The Relationship between HIV Infection and Cardiovascular Diseases

The Relationship between HIV Infection and Cardiovascular Diseases

Abstract

There have been more than 30 million people across the world, that have been diagnosed as living with HIV today.  According to data from the NCBI, 2 million new infections are reported every year. Additionally, HIV infections have often been directly linked to numerous amounts of cardiovascular diseases when compared to infections found in uninfected people.  For this reason, cardiovascular diseases continue to be recognized as some of the major reasons for mortality among patients suffering from HIV.  Studies have found that patients that are treated under antiretroviral therapy have higher risks of suffering from cardiovascular diseases. Studies have yet to prove whether HIV itself may be associated with the increasing number of patients suffering from cardiovascular diseases.

Introduction

The Human Immunodeficiency Virus is spread when the virus is directly inoculated into the blood or when there is direct contact with large amounts of mucosal fluids. Once the virus is introduced into the body, it attacks the CD4 cells and attaches itself onto these cells and other receptors such as the CCR5 and the CXR4 (UNAIDS). The virus then begins to infect the cells by transcribing the viral RNA onto the DNA. A series of activities then occur and eventually, the virus integrates into the host genome (Rivera, Grevious, Rodriguez et al., 2017). The virus may remain dormant or may begin to cause viral translation, which then leads to the various symptoms associated with the disease. When the virus begins to replicate, it leads to the destruction of the CD4 cells. This in turn affects the immune system of the infected patient and its dysfunction. When the CD4 cells decrease to a level less than 14%, the patient is said to be suffering from AIDS which is the acquired immunodeficiency syndrome. Once the patient is diagnosed as suffering from AIDS, it means that numerous amounts of opportunistic infections and malignances begin to develop on their body (MMWR, 1992).

Different patients experience different forms of infection depending on various underlying factors that can be allied with the different strains of HIV. For most people that suffer from the infection, they can continue to live with the disease for a long time, even as the virus continues to replicate and destroy the CD4 cells. The differences between this patients is whether they go through this time being clinically latent or suffering chronically (Hui, 2003). For some, theyare even able to control the levels of replication of the virus over time without the use of medication. However, without the necessary medication, most people develop HIV-related complications within 2 or 3 years after contact. It is estimated that the infections continue to increase through the years, and those living with the virus above the age of 50 years has also continued to rise (CDC, 2017).

Antiretroviral Therapy

The FDA in America has approved several Anteretroviral agents for use, amounting to sis in total. These are;

  1. Nucleoside reverse transcriptase inhibitors (NRTIs). These work by blocking the transcription process between the viral RNA and the host DNA.
  2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs). These work by blocking the operation of the transcriptase enzyme.
  3. Fusion inhibitors. These work at the initial point of contact. they are aimed at inhibiting the infusion of the virus with the host
  4. Entry inhibitors. These work at the entry point and block the entrance of the virus into the body of the host. They do this by blocking the CCR5 which is the surface co-receptor.
  5. Integrase inhibitors. These are aimed at preventing the integration of the DNA of the virus into the genome of the host.

Sometimes, patients are required to have a combination of the various ARV agents. The aim of the treatments is to ensure that the patient reaches an undetectable HIV viral load.

Although majority of the patients have grown tolerant of the ARV drugs, they still continue to face several side effects. Most of the side effects are mild, including nausea, diarrhea and vomiting  (Paula, Falcão and Pacheco, 2013). However, some of the drugs such as the Efavirenz affect the central nervous system and can cause symptoms such as vivid hallucinations and other related symptoms. Some of these drugs, especially the PIs are responsible for several severe side effects such as Lipodystrophy syndrome, which is manifested in the form of fart wasting in the peripheral area of the human body as well as accumulation of visceral fat (Feingold, Krauss, Pang, Doerrler, Jensen and Grunfeld, 1993).

Clearly, from the various studies that have been conducted in the past, the most difficult side effects in terms of management have been those that deal with the metabolism of the patients. The different drugs offered for treatment and management of HIV lead to complications with the metabolism. For this reason, patients often suffer from abdominal obesity, hypertension, and other related illnesses associated with the ARV therapies, especially the PI therapy. According to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP), the metabolic syndromes exhibited by the patients can become risky to their health of they exhibit any of the following characteristics:

  1. If; for women, the waist circumference is greater than 88 cm and if it is greater than 102 cm for men
  2. If the blood pressure is higher than 130/85 mm Hg or if they are receiving drug treatment for hypertension.
  3. If the triglycerides levels are higher than 150 mg/ dL
  4. If the fasting glucose is higher than 100 mg/dL
  5. If; the  HDL cholesterol is less than 50 mg/dL in women or less than 40 mg/dL in men (Moyle, 2007).

Further studies indicated that a majority of the HIV patients started suffering from metabolism related complications after they started receiving their ARV treatments. After a study by INITIO, it was discovered that, patients that developed metabolism complications during therapy had a higher chance of developing cardiovascular complications that could eventually lead to their death during treatment. Other studies found that incidences of metabolic complications increased by 14% among adults suffering from HIV (Lifson,  et al, 2013). As discussed easier, many of these incidences are often more than likely to end in cardiovascular complications. These incidences in HIV infected adults have been linked to high levels of leptin and C-receptive proteins coupled with the decrease in the levels of adiponectin (Samaras, Wand, Law, Emery, Cooper and Carr, 2007). Additionally, according to various amounts of research, an increase in the levels of exposure to NRTIs and PIs among patients has been associated to an increase in insulin resistance. For this reason, patients taking PIs and NRTIs were seen to have higher levels of Insulin resistance as compared to patients that atazanavir. This is because these drugs contained stavudine that was seen to significantly reduce the levels of insulin resistance among patients (Fleischma, Johnsen, Systrom., et al,.. 2007).

Traditional Cardiovascular Risk Factors Are Increased In HIV Patients

Additionally, even without considering how the intake of the various ARV drugs affect the metabolism rates among HIV patients, various studies have found that the traditional  cardiovascular risk factors are increased among HIV patients (Bernal, Enrique et al., 2008). For instance, people without HIV are less likely to suffer from cardiovascular infections as a result of smoking when compared to HIV patients (Ingle, et al, 2014). Similarly, because of an increase in stress and other life altering factors, HIV patients are more likely to form the habit of smoking than the general population (Marks, Gardner, Craw and Crepaz, 2010). This, coupled with the fact that HIV infections lead to a change in lipid metabolism increases the chances of HIV patients from suffering from cardiovascular infections. Levels of cholestral begin to heighten even further among HIV patients once they are subjected to ARV treatment therapies. Studies have found that patients’ levels of cholesterol began to rise once they began to take their ARV drugs. These levels were significantly higher than when they did not take the drugs even if they had already been infected (Lo and Grinspoon, 2008). Data analyzed from various SMART projects has also led to the conclusion that HIV infection and its treatment with ARV drugs lads to an increase in the levels of D-dimer and cytokine II-6. These two factors are known to be very proinflamatory and are thus directly associated with an increase in cardiovascular infections among HIV patients (Dau and Holodniy, 2008).

Further studies have indicated that CVDs seem to develop earlier in life for people infected with HIV. Data from the Swiss cohort studies showed that after accounting for various risk factors in both HIV infected and HIV_uninfected persons, the persons with HIV showed a twofold increase in myocardial infarction. In even more recent studies, patients with HIV showed a higher risk of suffering from coronary related diseases when CD4 cell counts were less than 200 cells/µl.  Inflammation is one of the main contributors in the formation of artherosclerosis and other CDV related complications. HIV, being viral in nature, is known to increase inflammation within those that are infected. Elevetated levels of s-CRP and IL-6 as well as endothelial dysfunction are all HIV related issues that point at inflammation. HIV enbles inflammation through various methods including the direct work of the HIV RNA as well as tat and gp 120, both of which are proteins associated with HIV. Of course, these inflammation markers go hand in hand with the viral load and thus the CD4 count.

Sililarly, HIVs effect on blood lipids.  Data showing the occurrence of dyslipedemia on HIV patients before their cART treatments have been recorded and proven many times. The data has shown that within these patients, there is decreased low-density lipoprotein cholesterol, high density lipoprotein cholesterol and total cholesterol. These decreases go hand in hand with elevated levels of triglycerides. Whether this increases in the levels of triglycerides are the cause of an increase in the cases of CVD even in the uninfected population has been greatly disagreed upon, however, the elevation of these levels in HIV patients is indicative of this fact.

Regardless of the controversies on whether patients on stable cART are prone to CDV more than uninfected persons, studies have proven that these patients often show early signs of subclinical atherosclerosis. Although patients on cART have similar myocardial perfusion reserves to those in the normal population, a longitudinal study of patients that have not been treated has proven that their myocardial perfusion reserves decrease upon the initiation cART.  Myocardial perfusion levels have been linked with endothelial function or dysfunction. The fact that studies indicate that they are affected when cART is introduced proves that cART may be linked to CDV in HIV patients.

Pathophysiology of HIV-Associated Cardiovascular Disease

Through out this essay, drugs offered to HIV patients as ARV therapy have been linked to various issues regarding the metabolism such as; chronic inflammation and hypercoagulability (Wang, et al. 2007). Another issue that has been addressed is the fact that some of these drugs, especially the PIs affect insulin sensitivity among patients. It has also been mentioned that these issue are the most likely link between HIV infections and cardiovascular diseases (Boccara, Franck, Lang et al., 2013). HIV patients, even without the influence of ARV treatment therapies, have higher chances of getting cardiovascular related diseases  (Brooks, Kaplan, Holmes, Benson, Pau and Masur, 2009). This is because HIV influences endothelial functions through activated monocytes and cytokine secreted as a result of the activation. It is easy to calculate the differences between inflammation in healthy patients and those suffering from HIV. This can be done simply by studying the higher levels of more sensitive C-reactive proteins among HIV patients (Freiberg. et al., 2007). This is an indicator of the fact that HIV patients are more likely to suffer from Cardiovascular diseases (Hsue, Lo, Franklin, Bolger, et al., 2004). Additionally, other factors that affect inflammation may be considered to study patients suffering from HIV. These include interleukins whose levels increase among patients suffering from HIV. In addition to these, endothelial markers increase in their amounts as well. These are manifested in the form of soluble vascular cell adhesion among others (Wolf, Tsakiris, Weber, Erb and Battegay, 2004). These increases act as the best indicators of the likelihood of the occurrences of cardiovascular cases among HIV patients (Carrieri, Protopopescu, Roux et al., 2010).

Cardiovascular Diseases and  HIV Infection

Researchers have for a long time known the links between HIV infection and endothelial functions. One such example is the fact that nitric oxide acts as a mediator between endothelial dysfunction and the HIV infection (Marianna et al., 2006). When a patient is infected NO is produced excessively due to the reduction in the expression of endothelial NO synthase known as (eNOS) and, as a result, the increase in appearance of an incredible NO synthase (iNOS) (Leuven, Franssen, Kastelein, Levi, Stroes and Tak, 2008). When this occurs, the excess NO produced reacts with oxygen radicals leading to the production of peroxynitrate. Peroxynytrate is destructive to the vascular endothelium. The destruction of this endothelium then leads to the reduction in the flow of the mediated dilation (Torre, 2006).

In the beginning of the use of ART drugs, mortality was high especially for the first year. However, these mortality rates decreased thereafter. Afterwards, many of the mortality cases occurred for reasons that were not directly linked to HIV infections (Salyer, Jeanne, Debra, Settle et al., 2006). However, it has been found that some of these mortality cases may in fact be connected after all. for HIV patients, there have been numerous cases of premature coronary artery pathology. Studies conducted on those that have already passed on have shown that there is some connection between HIV and vascular endothelial pathology (Passalaris, Sepkowitz and Glesby, 2000).  Reports have indicated that since the introduction of PIs in the year 1996, there has been an increase in the number of clinically evident cardiovascular diseases among HIV infected persons (Zanni, Schouten, Grinspoon et al.,  2014). According to a recent study in the United States, HIV infected patients have higher risks of MI when compared to those that are not infected ( Triant, Lee, Hadigan and Grinspoon, 2007). Another Danish study also found that patients that underwent highly active antiretroviral therapy (HAART) were at a higher chance of being admitted into hospitals after suffering from ischemic heart diseases when they were compared to patients that were not undergoing the same kinds of treatments (Obel, Thomsen and Kronborg, et al., 2007). Similarly, studies by Kaiser Permanenete found that there were more cases of cardiovascular diseases in HIV patients that were not under any ARV treatment programs when they were compared to uninfected cases (Klein, Hurley, Quesenberry and Sidney, 2002). A combination of this studies leads to two conclusions

  1. The first is that HIV patients are more susceptible to being affected by cardiovascular diseases than those members of the society that are not infected
  2. The second is that HAART and ARV treatments increase the cases of cardiovascular diseases among HIV patients.

Conclusion

The studies regarding HIV patients undergoing HAART and ARV treatments indicated that it was important for these patients to have high CD4 counts if proper prognosis was to be made. Thus, for future references, patients must also be offered care for diseases that are not connected to their HIV infections. Additionally, due to the fact that the infected population, especially in more developed countries, continues to age, it is important that the relevant professionals are prepared to be able to deal with more cases of cardiovascular diseases. For this reasons, professionals will have to include HIV care with Cardiovascular care. Research must also be done to further ensure that ARV programs do not continue to endanger the lives of HIV patients by creating environments that encourage cardiovascular related complications. HIV studies must include the study of other diseases that appear to affect patients and that have been the leading causes of mortality among those who are infected.

 

 

 

 

References

  1. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992 Dec 18;41(RR-17):1–19.[PubMed]
  2. HIV/AIDS Statistics and Surveillance. Centers for Disease Control
  3. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74(5):1045–52. [PubMed]
  4. Moyle G. Metabolic issues associated with protease inhibitors. J Acquir Immune Defic Syndr. 2007;45(Suppl 1):S19–26. [PubMed]
  5. Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia. Diabetes Care. 2007;30(1):113–9. [PubMed]
  6. Fleischman A, Johnsen S, Systrom DM, et al. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab. 2007;292(6):E1666–73.[PMC free article] [PubMed]
  7. Hsue PY, Lo JC, Franklin A, Bolger AF, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109(13):1603–8. [PubMed]
  8. Wolf K, Tsakiris DA, Weber R, Erb P, Battegay M. Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. J Infect Dis. 2002;185(4):456–62. [PubMed]
  9. van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford) 2008;47(1):3–7. [PubMed]
  10. Torre D. Nitric oxide and endothelial dysfunction in HIV type 1 infection. Clin Infect Dis. 2006;43(8):1086–7. [PubMed]
  11. Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery disease and human immunodeficiency virus infection. Clin Infect Dis. 2000;31(3):787–97. [PubMed]
  12. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506–12. [PMC free article] [PubMed]
  13. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis. 2007;44(12):1625–31. [PubMed]
  14. Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr. 2002;30(5):471–7. [PubMed]
  15. UNAIDS Joint United Nation Programme on HIV/AIDS. [PubMed]
  16. Hui DY. Effects of HIV protease inhibitor therapy on lipid metabolism. Prog Lipid Res. 2003;42(2):81–92. [PubMed]
  17. Dau B, Holodniy M. The relationship between HIV infection and cardiovascular disease. Curr Cardiol Rev. 2008;4:203–18. [PMC free article] [PubMed]
  18. Paula AA, Falcão MC, Pacheco AG. Metabolic syndrome in HIV-infected individuals: Underlying mechanisms and epidemiological aspects. AIDS Res Ther. 2013;10:32. [PMC free article] [PubMed]
  19. Brooks JT, Kaplan JE, Holmes KK, Benson C, Pau A, Masur H. HIV-associated opportunistic infections – Going, going, but not gone: The continued need for prevention and treatment         Clin Infect Dis. 2009;48:609–11. [PubMed]
  20. Marks G, Gardner LI, Craw J, Crepaz N. Entry and retention in medical care among HIV-diagnosed persons: A meta-analysis. AIDS. 2010;24:2665–78. [PubMed]
  21. Rivera M, Grevious S, Rodriguez A, et al. Update on Cardiovascular Disease and HIV. Heart Circ 2017; 1:006.
  22. Marianna K Baum, Carlin Rafie, Shenghan Lai, Lihua Xue, Sabrina Sales, J. B. Page, Ronald Berkman, Linden Karas, and Adriana Campa. 2006. “Coronary Heart Disease (CHD) Risk Factors and Metabolic Syndrome in HIV-Positive Drug Users in Miami”. American Journal of Infectious Diseases. 2 (3): 173-179.
  23. Bernal, Enrique, Mar Masiá, Sergio Padilla, Ildefonso Hernández, and Félix Gutiérrez. 2008. “Low Prevalence of Peripheral Arterial Disease in HIV-Infected Patients With Multiple Cardiovascular Risk Factors”. JAIDS Journal of Acquired Immune Deficiency Syndromes. 47 (1): 126-127.
  24. Boccara, Franck, Sylvie Lang, Catherine Meuleman, Stephane Ederhy, Murielle Mary-Krause, Dominique Costagliola, Jacqueline Capeau, and Ariel Cohen. 2013. “HIV and Coronary Heart Disease: Time for a Better Understanding”. Journal of the American College of Cardiology. 61 (5): 511-523.
  25. Carrieri M.P., Protopopescu C., Roux P., Spire B., et al. 2012. “Impact of immunodepression and moderate alcohol consumption on coronary and other arterial disease events in an 11-year cohort of HIV-infected patients on antiretroviral therapy”. BMJ Open. 2 (6).
  26. Ford, E.S., J.H. Greenwald, A.G. Richterman, A. Rupert, L. Dutcher, Y. Badralmaa, V. Natarajan, C. Rehm, C. Hadigan, and I. Sereti. 2010. “Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection”. 24 (10): 1509-1518.
  27. Hsu, Denise C., and Irini Sereti. 2016. “Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection”. 76 (5): 533-549.
  28. Hakeem A, S Bhatti, and M Cilingiroglu. 2010. “The spectrum of atherosclerotic coronary artery disease in HIV patients”. Current Atherosclerosis Reports. 12 (2): 119-24.
  29. Hsue P.Y., Squires K., Bolger A.F., Capili B., Mensah G.A., Temesgen Z., Wanke C.A., and Wohl D.A. 2008. “Screening and assessment of coronary heart disease in HIV-infected patients”. 118 (2): e41-e47.
  30. Lo J, and S Grinspoon. 2008. “Cardiovascular disease in HIV-infected patients: does HIV infection in and of itself increase cardiovascular risk?” Current Opinion in HIV and AIDS. 3 (3): 207-13.
  31. Lytwyn, Matthew, Nazanin Fallah-Rad, Jonathan Walker, Sheena Bohonis, Farrukh Hussain, Ivan Barac, and Davinder S. Jassal. 2010. “The Utility of Dobutamine Stress Echocardiography for the Diagnosis of Coronary Artery Disease in the HIV Population”. 27 (10): 1228-1232.
  32. Miller, Louis H., and John T. Coppola. 2011. “Noninvasive Assessment of HIV-related Coronary Artery Disease”. Current HIV/AIDS Reports. 8 (2): 114-121.
  33. Moreira Guimarães, M. M., D. Bartolomeu Greco, Á. H. Ingles Garces, A. R. De Oliveira, R. Bastos Fóscolo, and L. J. De Campos Machado. 2010. “Coronary heart disease risk assessment in HIV-infected patients: a comparison of Framingham, PROCAM and SCORE risk assessment functions”. International Journal of Clinical Practice. 64 (6): 739-745.
  34. Neumann, T., K. A. Lülsdorf, P. Krings, N. Reinsch, and R. Erbel. 2011. “Koronare Herzerkrankung bei HIV-infizierten Personen”. HERZ -MUNICH-. 36 (1): 18-23.
  35. Salyer, Jeanne, Debra E. Lyon, Jane Settle, R.K. Elswick, and Dwight Rackley. 2006. “Coronary Heart Disease Risks and Lifestyle Behaviors in Persons With HIV Infection”. Journal of the Association of Nurses in AIDS Care. 17 (3): 3-17.
  36. Triant, V. A. 2012. “HIV Infection and Coronary Heart Disease: An Intersection of Epidemics”. Journal of Infectious Diseases. 205 (suppl 3): S355-S361.
  37. Schambelan M., Wilson P.W.F., Yarasheski K.E., Cade W.T., Davila-Roman V.G., D’Agostino R.B., Helmy T.A., et al. 2008. “Development of appropriate coronary heart disease risk prediction models in HIV-infected patients”. 118 (2): e48-e53.
  38. Wang, X. et al. Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. J. Pathol. 171, 304–314 (2007).
  39. Mayne, E. et al. Increased platelet and microparticle activation in HIV infection: upregulation of P‑selectin and tissue factor expression. Acquir. Immune Defic. Syndr. 59, 340–346 (2012)
  40. Kaplan, R. C. et al. Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment. Acquir. Immune Defic. Syndr. 60, 359–368 (2012).
  41. Freiberg, M. S. et al. The association between hepatitis C infection and prevalent cardiovascular disease among HIV-infected individuals. AIDS 21, 193–197 (2007).
  42. Greene, M., Justice, A. C., Lampiris, H. W. & Valcour, V. Management of human immunodeficiency virus infection in advanced age. JAMA 309, 1397–1405 (2013).
  43. Ingle, S. M. et al. Impact of risk factors for specific causes death in the first and subsequent years of ART among HIV-infected patients. Infect. Dis. 59, 287–297 (2014).
  44. Palella, F. J. Jr et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. Acquir. Immune Defic. Syndr. 43, 27–34 (2006).
  45. Thienemann, F., Sliwa, K. & Rockstroh, J. K. HIV and the heart: the impact of antiretroviral therapy: a global perspective. Heart J. 34, 3538–3546 (2013).
  46. Lifson, A. R. et al. Smoking-related health risks among persons with HIV in the Strategies for Management of Antiretroviral Therapy clinical trial. J. Public Health 100, 1896–1903 (2010).
  47. Lewden, C. et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: the “Mortalite 2000 and 2005” surveys (ANRS EN19 and Mortavic). Acquir. Immune Defic. Syndr. 48, 590–598 (2008).
  48. Friis-Moller, N. et al. Cardiovascular disease risk factors in HIV patients—association with antiretroviral therapy. Results from the DAD study. AIDS 17, 1179–1193 (2003).
  49. Prevalence of tobacco use among adults and adolescents [online], http://gamapserver.who.int/gho/interactive_charts/tobacco/use/atlas.html (2009).
  50. Zanni MV, J Schouten, SK Grinspoon, and P Reiss. 2014. “Risk of coronary heart disease in patients with HIV infection”. Nature Reviews. Cardiology. 11 (12): 728-41.

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s


%d bloggers like this: