Introduction
Over thirty-five million of the world population is estimated to be living with the Human Immunodeficiency Virus (HIV), and sub-Sahara Africa alone is accounting for more than 71% of this infection (World Health Organisation [WHO], 2015). Nigeria which ranks second in the global burden has 3.3 million of her population living with the virus (United Nations General Assembly, 2010).
Following increasing survival of infected patients with highly antiretroviral therapy (HAART), liver disease is an emerging clinical problem among these groups of individuals (Smith et al., 2010). Liver diseases which range from abnormal liver function tests, to liver decompensation, non-alcoholic liver disease (NALD), non-alcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) are becoming common events among infected on HAART (Panos et al., 2009).
Abnormal liver function test is defined as either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1.25 times the upper limit of normal, and low serum albumin level of <3.5 gm/dl are measures of chronic liver disease. This was documented in 16% of cases in a Swiss cohort study of 2,365 HIV infected individuals who were not co-infected with either hepatitis B or C virus. Risk factors associated with elevated ALT were high HIV RNA, prolonged use of antiretroviral therapy (ART), high body mass index (BMI), alcohol abuse and increasing age (Kovari et al., 2010).
Ocama et al. in their 2010 cohort study of 546 HIV infected individuals in Kampala also documented 1.5% grade 3 AST elevations after 36 months of ART. Affectation of the liver can result from HIV infection itself, from use of ART, from co-morbidities, and alcohol use. HIV is known to infect predominantly CD4+ T-cells, monocyte/macrophages and dendritic cells; however a wide range of non-haemapoietic cells, including liver cells can also be infected by the virus. HIV can directly infect hepatocytes, hepatocyte cell lines, sinusoidal cells, hepatic stellate cells (HSCs) and Kupffer cells (KCs). An indirect effect of HIV on the liver is via the gastrointestinal tract (GIT). HIV infection of GIT associated CD4+ T-cells leads to increased permeability to bacterial endotoxins such as lipopolysaccharide (LPS) which can stimulate hepatocytes, KCs and HSCs to produce proinflammatory cytokines and chemokines that attracts activated lymphocytes and monocytes to the liver thus further inducing fibrosis (Housset et al., 2009).
Increased systemic levels of LPS are hypothesized to contribute to chronic immune activation in HIV-infected patients via activation of monocytes. Kupffer cells are the main cell type in the liver that responds to LPS. When stimulated through ligation of the LPS receptor, toll like receptor (TLR)-4, KCs produce proinflammatory cytokines. Hepatotoxicity from use of HAART may be related to different classes of ART combinations. These include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PI) (Nunez, 2010).
Overview of HIV/AIDS
According to Evian (2006), HIV stands for human immunodeficiency virus. If left untreated, HIV can lead to the disease called AIDS (acquired immunodeficiency syndrome).Unlike some other viruses, the human body cannot get rid of HIV completely. HIV attacks the body’s immune system, specifically the CD4 cells (T cells), which help the immune system fight off infections. If left untreated, HIV reduces the number of CD4 cells (T cells) in the body, making the person more likely to get infections or infection-related cancers.
Gallo (2006) stated that over time, HIV can destroy so many of the CD4 cells to a level that the body cannot fight off infections and disease. These opportunistic infections or cancers take advantage of a very weak immune system and signal that the person has AIDS, the last state of HIV infection.
AIDS stands for acquired immunodeficiency syndrome. AIDS is the final stage of HIV infection, and not everyone who has HIV advances to this stage (Sharp and Hahn, 2011).AIDS is the stage of infection that occurs when the immune system is badly damaged and the infected person become vulnerable to opportunistic infections. This usually occurs when the number of your CD4 cells falls below 200 cells per cubic millimeter of blood (200 cells/mm3), the individual is considered to have progressed to AIDS. (Normal CD4 counts are between 500 and 1,600 cells/mm3.) (Harden, 2012).
Historical background of HIV/AIDS
AIDS was first clinically observed in 1981 in the United States. The initial cases were a cluster of injecting drug users and homosexual men with no known cause of impaired immunity who showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to occur in people with very compromised immune systems (Gottlieb, 2006).
In the early days, the Centre for Diseases Prevention and Control(CDC) did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, which the discoverers of HIV originally named the virus. They also used Kaposi’s sarcoma and opportunistic infections, the name by which a task force had been set up in 1981 (CDC, 2012).
At one point, the CDC coined the phrase “the 4H disease”, since the syndrome seemed to affect homosexuals, heroin users, hemophiliacs, and Haitians. In the general press, the term “GRID”, which stood for gay-related immune deficiency, had been coined. However, after determining that AIDS was not isolated to the gay community, it was realized that the term GRID was misleading and the term AIDS was introduced at a meeting in July 1982. By September 1982 the CDC started referring to the disease as AIDS (Altman, 2008).
Further researches showed there HIV occurs in two variances which are HIV-1 and HIV-2. Both HIV-1 and HIV-2 are believed to have originated in non-human primates in West-central Africa and were transferred to humans in the early 20th century. HIV-1 appears to have originated in southern Cameroon through the evolution of a simian immunodeficiency virus (SIV) that infects wild chimpanzees. HIV-2 was also believed to have originated from an Old World monkey living in coastal West Africa (from southern Senegal to western Côte d’Ivoire) (CDC, 2012).
Prevalence of HIV/AIDS
HIV/AIDS is a global pandemic. As of 2014, approximately 37 million people have HIV worldwide with the number of new infections that year being about 2 million. This is down from 3.1 million new infections in 2001. Of these 37 million more than half are women and 2.6 million are less than 15 years old. It resulted in about 1.2 million deaths in 2014, down from a peak of 2.2 million in 2005 (Cohen and Hellmann, 2015).
Sub-Saharan Africa is the region most affected. In 2010, an estimated 68% (22.9 million) of all HIV cases and 66% of all deaths (1.2 million) occurred in this region. This means that about 5% of the adult population is infected and it is believed to be the cause of 10% of all deaths in children. Here in contrast to other regions women compose nearly 60% of cases. South Africa has the largest population of people with HIV of any country in the world at 5.9 million. Life expectancy has fallen in the worst-affected countries due to HIV/AIDS; for example, in 2006 it was estimated that it had dropped from 65 to 35 years in Botswana. Mother-to-child transmission, as of 2013, in Botswana and South Africa has decreased to less than 5% with improvement in many other African nations due to improved access to antiretroviral therapy (Mandell, 2014).
Although HIV prevalence is much lower in Nigeria (estimated 3.4% of the populations are living with HIV) than in many African countries, such as South Africa, Uganda, and Zambia, the size of Nigeria’s population means that in no distance future the number of people leaving with HIV will almost double. Approximately 210,000 people die yearly and the natural life expectancy is 56 years (Odutolu, 2006).
Signs and symptoms of HIV
The symptoms of HIV vary, depending on the individual and the stage of the disease: the early stage, the clinical latency stage, or AIDS (the late stage of HIV infection). Below are the symptoms that some individuals may experience in these three stages. Not all individuals will experience these symptoms.
Early Stage of HIV
According to Sattentau (2008), about 40% to 90% of people infected with HIV have flu-like symptoms within 2-4 weeks after HIV infection. Other people do not feel sick at all during this stage, which is also known as acute HIV infection. Early infection is defined as HIV infection in the past six months (recent) and includes acute (very recent) infections. Flu-like symptoms can include:
- Fever
- Chills
- Rash
- Night sweats
- Muscle aches
- Sore throat
- Fatigue
- Swollen lymph nodes
- Mouth ulcers
These symptoms can last anywhere from a few days to several weeks. During this time, HIV infection may not show up on some types of HIV tests, but people who have it are highly infectious and can spread the infection to others. However, these symptoms alone are not enough to assume that an individual has HIV because each of these symptoms can be caused by other illnesses. And some people who have HIV do not show any symptoms at all for 10 years or more; only a HIV test can be used to confirm the presence of HIV(Sattentau, 2008).
Clinical latency stage
After the early stage of HIV infection, the disease moves into a stage called the clinical latency stage (also called “chronic HIV infection”). During this stage, HIV is still active but reproduces at very low levels. People with chronic HIV infection may not have any HIV-related symptoms, or only mild ones. For people who are not taking medicine to treat HIV (called antiretroviral therapy or ART), this period can last a decade or longer, but some may progress through this phase faster. People who are taking medicine to treat HIV, and who take their medications the right way, every day, may be in this stage for several decades because treatment helps keep the virus in check (Sigal et al., 2011)
Progression to AIDS
For people with HIV infection who are not on ART, eventually the virus will weaken the body’s immune system and progress to AIDS (acquired immunodeficiency syndrome), the late stage of HIV infection. Symptoms of this stage as highlighted by Weiss (2013) can include:
- Rapid weight loss
- Recurring fever or profuse night sweats
- Extreme and unexplained tiredness
- Prolonged swelling of the lymph glands in the armpits, groin, or neck
- Diarrhoea that lasts for more than a week
- Sores of the mouth, anus, or genitals
- Pneumonia
- Red, brown, pink, or purplish blotches on or under the skin or inside the mouth, nose, or eyelids
- Memory loss, depression, and other neurologic disorders
Means of transmission of HIV
According to Markowitz (2007), HIV is transmitted by four main routes:
- Sexual contact,
- Exposure to infected body fluids or tissues
- From mother to child
- Sharing of hypodermic needles
Sexual contact
The most frequent mode of transmission of HIV is through sexual contact with an infected person. The majority of all transmissions worldwide occur through heterosexual contacts (i.e. sexual contacts between people of the opposite sex); however, the pattern of transmission varies significantly among countries. In the United States, as of 2009, most sexual transmission occurred in men who had sex with men with this population accounting for 64% of all new cases (Sepkowitz, 2010).
Risk of transmission increases in the presence of many sexually transmitted infections and genital ulcers. Genital ulcers appear to increase the risk approximately fivefold. Other sexually transmitted infections, such as gonorrhoea, Chlamydia, trichomoniasis, and bacterial vaginosis, are associated with somewhat smaller increases in risk of transmission (Evian, 2006).
Exposure to infected body fluids or tissues
The second most frequent mode of HIV transmission is via blood and blood products. Blood-borne transmission can be through needle-sharing during intravenous drug use, needle stick injury, transfusion of contaminated blood or blood product, or medical injections with unsterilised equipment.
Unsafe medical injections play a significant role in HIV spread in sub-Saharan Africa. In 2007, between 12 and 17% of infections in this region were attributed to medical syringe use. The World Health Organization estimates the risk of transmission as a result of a medical injection in Africa at 1.2%. Significant risks are also associated with invasive procedures, assisted delivery, and dental care in this area of the world. People giving or receiving tattoos, piercings, and scarification are theoretically at risk of infection (Sepkowitz, 2010).
From mother-to-child
HIV can be transmitted from mother to child during pregnancy, during delivery, or through breast milk resulting in infection in the baby. This is the third most common way in which HIV is transmitted globally. In the absence of treatment, the risk of transmission before or during birth is around 20% and in those who also breastfeed 35%. With appropriate treatment the risk of mother-to-child infection can be reduced to about 1%. Preventive treatment involves the mother taking antiretrovirals during pregnancy and delivery, an elective caesarean section, avoiding breastfeeding, and administering antiretroviral drugs to the newborn (Sepkowitz, 2010).
Sharing of hypodermic needles
Sharing of hypodermic needles leads to the spread of HIV/AIDS. According to Cohen and Hellmann (2015),at the start of every injection, blood is introduced into the needle and syringe. Therefore, a needle and syringe that an HIV-positive person has used can contain blood with the virus in it. Transmission occurs when another person then uses the same syringe without cleaning it. The reuse of a blood-contaminated needle or syringe by another person can be an effective means of transmission because a large quantity of blood can be injected directly into the bloodstream.
Markowitz (2007) stated that although HIV does not generally survive well outside the body, it can survive for long periods of time (over 28 days) if hermetically sealed in syringe. There is a risk of HIV infection through intravenous injecting, subcutaneous injecting (injecting into the fat under the skin) and intramuscular injection. CDC (2012) stated that HIV infection from blood can occur in other ways as a result of injecting drug use:
- Through sharing water used to flush blood out of a needle and syringe.
- Through sharing syringes that have been cleaned in a way that does not eliminate all the blood they contain.
- Through reusing bottle caps, spoons or other containers used to dissolve drugs in water and to heat drug solutions.
- Through unsafe disposal of needles or syringes used for injecting drugs, leading to accidents in which blood gets into the body of another person.
Management of HIV/AIDS
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient’s total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death (Moore and Chaisson, 2009).
There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 NRTIs as a “backbone” along with 1 NNRTI, PI or INSTI as a “base.” (United States Department of Health and Human Services, 2015).
1. Entry inhibitors
Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Example entry inhibitors are maraviroc and enfuvirtide (Bai et al., 2013).
2. Nucleoside/nucleotide reverse transcriptase inhibitors
Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus and hence unable to become integrated into the DNA in the nucleus of the human cell; it must be “reverse” transcribed into DNA. Since the conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral protein which makes it a selective target for inhibition. NRTIs are chain terminators such that once incorporated, work by preventing other nucleosides from also being incorporated into the DNA chain because of the absence of a 3′ OH group. Both act as competitive substrate inhibitors. Examples of currently used NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir (Das and Arnold, 2013).
3. Non-Nucleoside reverse transcriptase inhibitors
Non-Nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine (Das and Arnold, 2013)
4. Integrase inhibitors
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. Example of integrase inhibitors are elvitegravir and dolutegravir (Keith, 2013).
5. Protease inhibitors
Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir (Wensing et al., 2010)
6. Combination therapy
Antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible, thus reducing the potential pool of spontaneous resistance mutations. Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs being taken arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect (United States Department of Health and Human Services, 2015).
Liver abnormalities associated with HIV/AIDS management
Highly active antiretroviral therapy (HAART) in Human Immuno Deficiency Virus (HIV) infected patients has led to dramatic improvements in the survival of patients. However, antiretroviral drugs have been associated with both short and long-term toxicities including hepatotoxicity, which may be life threatening (Kalyesubula et al.,2011). Elevations in serum hepatic enzymes have been described in association with all major classes of antiretroviral therapy (ART) (Mankhatithan et al.,2011).
However, the complexity of medication used in antiretroviral therapy complicates the understanding of the independent effects of each drug in the development of drug induced liver injury. Therefore, prevention and management of antiretroviral therapy related toxicity has emerged as a major issue for HIV/AIDS treatment and care. The pathogenesis of drug-induced liver disease normally involves the participation of the parent drug or its metabolite that either affects the cell biochemistry directly or indirectly by eliciting an immune response. As HIV-infected patients live longer, they develop long term manifestations of chronic HIV infection and treatment complication. The severity of ART may range from the absence of symptoms to liver decomposition and the outcome ranges from spontaneous resolution to liver failure and death (Eluwa et al., 2012).
Alanine aminotransferase and aspartate aminotransferase are hepatic enzymes that could be used as markers of hepatocellular injury (Zechini et al., 2014). Studies have revealed that 14–20 % of adults on ART had elevated serum liver enzymes as a marker of hepatocellular injury (Puoti et al., 2009). Liver enzyme elevations (LEEs) are frequently associated with use of potent antiretroviral combination therapy. The most well-established risk factors for LEEs are chronic hepatitis B and C infections. In addition, several other parameters (e.g., a greater increase in CD4 cell count after the start of antiretroviral therapy and higher baseline levels of alanine aminotransferase (ALT), systemic opportunistic infections, cirrhosis, alcohol or drug induced hepatotoxicity, age and gender are risk factors for LEEs (Joshi et al.,2011).
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