PHARMACOECONOMIC ANALYSIS OF HIV/AIDS MANAGEMENT PHARMACY

CHAPTER TWO

LITRATURE REVIEW

1. Overview of HIV/AIDS

HIV is a retrovirus that infects cells of the immune system, destroying or impairing their functions (WHO, 2008). HIV has a high affinity for the cluster of differentia 4 (CD4) receptor on T lymphocytes and its major effect on the immune system is a progressive depletion of CD4 T lymphocytes (Martindale, 2008). Thus, infection is followed by development of anti-HIV antibodies known as seroconversion, during which the patient may remain asymptomatic or have transient symptoms such as rash, sore throat, and lymphadenopathy (Martindale, 2008). Despite the presence of the anti-HIV antibodies, the infection progresses over a period of months to several years ultimately resulting to a persistent generalized lymphadenopathy (lymphadenopathy syndrome) or a more serious collection of symptoms known as AIDS-related complex (ARC), which include fatigue, weight loss, recurrent fever, diarrhoea, and persistent opportunistic infections (Martindale, 2008). AIDS is characterised by severe impairment of the immune system leading to the development of secondary infections - opportunistic infections (OIs) which could be life-threatening and include Pneumocystis carinii pneumonia (PCP), Toxoplasma encephalitis, oropharyngeal and oesophageal candidiasis, cryptococcal meningitis, cytomegalovirus retinitis, and tuberculosis (TB), or to secondary neoplasms such as Kaposi's sarcoma, primary central nervous system (CNS) lymphomas, invasive cervical cancer, and non-Hodgkin's lymphoma. Other complications may include dementia and thrombocytopenia (Martindale,2008).

Two subtypes of HIV have been found - HIV-1, which is the most common and occurs worldwide and HIV-2, which is found mainly in Africa and is associated with a slower progression to AIDS than HIV-1 (Reeves et al., 2002). Thus, most untreated people infected with HIV-1 eventually develop AIDS. These individuals mostly die from OIs or malignancies associated with the progressive failure of the immune system. HIV progresses to AIDS at a variable rate influenced by the viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV infection: some will have progressed much sooner, and some will take much longer (CASCADE EU, 2000). Treatment with antiretrovirals (ARVs) increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy (ART) was estimated to be more than 5 years as of 2005 (Schneider et al., 2005). Without ART, someone who has AIDS typically dies within a year (Morgan et al.,2002).

OIs, which may be caused by bacteria, virus, fungi or protozoa, are the major cause of morbidity and mortality in patients with HIV-1 infection. HIV/AIDS patients are especially susceptible to OIs because of their suppressed immune system, psychological stress which in turn can influence the immune system and depletion of nutritional status (Benson et al., 2009). OIs are sometimes the initial presentation of HIV disease and affected patients may have ignored the warning signs, attribute it to other illnesses or may just not have wanted a voluntary counselling and testing (VCT). Often, OIs may be the first signs of immunologic deterioration and tend to occur as CD4 counts drop though children < 1 year of age may get OIs with ―normal‖ CD4 counts (Benson et al., 2009).

The use of ART has reduced the incidence of OIs for patients with access to HIV care, however a number of patients in the developed and developing world do not have access to care and have OIs. Also, others who do not have a sustained response to ARV agents for multiple reasons which include poor adherence, drug toxicities, drug interactions, or initial acquisition of a drug-resistant strain of HIV-1 will have OIs. Thus, OIs will continue to cause substantial morbidity and mortality in HIV/AIDS patients especially in those with HIV-1 infection (Benson et al.,2009).

1. Method of Transmission ofHIV/AIDS

HIV infects the cells of a living organism and it is found in blood and other body fluids. The virus cannot live for long outside the body consequently; the body fluid from an infected person has to come in contact with another person‘s body fluid to complete the process of transmission. The routes through which HIV can thus be transferred include;

Sexualcontact

Exposure to infected blood or blood products Perinatally from an infected mother to herbaby.

Though the virus has been isolated from blood, semen, vaginal secretions, breast milk, saliva, tears, Cerebrospinal fluid, amniotic fluid and urine, evidence has shown that transmission occur in the first four, in urine and amniotic fluid only when it contains visible blood and with saliva only when large volumes are exchanged (Kennedy et al., 2009).

Two methods of transmission occur: horizontal and vertical.

Horizontal Transmission: the virus is transmitted from one person to another (direct contact). It could be through

Unprotected sexual intercourse (vaginal, anal, and oral) with an HIV infected person. Studies have shown that the receptive partner in intercourse has a greater chance of acquiring HIV than the insertive partner. Other factors associated with an increased risk of HIV infection are exposure to blood such as genital ulcer disease, trauma during sex, menstruation of the HIVinfected woman and exposure to inflammation of the genital or rectal mucosa which can occur with sexually transmitted infections (STIs).

Sharing of drug needles or syringes with an HIV-infected person: a study has shown this to have an approximate risk of 0.67% perexposure.

Contamination of mucous membranes or break in the skin: This is mostly suffered by health worker when they are in contact with infected individuals. As reported by Russel et al. (2004), a study has shown that the overall risk of HIV infection after percutaneous exposure to infected blood is 0.3% and after mucous membrane exposure is0.09%.

Vertical Transmission: this is usually between a mother and her infant and occurs at various stages during the perinatal period;

During ante partum/pregnancy: this mostly occurs through the placenta. It may occur after placental disruption as in placental abruption or during amniosynthesis.

During intrapartum/Childbirth: this may result from maternal-foetal transfusion of blood during labour and through contact of the foetus with infected blood or other maternal secretions during thedelivery.

During postpartum/breastfeeding: this may occur by inoculation if the infant is injected before the mothers‘ secretions are removed from the body or through breastfeeding because of prolonged exposure of the infants oral or gastrointestinal tract to infected breastmilk.

1. Impact ofHIV/AIDS

Over the past 25 years, nearly 25 million people have died from AIDS. HIV/AIDS has caused debilitating illness and premature death in people during their prime years of life and has devastated families and communities. It has complicated efforts to fight poverty, improve health, and promote development especially in the developing countries which are most affected by theepidemic.

HIV/AIDS diminishes a person‘s ability to support, work and provide for his or her family. Also the treatment and health-care costs related to HIV/AIDS consume household incomes in developed countries as well as in developing countries. Though the anti-retroviral drugs may be ―free‖ in developing countries, the overall costs as a result of OIs are more than a number of infected individuals can contend with. The combined effect of reduced income and increased costs impoverishes individuals and households.

HIV/AIDS deepens socioeconomic and gender disparities. Women are at high risk of infection and have few options for providing for their families. Children affected by HIV/AIDS, due to their own infection or parental illness or death, are less likely to receive an education, as they leave school to care for ailing parents and younger siblings or lose their educational sponsors. The impact of HIV/AIDS on women and girls has been particularly devastating given the epidemiologic data. And this cannot be overemphasized. The children represent a generation and their loss would present with a myriad of economic problems; the women are equally asimportant.

HIV/AIDS has also strained the resources of communities; hospitals, schools and businesses. A number of health care workers, teachers, and business and government leaders have been lost to HIV/AIDS (WHO, 2009).

1. Factors Militating against Accessing ART and HIVCare
2. Stigma: individuals are inclined to hide the sickness from their boss, spouse or partner, family and community because of the stigma associated with HIV/AIDS. This may keep them from seeking VCT or ART services out of fear of repercussions from disclosure, from peers, clients andco-workers.
3. Lack of resources and access to HIV/AIDS treatment and care: Many individuals in need of medication lack access to ARVs either because they live in rural or remote areas far from a health centre with no money for transportation or because they are not aware of theirstatus.
4. Lack of power and control (women): In most developing countries men are the sole breadwinners in a household hence women are afraid of blame, physical abuse or abandonment after disclosing their infection to their husband or partner. The laws in many countries leave women without property or inheritance rights and these fears make women keep their status a secret, exposing themselves, their children and spouses to severe ill health by not accessing proper HIV/AIDS management andcare.
5. Lack of other medications: HIV as mentioned earlier attacks the immune system as such infected individuals suffer a number of opportunistic and related infections, such as TB, malaria, Hepatitis C, pneumonia or cancer. Access to drugs for these may be difficult as they may not be available at local health centres. In patients opportune to have health insurance policies (example NHIS), the fragmented state of our health care system which does not reconcile patient medical history does not allow them fully to benefit from thesepolicies.
6. Lack of access to nutrition and clean water: ARVs alone are not enough to combat ill health. The decline in immunity could benefit from a number ofgood hygiene (food, personal and environmental) as such adequate nutrition is an integral complement to treatment. Famines, droughts, political events and loss of ability to farm (in cases of morbidity) may reduce supplies of food and clean water. Lack of access to these basic necessities is particularly harmful to pregnant women, children and those on ARV therapy. Generally, a proper diet reduces growth and developmental deficits among children and unwanted weight loss among adults. Clean water is essential for some paediatric formulations ofARVs.
7. Uncertainty of the future: People living with HIV may have to deal with delays in or diminished supplies of their ARVs, increasing the possibility of developing resistance to their drugs and the necessity for costly second-line drugs. Governments may lack the will and the resources to secure sustainable sources of ARVs and to build capacity for the provision of care and treatment. The issue of sustainability of programs especially health care programs has been a problem in developing countries. In order to tackle this, most care programs are integrated into existing health institutions. Doing that alone will not solve the problem as the institutions already have their finances stretched. Integrating it in health insurance programs would go a long way in providing quality health care to individuals with only immediate worry for food, utility and other basic necessities and nothealth.

1. HIV Treatment inNigeria

The treatment method adopted for the management of HIV/AIDS in Nigeria is in line with the WHO guidelines for the diagnosis and treatment of HIV infection and related disorders in resource-limited settings. The treatment is based on the CD4 count of the individuals.

In general, HIV infections eventually result in AIDS, which is invariably fatal. However, in a small proportion of patients the immune system stabilizes after an initial decline in CD4 count despite continued HIV infection. Cases of clearance of HIV infection in neonates infected prenatally have been reported. Variation in the genes for recently identified co-receptors necessary for HIV infection may be involved and may offer new therapeutic targets as is being explored (WHO et al., 2008).

Treatment strategies for HIV infection have been changing rapidly with the advent of new antiretroviral drugs and improved timing of treatment and guidelines for the treatment of HIV infection. There has been an ongoing debate as to whether to start treatment early in the course of the infection or to delay until the disease progresses.

2.1.5 The main drugs used in combination therapy are:

Nucleoside Reverse Transcriptase Inhibitors: zidovudine, abacavir, didanosine, lamivudine, stavudine, and zalcitabine.

HIV-Protease Inhibitors: amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir.

Non-nucleoside Reverse Transcriptase Inhibitors: delavirdine, efavirenz, and nevirapine).

The Fusion Inhibitor, enfuvirtide may herald a new class of drugs and acts by blocking fusion of HIV with cells, thereby blocking entry (WHO, 2020).

Combination therapy is the mainstay in ART with the ARVs given early in the infection to improve efficacy, minimise toxicity, and delay drug resistance. Usually, combinations of three ARVs, typically two nucleoside reverse transcriptase inhibitors plus either an HIV-protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, referred to as highly active antiretroviral therapy (HAART), have produced reductions in viral loads, often to levels below the limits of detection, and have been associated with sustained improvements in disease progression (WHO, 2020). It appears that it is necessary to suppress viral replication to this extent in order to inhibit the emergence of resistant variants and consequent disease progression. Decline in CD4 count has been arrested or reversed in patients on HAART, even in the absence of profound suppression of viraemia, and there is also some evidence that immune function may be partially restored in the long term (CDC, 2008). Declining morbidity and mortality among patients with HIV infection have been attributed to the introduction of these effective treatment regimens. Systematic review and meta- analysis has concluded that triple therapy regimens are superior to dual therapy or mono-therapy which was the initial ARV treatment strategy. Quadruple therapy regimen has also been of benefit (CDC, 2008 and WHO,2020).

HAART regimens have been shown to be more effective in antiretroviral-naive patients, than those who have received previous treatment. When a new regimen is started, drugs should be started simultaneously rather than sequentially. But when drug regimen are being changed it should be entirely to drugs that have not been taken previously, or at least two of a triple-drug regimen should be changed this is not always achieved though. Also, discontinuation of HAART regimens in the face of undetectable viral level has shown that there is usually a rapid return to pre-treatment levels once treatment is stopped. The continued effectiveness of any HAART regimen isdependent on compliance with treatment, since lapses in compliance can rapidly lead to the emergence of HIV variants resistant to one or more of the drugs being used and consequent disease progression (WHO et al., 2008). However, compliance is difficult to maintain due to the complexity of many regimens and to poor tolerability and long- term adverse effects of the drugs used. To promote compliance as a result of pill burden, fixed dose formulations have evolved in most cases combining the three regimens ortwo.

1. Pharmacoeconomics

The roots of pharmacoeconomics are in health economics, a specialised aspect of economics developed in the 1960s. The concepts involved in pharmacoeconomics, such as cost-effectiveness and cost-benefit analysis, have been developed from the late 1970s. Beginning in the 1980s, measurement tools for health and clinical outcomes assessment were created and have subsequently been improved. Pharmacoeconomics emerged in the late 1980s as an independent entity among the varied specialised economic methods.

Over the past 20 years, pharmacoeconomics has become more important due to an increased emphasis on efficient drug therapies for disease, which increase health costs. Pharmacoeconomics is an innovative method that aims to decrease health expenditures, whilst optimising healthcare results.

The increasing cost of healthcare products and services has become a great concern for patients, healthcare professionals, insurers, politicians and the public. This increasing concern has prompted demand for the use of economic evaluations of alternative healthcare outcomes. This escalation in healthcare spending is due to increased life expectancy, increased technology, increased expectations, increased standards of living and an increased demand in healthcare quality and services. Healthcare resources are not easily accessible and affordable to many patients; therefore pharmacoeconomic evaluations play an important role in the allocation of these resources. Pharmacoeconomics strives to guide the utilisation of healthcare resources optimally. Pharmacoeconomics addresses both economic and humanistic outcomes and it includes ideas and methods from a variety of domains including statistics, clinical epidemiology, economics, and decision analysis etcetera.

Pharmacoeconomics involves the utilisation of two major methodologies for health economics analysis: cost analysis and cost outcomes. Cost analysis considers the costs of providing healthcare products or services, but does not consider the outcomes experienced by patients or providers (Wertheimer et al., 2003).

There are four types of cost-outcomes analysis:

• Cost-minimisationanalysis;
• Cost-effectivenessanalysis;
• Cost-benefit analysis;and
• Cost-utilityanalysis.

The type of analysis used depends on the nature of the problem being studied.

1. Cost-Effectiveness Analysis is used to compare two or more treatment options for a specific condition. Cost-effectiveness is dependent on the value in nonmonetary terms that is placed on the outcome in relation to thecost.
2. Cost-Minimisation Analysis is a type of cost-effectiveness analysis that is used if two alternative therapies are determined to be the same, essentially. After determining the effectiveness, this method determines which treatment minimises costs. The pharmacoeconomic tool compares all the costs and consequences of two ormore therapeutic interventions. The objective of this method is to select the least costly among multiple equivalent interventions. This method is frequently used to compare brands with generics, different routes of administration and different settings of administration.
3. Cost-Benefit Analysis compares the costs and outcomes of alternative therapies and the outcome is then expressed in monetary terms. Cost-benefit analysis allows researchers to make comparisons across a wide variety of alternatives. It compares the costs involved in implementing a programme with the value of the outcome. Since the endpoints are measured in monetary terms, different endpoints can be studied, such as a surgical procedure compared with a pharmaceuticalintervention.
4. Cost-Utility Analysis is performed in the same manner as cost-effectiveness analysis except that the endpoint differs. The endpoint of cost-utility analysis is described as ‗quality-adjusted life years saved‘. This allows cost-utility analysis to compare therapies for different diseases. Cost-utility analysis integrates both the costs and the consequences of a therapy into itscomparison.

Cost utility measures the final outcomes in changes of life-expectancy. This method is often used when a programme affects morbidity and mortality.

Pharmacoeconomics is a multidisciplinary field; hence groups involved in pharmacoeconomics include pharmacoeconomists, epidemiologists, statisticians, data personnel and research personnel.

Data may be collected in a variety of ways, including patient self report questionnaires and direct data abstraction from patients‘ medical and employment records and bills.

There are three types of pharmacoeconomic studies:

• Prospective;
• Retrospective;and
• Model

Prospective studies are experimental studies that can be an additional part of a randomised clinical trial or strictly an economic evaluation. Prospective studies are the least useful because they require extensive time and money.

Retrospective studies are data analyses of clinical trials or cohort studies that were conducted previously. This type of study involves a comparison of treatment users and non-users that are followed from some point in the past to the present. Retrospective studies are the ideal study method.

Model studies are performed as a method of displaying data obtained from a variety of resources if previously studied data is unavailable. Modelling is an inexpensive and effective way of illustrating existing available data regarding the costs and outcomes of alternative therapeutic interventions.

The goal of these methods of pharmacoeconomic evaluation is to assess the value of pharmaceutical products and services while incorporating clinical, economic and humanistic outcomes.

Pharmacoeconomic analysis is important since payers such as third-party payers or government/ private health plans utilise them when determining whether to reimburse a claim. Physicians need to be aware of effective therapies that minimise costs.

1. Cost-of -IllnessAnalysis

The COI is defined as the value of the resources that are expended or foregone as a result of a health problem. The COI includes health sector costs, the value of lost productivity by the patient (indirect cost), and the cost of pain and suffering (intangible costs) (CDC, 2009). COI is a pre-requisite for any of the pharmacoeconomic methods.

Various definitions of Pharmacoeconomics have evolved and these include:

Pharmacoeconomics refers to the scientific discipline that compares the value of one pharmaceutical drug or drug therapy to another. It is a sub-discipline of health economics. A Pharmacoeconomic study evaluates the cost (expressed in monetary terms) and effects (expressed in terms of monetary value, efficacy or enhanced quality of life) of a pharmaceutical product. Pharmacoeconomic studies serve to guide optimal healthcare resource allocation, in a standardized and scientifically grounded manner (Wikipedia,2009).

The description and analysis of the cost of drug therapy to health care systems and the society. Value-based pricing demands relative assessment of both the value of the pharmaceutical or medical devices and the relative cost. This sort of assessment is the very substance of pharmacoeconomics. In other words, pharmacoeconomics is the science of setting a price commensurate with value (Crecon, 2007).

The scientific discipline of pharmacoeconomics uses various techniques to assess the value of pharmaceutical interventions and health strategies. Pharmacoeconomics evaluations provide information to optimally allocate health care resources and it is a sub-discipline of health economics (Health Economics, 2009).