Pharmacodynamics: Highly Active Antiretroviral Therapy

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Table of Contents

Abstract
Introduction
Methodology
Conclusion
References

Abstract

The current review has attempted to interrogate the pharmacological effects of HAART in the management of patients with HIV/AIDS and the nursing implications involved. It has been demonstrated that most HAART regimens characteristically consist of two NRTIs (to act as the nucleoside backbone) combined with an NNRTI or one to two PIs; however, it is of importance for nursing professionals to consider drug potency, tolerability, the potential for adherence and resistance when selecting the right combination of antiretroviral drugs for use by HIV-positive patients.

From the review, it is clear that the effects of HAART on HIV-infected patients include harmful side effects associated with exposure to therapy, drug resistance, and treatment failure. Nursing implications associated with the use of HAART regimens include ensuring strict patient compliance with therapy, gaining knowledge and understanding of the new antiretroviral therapies, nursing awareness to enhance effective pharmacovigilance practice, and ensuring effective counseling and education of patients.

Introduction

Since the first cases of the human immunodeficiency virus (HIV) and subsequent acquired immune deficiency syndrome (AIDS) were described in the 1980s by the U.S. centers for disease control and prevention, the disease continues to spread worldwide and remains a major health concern affecting excess of 40 million people at the global level (Martin, Salzwedel, & Allaway, 2008; Tan et al., 2011). However, the initiation of highly active antiretroviral therapy (HAART) in 1996 and subsequent use has led to a substantial decline in the morbidity and mortality of HIV infected patients (Hoogbruin, 2011; Turcotte & Raines, 2008), with available literature showing the therapy works by combining different modes of action to enhance the prognosis of patients living with HIV/AIDS (Martin et al., 2008). The current review attempts to interrogate the pharmacological effects of HAART in the management of patients with HIV/AIDS and the nursing implications involved.

Methodology

The terms ‘highly active antiretroviral therapy, ‘pharmacodynamic properties of HAART’, ‘effects of HAART’, and ‘HAART nursing implications’ have been used to conduct electronic searches from 2008 to March 2014 of the following databases: Academic Search Premier, PUBMED, CINAHL, and Health Source Nursing/Academic Edition. It is important to note that the search strategy has been an iterative process that has included evaluating reference lists of selected studies to identify additional citations for inclusion in this review.

Understanding HAART

Available scholarship on HIV/AIDS treatment and management demonstrates that the “commonly used antiviral drugs are nucleoside inhibitors and inhibitors of the HIV protease that is involved in the maturation of new virus particles” (Martin et al., 2008 p. 107). However, as insinuated by these authors, HIV replication is inaccurate and some of the mutant strands generated lead to the onset of feasible viruses that are resistant to most of the antiretroviral medicines found in the market today. The marked resistance informed the urgent need for researchers and practitioners to start combining various antiretroviral medicines in an attempt to achieve a highly active antiretroviral therapy known in the medical field as HAART. Indeed, according to Tan et al (2011), most HAART regimens combine over three drugs with the view to minimizing the probability of drug resistance, hence dramatically enhancing the quality of patient’s life.

Consequently, HAART has been defined in the literature as a “regimen of three or more drugs containing at least one protease inhibitor or nonnucleoside reverse transcriptase inhibitor or a triple nucleoside reverse transcriptase inhibitor regimen containing abacavir” (Kang & Cu-Uvin, 2012 p. 373). Advocated by the World Health Organization (WHO) since 2001, the HAART approach not only seeks to rapidly improve HIV related challenges in resource-limited settings, but also to optimize survival rates at the population level through standardized sequencing of available antiretroviral medicines provided to patients using simplified approaches including clinical decision-making and laboratory screening (Bayou, Woldu, Meskel, & Mezgebe, 2014).

Pharmacological Properties of HAART

Tan et al (2011) acknowledge that “the current anti-HIV drugs approved by Food and Drug Administration (FDA) belong to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), fusion inhibitors (FIs) and entry inhibitors” (p. 25). A study conducted by Rajesh et al (2013) demonstrates that first-line antiretroviral therapy (ART) included in most HAART-based regimens “consist of either zidovudine (ZDV) or stavudine (D4T) with lamivudine (3TC) in combination with either efavirenz (EFV) or nevirapine (NVP)” (p. 54). The HAART regimens are essentially based on their mechanisms of action in suppressing HIV replication (Lehne, 2013), and may consist of lamivudine in combination with nevirapine and zidovudine, lamivudine in combination with nevirapine and stavudine, lamivudine in combination with stavudine and efavirenz, and lamivudine in combination with zidovudine and efavirenz (Rajesh et al., 2013). In most cases, HAART regimens characteristically consist of two NRTIs (to act as the nucleoside backbone) combined with an NNRTI or one to two PIs; however, it is of importance for nursing professionals to consider drug potency, tolerability, the potential for adherence, and drug resistance when selecting the right combination of antiretroviral drugs for use by HIV-positive patients (Floridia, Giuliano, Palmisano, & Vella, 2008; Lehne, 2013).

Extant pharmacological research demonstrates that zidovudine, a synthetic antiretroviral agent, is a nucleoside reverse transcriptase inhibitor (NRTI) that has received a widespread recommendation from WHO for use as a first-line antiretroviral drug in recourse and developing countries throughout the world (Rajesh, Vidyasagar, Varma, Mohiuddin, & Noorunnisa, 2011). Zidovudine and other NRTI-based antiretroviral drugs in the HAART regimen suppress HIV replication by inhibiting the action of HIV reverse transcriptase (Lehne, 2013); however, the NRTI-related lactic acidosis is a severe, life-threatening impediment of NRTI treatment which seems to be more recurrent in women, particularly if obese (Floridia et al., 2008). Common NRTI drugs in the market today include zidovudine, lamivudine, stavudine, didanosine, abacavir, tenofovir, emtricitabine, and zalcitabine (Agosto, Zhong, Munro, & Mothes, 2014).

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that suppresses HIV replication by inhibiting the action of HIV reverse transcriptase (Lehne, 2013), and is particularly used in pregnant women and children due to less severe side-effects (Floridia et al., 2008). However, the drug is associated with skin rashes and hepatotoxicity, particularly in instances whereby the HIV-positive patient exhibits a high CD4 cell count than is normally required (more than 250 CD4 cells/mm3 in women) (Floridia et al., 2008). Other common NNRTI-based antiretroviral drugs available in the market today include efavirenz and delavirdine (Kang & Cu-Uvin, 2012).

Nelfinavir, ritonavir, and indinavir are protease inhibitors (PI) commonly used in HAART regimens since they act to inhibit HIV protease enzyme, hence ensuring that an enabling environment for HIV replication is not available (Lehne, 2013). Other PI-based antiretroviral drugs include saquinavir, lopinavir, atazanavir, amprenavir, and fos-amprenavir. Recent advances in pharmacological research on antiretroviral drugs have seen the introduction of the fourth class of ARV agents such as enfuvirtide (Kang & Cu-Uvin, 2012). Most of the drugs considered under this regime are fusion inhibitors that operate by blocking HIV cell entry, leading to successful clearance of HIV particularly when applied in combination with other antiretroviral drugs found in the market today. However, a drug such as enfuvirtide is yet to be availed in an oral format, not mentioning that its high cost leads healthcare practitioners to only consider it in situations where the patient has exhausted all other available ARV options (Agosto et al., 2014).

Research has also demonstrated that Bevirimat, a new maturation inhibitor with a mode of action distinct from other antiretroviral agents, can act as a potentially viable addition to HAART regimens due to its effectiveness in terms of inhibiting replication of both wild-type and drug-resistant HIV-1 isolates (Martin et al., 2008). These authors conclude their study by noting that “in vitro studies demonstrate that Bevirimat exhibits no cross-resistance with other antiretroviral classes and Bevirimat-resistance viruses retain susceptibility to all other approved and investigational classes of antiretroviral therapy” (p. 111). Bevirimat administered orally in clinically significant dose-dependent formulations not only decreases the viral load among HIV-1 infected persons but also demonstrates sustainable clinical activity in patients with HIV-1 strands resistant to other antiretroviral drugs.

Still, other studies have examined the efficacy of complementary and alternative therapies (treatments and healthcare practices not taught extensively in medical and/or nursing schools, not normally utilized in hospital settings, and not normally reimbursed by medical insurance entities) in the treatment and management of HIV symptoms or side effects emanating from HAART regimens (Hoogbruin, 2011). In his study, this author concludes that complementary and alternative therapies can be used in combination with HAART, but sufficient care should be taken as the decision to include these therapies in the mainstream treatment regimens is substantially influenced by factors such as the capability to adjust and adapt to illness-related symptomatology, individual treatment outcomes and side effects, as well as the need for a 100% HAART adherence.

Overall, the assessment of the pharmacological properties of the antiretroviral drugs commonly included in HAART regimens demonstrates that immune reconstitution associated with HAART can initiate clearance of HIV using the suppression or inhibition technique. It is without a doubt that combination therapies under the HAART regimens are exceedingly successful in suppressing HIV replication in patients, hence maintaining the viral load below detection levels.

Actual & Potential Effects of HAART in patients with HIV/AIDS

Several authors have focused attention on evaluating the actual and potential effects of HAART in patients living with HIV/AIDS. Turcotte and Raines (2008) identify harmful side effects associated with exposure to therapy, including disturbances in lipid metabolism and subsequent development of cardiac disease, liver, and renal diseases. Other studies have shown that some HAART-constituent drugs such as zidovudine have been known to cause bone marrow toxicity and subsequent severe anemic episodes that resolve quickly when the drug is stopped (Kang & Cu-Uvin, 2012), while stavudine and nevirapine have been shown to enhance peripheral neuropathy and skin rash, respectively (Rajesh et al., 2013). Martin et al (2008) suggest that patients using HAART continue to experience “long-term side effects of antiretroviral therapy, drug toxicity, and drug-drug interactions, all of which could adversely affect treatment options and outcome” (p. 107). Long-term ARV toxicity is identified in the literature as a significant vulnerability to achieving long-term life prognosis and enhanced quality of life in HIV/AIDS patients (Bayou et al., 2014). However, nursing professionals should exercise caution as some HAART regimens have been positively associated with a reduction in the rate of both incidence and progression of known opportunistic malignancies, including cervical dysplasia, Kaposi sarcoma, and some lymphomas (Firnhaber et al., 2012).

Drug resistance has also been identified as a major problem in the use of HAART to treat patients with HIV/AIDS. Turcotte and Raines (2008) acknowledge that “rapid viral replication and the high rate of reverse transcriptase have led to high rates of resistance to HAART, with about 10% of newly acquired infections in the United States and Europe being resistant to at least one of the three major drug classes” (p. 1357). Martin et al (2008) report that most of the patients who attain unnoticeable plasma HIV type-1 (HIV-1) are eventually exposed to treatment failure due to the development of antiretroviral resistance. Additionally, these authors acknowledge that patients under HAART regimens are continually exposed to cross-resistance among the predominant antiretroviral drugs used, ultimately constraining the accessible options for salvage therapy particularly in patients who suffer from manifold episodes of virological failure and other more severe side effects.

Lastly, treatment failure is one of the underlying challenges that initiate multiple adverse effects on patients using common HAART regimens. Indeed, Rajesh et al (2011) report that about 25% of the estimated 3 million people on HAART across the world have no option but to terminate their preliminary HAART regimen due to treatment failure, described as the incapacity of the combined antiretroviral drugs to suppress HIV viral replication to below the internationally recognized limit of detection (50 copies/µl).

Nursing Implications Associated with the Use of HAART

Nursing professionals should realize that “the rapid development of resistance [to HAART] necessitates strict patient compliance with therapy” (Turcotte & Raines, 2008 p. 1357). Patients using HAART regimens need to be managed carefully, especially in terms of stock management, drug ordering procedures, supply chain integrity, and comprehensive patient counseling, to ensure that they comply with therapy and hence significantly reduce drug resistance and drug-to-drug interactions (Tan et al., 2011). Nursing professionals, especially in developing countries faced with a limited supply of the required drugs, must always ensure they coordinate the HAART regimens effectively and only switch as many patients to HAART as the existing stock would allow avoiding creating a situation whereby patients are switched back and forth between HAART and individual drugs due to insufficient stock (Bayou et al., 2014).

Nursing professionals also need to be at the forefront in gaining knowledge and a deep understanding of the new antiretroviral therapies that may be included in HAART-based treatment and management regimes for HIV/AIDS to improve drug tolerability and safety profiles (Martin et al., 2008). In introducing the HAART approach to HIV-positive patients, nursing professionals need to develop a deeper understanding of the factors that may facilitate or hinder treatment, including plasma HIV-RNA levels assessed on two separate occasions, absolute CD4+ T lymphocyte count of patients and shifts in these counts, examination of adherence to available drugs, remaining treatment options that could be used on patients, potential resistance patterns from prior antiretroviral therapies, as well as preparation of the patient for the implications of the HAART regimen (Bayou et al., 2014). Contemporary nursing professionals should also demonstrate adequate knowledge and understanding of the determinant factors for ART change as this may help in reducing the risk factors involved, especially in terms of initiating a regimen change, treatment failure, drug resistance, and increase in the quality of life of HIV patients.

To ensure effective pharmacovigilance practice, health institutions, governments, donor agencies, and other interested partners should facilitate the initiation of programs that enhance nursing awareness of the safety aspects of HAART (Rajesh et al., 2013). Lastly, it should be the nurses’ role to counsel and educate patients under HAART regimens about potential side effects and what to do when faced with potentially life-threatening side effects (Tan et al., 2011). Most patients will settle with reassurance (Kang & Cu-Uvin, 2012), hence nursing professionals should be at the forefront in providing psychological and spiritual support to patients under HAART through undertaking extensive counseling sessions (Bayou et al., 2014).

Conclusion

This review has interrogated the pharmacological effects of HAART in the management of patients with HIV/AIDS and the nursing implications involved. It has been shown that HAART demonstrates substantial reductions in the mortality rate and enhances the lifespan of HIV-positive patients by sustaining viral loads beneath detection levels, therefore successfully preventing the onset of AIDS and subsequent opportunistic diseases. It has also been demonstrated that most HAART regimens characteristically consist of two NRTIs (to act as the nucleoside backbone) combined with an NNRTI or one to two PIs, but nursing professionals and other health workers should consider drug potency, tolerability, the potential for adherence and drug resistance when selecting the right combination of antiretroviral drugs for use by HIV-positive patients. It is without a doubt that combination therapies under the HAART regimens are exceedingly successful in suppressing HIV replication in patients, hence maintaining the viral load below detection levels. The review has shown that the effects of HAART on HIV-infected patients include harmful side effects associated with exposure to therapy, drug resistance, and treatment failure. Lastly, nursing implications associated with the use of HAART regimens have been shown as exercising strict patient compliance with therapy, gaining knowledge and deep understanding of the new antiretroviral therapies, nursing awareness to enhance effective pharmacovigilance practice, and ensuring effective counseling and education of patients.

References

Agosto, L.M., Zhong, P., Munro, J., & Mothes, W. (2014). Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission. PLoS Pathogens, 10(2), 1-12.

Bayou, T., Woldu, M., Meskel, G.G., & Mezgebe, H. (2014). Factors determinant for change of initial antiretroviral treatment regimen among patients on ART follow-up clinic of Mekelle Hospital, Mekelle, Ethiopia. International Journal of Basic & Clinical Pharmacology, 3(1), 44-49.

Firnhaber, C., Westreich, D., Schulze, D., Williams, S., Siminya, M., Michelow, P…Smith, J.S. (2012). Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa. Journal of the International AIDS Society, 15(2), 33-51.

Floridia, M., Giuliano, M., Palmisano, L., & Vella, S. (2008). Gender differences in the treatment of HIV infection. Pharmacological Research, 58(2), 173-182.

Hoogbruin, A. (2011). Complimentary and alternative therapy (CAT) use and highly active antiretroviral therapy (HAART): Current evidence in the literature, 2000-2009. Journal of Clinical Nursing, 20(7/8), 925-939.

Kang, M., & Cu-Uvin, S. (2012). Association of HIV viral load and CD4 cell count with human papillomavirus detection and clearance in HIV-infected women initiating highly active antiretroviral therapy. HIV Medicine, 13(6), 372-378.

Lehne, R. (2013). Pharmacology for nursing care (8th ed.). Philadelphia: Elsevier Saunders.

Martin, D.E., Salzwedel, K., & Allaway, G.P. (2008). Bevirumat: A novel maturation inhibitor for the treatment of HIV-1 infection. Antiviral Chemistry & Chemotherapy, 19(3), 107-113.

Rajesh, R., Vidyasagar, S., Varma, D.M., Mohiuddin, S., & Noorunnisa, A. (2011). Evaluation of incidence of Zidovudine induced anemia in Indian human immunodeficiency virus positive patients in comparison with stavudine based highly active antiretroviral therapy. International Journal of Risks & Safety in Medicine, 23(3), 171-180.

Rajesh, R., Vidyasagar, S., Varma, D.M., Naik, A., Hegde, B.M., Guddatu, V…Kamath, A. (2013). A prospective study of highly active antiretroviral therapy in Indian immunodeficiency virus patients. A prospective study of highly active antiretroviral therapy in Indian immunodeficiency virus patients. International Journal of Risk & Safety in Medicine, 25(1), 53-65.

Tan, J.J., Liu, C., Wang, Y., Hu, L.M., Wang, C.X., & Liang, X.J. (2011). The state of the science: A 5-year review on the computer-aided design for global anti-aids drug development. In E. Barros (Eds.), HIV-infection-impact, awareness and social implications of living with HIV (pp. 25-46). Rijeka, Croatia: InTech.

Turcotte, R.F., & Raines, R.T. (2008). Design and characterization of an HIV-specific ribonuclease zymogen. Aids Research and Human Retroviruses, 24(11), 1357-1363.

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