PAH by three-fold [12].
●Other studies have reported a higher prevalence in men, perhaps reflecting the higher prevalence of HIV in men [8,37].
●One French cohort of HIV-PAH patients reported a high prevalence of drug abuse (59 percent) in this population suggesting that drug abuse was a risk factor for the development of PAH in HIV patients [38].
●Ritonavir was suggested in one study as a risk factor for the development of PAH but the data to support this risk is poor and should not prevent clinicians from prescribing it for the treatment of HIV [39].
The CD4 count does not predict the likelihood of developing HIV-PAH or its hemodynamic severity.
Given the low rate of PAH in HIV, routine screening of asymptomatic patients with echocardiography has not been typically performed for early detection. However, guidelines from the 2018 6th world symposium on pulmonary hypertension suggest performing echocardiography in patients who are symptomatic or who have more than one risk factor (eg, female sex, hepatitis C infection, known Nef or Tat mutations, origin from a high-prevalence country, and/or African-American) as a way to enrich the likelihood of earlier diagnosis [1].
Patients with HIV-PAH may present with more severe PAH. One study reported that 55 percent of patients with HIV-PAH present with advanced ventricular dysfunction, compared with PAH patients from other etiologies [40].
Diagnosis — The diagnosis of HIV-PAH requires confirmation of PAH and exclusion of alternative causes of PH (table 1) as well as confirmation of HIV infection:
●Confirming PAH and excluding alternative causes of PH – The evaluation of patients with suspected HIV-PAH is similar to that in uninfected patients with PAH, during which, alternative types of PH (group 2 through 5) are excluded. Although 18 percent of patients with HIV-PAH have contributing etiologies (eg, chronic liver disease, drug abuse), distinguishing among the relative contributions of each is not feasible [2]. The diagnostic evaluation and criteria for patients with suspected PAH is discussed in detail separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 1: Pulmonary arterial hypertension'.)
●Confirming HIV infection – HIV infection is usually confirmed by a testing algorithm that uses an antigen/antibody combination HIV-1/HIV-2 immunoassay plus a confirmatory HIV-1/HIV-2 antibody differentiation test, the details of which are discussed separately. (See "Screening and diagnostic testing for HIV infection".)
TREATMENT — Patients with HIV-PAH should be treated with general measures which target factors contributing to the PAH and sequelae of the PAH (algorithm 1). Some patients may also be candidates for PAH-directed therapy, which targets the PAH itself. Although treatment is very similar to that in uninfected individuals with PAH, there are subtle difference for patients with HIV-PAH, which is the focus of this section. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
General measures
Antiretroviral therapy — Antiretroviral therapy (ART) should be offered to all HIV-infected patients, regardless of their CD4 count and irrespective of whether or not PAH is present. ART results in sustained suppression of HIV-RNA, improved cellular immunity (ie, CD4 count), reduced HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T-cell activation), and decreased HIV transmission to others. More detailed discussions of when to initiate therapy and how to choose a regimen are found elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
The benefit of ART in treating HIV-PAH is unclear since data reporting the safety and efficacy of ART in this population are conflicting, and are from small retrospective studies that used older ART regimens (eg, the studies were conducted before the widespread use of integrase strand transfer inhibitors). As examples:
●In one retrospective analysis of 35 patients with HIV-PAH, combination ART therapy resulted in improved pulmonary pressures (median decrease of 25 mmHg in right ventricle:right atrial [RV:RA] pressure gradient on Doppler echocardiography), when compared with single agent therapy (decrease RV:RA gradient 3 mmHg), or no therapy (increase in RV:RA gradient 25 mmHg) [41]. In addition, there were fewer deaths attributable to PAH among patients who received combination ART compared with no therapy (5 versus 38 percent). These results should be interpreted with caution because the pressures were not measured directly by right heart catheterization; in addition the patients who received combination ART were managed during a different therapeutic era for PAH and were, therefore, more likely to receive prostanoid therapy as opposed to other PAH therapies that are now available.
●Another study reported that ART improved exercise capacity without significant changes in pulmonary hemodynamics [42]. Antiretroviral agents used in these regimens included zidovudine, didanosine, indinavir plus ritonavir, and efavirenz.
●Another study in an Indian cohort, which was conducted from 2008 to 2011, suggested hemodynamic benefits in patients with World Health Organization (WHO) functional class I and II (table 2) but not in those with advanced disease [43].
●In contrast, a cohort study of 82 patients with HIV-PAH, which enrolled patients from 1986 to 2000, found that in the absence of epoprostenol, survival worsened when patients were begun on ART, compared to improved survival when epoprostenol was included in the treatment regimen [38].
The effect of specific antiretroviral agents on the progression of PAH is unclear. In one study of HIV-infected individuals, among the 656 patients who had pulmonary hypertension (PH) identified by echocardiography, the protease inhibitor, ritonavir, was independently associated with the development of PH (odds ratio [OR] 1.75) [39], while another study reported that non-nucleoside reverse transcriptase inhibitors were not associated with the worsening of PAH [12].
Conventional and supportive therapies — Similar to patients with group 1 PAH, all patients with HIV-PAH should exercise as tolerated, receive routine vaccinations (figure 2), be counseled against smoking and pregnancy, and be treated with supportive measures including oxygen and diuretics, when indicated. We do not routinely anticoagulate patients with HIV-PAH, since data are conflicting in the non-HIV population. Evidence to support this approach is typically extrapolated from patients with non-HIV-related PAH, the details of which are discussed separately. (see "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults" and "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy')
WHO functional class I
Observation — WHO functional class I patients (table 2) do not require pharmacologic therapy; however, they should be clinically monitored (eg, every three to six months) for disease progression to a functional level that may warrant therapy.
WHO functional class II-IV — Similar to patients with non-HIV-related PAH, patients with WHO functional class II, III, or IV (table 2) should be referred to a specialized center to be evaluated for PAH-specific therapy. PAH-specific therapy is directed at PAH itself rather than the underlying cause. Therapy is determined by many factors, particularly WHO functional class (table 2) as well as potential interactions with the patients HIV medications. Comanagement with both a pulmonary hypertension (PH) expert and an HIV expert is recommended. The evidence supporting PAH-specific therapy comes primarily from studies that included mostly patients with idiopathic PAH (IPAH) with only a small proportion (<25 percent) or no patients with HIV-PAH included in the analyses (see "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'). Evidence to support similar benefits in patients with HIV-PAH is limited and is the focus of this section.
Pulmonary arterial hypertension-directed therapy
Agent selection — There are several classes of agents including endothelin receptor antagonists, nitric oxide (NO) cyclic guanosine monophosphate (GMP) enhancers (phosphodiesterase inhibitors and guanylate cyclase stimulants), and prostacyclin pathway agonists (table 3). In general, the principles of agent selection are similar to that in the non-HIV-infected PAH population with special considerations in HIV-infected patients:
●Calcium channel blockers (CCBs) should be avoided. (See 'Avoidance of calcium channel blockers' below.)
●Certain endothelin receptor antagonists and phosphodiesterase inhibitors may require dose adjustments if the patient is on an ART regimen that includes a pharmacologic boosting agent (ie, ritonavir or cobicistat). A shared decision by the patient, and PH and HIV experts that weighs the risks of drug interactions and benefits of a specific therapy is critical. Specific drug interactions and management suggestions may be determined by using the drug interactions program included with UpToDate. (See 'Endothelin receptor antagonists' below and 'Phosphodiesterase inhibitors' below.)
Further details regarding agent selection in patients with non-HIV-PAH are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class II and III or low/intermediate risk (combination oral therapy)' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen)' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Avoidance of calcium channel blockers — In contrast to patients with PAH who have positive vasoreactivity testing and do not have HIV, patients with HIV-PAH are not typically treated with CCBs. However, although anecdotal cases of CCB responses exist, their administration is extremely rare and the approach should be cautious. This approach is based upon the observation that vasoreactivity only occurs in a small proportion of HIV-PAH patients (approximately 1.6 percent) and long-term response to CCBs has been reported in only a small number of those patients. In addition, intolerable side effects including hypotension and interaction with antiretroviral therapy, especially protease inhibitors, can develop in this population [10,44,45]. Since CCBs are not typically prescribed, patients with HIV-PAH do not need to undergo routine vasoreactivity testing. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)
Combination therapy — Combining agents from two classes is commonly used in patients with group 1 PAH but has not been specifically studied in patients with HIV-PAH. Nonetheless, the principles of agent selection are similar such that most patients with HIV-PAH and WHO functional class II, III, and IV should receive combination therapy. However, the major difference is that agents are typically added sequentially due to the potential for drug interaction. Further details regarding PAH-specific therapy are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Endothelin receptor antagonists — There are limited data supporting use of endothelin receptor antagonists (ERAs) in patients with HIV-PAH.
●Bosentan — Several trials have shown benefits with bosentan [42,46,47]:
•In one uncontrolled clinical trial of 16 patients with HIV-PAH, 16 weeks of oral bosentan resulted in improved exercise capacity, functional class, mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), right ventricle size and function, and quality of life [46].
•A subsequent retrospective study evaluated the effects of bosentan in patients with HIV-PAH over a longer duration [47]. The study enrolled 59 patients (12 from the above study); 56 patients were evaluated after four months of therapy and 38 were evaluated over a mean of 29 months. The improvements in exercise capacity, PVR, and functional class persisted for at least 2.5 years. Survival at 1, 2, and 3 years was 93, 86, and 66 percent, respectively.
●Ambrisentan and macitentan – These selective ERAs have been insufficiently studied in patients with HIV-PAH with only small numbers of HIV patients included in larger trials (ARIES [Ambrisentan] [48] and SERAPHIN [macitentan] [49]).
If bosentan is used, dose modifications are required in patients who are receiving an ART regimen that includes a pharmacologic boosting agent (ritonavir or cobicistat; refer to the drug interactions program within UpToDate for specific recommendations). In contrast, ambrisentan does not need any dose adjustments. There are no data on how to manage macitentan and an alternative ERA should generally be used, or the ART regimen modified, if possible. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)
Further data supporting efficacy of these agents in patients with non-HIV-related PAH (mostly IPAH) are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Nitric oxide-cyclic guanosine monophosphate enhancers — Agents in this class include phosphodiesterase type 5 (PDE5) inhibitors and guanylate cyclase stimulants. Limited data in patients with HIV-PAH demonstrate improvement in pulmonary hemodynamics, functional class, and exercise capacity.
Phosphodiesterase inhibitors
●Sildenafil – Although there have been case reports suggesting that sildenafil can improve symptoms and hemodynamics in patients with HIV-PAH, the preponderance of evidence suggests that it should be avoided in those receiving an ART regimen that includes a pharmacologic boosting agent, such as ritonavir or cobicistat. Boosting agents are used in combination with protease inhibitors or the integrase strand transfer inhibitor elvitegravir. This approach is due to the fact that sildenafil significantly decreases protease inhibitor levels and that the boosting agents significantly increase sildenafil levels [47,50-54].
●Tadalafil and Vardenafil – Other PDE5 inhibitors (tadalafil and vardenafil) have not been adequately studied in patients with HIV-PAH, although one trial of 18 patients with HIV-PAH (on different classes on PAH-directed therapy) included three patients taking tadalafil [36]; no specific adverse effect were reported. In our experience, when tadalafil (usually in combination with ambrisentan) is indicated and the patient is on a regimen that contains a pharmacologic boosting agent (eg, pharmacologically boosted darunavir, elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide), most experts will consider the feasibility of switching antiretroviral therapy to a regimen that does not include a boosting agent. Alternatively, the dose of tadalafil can be adjusted (refer to the drug interactions program within UpToDate for specific information).
Further data supporting their efficacy in patients with non-HIV-related PAH (mostly IPAH) are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Guanylate cyclase stimulant — Riociguat is a guanylate cyclase stimulant of proven benefit in patients with chronic thromboembolic pulmonary hypertension. It has not been studied in patients with HIV-PAH but trials are underway. Given the cytochrome CYP inhibition of protease inhibitors, riociguat levels would increase with concomitant use, but the clinical significance is unknown, although limited data suggest reasonable tolerance of riociguat in this population [55]. Thus, we feel that riociguat should be avoided until more information is available. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy", section on 'Medication selection' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Prostacyclin pathway agonists — Limited data in patients with HIV-PAH demonstrate improvement in pulmonary hemodynamics, functional class, and exercise capacity with prostacyclin pathway agonists.
●Epoprostenol – Several trials have shown efficacy of epoprostenol in patients with HIV-PAH [38,56-61]:
•In an uncontrolled clinical trial of six patients with HIV-PAH, intravenous epoprostenol resulted in a reduction in the mPAP by 8.5 mmHg and PVR by 216 dynes/sec per cm-5), an increase in the cardiac output by 2 L/min and CI by 1.1 L/min per m2, and improvement in functional class (table 2) [58]. Repeat catheterization of five patients after one year demonstrated further improvement in pulmonary hemodynamics (figure 3) which continued for up to four years (two patients). The frequency of adverse effects and complications were similar compared with that reported in patients with IPAH. Although five of the six patients died, none of the deaths were due to PAH.
•Inhaled epoprostenol was evaluated in two patients with HIV-PAH [57]. Seven months of inhaled epoprostenol therapy was associated with improved exercise capacity, functional class, mPAP, and PVR.
●Treprostinil – In an uncontrolled clinical trial of three patients with HIV-PAH, subcutaneous treprostinil resulted in improved exercise capacity and functional class at one year [61]. In addition, the systolic pulmonary artery pressure (estimated by echocardiography) improved in two of the patients. No serious adverse events were observed.
●Iloprost – In an uncontrolled trial of eight patients with HIV-PAH, inhaled iloprost resulted in acute improvement of the PVR and CI [60]. Hemodynamic improvement persisted and exercise capacity also improved in the four patients who continued with long-term iloprost.
●Selexipag – This oral agent has not been specifically tested in HIV-PAH.
Further data supporting efficacy of these agents in patients with non-HIV-related PAH (mostly IPAH) are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Refractory disease
Right to left shunts and lung transplantation — While shunts may be appropriate (eg, atrial septostomy) in those with severe symptomatic HIV-PAH that is refractory to combination therapy, HIV is typically considered by most transplant centers as a relative contraindication to lung transplantation. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Right-to-left shunt'.)
PROGNOSIS — Mortality was originally high among patients with HIV-PAH but is improving in the era of PAH-directed therapy and antiretroviral therapy (ART). Although not directly compared, the outcome approaches that of patients with idiopathic PAH (table 1). Compared with patients with HIV who do not have PAH, HIV-PAH is an independent predictor of death. (See "The natural history and clinical features of HIV infection in adults and adolescents" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
Data from the early 2000s suggested high mortality ranging from roughly 27 to 66 percent [2,38,41,62]. In contrast, data after 2010 suggest improved mortality rates. In a series of 77 patients with HIV-PAH, the one- and three-year survival rates were 88 and 72 percent, respectively [63]. All of the patients in the series received ART and 50 patients (65 percent) received PAH-directed therapy.
Although data are limited, it is well established that PAH in the setting of HIV is an independent risk factor for death [62]. Data also support that HIV-PAH prognosis is worse than that of idiopathic PAH [6,64].
A low CD4 count may be associated with increased mortality due to HIV-PAH [38,63]. Otherwise, it is assumed that poor prognostic indicators are similar to those in non-HIV-related PAH. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)
SUMMARY AND RECOMMENDATIONS
●Definition – Human immunodeficiency virus-related pulmonary arterial hypertension (HIV-PAH) refers to pulmonary arterial hypertension (PAH) that develops in a patient who has HIV infection. (See 'Introduction' above.)
●Epidemiology – Although PAH is a rare complication of HIV infection, it is more prevalent than PAH is among HIV-uninfected individuals. Furthermore, studies likely underestimate its true prevalence. (See 'Prevalence' above.)
●Pathogenesis – Pathogenetic mechanisms are likely shared between HIV- and idiopathic PAH. Additional HIV-specific factors also likely play an important role, although the relative contributions host and viral factors are difficult to discern since many patients with HIV infection have coexisting conditions that are independently associated with PAH (eg, intravenous drug use or chronic liver disease). (See 'Pathogenesis' above.)
●Diagnostic evaluation – Most patients with HIV-PAH have known HIV infection and present with new symptoms related to PAH (eg, progressive dyspnea). Diagnosis of HIV-PAH requires confirmation of PAH by right heart catheterization, the exclusion of group 2, 3, 4, and 5 pulmonary hypertension (PH) (table 1), and confirmation of HIV infection by serologic testing. (See 'Diagnostic evaluation' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 1: Pulmonary arterial hypertension'.)
●Treatment – In patients with HIV-related PAH, treatment with general measures and PAH-specific therapies (endothelin receptor antagonists, nitric oxide-cyclic guanosine monophosphate enhancers [phosphodiesterase inhibitors and guanylate cyclase stimulants], and prostacyclin pathway agonists (table 3)) are nearly identical to that for other types of PAH. However, data to support select agents is limited in patients with HIV-PAH. In addition, when combination therapy is used, we prefer add in (sequential) therapy to monitor adequately for drug interactions. (See 'Treatment' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Aspects of treatment that are unique to patients with HIV-PAH include:
•There is no evidence that antiretroviral therapy (ART) is beneficial for the treatment of HIV-PAH. However, most patients with HIV infection are treated with ART irrespective of whether or not PAH is present. (See 'Antiretroviral therapy' above and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
•We do not routinely anticoagulate patients with HIV-PAH since there are no direct data in HIV infected patients that report benefit and indirect data from non-HIV-PAH populations are conflicting. (See 'Conventional and supportive therapies' above.)
•Most patients with HIV-PAH do not need to undergo vasoreactivity testing since calcium channel blocker (CCB) therapy is rarely of benefit and may be associated with an increased risk of adverse effects when compared with uninfected patients with PAH. (See 'Avoidance of calcium channel blockers' above.)
•Bosentan (endothelin receptor antagonist) and sildenafil (phosphodiesterase inhibitor) should be avoided in patients taking pharmacologically boosted regimens (eg, ritonavir and cobicistat-containing regimens) due to the likelihood that drug-drug interactions (DDIs) alter the efficacy of both ART and PAH regimens. Alternatively, switching antiretroviral therapy to a regimen that does not include a boosting agent, is appropriate, if feasible. Although data are less robust for similar DDIs, we suggest the same approach for patients who are potential candidates for macitentan, tadalafil and riociguat. Alternatively, dose adjustments can be made with close follow-up of CD4 counts and viral levels. Refer to the drug interactions program within UpToDate for specific recommendations. (See 'Agent selection' above and 'Endothelin receptor antagonists' above.)
•For patients with severe end-stage HIV-PAH, HIV infection is typically considered a relative contraindication to lung transplantation. (See 'Right to left shunts and lung transplantation' above.)
●Prognosis – The outcome of HIV-PAH has improved and is now approaching that of patients with idiopathic PAH. However, among patients with HIV, HIV-PAH is an independent predictor of mortality. (See 'Prognosis' above.)
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