CHAPTER 1
INTRODUCTION
1.1 Overview
HIV stands for human immunodeficiency virus. If left untreated, HIV can lead to the disease AIDS (acquired immune deficiency syndrome).Unlike some other viruses, the human body can’t get rid of HIV completely. So once one has HIV, they have it for life (AIDS, HIV and The Immune System, 1997).
HIV is one member of the group of viruses known as retroviruses. The term "retrovirus" stems from the fact that these kinds of viruses are capable of copying RNA into DNA. The virus has two exact copies of single-stranded RNA as its basic genetic material (genome) in the very center of the organism. The genome is surrounded by a spherical core made of various proteins in tightlypacked association with one another. The core is itself surrounded by a membrane (called an "envelope", made of fat [lipids] and various membrane-bound proteins). One of the membranebound proteins can bind to a particular protein on the surface of certain immune cells, called Tcells which results in the virus becoming physically attached. Upon binding, the virus is brought inside of the T-cell and the envelope is removed by enzymes normally present inside the cell. The internal core is thus exposed, and it too is broken-down. This last phase results in exposure of the virus's RNA genetic material. An enzyme attached to the RNA, known as "reverse transcriptase", begins to make a complimentary base-pair single-strand copy of the RNA into DNA. The single strand of DNA is also copied by the same enzyme to form double-stranded DNA. This DNA inserts somewhere into one of the 46 chromosomes within our cells, and there it is used as a template for production of all of the things necessary to form new virus particles (replication of the virus). These new virus particles can be subsequently released from the infected cell, and can infect adjacent cells (AIDS, HIV and The Immune System, 1997).
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. Over time, HIV can destroy so many of these cells that the body can’t fight off infections and disease. 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.gov, 2017e).
1.2 HIV strains and types
Each time HIV replicates (by infecting a new cell), small changes or mutations may occur. This means there are many different forms of HIV, including within the body of a single person living with HIV. There are two types of HIV (AVERT, 2017c).
1.2.1 HIV-1 and HIV-2
HIV type 1 and HIV type 2 are two distinct viruses. Worldwide, the predominant virus is HIV-1.
The relatively uncommon HIV-2 virus is concentrated in West Africa, but has been seen in other countries. It is less infectious and progresses slower than HIV-1. While commonly used antiretroviral drugs are active against HIV-2, optimum treatment is poorly understood (AVERT, 2017c).
The strains of HIV-1 can be classified into four groups. The most important group, M, is the ‘major’ group and is responsible for the majority of the global HIV epidemic. The other three groups are N, O and P. They are quite uncommon and only occur in Cameroon, Gabon and Equatorial Guinea (AVERT, 2017c).
1.2.3 Subtypes within HIV-1 group M
Within group M there are known to be at least nine genetically distinct subtypes of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K. Additionally, different subtypes can combine genetic material to form a hybrid virus, known as a ‘circulating recombinant form’ (CRFs), of which quite a few have been identified (AVERT, 2017c).
The dominant HIV subtype in the Americas, Western Europe and Australasia is subtype B. As a result, the great majority of HIV clinical research has been conducted in populations where subtype B predominates. However this subtype represents only 12% of global HIV infections. In contrast, less research is available for subtype C, although just under half of all people living with HIV have subtype C. It is very common in the high prevalence countries of Southern Africa, as well as in the horn of Africa and India (AVERT, 2017c).
The greatest diversity of subtypes is found in Cameroon and the Democratic Republic of Congo - the region where the HIV-1 epidemic originated. However, these geographical patterns in the distribution of subtypes are changing over time, due to migration and the mixing of populations. Some studies suggest that certain subtypes have a greater risk of transmission or faster disease progression than others. On the other hand, antiretroviral drugs (ARVs), although largely developed in relation to subtype B, have generally proven to be effective against a wide range of subtypes (AVERT, 2017c).
Nonetheless, comparative research on these important issues is relatively limited, partly because individuals with different subtypes are found in distinct geographical locations. A more practical concern is the tests used to diagnose HIV and monitor the level of virus in the body (viral load). Tests that are sensitive to the full range of subtypes (and to group O and HIV-2) do exist but may not be readily available in all settings. This is a concern in places where diverse subtypes are prevalent (AVERT, 2017c).
1.3 Acquired immune deficiency syndrome (AIDS)
AIDS stands for acquired immunodeficiency syndrome. AIDS is the final stage of HIV infection, and not everyone who has HIV advances to this stage (AIDS.gov, 2017).
AIDS is the stage of infection that occurs when one’s immune system is badly damaged and one become vulnerable to opportunistic infections. When the number of CD4 cells falls below 200 cells per cubic millimeter of blood, patients are considered to have progressed to AIDS. (The CD4 count of an uninfected adult/adolescent who is generally in good health ranges from 500 cells/mm3 to 1,600 cells/mm3.) People can also be diagnosed with AIDS if they develop one or more opportunistic infections, regardless of their CD4 count (AIDS.gov, 2017).
Without treatment, people who progress to AIDS typically survive about 3 years. Once patients have a dangerous opportunistic illness, life-expectancy without treatment falls to about 1 year. However, if they are taking ART and maintain a low viral load, then they may enjoy a near normal life span. Patients will most likely never progress to AIDS (AIDS.gov, 2017).
1.4 Opportunistic infections and their relation to HIV/AIDS
People with healthy immune systems can be exposed to certain viruses, bacteria, or parasites and have no reaction to them—but people living with HIV/AIDS can face serious health threats from what are known as “opportunistic” infections (OIs). These infections are called “opportunistic” because they take advantage of weakened immune system, and they can cause devastating illnesses. OIs are signs of a declining immune system. Most life-threatening OIs occur when CD4 count is below 200 cells/mm3. OIs are the most common cause of death for people with HIV/AIDS. The CDC developed a list of more than 20 OIs that are considered AIDS-defining conditions (AIDS.gov, 2017b).
If people have HIV and one or more of these OIs, they will be diagnosed with AIDS, no matter what their CD4 count happens to be:
-Candidiasis of bronchi, trachea, esophagus, or lungs
-Invasive cervical cancer
-Coccidioidomycosis
-Cryptococcosis
-Cryptosporidiosis, chronic intestinal
-Cytomegalovirus disease (particularly CMV retinitis)
-Encephalopathy, HIV-related
-Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis
-Histoplasmosis
-Isosporiasis, chronic intestinal (greater than 1 month's duration)
-Kaposi's sarcoma
-Lymphoma, multiple forms
-Mycobacterium avium complex
-Tuberculosis
-Pneumocystis carinii pneumonia
-Pneumonia, recurrent
-Progressive multifocal leukoencephalopathy
-Salmonella septicemia, recurrent
-Toxoplasmosis of brain
-Wasting syndrome due to HIV
Because they can be so dangerous to patient’s health, it is essential to understand the signs, symptoms, prevention, and management of OIs (AIDS.gov, 2017b).
1.5 Origin of HIV AND AIDS
Scientists identified a type of chimpanzee in Central Africa as the source of HIV infection in humans. They believe that the chimpanzee version of the immunodeficiency virus (called simian immunodeficiency virus, or SIV) most likely was transmitted to humans and mutated into HIV when humans hunted these chimpanzees for meat and came into contact with their infected blood (CDC.gov, 2017a).
HIV is a type of lentivirus, which means it attacks the immune system. In a similar way, the SIV virus (simian immunodeficiency virus) attacks the immune systems of monkeys and apes (AVERT, 2017b).
Studies show that HIV may have jumped from apes to humans as far back as the late 1800s. Over decades, the virus slowly spread across Africa and later into other parts of the world. The virus has existed in the United States since at least the mid to late 1970s (CDC.gov, 2017a).
1.5.1 Crossing of HIV from chimps to humans
The most commonly accepted theory is that of the 'hunter'. In this scenario, SIVcpz was transferred to humans as a result of chimps being killed and eaten, or their blood getting into cuts or wounds on the human hunter. Normally, the hunter's body would have fought off SIV, but on a few occasions it adapted itself within its new human host and became HIV-1 (AVERT, 2017b).
There are four main groups of HIV strains (M, N O and P), each with a slightly different genetic make-up. This supports the hunter theory because every time SIV passed from a chimpanzee to a human, it would have developed in a slightly different way within the human body, and produced a slightly different strain. This explains why there is more than one strain of HIV-1 (AVERT, 2017b).
1.5.2 Ways of HIV-2 get passed to humans
HIV-2 comes from SIV in sooty mangabey monkeys rather than chimpanzees. The crossover to humans is believed to have happened in a similar way (through the butchering and consumption of monkey meat). It is far rarer, and less infectious than HIV-1. As a result, it infects far fewer people, and is mainly found in a few countries in West Africa like Mali, Mauritania, Nigeria and Sierra Leone (AVERT, 2017b).
1.6 HIV and the Immune System
One of the proteins that envelope HIV named gp 120, (a sugar-containing protein called a glycoprotein) “recognizes" a protein on helper T-cells named CD4, and physically associates with it. The CD4 protein is a normal part of a helper (both Th1 and Th2) T-cell's membrane. Thus, CD4 is a specific receptor for HIV. This virus however, can also infect other cells which include macrophages and certain other kinds of cells which can engulf substances through a process known as phagocytosis. As a consequence of the interaction with CD4 on helper T-cells, HIV specifically infects the very cells necessary to activate both B-cell and cytotoxic T-cell immune responses. Without helper T-cells, the body cannot make antibodies properly, nor can infected cells containing HIV (an intracellular pathogen) be properly eliminated. Consequently, the virus can multiply, kill the helper T-cell in which it lives, infect adjacent helper T-cells, repeat the cycle, and on and on, until eventually there is a substantial loss of helper T-cells ( AIDS, HIV and The Immune System, 2017).
The fight between the virus and the immune system for supremacy is continuous. Our body responds to this onslaught through production of more T-cells, some of which mature to become helper T-cells. The virus eventually infects these targets and eliminates them, too. More T-cells are produced; these too become infected, and are killed by the virus. This fight may continue for up to ten years before the body eventually dies, apparently because of the inability to any-longer produce T-cells. This loss of helper T-cells finally results in the complete inability of our body to ward-off even the weakest of organisms (all kinds of bacteria and viruses other than HIV) which are normally not ever a problem to us. This acquired condition of immunodeficiency is called, AIDS (AIDS, HIV and The Immune System, 2017).
1.7 The HIV Life Cycle
Binding and Fusion: HIV begins its life cycle when it binds to a CD4 receptor and one of two coreceptors on the surface of a CD4+ Lymphocyte. The virus then fuses with the host cell. After fusion, the virus releases RNA, its genetic material, into the host cell. (AIDSinfo,2017)
Reverse Transcription: An HIV enzyme called reverse transcriptase converts the single stranded
HIV RNA to double-stranded HIV DNA. (AIDSinfo,2017)
Integration: The newly formed HIV DNA enters the host cell's nucleus, where an HIV enzyme called integrates "hides" the HIV DNA within the host cell's own DNA. The integrated HIV DNA is called provirus. The provirus may remain inactive for several years, producing few or no new copies of HIV (AIDSinfo, 2017).
Transcription: When the host cell receives a signal to become active, the provirus uses a host enzyme called RNA polymerase to create copies of the HIV genomic material. Transcription of the viral genes env, gag and pol takes place to produce viral RNA, some of which will be incorporated into new virions and the rest is used in translation to produce three large, nonfunctional polyproteins, one derived from env, one from gag and the other from gag-pol gene (Virology Journal, 2017).
Assembly: An HIV enzyme called protease cuts the first long chains of HIV proteins into smaller individual proteins and produce viral glycoproteins (gp120, gp41), which are incorporated into cell membrane. The remaining two polypeptides remain intact and move to the inner surface membrane (Virology Journal, 2017).
Budding: The newly assembled virus pushes out ("buds") from the host cell. During budding, the new virus steals part of the cell's outer envelope. This envelope, which acts as a covering, is studded with protein/sugar combinations called HIV glycoproteins. These HIV glycoproteins are necessary for the virus to bind CD4 and coreceptors. The new copies of HIV can now move on to infect other cells (AIDSinfo, 2017).
1.8 Stages of HIV
Without treatment, HIV advances in stages, overwhelming immune system and getting worse over time. The three stages of HIV infection are: (1) acute HIV infection, (2) clinical latency, and (3) AIDS (acquired immunodeficiency syndrome) (AIDS.gov,2017c).
1.8.1 Acute infection stage
Within 2-4 weeks after HIV infection, many people develop flu-like symptoms, often described as “the worst flu ever.” Symptoms can include fever, swollen glands, sore throat, rash, muscle and joint aches and pains, and headache. This is called “acute retroviral syndrome” (ARS) or “primary HIV infection,” and it’s the body’s natural response to the HIV infection. During this early period of infection, large amounts of virus are being produced in the body. The virus uses CD4 count to replicate and destroys them in the process. Because of this, CD4 cells can fall rapidly. Eventually the immune response will begin to bring the level of virus in the body back down to a level called a viral set point, which is a relatively stable level of virus in the body. At this point, your CD4 count begins to increase, but it may not return to pre-infection levels. During the acute HIV infection stage, people are at high risk of transmitting HIV to the sexual or drug using partners because the levels of HIV in the blood stream are very high (AIDS.gov,2017c).
1.8.2 Clinical latency stage
After the acute stage of HIV infection, the disease moves into a stage called the “clinical latency” stage. “Latency” means a period where a virus is living or developing in a person without producing symptoms. During this stage, people who are infected with HIV experience no symptoms, or only mild ones. (This stage is sometimes called “asymptomatic HIV infection” or “chronic HIV infection” (AIDS.gov, 2017c).
During this stage, the HIV virus continues to reproduce at very low levels, although it is still active. If patients take ART, they may live with clinical latency for several decades because treatment helps keep the virus in check. For people who are not on ART, the clinical latency stage lasts an average of 10 years, but some people may progress through this stage faster. People in this symptom-free stage are still able to transmit HIV to others, even if they are on ART, although ART greatly reduces the risk of transmission (AIDS.gov, 2017c).
1.9 Mode of Transmission
HIV is not spread easily. Only certain body fluids from a person who has HIV can transmit HIV.
The body fluids are:
• Blood
• Semen (cum)
• Pre-seminal fluid (pre-cum)
• Rectal fluids
• Vaginal fluids
• Breast milk
These body fluids must come into contact with a mucous membrane or damaged tissue or be directly injected into the bloodstream (by a needle or syringe) for transmission to occur. Mucous membranes are found inside the rectum, vagina, penis, and mouth (AIDS.gov, 2017a).
HIV is spread mainly by
• Having anal or vaginal sex with someone who has HIV without using a condom or taking medicines to prevent or treat HIV.
• Anal sex is the highest-risk sexual behavior. Vaginal sex is the second highest-risk sexual behavior.
• Sharing needles or syringes, rinse water, or other equipment used to prepare injection drugs with someone who has HIV. HIV can live in a used needle up to 42 days depending on temperature and other factors (AIDS.gov, 2017a).
Less commonly, HIV may be spread
• From mother to child during pregnancy, birth, or breastfeeding. Although the risk can be high if a mother is living with HIV and not taking medicine.
• By being stuck with an HIV-contaminated needle or other sharp object. This is a risk mainly for health care workers (AIDS.gov, 2017a).
In extremely rare cases, HIV has been transmitted by
• Oral sex—putting the mouth on the penis, vagina or anus. In general, there is little to no risk of getting HIV from oral sex. But transmission of HIV, though extremely rare, is theoretically possible if an HIV-positive man ejaculates in his partner’s mouth during oral sex.
• Receiving blood transfusions, blood products, or organ/tissue transplants that are contaminated with HIV. This was more common in the early years of HIV, but now the risk is extremely small because of rigorous testing of the blood supply and donated organs and tissues.
• Eating food that has been pre-chewed by an HIV-infected person. The contamination occurs when infected blood from a caregiver’s mouth mixes with food while chewing.
The only known cases are among infants.
• Being bitten by a person with HIV. Each of the very small number of documented cases has involved severe trauma with extensive tissue damage and the presence of blood. There is no risk of transmission if the skin is not broken.
• Contact between broken skin, wounds, or mucous membranes and HIV-infected blood or blood-contaminated body fluids.
• Deep, open-mouth kissing if the person with HIV has sores or bleeding gums and blood from the HIV-positive partner gets into the bloodstream of the HIV-negative partner. HIV is not spread through saliva (AIDS.gov, 2017a).
1.10 Symptoms of HIV
The symptoms of HIV vary, depending on the individual and what stage of the disease people are in; 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 (AIDS.gov, 2017d).
1.10.1 Early stage of HIV
Some people may experience a flu-like illness within 2-4 weeks after HIV infection. But some people may not feel sick during this stage.
Flu-like symptoms can include:
-Fever - Rash
-Night sweats -Chills
-Muscle aches -Swollen lymph nodes
-Sore throat -Fatigue
-Mouth ulcers
These symptoms can last anywhere from a few days to several weeks. During this time, HIV infection may not show up on an HIV test, but people who have it are highly infectious and can spread the infection to others. 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 (AIDS.gov, 2017d).
1.10.2 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 (AIDS.gov, 2017d).
1.10.3 Progression to AIDS: AIDS (acquired immunodeficiency syndrome) is the late stage of HIV infection. Symptoms 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
-Diarrhea 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.
Each of these symptoms can also be related to other illnesses. So the only way to know for sure if anyone has HIV is to get tested.
Many of the severe symptoms and illnesses of HIV disease come from the opportunistic infections that occur because the body’s immune system has been damaged (AIDS.gov, 2017d).
1.11 Tests for HIV
There are three broad types of tests available: antibody tests, combination or fourth-generation tests, and nucleic acid tests (NAT). HIV tests may be performed on blood, oral fluid, or urine (CDC, 2017b).
1.11.1 Antibody test
Most HIV tests, including most rapid tests and home tests, are antibody tests. Antibodies are produced by the immune system when people exposed to viruses like HIV or bacteria. HIV antibody tests look for these antibodies to HIV in the blood or oral fluid. In general, antibody tests that use blood can detect HIV slightly sooner after infection than tests done with oral fluid (CDC, 2017b).
It can take 3 to 12 weeks (21-84 days) for an HIV-positive person’s body to make enough antibodies for an antibody test to detect HIV infection. This is called the window period. Approximately 97% of people will develop detectable antibodies during this window period. If one gets a negative HIV antibody test result during the window period, they should be re-tested 3 months after your possible exposure to HIV (CDC, 2017b).
The OraQuick HIV Test, which involves taking an oral swab, provides fast results. People have to swab their mouth for an oral fluid sample and use a kit to test it. Results are available in 20 minutes. The Home Access HIV-1 Test System is a home collection kit, which involves pricking the finger to collect a blood sample, sending the sample by mail to a licensed laboratory, and then calling in for results as early as the next business day. This test is anonymous. The manufacturer provides confidential counseling and referral to treatment (CDC, 2017b).
1.11.2 Combination or fourth-generation test
It looks for both HIV antibodies and antigens. If anyone infected with HIV, an antigen called p24 is produced even before antibodies develop. Combination screening tests are now recommended for testing done in labs and are becoming more common in the United States. There is now rapid combinations test available (CDC, 2017b).
It can take 2 to 6 weeks (13 to 42 days) for a person’s body to make enough antigens and antibodies for a combination, or fourth-generation, test to detect HIV. This is called the window period. If anyone gets a negative combination test result during the window period, they should be retested 3 months after your possible exposure (CDC, 2017b).
1.11.3 A nucleic acid test (NAT)
It looks for HIV in the blood. It looks for the virus and not the antibodies to the virus. The test can give either a positive/negative result or an actual amount of virus present in the blood (known as a viral load test). This test is very expensive and not routinely used for screening individuals unless they recently had a high-risk exposure or a possible exposure with early symptoms of HIV infection (CDC, 2017b).
It can take 7 to 28 days for a NAT to detect HIV. Nucleic acid testing is usually considered accurate during the early stages of infection. However, it is best to get an antibody or combination test at the same time to help the doctor interpret the negative NAT. This is because a small number of people naturally decrease the amount of virus in their blood over time, which can lead to an inaccurate negative NAT result. Taking pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) may also reduce the accuracy of NAT if people have HIV (CDC, 2017b).
1.12 HIV treatment
HIV treatment doesn't cure HIV. When successful, it reduces the amount of the virus (your 'viral load') to very low ('undetectable') levels. that it is not able to cause damage to the immune system. It's now recommended that everyone diagnosed with HIV starts treatment straight away regardless of their CD4 count. Once patients start treatment, it is likely they will be taking it for the rest of their life. Treatment with anti-HIV drugs is sometimes called combination therapy because people usually take three different drugs at the same time. It is also known as antiretroviral therapy, or highly active antiretroviral therapy - HAART for short (Terrence Higgins Trust, 2017).
1.12.1 Types of HIV treatment
Over 25 anti-HIV drugs are now available, in six 'classes' of drugs. Each class works against HIV in a particular way. People will take a combination of drugs – usually three.
The classes of anti-HIV drugs are:
• Nucleoside reverse transcriptase inhibitors (NRTIs or ’nukes’).
• Nucleotide reverse transcriptase inhibitors (NtRTIs).
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs or ‘non-nukes’).
• Protease inhibitors (PIs).
• Fusion and entry inhibitors.
• Integrase inhibitors.
(Terrence Higgins Trust, 2017)
1.12.1.1 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
They work by interrupting the life cycle of HIV as it tries to copy itself. These drugs also have other actions that prevent HIV from replicating in the body (Healthline, 2017).
1.12.1.2 Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
These drugs work in the same way as NRTIs. They stop the virus from replicating itself in your body (Healthline, 2017).
1.12.1.3 Protease inhibitors
They work by binding to protease. This is a protein that HIV needs to replicate in the body. When protease can’t do its job, the virus can’t complete the process that makes new copies. This reduces the number of viruses that can infect more cells (Healthline, 2017).
1.12.1.4 Entry inhibitors (including fusion inhibitors)
Entry inhibitors are another class of HIV medications. HIV needs a host T cell in order to make copies of itself. These drugs block the virus from entering a host T cell. This prevents the virus from replicating itself. These drugs also prevent the destruction of targeted cells. This action helps your immune system work better (Healthline, 2017).
1.12.1.5 Integrase Inhibitors
These stop HIV from making copies of itself by blocking a key protein that allows the virus to put its DNA into the healthy cell's DNA. They're also called integrase strand transfer inhibitors (INSTIs) (Healthline, 2017).
1.1 Table: Classes of drugs with examples
Class | Drug |
NRTI | Abacavir Efavirenz Emtriacitabine Tenofovir disoproxil fumarate Lamivudine Zidovudine Rilpivirine Didanosine Stavudine (Healthline,2017) |
NNRTI | Rilpivirine Etravirine Delavirdine mesylate Efavirenz Nevirapine (Healthline,2017) |
Protease inhibitor | Tipranavir Indinavir Atazanavir Saquinavir Lopinavir Fosamprenavir Ritonavir Cobicistat Darunavir Atazanavir Nelfinavir (Healthline,2017) |
Entry inhibitor | Enfuvirtide ibalizumab, PRO 140, and others are being tested for approval. (WebMD,2017a) |
Integrase inhibitor | Dolutegravir Elvitegravir Raltegravir (Healthline,2017) |
1.12.1.6 Chemokine co-receptor antagonists (CCR5 antagonists)
CCR5 antagonists prevent the spread of HIV. These drugs block infection in one of two molecules found on the surface of each body cell. Because it only affects one molecule, this drug is usually used with other medications for full HIV treatment. An example of this type of drug includes:
Maraviroc (Healthline, 2017).
1.12.1.7 Cytochrome P4503A (CYP3A) inhibitors
CYP3A is an enzyme that protects liver and gastrointestinal (GI) health. HIV can destroy this enzyme, leading to problems with your liver and GI tract. CYP3A inhibitors protect these enzymes to keep you healthy. These drugs affect your liver and come with the risk of jaundice. This may cause yellowing of your skin and the whites of your eyes. An example of this type of drug includes: Cobicistat (Tybost) (Healthline, 2017).
1.12.1.8 Immune-based therapies
Because HIV affects your immune system, researchers are studying ways that drugs can help boost immunity. Certain immune-based treatments have been successful in some people. Like some protease inhibitors, these drugs are used off-label for HIV. They are used along with other HIV medications. An example of an immune-based therapy includes: hydroxychloroquine sulfate which is a drug approved to treat autoimmune diseases such as lupus and rheumatoid arthritis (Healthline, 2017).
1.13 Side effects of HIV therapy
There are many potential side effects associated with antiviral therapies. The most common ones for each class of drug are summarized in readily available product information. Some specific toxicities are summarized by class below:
• Most NRTIs can cause mild nausea and loose stools. In general, these symptoms resolve with time.
• ZidovuZdin has been associated with decreased production of blood cells by the bone marrow, most often causing anemia, and occasionally hyperpigmentation (most often of the nails).
• Stavudine can damage nerves and cause peripheral neuropathy, a neurological condition with numbness and/or tingling of the feet and hands, and inflammation of the pancreas (pancreatitis) that causes nausea, vomiting, and mid/upper abdominal pain.
• DDI also causes pancreatitis and, to a lesser extent, peripheral neuropathy. Peripheral neuropathy can become permanent and painful, and pancreatitis can be life-threatening if therapy is not discontinued. The drug ddC also is associated with peripheral neuropathy, as well as oral ulcers.
• Abacavir Sulfate can cause a hypersensitivity reaction during the first two to six weeks of therapy in approximately 5% of individuals. The hypersensitivity reaction most often causes fever and other symptoms, such as muscle aches, nausea, diarrhea, rash, or cough.
• Tenofovir Disoproxil Fumarate is generally well tolerated although there may be rare kidney damage and may have a greater impact on reducing bone density than other agents.
• Emtricitabine is also well tolerated except for the occasional development of hyperpigmentation, most often on the palms and soles. This hyperpigmentation occurs more frequently in people of color.
• Although all NRTIs can be associated with lactic acidosis (a serious condition in which lactic acid accumulates in the blood), it may occur more often with some drugs, such as d4T. Although this complication of treatment is rare, it can be severe and life threatening. Early symptoms of lactic acidosis are nausea, fatigue, and sometimes shortness of breath. Lactic acidosis needs to be watched for and, if suspected, requires that therapy be discontinued until symptoms and laboratory test abnormalities resolve.
• There has been a great deal of attention given to the more recently identified problem of "lipodystrophy." Individuals suffering from this syndrome can be categorized as having lipohypertrophy (fat accumulation) syndromes, such as the "buffalo hump" on the back of the neck, breast enlargement, or increased abdominal girth. The NRTIs appear to be most closely linked to lipoatrophy, in particular D4T and to a lesser extent
ZDV. In fact, some studies have suggested slow accumulation of fat in those who modify
the NRTI component of their regimen. Some NRTIs also have been linked to elevation in lipid (fat) levels in the blood.
• NNRTIs: the most common side effect associated with NNRTIs is a rash.
• Side effects associated with Efavirenz are mostly dizziness, confusion, fatigue, and vivid dreams. These tend to be most prominent during the first weeks of therapy and then often decrease in severity.
• Fusion inhibitors: the only drug in this class is T-20. The most common side effects are redness and pain at the site of injection.
• CCR5 antagonist: although there were some early concerns of liver inflammation for drugs in this class.
• Integrase strand transfer inhibitors: RAL has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems and of increasing depression that needs to be watched for when starting this or any new medications (WebMD, 2017a).
1.14 Monitoring antiviral therapy
The goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing important side effects or selecting for drug-resistant virus. Currently, the best marker of a drug's activity is a decrease in the viral load. Ideally, prior to initiating treatment, the viral load and the CD4 cell count should be checked and the viral load test then repeated after approximately four weeks of treatment. If the patient is beginning a regimen that includes two to three drugs for which the patient's virus does not appear to be resistant, it is expected that the amount of virus should decrease by at least a hundredfold during this interval. The ultimate goal is for the viral load to decrease to undetectable levels which should occur by approximately 12-24 weeks. There are some individuals that despite taking all of their medications correctly will suppress their viral load to less than 200 copies/mL but not consistently undetectable levels. It is not completely known how to optimally manage this situation but many experts would continue to monitor on current therapy as long as viral load remains below 200 copies/mL. Those who are not having an appropriate response to therapy need to be questioned to make sure that they are taking their medications correctly, and if not, why. If the viral load is not going to undetectable levels and the patient is taking the medications correctly, then it is likely that there is a resistant virus to some of the medications. (WebMD. 2017b)
1.15 Risks of missing doses or stopping antiviral therapy
It is strongly advised that individuals on an antiviral regimen not miss any doses of their medications. Unfortunately, life is such that doses often are missed. Reasons for missing doses range from just forgetting to take the medication, leaving town without the medication, or because of a medical emergency, such as the need for urgent surgery. For example, after an appendectomy for acute appendicitis, a patient may not be able to take oral medication for up to several days. When a dose is missed, the patient should contact his or her physician without delay to discuss the course of action. The options in this situation are to take the missed doses immediately or simply resume the drugs with the next scheduled dose. (WebMD. 2017b)
Although every missed dose increases the chance that the virus will develop resistance to the drugs, a single missed dose should not be cause for alarm. On the contrary, it is an opportunity to learn from the experience and determine why it happened, if it is likely to happen again, and what can be done to minimize missing future doses. Furthermore, if a patient cannot resume medication for a limited time, such as in a medical emergency, there still is no cause for alarm. In this circumstance, the patient should work with their HIV provider to restart therapy as soon as is feasible. Stopping antivirals is associated with some risks of developing drug resistance, and those who wish to stop therapy for any one of a number of reasons should discuss this with their health-care professional in advance to establish the best strategy for safely accomplishing this (WebMD. 2017b).
1.16 Treatment for HIV during pregnancy
One of the greatest advances in the management of HIV infection has been in pregnant women. Prior to antiviral therapy, the risk of HIV transmission from an infected mother to her newborn was approximately 25%-35%. The first major advance in this area came with studies giving ZDV after the first trimester of pregnancy, then intravenously during the delivery process, and then after delivery to the newborn for six weeks. This treatment showed a reduction in the risk of transmission to less than 10%. Although less data are available with more potent drug combinations, clinical experience suggests that the risk of transmission may be reduced to less than 5%. Current recommendations are to advise HIV-infected pregnant women regarding both the unknown side effects of antiviral therapy on the fetus and the promising clinical experience with potent therapy in preventing transmission. In the final analysis, however, pregnant women with HIV should be treated essentially the same as nonpregnant women with HIV. Exceptions would be during the first trimester, where therapy remains controversial, and avoiding certain drugs that may cause greater concern for fetal toxicity, such as Efavirenz (WebMD. 2017b).
All HIV-infected pregnant women should be managed by an obstetrician with experience in dealing with HIV-infected women. Maximal obstetric precautions to minimize transmission of the HIV virus, such as avoiding scalp monitors and minimizing labor after rupture of the uterine membranes, should be observed. In addition, the potential use of an elective Caesarean section (C-section) should be discussed, particularly in those women without good viral control of their HIV infection where the risk of transmission may be increased. Breastfeeding should be avoided if alternative nutrition for the infant is available since HIV transmission can occur by this route. When breastfeeding is done, it should be in conjunction with antiretroviral therapy for the mother if at all possible (WebMD. 2017b).
1.17 Prevention
HIV is often spread by people who don't know they have it. So it's always important to protect ourselves and others by taking these steps:
• Practice of safer sex: Using a condom every time having sex (including oral sex) until makes sure that the partners aren't infected with HIV or other sexually transmitted infection (STI).
• Not having more than one sex partner at a time. The safest sex is with one partner who has sex only with one.
• Talking with partner before having sex for the first time. Finding out if he or she is at risk for HIV. Get tested together. Getting tested again at 6, 12, and 24 weeks after the first test can be done to be sure neither of them are infected. Using condoms in the meantime.
• Avoid drinking a lot of alcohol or using illegal drugs before sex. People may let down their guard and not practice safer sex.
• Not sharing personal items, such as toothbrushes or razors.
• Never share needles or syringes with anyone.
• If anyone is at high risk for getting infected with HIV, he\ she can take antiretroviral medicine to help protect themselves from HIV infection. Experts may recommend this for:
Ø People whose sexual practices put them at high risk for HIV infection, such as men who have sex with men and people who have many sex partners.
Ø People who inject illegal drugs, especially if they share needles.
Ø Adults who have a sex partner with HIV.
To keep the risk low, people still need to practice safer sex even while they are taking the medicine (WebMD. 2017b).
1.18 Myths of HIV
• HIV is a death sentence: “With proper treatment, we now expect people with HIV to live a normal life span,” says Dr. Michael Horberg, national director of HIV/AIDS for Kaiser Permanente. “Since 1996, with the advent of highly active, antiretroviral therapy, a person with HIV in an industrialized nation can expect to live a normal life span, so long as they take their prescribed medications,” adds Dr. Amesh A. Adalja, a board-certified infectious disease physician with the University of Pittsburgh.
• One can tell if someone has HIV/AIDS by looking at them: Often, there are no visible signs of HIV/AIDS. “Some people develop HIV symptoms shortly after being infected. For others, it can take up to 10 years for symptoms to appear,” says Dr. Gerald Schochetman, senior director of infectious diseases with Abbott Diagnostics. Schochetman worked at the CDC during the height of the AIDS crisis. Further, the first symptoms of HIV, including a fever, fatigue, and muscle aches, may only last for a few weeks. “Thus, it’s very hard for people to know if they or someone else has HIV without being properly tested,” says Schochetman.
• Straight people don’t have to worry about HIV infection: “We know that the highest risk group is men who have sex with men,” says Dr. Horberg. This group accounts for about 78 percent of new infections, according to the CDC. “However, heterosexuals accounted for 24 percent of new HIV infections in 2010, and about two-thirds of those were women.”
• HIV-positive people can’t safely have children: It is possible to have a child if one and his\her partner is HIV-positive. While it’s impossible to guarantee that the infection won’t pass on to the child, the U.S. Department of Health and Human Services says there are ways to greatly reduce the risk. For example, an HIV-positive woman can take antiretroviral therapy (ART) before and during pregnancy. “As long as a partner takes their medication correctly and has an undetectable viral load, the likelihood of transmitting the infection to their child is pretty slim to none,” explains psychotherapist Keeley Teemsma, who has specialized in the treatment of HIV/AIDS patients.
• HIV always leads to AIDS: HIV is the infection that causes AIDS. But this doesn’t mean all HIV-positive individuals will actually develop AIDS. “With current therapies, levels of HIV infection can be controlled and kept low, maintaining a healthy immune system for a long time and therefore preventing opportunistic infections and a diagnosis of AIDS,” explains Dr. Richard Jimenez, professor of public health at Walden University.
• With all of the modern treatments, HIV is no big deal: This sort of attitude has led some to practice carefree and reckless sexual behavior. “The younger generation has lost some fear of HIV because of the success of treatment,” explains Dr. Adalja. “This has caused them to engage in risky behaviors, leading to high rates of infection in young men who have sex with other men.”
• If I take PrEP, I don’t need to use a condom: PrEP (pre-exposure prophylaxis) is a medication that can prevent HIV infection in advance. According to Dr. Horberg, a recent study from Kaiser Permanente followed people using PrEP for two and a half years, and found that it was effective at preventing HIV infections. However, it doesn’t protect against other sexually transmitted diseases or infections. “Prep is recommended to be used in combination with safer sex practices, as our study also showed that half of the patients participating were diagnosed with a sexually transmitted infection after 12 months,” says Dr. Horberg.
• If one test negative for HIV, he\she can have unprotected sex: If you or your partner was recently infected with HIV, it may not show up on an HIV test until about three months later. “Traditionally used antibody-only tests work by detecting the presence of antibodies in the body that develop when HIV infects the body,” explains Dr. Schochetman. “But it takes about three weeks for there to be enough antibodies for detection. “Before you should even consider having unprotected sex, you should take a second HIV test three months after the first, to confirm your negative reading. If you are having regular sex, the San Francisco AIDS Foundation suggests getting tested every three months. Other tests, known as HIV combo tests, can detect the virus earlier.
• If both partners have HIV, there’s no reason for a condom: Not all strains of HIV are the same, and being infected with more than one can lead to greater complications, or a “superinfection,” according to Dr. Schochetman. “The new HIV strain may exhibit a different drug resistance profile than the original HIV infection,” he explains. “And the new virus may show resistance to the current treatment, or cause the current treatment option to be ineffective” (Healthline, 2017).
1.19 Epidemiology
HIV continues to be a major global public health issue. In 2015, an estimated 36.7 million people were living with HIV (including 1.8 million children) – a global HIV prevalence of 0.8%.1 2.The vast majority of this number live in low- and middle- income countries. In the same year, 1.1 million people died of AIDS-related illnesses.Since the start of the epidemic, an estimated 78 million people have become infected with HIV and 35 million people have died of AIDS-related illnesses(AVERT,2017a).
In 2015, there were roughly 2.1 million new HIV infections, 150,000 of which were among children. Most of these children live in sub-Saharan Africa and were infected via their HIVpositive mothers during pregnancy, childbirth or breastfeeding (AVERT, 2017a)
Progress in decreasing new HIV infections among adults has slowed in recent years. Since 2010, the annual number of new infections among adults (15+) has remained static at 1.9 million (AVERT, 2017a).
A comparison of country data shows huge discrepancies in efforts to slow the spread of new infections. Some countries have achieved a decline of 50% or more in new HIV infections among adults over the last 10 years, while many have made no measurable progress. Yet others are experiencing worrying increases in new HIV infections (AVERT, 2017a)
In 2015, US$ 19 billion was invested in the HIV and AIDS response in low- and middle- income countries with 57% of the total HIV resources in these countries coming from domestic budgets. Rising numbers of new HIV infections in many countries means that US$ 26.2 billion will be required for the response to the epidemic in 2020, with US$ 23.9 billion required in 2030 (AVERT, 2017a).
1.20 Scenario in Bangladesh
Bangladesh remains a low HIV prevalence country with less than 0.1% overall prevalence in general population over the years. The HIV prevalence remains less than 1% both among key and bridge populations. Till date, the country has registered a total of 3674 cases of HIV infection. However, the estimated number of people living with HIV is around 9500. Although the prevalence remains low, Bangladesh is one of the only four countries in Asia and the Pacific where prevalence has increased more than 25% over a decade till 2012.
• In 2014 Number of people living with HIV are 8,900 [8,000 - 9,800]
• Adults aged 15 to 49 prevalence rate <0.1% [<0.1% - <0.1%]
• Adults aged 15 and up living with HIV 8,600 [7,700 - 9,400]
• Women aged 15 and up living with HIV 2,900 [2,600 - 3,100]
• Children aged 0 to 14 living with HIV <500 [<500 - <500]
• Deaths due to AIDS <1000 [<1000 - 1,200]
• Orphans due to AIDS aged 0 to 17 N/A (UNAIDS, 2015).
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