Impact of Human Immunodeficiency Virus Protease Inhibitors, Rosuvastatin Therapy and Human Endothelial Growth Factor Receptor 2 Inhibitors on Healthcare Treatments.
The revolutionary advances in medical research in the past two decades have had tremendously positive impacts on disease treatment and prevention. This has given patients longer life expectancy along with improved quality of life and resulted in decreased mortality rates caused by disease. HIV protease inhibitors (HIV-PI), Rosuvastatin therapy and HER-2 therapy treatment (HER-2); are three of the most significant advances in the healthcare field.
Human Immunodeficiency Virus Protease inhibitor
In 2000, Centers of Disease Control and Prevention recorded, that HIV/AIDS related deaths decreased significantly from 61.8% to 22.6% due to HIV protease inhibitors in 1996.
Number and percentage of HIV/AIDS cases and mortality rates in the US from 1993 to 2000 Adapted From World Health Organization/UNAIDS. AIDS epidemic update: December 2000.
Table 1.Shows that mortality rates decreased significantly after the use of HIV-PI in 1996.
HIV-PI inhibits the maturation of HIV viral particles by blocking the active site of the protease enzyme, before cleaving of gag-pol polyprotein occurs and produces mature active proteins. (Chu; et al, 2015) (See figure 1).Okoye and Picker (2013) confirmed that HIV specifically infected and killed CD4+ cells, hence significantly reducing number of t helper cells. In figure 2, Rosenberg; et al(1997) examined the relation between HIV viral load and CD4+ t cell by linear regression.
Figure 1. Shows HIV protease inhibitor binding to HIV protease enzyme (Chu; et al 2015).
Figure 2. Shows that P-24 specific CD4 lymphocyte are inversely correlated with HIV viral load (Rosenberg; et al 1997).
Wood (2011), observed that people with HIV had significantly lower CD4+ t cell counts than average. To confirm this Cameron et al (1998) carried out a double blind, randomised, placebo controlled, multicentre trial to test effect of ritonavir (HIV protease inhibitor drug) on CD4+ and CD8 cell count, and death rate(see figure 3). 1090 randomised patients, 543 Ritonavir and 547 placebo, two of each group received no medication. Only 21.9% Ritonavir group experienced AIDS-defining event or death compared to 37.5% in placebo group(see figure 4).This finding was consistent with the hypothesis that HIV-PI prevents decrease in CD4+ t cell count, as shown in figure 5, therefore increasing survival rates in HIV patients. A meta-analysis of 14 different randomised control trials demonstrated sufficient evidence that HIV protease inhibitors were efficacious in viral load reduction and increased CD4+ count in HIV patients. (Berhan & Berhan 2013) These studies demonstrated that HIV protease inhibitors have made a vital contribution to healthcare science by reducing HIV mortality rates.
Figure 3. Shows that CD4+ and CD8 cell count increased significantly in Ritonavir group compared to placebo group patients(Cameron; et al,1998).
Figure 4. The relative risk of death ratio was lower in Ritonavir group than placebo (Berhan & Berhan, 2013).
Human endothelial growth factor receptor 2 Inhibitor (HER-2)
In the 1980’s it was identified that a mutated gene, HER-2, stimulated excessive cell growth in breast cancer which lead to the discovery of Trastuzumab, a HER-2 inhibitor therapy in 1998 (Slamon et al, 2001). Since then the outcome of survival rates and objective response rates in patients with HER-2 positive breast cancer have improved significantly(Phillips et; al, 2008). Journal of National Cancer Institute reported 50% reduction of relapse in HER-2 positive breast cancer patients and 30% decrease in mortality rates(Kohler et al 2015). This treatment is a highly significant advance due to 25-30% of human breast cancers demonstrating an inceased expression of the HER-2 protein which causes recurring relapse of the tumour(Yarden 2001).
The growth of HER-2 over-expressing cells is blocked by Trastuzumab, a monoclonal antibody against HER2, this binds specifically to the extracellular domain of the HER-2 receptor which induces growth inhibition. It also inhibits cleavage of biomarkers of HER-2 and intracellular signalling, reduces DNA repair and activates antibody-dependant cellular cytotoxicity hence reducing/inhibiting HER-2 growth.
Smith; et al (2007), tested the outcome of survival rates in trastuzumab through a randomised control trial which observed the drugs effect after chemotherapy, over a 1 year period in patients with HER-2 positive breast cancer. 1703 patients had been randomised with trastuzumab and 1698 patients in the observation group were observed for a median of 23.5 months. Results showed trastuzumab lowered risk of death in breast cancer patients(See figure 6). The secondary endpoint of the randomised control trial by Slamon et al(2001) demonstrated a significantly higher objective response rate and increased percentage of complete responses (no detection of malignancy using radiographic imaging) in chemotherapy plus trastuzumab compared to chemotherapy alone, as shown in table 2.
Figure 5.The hazard ratio (HR) for the risk of death between trastuzumab and control group was 0·66 (95% CI 0·47–0·91; p=0·0115) (Smith; et al, 2007).
Table. 2 Effect of Chemotherapy Plus Trastuzumab Compared to Chemotherapy Alone in HER-2 Positive Breast Cancer Patients Adapted From Slamon et al; (2001).
Rosuvastatin Therapy
World Health Organization reported in 2014 that the leading cause of death worldwide is Coronary Heart Disease, because of this statins have shown to be a crucial part of Healthcare treatment. Rauchhaus et; al (2003) demonstrated that oral administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors showed decrease in plasma total cholesterol levels specifically Rosuvastatin, recently developed in 2003. This occurs since HMG-CoA reductase is reversibly inhibited by rosuvastatin then converted to mevalonate, this limits the biosynthesis of cholesterol which increases production of HMG-CoA reductase and LDL receptors resulting in cholesterol being expelled rapidly from the body(Lennenars & Fager 1997).
Figure 6. Shows that statins decrease the synthesis of mevalonate and cholesterol. (Schmitz & Torzewski, 2002).
A 6-week parallel-group, open-label, randomised, multicentre trial was conducted by Jones et; al (2003) to compare the effects of rosuvastatin versus atorvastatin, simvastatin and provastin at 10 mg, 20 mg and 40 mg and their ability to reduce low-density lipoprotein (LDL) cholesterol to reach National Centers of Environmental Prediction’s (NCEP) Adult Treatment Panel goals(See figure 1). Rosuvastatin was more efficacious than other statins since 79% of patients reached the NCEP goal at 10 mg this was close to the percentage of patients who reached this goal with the highest dose of Atorvastatin(81%) and Simvastatin(77%). Shows Rosuvastatin patients reached NCEP goal with lower dose compared to Artovastatin, Simvastatin and Pravastatin. (Jones et al, 2003)
Rosuvastatin showed significant improvements in lowering LDL levels, its efficacy and safety was investigated by Tavazzi et; al (2008) in patients with chronic heart failure through a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres. Due to similar probability of death (both cardiovascular and non-cardiovascular related) in both groups in figure 2, it was concluded that Rosuvastatin was safe for use in chronic heart failure.
Figure 8. Shows there was no significant difference in death rates between placebo and Rosuvastatin patients (Tavazzi et al, 2008).
Stem Cell Therapy for Cardiovascular Disease
In 2007, American heart Association estimated that in 1 year up to 1 million people in the US will suffer from heart attacks.Heart Disease is the number one cause of death worldwide and studies demonstrated that cardiomyocytes decreased with age resulting in weaker heart function(Murray et al 2012),(Olivetti 1991). The discovery of multipotent cardiac stem cells may have the capacity to renew myocardium to repair the heart after myocardial infarction(MI)( Anversa & Nadal-Ginard 2002).
Cardiac-derived cells(CDCs) are expanded in vitro and transplanted through intracoronary catheter delivery. Bone marrow mononuclear cells(BMNCs) are removed from the bone marrow are transplanted through intramyocardial injection, mesenchymal stem cells also derived from the bone marrow require in vitro before transplantation. After In vitro expansion and cardiac differentiation cardiomyocytes are obtained from human pluripotent stem cells (hPSCs). Paracrine signalling occurs inducing transplated cells to secrete paracrine factor to infarcted myocardium.
Xu et al (2004) examined whether mesenchymal stem cells from adult human bone marrow differentiate into cardiomyocyte, in vitro. These findings confirmed that cardiomycocytes can be generated from stem cells. Orlic et al (2001), confirmed that bone marrow cells regenerated infarcted myocardium this is shown in figure
Figure 9. Cell transplantation to repair damaged cardiomyocytes through paracrine mediated effects.(Orlic et al 2001).
Figure 10. Arrowheads show cells from bone marrow regenerating myocardium (Gerbin & Murry 2015).
Overall, it is clear that HIV protease inhibitors, HER-2 inhibitors and Statin therapy have further developed healthcare science by extending longevity. HIV inhibitors have greatly reduced mortality rates whereas HER-2 inhibitors advanced the understanding of HER-2 signalling pathways. In 2016, National Institue for Health and Care Excellence updated guidelines for statins, 40% of adults in the UK are now prescribed statins, the high demand for statins shows its importance. Stem cell therapy for cardiac disease has shown great potential to regenerate damaged heart tissue, this technique shows promising results and have the ability to advance into clinical use within the next ten years which could greatly reduce mortality rates in Cardiovascular Disease(Wu et al 2015).
Bone marrow cells and myocardial regeneration.
[Online image] [Accessed on 4/11/16]