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Cures for Hiv

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What are scientists doing to solve of the problem of HIV?
What are scientists doing to solve of the problem of HIV?

By Prerana Bhandari
St Olaves Grammar School
By Prerana Bhandari
St Olaves Grammar School
Image taken from: http://cdn.zmescience.com/wp-content/uploads/2014/04/hiv_virus.jpg
This human T cell (blue) is under attack by HIV (yellow), the virus that causes AIDS.
Image taken from: http://cdn.zmescience.com/wp-content/uploads/2014/04/hiv_virus.jpg
This human T cell (blue) is under attack by HIV (yellow), the virus that causes AIDS.

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Contents: 1. Biological Problem 2. Pathology 3. Solutions for HIV: 4. 14

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Main Solution: Stribild or Quad study 102 and 103: 5. Evaluation of Stribild: Are the processes and methods appropriate for producing valid and reliable data and effective solutions? 6. How Stribild works 7. Limitations of Stribild 8. Benefits and Risks of Stribild to humans 9. Alternate solutions 10. Conclusion 11. References 12. Evaluation of sources
What are scientists doing to solve of the problem of HIV?
Biological Problem:
HIV (human immunodeficiency virus) is a virus which attacks the immune system, and weakens your ability to fight infections and disease and the final stage of HIV; AIDS (acquired immune deficiency) is when your body can no longer fight life-threatening infections. Majority of HIV suffers will not develop AIDs if diagnosis is fast and treatment starts early. [22]
The main biological problem with HIV is the fact that it effects almost 35 million people and the majority of who live in less developed countries (refer to figure 1 and 2) where people may find it hard extremely hard to afford treatment. This makes is extremely hard to eradicate meaning there are millions of new cases every year and the virus keeps spreading throughout the poorer countries. [16]
Another huge problem is the fact that it is incurable. The currents treatments all tackle the symptoms but none are able to eradicate the virus permanently.[23] This is because unlike other viruses, it hides away in Helper T-Cells (the white blood cells which help to detect infections), and destroys them (this mechanism will be explained in the pathology section). HIV/AIDS does not kill people. HIV infects a kind of white blood cell called a CD4 lymphocyte, a key player in the immune response. What makes HIV so difficult to treat is that it infects the very cells that are supposed to rub out viral infections to the point that the body can't fight off other infections. This is why the white blood cell concentration (especially CD4+ cell counts) are monitored thoroughly when treating HIV. AIDS suffers die of other diseases that should be harmless to healthy people.
Another problem with the HIV virus is it cannot be detected in its dormant/resting state, so trying to vaccinate using antibodies like we would for a normal virus is useless. So even when the active form of the virus has been “wiped out” by standard treatments, a reservoir of dormant HIV viruses are still present in the white blood cells, which will eventually become active and re-infect the body. Essentially, similar to cancer, you are trying to target “normal” body cells that have malfunctioned or been intruded by pathogens and it is very hard for us to use present technologies to differentiate between healthy and infected body cells. [13]
Introduction:
HIV was first identified in Los Angeles in 1981 but it is believed to have originated from central Africa in the 1950s. A HIV related virus (SIV: Simian immunodeficiency virus) was somehow transferred from Africa green monkeys to humans, mutated and evolved into HIV. [11] It has now spread throughout the world and at the end of 2013 there were 35 million people were living with HIV. [15] HIV is dangerous because it attacks helper T cells. It is a retrovirus which incorporates its own genetic material into that of the host cell. As the DNA replicates, the HIV positive person may be symptomless for years. When active, HIV uses the host cells machinery to make new viruses and when enough new viruses are made the host cells burst opens and dies and the virus find another host cell, consequently supressing the immune system. This means patients are more vulnerable to other diseases such as Kapsosi’s sarcoma (shown in figure 7), which would normally be fought off by the immune system. Death can result from opportunistic diseases such as cancer and pneumonia or pre-existing diseases such are tuberculosis. [13]

Figure 1: http://www.travelsante.com/sources/carte-maladies-2011/hiv_2011.jpg
Figure 1: http://www.travelsante.com/sources/carte-maladies-2011/hiv_2011.jpg

Figure 2: http://www.avert.org/worldwide-hiv-aids-statistics.htm
Figure 2: http://www.avert.org/worldwide-hiv-aids-statistics.htm

HIV mainly affects less economically developed counties, though HIV is prevalent in Russia as shown in the figure 1 above. The number of cases is quite high in America as shown by figure 2. Despite this, death caused by HIV and AIDS is quite low compared to the mortality rates of people with HIV in the sub-Saharan area. Men and women are at equal risk, though the incidence of HIV is highest in homosexual men. [16] It is mainly transmitted sexually, both between heterosexual couples and homosexual couples. The first documented case occurred as a result of gay sex. This resulted in a social stigma towards homosexual men, leading to a misconception that gay men were spreading HIV/AIDS. [11] It is in fact passed on though infected vaginal fluids or semen to the blood of damaged tissue in the rectum, vagina or penis. It can also be transferred through transfusion of infected blood, through needles of drug users for example and though the placenta of an infect mother or through breast feeding. However, the virus is fairly weak and does not survive outside the body though ordinary social contact with a HIV positive person does not have a risk of infection. [22]
HIV is also very variable and it can escape detection by frequently changing the shape of its antigens. Even though we cannot completely cure HIV, chemotherapy and combination therapy can be used to supress symptoms and improve life expectancy. Figure 3 shows the increase in life expectancy from 2000-2012. In 1996, when such drugs were starting to become widespread, the UK Medical Research Council estimated a 20-year-old with HIV, who was receiving treatment, could expect to live to an average age of 50. By 2008, this group could expect to live to an average age of almost 66 - a 16-year improvement. Though without treatment average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. After the diagnosis of AIDS, if treatment is not available, survival ranges between 6 and 19 months. [14] Gene Therapy and Bone marrow transplants are being thoroughly researched into and it may be a possible cure in the future. [17]
Figure 3 https://inequalitiesblog.files.wordpress.com/2013/02/gains_in_life_expectancy.jpg
Figure 3 https://inequalitiesblog.files.wordpress.com/2013/02/gains_in_life_expectancy.jpg
HIV also has a considerable impact on the economics of a country by reducing the taxable population and increasing the amount of money needed to be spent on healthcare. A study in Côte d'Ivoire showed that households having a person with HIV/AIDS spent twice as much on medical expenses as other households. [25]

Pathology: HIV is a retrovirus (has an outer envelope and replicates through reverse transcriptase as shown in figure 4) that attacks T-lymphocyte white blood cells using their cellular machinery to replicate, eventually causing them to burst open and release the new viruses which latch onto a new host cell and repeating this process. This process severely supresses the immune system, leading HIV positive people to become very vulnerable to diseases such as hepatitis C. [13]

Figure 4: labelled HIV virus http://upload.wikimedia.org/wikipedia/commons/6/63/HIV_Virion-en.png
Figure 4: labelled HIV virus http://upload.wikimedia.org/wikipedia/commons/6/63/HIV_Virion-en.png

T helper cells: T helper cells are lymphocytes that mature in thymus, produced as response to a cell-mediated immune response. Each cell has a particular receptor protein on its surface specific to a particular antigen. That particular antigen triggers the T helper cells multiply mitotically. Some resulting cells remain in the blood and lymph as memory cells will others activate other cells such as macrophages, suppressor T cells and killer T cells. T helper cells also activate B cells, communicating through the means of cytokines, which act as inhibitors and activators of different cell activities such as differentiation and growth. [17]
HIV and T-helper cells:
The bullet shaped viral capsid, made from the protein p24 contains three enzymes required for HIV replication called reverse transcriptase, integrase and protease and HIV's genetic material, which consists of two identical strands of RNA. The HIV virus binds to the CD4 surface receptor which is exclusive to T helper cells. This causes a conformational change. Once attachment is finished, penetration occurs. The nucleocapsid is injected directly into the cell's cytoplasm. Gp120 (shown in figure 4) contains three glycoproteins and, once gp120 attaches itself to CD4, these three proteins spread, allowing the gp41 protein, which is normally hidden by the gp120 proteins, to become exposed and bind to the chemokine receptor (CCR5). Once this has occurred, the viral envelope and the cell membrane fuse. [13]
The nucleocapsid is then partially dissolved to release the genetic material of the virus into the T-helper cells. Through the aid of the enzyme reverse transcriptase, a single strand RNA is converted into double stranded DNA, using nucleotides from the cytoplasm of the T cell. Once pro-viral DNA synthesis is complete, integration takes place. It is unclear how HIV transports the pre-integration complex across the nuclear membrane, but once the DNA has successfully breached the membrane, intergrase inserts the virus’ DNA into the T cell’s. [13]
The cell is now latently infected with HIV and the infected DNA is referred to as the provirus which waits activation. When activated, cellular machinery of the T-cells produces necessary components of HIV. Two strands of RNA are constructed using the transcription process and transported out of the nucleus. One strand is translated into subunits of HIV such as protease, reverse transcriptase, integrase, and structural proteins. The other strand becomes the genetic material for the new viruses. The subunits now separate and assemble into a new virus. The separation is done with the help of the viral protease enzyme. The assembly occurs when the different subunits mesh with the membrane and deform it causing the nucleocapsid to take shape and the RNA to become enclosed in it. Then the genetic material in the nucleocapsid merges with the deformed cell membrane to form the new viral envelope and a new outer coat made from the host cell's membrane, the newly formed HIV pinches off and enters circulation and starts the whole process again. [13]
The T-cells are destroyed (the mechanism of how is unclear) at a colossal rate and eventually T-cell numbers begin to decrease and eventually there aren’t enough to effectively defend the body. This is known as AIDS. Figure 6 shows the CDA count as the HIV infection progresses. The main causes of death from HIV/AIDS are opportunistic infections and cancer, due to the progressive failure of the immune system. [13]
Figure6: 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
Figure6: http://aras.ab.ca/articles/scientific/GraphEvolutionFigures/niaid.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
Tuberculosis co-infection is one of the leading causes of sickness and death in those with HIV/AIDS being present in a third of all HIV infected people and causing 25% of HIV related deaths. Hepatitis C is another common co-infection and the most common cancers associated with HIV/AIDS are Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphoma. Even with anti-retroviral treatment, the long term effects HIV-infected people may experience neurocognitive disorders, osteoporosis, neuropathy, cancers, nephropathy, and cardiovascular disease. [11]

Figure 7: Kaposi’s sarcoma http://www.avert.org/sites/default/files/image/5474/5474-kaposis-sarcoma-615x300.jpeg
Figure 7: Kaposi’s sarcoma http://www.avert.org/sites/default/files/image/5474/5474-kaposis-sarcoma-615x300.jpeg

Solutions for HIV:
Over the last decade, there has been tremendous progress in the fight against HIV/AIDS with huge advances in treatment effectiveness, easy access to affordable drugs, and ways to prevent further transmission of the deadly virus. Because of this, being diagnosed with HIV today is no longer an early death sentence. However, there is still no functional cure for HIV. Never the less, the most common means of treating the symptoms of HIV is through ART (antiretroviral therapy), the goal of which is to reduce the amount of replicating (active) virus to a minimum, to prevent infection of new cells and further damage to the immune system. Presently there are no anti-HIV drugs available that can permanently eradicate or kill the virus throughout the body. The amount of replicating virus in the blood can be measured using a simple blood test, called a viral load test. The most commonly used test can detect virus particles down to 50 copies of the virus per ml. If your viral load is lower than this, the result is referred to as ‘undetectable’. Chemotherapy may be used [17], but quite rarely and bone marrow transplant is still being researched into. [12]
Traditionally, combination treatment would be given in the form of 2-3 different pills but in recent years, drug companies have worked together to combine these complex regimens into simpler formulas, called fixed-dose combinations. For instance, there are now several options that combine 3 drugs into one pill taken once daily. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken and thus their long term effectiveness. Not taking anti-retrovirals regularly is a cause of resistance development in people who have started taking them previously: [9] Here are the Current World Health Organization guidelines (dated June 30, 2013) on starting HIV treatment: * Initiate ART if CD4 cell count ≤500 cells/ml * As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤ 350 cells/mm * Initiate ART regardless of WHO clinical stage or CD4 cell count in * Active TB disease * HBV coinfection with severe chronic liver disease * Pregnant and breastfeeding women with HIV * HIV-positive individual in a serodiscordant partnership (to reduce HIV transmission risk) [10]

Main Solution: Stribild or Quad (fixed-dose combination) study 102 and 103:
Stribild is a fixed combination containing the drugs elvitegravir, emtricitabine, tenofovir and cobicistat, that was recently approved by the FDA in 2012 for the treatment of adult patients. [9] In a trial called GS-US-236-0102 (we shorten this to trial ‘102), researchers compared the following regimens in a randomized, placebo-controlled design: * Stribild * Atripla (a fixed-dose tablet containing efavirenz, tenofovir and FTC which was the leading fixed dose treatment at the time.)

In trial GS-US-236-0103 (shortened to trial ‘103), researchers compared the following regimens also in a randomized, placebo-controlled design: * Stribild * Atazanavir (Reyataz) + ritonavir (Norvir) + tenofovir + FTC [5]

Methodology:

Figure 8: https://www.stribild.com/hcp/Content/img/Study_103_and_102.png
Figure 8: https://www.stribild.com/hcp/Content/img/Study_103_and_102.png

1. Subjects were randomized in a 1:1 ratio as shown in figure 8. 2. Patients randomly either had elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) once a day for 144 weeks or the other proven combinations (shown in figure 8) once a day. 3. No pregnant women were included in either trial. 4. Each trial compared stribild against medicines proven to treat HIV-1. 5. The trials included both men and women; however, most of the patients in these studies were men. 6. All patients in each trial were adults who had never taken an HIV-1 medicine before and had normal kidney function. 7. The study protocol is shown in figure 9. Two randomized, double-blind, active-controlled trials in treatment-naive HIV-1 infected adults with baseline estimated creatinine clearance ≥70 mL/min

Figure 9: https://www.stribild.com/hcp/Content/img/Baseline_Characteristics.png
Figure 9: https://www.stribild.com/hcp/Content/img/Baseline_Characteristics.png

8. After three years, doctors were told which drugs the patients had been taking, and they measured the results. 9. This was sponsored by the actual company that produces Stribild. However the protocol was approved by the human research committee. 10. Consent was taken from each participant before starting the trials [4][5]
The following criteria were assessed after each time period (48, 96 and 144 weeks):

1. Virological success: To actually see what effect the drugs were having on the virus. Measured the percentage of people that had HIV-1 RNA <50 copies/mL in the blood. [5] 2. Response depending on viral baseline load: to see if the response to the drug was dependant on baseline viral loads (amount of virus in the blood before treatment starts). Subjects were stratified by baseline HIV-1 RNA (≤100,000 copies per mL or >100,000 copies per mL) and then the percentage of people with an undetectable viral load was compared. [5] 3. Mean increase from baseline in CD4 cell count at week 144. The concentration of cells per mmᵌ was measured at the start and at the end from all the patients and an average was taken. [5] 4. Development of resistance to the drug (Viremic subjects defined as having HIV-1 RNA >400 copies/mL at virologic failure, week 144, or time of study discontinuation. Viremic subjects who received at least 8 weeks of treatment and had evaluable genotypic data were included in this analysis.) [5] 5. Lastly, the patients were asked about the adverse effects they felt at each consultation. This was to make sure there are no severe and frequently occurring side effects and also to ensure the safety of the patient. [5] Results: Out of the 701 people who were trialing stribild, 4% left the trail early due to adverse side effects and 1 person died due to suicide. However these drop out and death rates were higher in the other combination drugs; Atripla – 5% of participant, Atazanavir-based regimen – 5% of participants Atripla – 2 people atazanavir-based regimen – 3 people. [1][2]

Causes of death:

* Suicide – 2 people; one was taking Atripla and one was taking the Quad. According to the FDA, the latter person had a history of “major depression, bipolar disorder, insomnia and amphetamine abuse.” His depression was stable when he entered the study. * cancer (metastatic carcinoma) – 1 person * overwhelming bacterial infection – 1 person * life-threatening pneumonia – 1 person * cardiac arrest due to “an overdose of recreational drugs” – 1 person[6]

Adverse effects included: diarrhea, nausea, fatigue, fever, increased levels of the waste product creatinine in the blood and kidney failure. The last only occurred in stribild users.

Adverse events affecting muscles and/or bones were more common among Stribild users:

* Stribild – 21% * Atripla – 16% * atazanavir-based regimen – 16%[6]

Results: Main graph (virological response):

Figure 10: https://www.stribild.com/hcp/Content/img/Viral_Suppression_Rates.png
Figure 10: https://www.stribild.com/hcp/Content/img/Viral_Suppression_Rates.png

Figure 10 shows that Stribild had the highest percentage of people who were below a detectable viral load in 3 out of 4 groups. Stribild is also generally more effective on people with a lower baseline viral load and it is effective on a little less than 80% of the population. The graph below (figure 11) shows that the percentage of successful treatments decreased from straight after started to the end of the 3 years showing that this drug might not be a good long term treatment. There are also fluctuations as the percentage do go up and down; it isn’t just a linear progression. This decrease may be due to development of drug resistance. Stribild is also almost always just as, or more effective than the other combinations. In conclusion, compared to the other combinations Stribild is generally more effective a little bit safer, but it does have considerable side effects with a 4% drop out rate. The results of study 102 are less favourable to Stribild than the results of study 103 because it shows the other combination to be more effective again people with higher baseline viral loads (amount of virus before treatment starts).[5]
Figure 10 shows that Stribild had the highest percentage of people who were below a detectable viral load in 3 out of 4 groups. Stribild is also generally more effective on people with a lower baseline viral load and it is effective on a little less than 80% of the population. The graph below (figure 11) shows that the percentage of successful treatments decreased from straight after started to the end of the 3 years showing that this drug might not be a good long term treatment. There are also fluctuations as the percentage do go up and down; it isn’t just a linear progression. This decrease may be due to development of drug resistance. Stribild is also almost always just as, or more effective than the other combinations. In conclusion, compared to the other combinations Stribild is generally more effective a little bit safer, but it does have considerable side effects with a 4% drop out rate. The results of study 102 are less favourable to Stribild than the results of study 103 because it shows the other combination to be more effective again people with higher baseline viral loads (amount of virus before treatment starts).[5]

Figure 11: https://www.stribild.com/hcp/Content/img/Study_103_ITT.png
Figure 11: https://www.stribild.com/hcp/Content/img/Study_103_ITT.png

Figure 12: https://www.stribild.com/hcp/Content/img/Resistance_Profile.png
Figure 12: https://www.stribild.com/hcp/Content/img/Resistance_Profile.png
Other results:

Figure 13: https://www.stribild.com/hcp/Content/img/Drug_Resistance_Mutations_Combined.png
Figure 13: https://www.stribild.com/hcp/Content/img/Drug_Resistance_Mutations_Combined.png

The problem of drug resistance is average in Stribild, compared to other drugs (as shown in figures 12 and 13), implying that it may not be the most sustainable treatment or any more advanced in this area than the other drugs. ATV+RTV+FTC had the least drug resistance whereas EFV/FTC/TDF had the almost double the drug resistance of Stribild. The intergrase inhibitor in Stribild seemed to be the main problem so further research may have to be done on a replacement or improving the existing drug. Also not everyone was analysed, so we do not know the exact number of people that developed a resistance to any aspect of this treatment. Also we can only speculate the number of people that may develop a resistance to these drugs in the future. These results definitely imply that a new fixed dose combination may have to be developed as a replacement soon or atleast the exiating treatment will have to be improved.
The problem of drug resistance is average in Stribild, compared to other drugs (as shown in figures 12 and 13), implying that it may not be the most sustainable treatment or any more advanced in this area than the other drugs. ATV+RTV+FTC had the least drug resistance whereas EFV/FTC/TDF had the almost double the drug resistance of Stribild. The intergrase inhibitor in Stribild seemed to be the main problem so further research may have to be done on a replacement or improving the existing drug. Also not everyone was analysed, so we do not know the exact number of people that developed a resistance to any aspect of this treatment. Also we can only speculate the number of people that may develop a resistance to these drugs in the future. These results definitely imply that a new fixed dose combination may have to be developed as a replacement soon or atleast the exiating treatment will have to be improved.

Figure 14: https://www.stribild.com/hcp/Content/img/Mean_CD4.pnghttps://www.stribild.com/hcp/Content/img/Mean_CD4.png
Figure 14: https://www.stribild.com/hcp/Content/img/Mean_CD4.pnghttps://www.stribild.com/hcp/Content/img/Mean_CD4.png

Contrasting with the trends shown in the main graph, the results for 103 are less favourable towards Stribild than 102 (as shown in figure 14) and there is quite a wide range between the two average increases in baseline for patients taking Stribild showing that the treatment might not be very reliable and will have different levels of effectiveness on each patient. The average of the two results for stribild is 280 which is higher than both of the other combinations, implying that it is still more effective on average compared with the other drugs. All treatments showed an increase in CD4 cells showing that they are all effective treatments. These results may imply that Stribild is a hit and miss treatment and may not be effective on everybody.
Contrasting with the trends shown in the main graph, the results for 103 are less favourable towards Stribild than 102 (as shown in figure 14) and there is quite a wide range between the two average increases in baseline for patients taking Stribild showing that the treatment might not be very reliable and will have different levels of effectiveness on each patient. The average of the two results for stribild is 280 which is higher than both of the other combinations, implying that it is still more effective on average compared with the other drugs. All treatments showed an increase in CD4 cells showing that they are all effective treatments. These results may imply that Stribild is a hit and miss treatment and may not be effective on everybody.

Evaluation of Stribild: Are the processes and methods appropriate for producing valid and reliable data and effective solutions? These research projects are generally quite reliable because * It played a major part in the approval of Stribild as a treatment by the FDA and the protocol was approved by the relevant organisations, showing that the investigations were sufficiently well designed. * They were double blinded trials (both the subjects nor the researcher knew which drug each subject was taking) meaning that there was little room for bias as neither the doctor nor the patient knew which drug they were taking. * The patients were randomized was performed by an unrelated party to avoid bias as much as possible. * The results were being taken by doctors who are professionally trained to do this kind of thing, which decreases the chances of human error and bad scientific practice. * People from many different ethnicities were included in the trial making the data more representative of the total population. * Both heterosexual and male homosexual couples were included in the trial, again making the data more representative of everybody that may need to use these drugs. * The number of people being trialled was also quite big, making the data more reliable and representative. It is also easier to spot if there is a pattern in the people that the medication is ineffective on. * The two different trials had similar results showing the data is reproducible. * Stribild is now the number one prescribed treatment for adults with HIV showing that most doctors do believe that it is an effective treatment for HIV. * Factors such as baseline viral load were recorded beforehand to make sure they were having any effect on the results, or at least to take their effect into account, makimg this a fairer investigation with potentially more valid results.[5][4][6] However there are still a few drawbacks of these trials: * The biggest drawback being that these trials were sponsored by the company producing Stribild, so there is chance of bias towards Stribild. For example, the 4 different stages at which the results of the treatment were reported were during the peaks of Stribild’s effectiveness. These weeks may have been deliberately chosen to favour Stribild. * 90% of the people in the trial were men which means that the results aren’t very representative towards women with HIV.[5] * There seems to be no evidence that diet, exercise, drug use etc was kept constant which could have affected the results. In fact, one of the people taking part in the trial actually died from too much recreational drug use so these factors were most probably not controlled. However, it is arguable that this is more representative of the general public using this medication, as these factors would not be controlled. * Most of the people were white and only around 5% were Asian, which might imply that there is little evidence that this treatment would work for all ethnicities because the sample is dominated by one ethnicity. [5] * There hasn’t been any significant meta-analysis for studies involving Stribild, mostly because it hasn’t been approved for very long, so we could be missing vital statically information (such as average increase in CR4+ cells might be very different to what individual studies show. * Some people also dropped out and a few even died during this trial (though researcher claim that this was nothing to do medication) so there safety of this treatment should be further looked into. * Although the two trials produced similar results there was still quite a spread between them, which might imply that the method isn’t controlling all the control variables, or the drug is effective on everyone and does not provide reliable results. * The average age is 38, but the range of the people in the trial could also affect how well the treatment works. * Some of these patients were already suffering with other diseases which might have weakened their immune system, which would affect the CD4 cell counts, implying that the results might not be entirely reliable. In conclusion, I think this was a fairly well designed trial but there are definitely areas for improvement and further trials should be done by an unbiased sponsor to study the effective of this treatment.
How Stribild works: Stribild contains 4 main ingredients. Three of the four actively fight HIV: the integrase inhibitor elvitegravir and the nucleotide/nucleoside reverse transcriptase inhibitors tenofovir and emtricitabine. The fourth medication is cobicistat is needed to boost the blood levels and effectiveness of elvitegravir.[3] Elvitergravir (approved by the FDA as a stand-alone drug in 2014): After HIV's genetic material is deposited inside a cell, its RNA is reverse transcribed into DNA. A viral enzyme called integrase then intergrates HIV's DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. This inhibits the HIV pre-integration complex from traveling to the nucleus and using the cellular machinery to multiply, hence making the infection process unsuccessful. There still a lot of research on this relatively new type of drug and only a few are approved for standalone usage.[25] Tenofovir and Emtricitabine: These are nucleoside reverse transcriptase inhibitors (NRTIs) and are commonly referred to as the ‘backbone’ of a combination with nearly all patients starting therapy having at least 2 drugs from this class included their combination. HIV cannot reproduce on its own, needing a human cell to manufacture new viruses. The new virus particles are then released so that they can infect other healthy cells. Inside the cell, NRTIs are activated – the triphosphate form by a process called phosphorylation (addition of a phosphate (PO43−) group to a protein or other organic molecule). In their active form they block the action of the reverse transcriptase enzyme meaning that the DNA is never produced so the HIV infection is unsuccessful. [26]
Cobicistat: This drug inhibits enzymes in the liver that are involved in metabolizing other HIV medications used such as elvitegravir. Combining cobicistat with elvitegravir results in higher concentrations of the intergrase inhibitor in the body with lower doses, enhancing the viral suppression power and lowering its adverse side-effects. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications. It was recently approved by the FDA in 2012. [27] Limitations of Stribild: The use of ARTs such as Stribild has enormous positive implications, increasing the life expectancy of a HIV positive person significantly. Without such treatments, being diagnosed with HIV was comparable to a death sentence. However there are many economic and social implications both positive and negative associated with the use of ARTs: 1. Economic Disadvantages: Many HIV prevention drugs are still being researched especially groups such as intergrase inhibitors. Furthermore, there is still more research being done into new drugs as people are developing drug resistance quite frequently, especially when doses are missed. This is expensive to the government and may have negative effects on the economy of a country. Ensuring the safety of the people doing the research on Stribild and paying for very expensive equipment demands a lot of money. Furthermore training all the different parties such as pharmacists and researchers on the use of new drugs such as Stribild also cost a lot of money. Distribution, storage, HIV prevention techniques, such as education and care and housing for the patients also cost a lot of money. Furthermore, scientists are still trying to look for a cure which only adds a significant amount of money to the total cost. Greater economic strain is felt by HIV positive people living in low income places, as they are not able to pay for expensive treatments like Stribild or may have to take loans. People who are infected with HIV are not able to work, which greatly reduces the labour force and people that are able to pay sufficient taxes which reduces money received by the government. On top of that, healthcare costs increase drastically, which only increases the financial strain on these countries. However there are other, more developed countries, are sources of funding for poorer countries, or example half of the total $2 billion NIH AIDS research budget supports basic research intended to benefit HIV-infected individuals, including those in developing countries. [7] Figure 19: http://kaiserfamilyfoundation.files.wordpress.com/2014/06/federal-funding-for-hivaids-by-category-fy2015-hivaids.png?w=735&h=551&crop=1
Figure 19: http://kaiserfamilyfoundation.files.wordpress.com/2014/06/federal-funding-for-hivaids-by-category-fy2015-hivaids.png?w=735&h=551&crop=1
Figure 19 shows that the most expensive aspect of HIV is actually treating it so reducing incidences of HIV would greatly decrease the negative impact of the cost of treating it. 2. Economic Advantages: Treating HIV effectively means there is lower chance of it being passed on from one person to another, which would decrease the economic effects on future generations. Spending money on educating people and other prevention methods will also decrease the chances of transmission. Preventing AIDs is a lot cheaper than treating it. One review reported that the annual costs associated with sickness and reduced productivity as a result of HIV/AIDS ranged from $17 (£12; €19) per employee in a Kenyan car manufacturing firm to $300 in the Ugandan Railway Corporation. The pandemic has reduced average national growth rates by 2-4% a year across Africa. Therefore preventing HIV, by using fixed dose combinations like Stribild, would alleviate these negative effects on the country’s economy. Patients also have to visit hospitals less frequently as the medication would cause them to be less susceptible to other infections, saving money for the patient, carers and the hospital as they have to hire less staff. [8] This money could then be used to improve living standards of people in those countries. 3. Social Disadvantages: There are some disadvantages of using Stribild, such as having to take a pill daily and having to go to regular check-ups which greatly decrease the patient’s standard of living and it may put them in awkward social situations of having to explain a topic with a lot of social stigma around it, to relatives, friends and neighbours. The side effects of Stribild may also cause the patient discomfort or even suffering. Side effects include: * Build-up of an acid in your blood (lactic acidosis): Symptoms of lactic acidosis include feeling very weak or tired, unusual (not normal) muscle pain, trouble breathing, stomach pain with nausea or vomiting, feeling cold especially in your arms and legs, feeling dizzy or lightheaded, and a fast or irregular heartbeat * Serious liver problems. The liver may become large (hepatomegaly) and fatty (steatosis). * New or worse kidney problems, including kidney failure. * Bone problems, including bone pain or bones getting soft or thin, which may lead to fractures. * Changes in body fat can happen in people taking HIV-1 medicines * Changes in your immune system. [4] 4. Social Advantages:
Taking this fixed dose would cause the patient’s quality of life to be greatly improved, as they are less likely to suffer from painful diseases such as Kaposi's sarcoma. They will also be able to work for much longer and with less disruption caused by HIV, allowing them to remain independent for much longer and feel like less of a burden on their family. HIV may also cause drastic physical changes such skin lesions on the face, neck, arms and legs. Areas of thrush can also appear on the tongue or inside of the mouth. [22]Physical signs that alter the appearance can have an impact on sufferers because others may be judgmental or hesitant to approach causing them to become depressed or feel excluded from society, but combination therapy, such as Stribild can decrease the severity of these symptoms giving the patient confidence and make them feel less isolated. Use of these drugs also impacts the family of the sufferer, as if their family member falls ill less frequently there is less pressure on them to care of the HIV positive family member

Benefits and Risks of Stribild to humans: Benefits: Individual patients benefit greatly from this treatment, as there are indications that early diagnosis and treatment of HIV by ARTs increase life expectancy (as shown in figure 3). Stribild is proven to be more effective than other leading ART combinations. [1][2] ART has reduced HIV-related morbidity and mortality and has reduced perinatal and behaviour-associated transmission of HIV. HIV suppression with ART may also decrease inflammation and immune activation which is thought to contribute to higher rates of cardiovascular and other end-organ damage reported in HIV-infected patients. It also preserves CD4 T-cell numbers. The drugs improve the health and wellbeing of an infected person. [6] Aside from positive physical effects, they have great psychological effects on the patients through both the placebo effect, where just the act of taking the medication tricks their brain into thinking their condition has gotten better, and a healthier body as it makes them stronger making the patient feel happier and self-sufficient. This treatment also allows people that wouldn’t normally be able to work to add to the labour force and work towards improving the economy of the country which would help the people nationally. In fact HIV is said to potentially decrease imports and exports from Kenya [15], so if all of the people suffering from HIV were treated with Stribild, imports/exports would be increased which would benefit all the citizens of Kenya. They reduce the burden because they are relatively independent and fall ill less frequently and with less severity on social services and their families which improves quality of life for everybody. The drugs also decrease transmission rates as HIV which means that HIV would be a lot less of a problem for future generations. The drugs can also completely prevent HIV from infecting you at very early stages of infection, though treatments such as Post-exposure prophylaxis (PEP) are more commonly prescribed in such cases as they are less expensive. [1][2] Treating people with these drugs almost completely diminish their symptoms, which maybe take away the some of the social stigma surrounding HIV.
Risks:
However there are many risks associated with the use of antiretroviral drugs. Firstly the drugs used in Stribild have only been approved for 2 years [9], meaning some side effects may not have been identified yet, especially since the two main studies done on it only had 10% female participants. The current side effects are already pretty severe as mentioned before and common side effects include Nausea (reported by 16 out of every 100 people) and Diarrhoea (reported by 12 out of every 100 people)[4]. The drug is also not safe to be used if the patient suffers from chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients co-infected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, components of Stribild. This implies that there might be other co-infections that this drug is not safe to use with. In clinical trials, in HIV-1 infected adults, tenofovir DF (a component of Stribild) was associated with slightly greater decreases in bone mineral density.[4]
The drugs are very expensive for the NHS and other country’s healthcare systems to fund so they have to be very selective about the people the drugs are prescribed to. An idea that people of working age should be given priority was brought up and this could lead a discrimination against the old and crippled and trigger the formation of a new hierarchy system. Maybe with further research the drugs will get cheaper but this is highly unlikely as many people in poorer countries especially, cannot afford full doses which increase the rate of drug resistance, meaning that more money has to be spent on trying to discover newer, alternative cures for HIV. The more we use these drugs, the faster the process of natural section occurs and the faster we have to come up with new drugs and this raises many ethical questions about who should be treated and who shouldn’t be treated. We can also never be sure that the drugs are 100% effective on everybody.
Alternate solutions: There are not many widely alternative solutions to the problem of HIV but there has been some research on possible cures such as:

Bone Marrow transplant:
Early in the epidemic, immune suppression followed by a bone marrow transplant from a donor without HIV was thought to be a way of getting rid of HIV-infected CD4 cells; bone marrow transplant from a baboon was even tried. A few people with AIDS who received bone marrow transplants before highly active antiretroviral therapy had undetectable HIV after the transplant, but eventually the virus returned.[18] In 2007, French researchers reported on an HIV infected man who was taking HAART and had an undetectable blood viral load before prior to a bone marrow transplant. After the transplant, tests did not find any HIV genetic material in more than a million tested cells. But after the man had to stop ART therapy due to drug toxicity, both his blood viral load and HIV proviral DNA in cells again became detectable. [18]

However, in an HIV-infected man in Berlin who stopped ART after bone marrow transplant has remained free of virus for 38 months according to the most sensitive tests available. The patient's own CD4 cells have entirely disappeared; due to the immunosuppressive therapy used, and have been replaced by cells produced by the donor bone marrow. The researchers who were involved with the operation and follow-up have declared the man cured of HIV infection, but the procedure used in this case is unlikely to be possible in many people due to the chemotherapy, and the need for a CCR5-matched bone marrow transplant. The reasons for this outcome are unclear; many features of the case appear only have incomplete explanations, even when investigated further. For example, the marrow donor had a homozygous CCR5-delta32 mutation, resulting CCR5 co-receptors in the donor's immune cells not being there at all. But this would only protect from infection by R5-tropic virus, and does not explain why they did not become infected with X4-tropic virus, to which they should still be susceptible and which had been identified in the recipient prior to the transplant.[19][20]

Despite the unanswered questions, researchers are already beginning to research how CCR5-deficient cells might be transferred to patients from donors or produced by gene therapy.
Chemotherapy:
Low-dose chemotherapy (consisting of cyclophosphamide aka CTX) doesn’t cure HIV but it can supress the virus. It also only tends to be used in cases where HIV infection and cancer are present in the patient or if the fixed dose combinations don’t work or if the patient is unable to talk these medications. Current ARTs, such as Stribild, can greatly reduce the levels of HIV in the human body. However, HIV can hide in certain immune cells and escape the drugs' attack. Chemotherapy using CTX destroys these immune cells. When used with standard anti-HIV drug treatments, CTX speeds up the elimination of HIV-infected cells. [21[17] There have been a few studies, such as one in 2011, in Vancouver called HIV-Associated Burkitt Lymphoma: Good Efficacy and Tolerance of Intensive Chemotherapy, but the sample sizes have been too small for there to be sufficient evidence and chronic therapy can cause toxicity in the patient and cause horrible side effects. [17] Chemotherapy is designed to wipe out rapidly dividing tumour cells. The cells of the immune system that contain latent HIV include a group of cells called “resting CD4+ T cells” by researchers. These cells are not active and chemotherapy might not kill them. Though, some scientists have said that the drug targets an enzyme that allows the virus to lie latent, so it would flush out even the latent virus. It is a fairly expensive treatment, so it won’t be much help in poorer countries where HIV is much more of a problem. Conclusion: Based on my research I feel as though we have a long way to go before we get anywhere near a complete cure for HIV and I don’t feel as though any of the current treatments are perfect or safe. The most common treatment are the ARTs but not everyone is eligible for this treatment and other more expensive treatments such as chemotherapy will not be able to treat most peole. However there is a lot of research still being done into HIV and we can be hopeful that soon a cure for HIV will be found.

References: 1. Clumeck N, Molina JM, Henry K, et al; GS-236-0103 Study Team. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e121-e124. accessed on 5/02/2015) 2. Wohl DA, Cohen C, Gallant JE, et al; for the GS-US-236-0102 Study Team. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimenefavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e118-e120. accessed on 5/02/2015) 3. What is STRIBILD? Available at https://www.stribild.com/hiv-1-medicine (accessed on 5/02/2015) 4. July 2012 Quad (Stribild) — Safety and effectiveness issues in depth. Available at http://www.catie.ca/en/treatmentupdate/treatmentupdate-191/anti-hiv-agents/quad-safety-and-effectiveness-issues-depth (accessed on 5/02/2015) 5. Study 102 and 103 available at https://www.stribild.com/hcp/stribild-study-designs (accessed on 5/02/2015) 6. Long-Term Data In Treatment-Naïve Patients Highlight Stribild’s Sustained Efficacy, Safety and Tolerability Profile available at http://www.gilead.com/news/press-releases/2013/10/gileads-single-tablet-hiv-regimen-stribild-demonstrates-durable-viral-suppression-through-three-years-of-therapy(accessed on 5/02/2015) 7. Jun 25, 2014, U.S. Federal Funding for HIV/AIDS: The President’s FY 2015 Budget Request available at http://kff.org/global-health-policy/fact-sheet/u-s-federal-funding-for-hivaids-the-presidents-fy-2015-budget-request/ (accessed on 5/02/2015) 8. Funding for HIV available at http://www.avert.org/funding-hiv-and-aids.htm (accessed on 5/02/2015) 9. Management of HIV/AIDS available at http://en.wikipedia.org/wiki/Management_of_HIV/AIDS#Fixed-dose_combinations(accessed on 5/02/2015) 10. Current guidelines available at http://www.bhiva.org/guidelines.aspx (accessed on 5/02/2015) 11. HIV/AIDS avaliable at http://en.wikipedia.org/wiki/HIV/AIDS (accessed on 5/02/2015) 12. What are the side effects? Available at https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/treatment-options/side-effects/ (accessed on 5/02/2015) 13. The HIV life cycle available at http://www.thebody.com/content/art14193.html 14. How older people with HIV are facing the future By Philippa Roxby available at http://www.bbc.co.uk/news/health-25041911 (accessed on 5/02/2015) 15. Global HIV and AIDS estimates, 2011 available at http://www.avert.org/worldwide-hiv-aids-statistics.htm (accessed on 5/02/2015) 16. Data and statistics available at http://www.who.int/hiv/data/en/ (accessed on 5/02/2015) 17. Kent, M.K 2000, Advanced Biology, Oxford, Oxford university press. accessed on 5/02/2015) 18. Avettand-Fenoel V et al. Failure of bone marrow transplantation to eradicate HIV reservoir despite efficient HAART. AIDS 21: 775-786, 2007 (accessed on 5/02/2015) 19. Hutter G et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med. 360: 692-8, 2009 (accessed on 5/02/2015) 20. Allers K et al. Evidence for the cure of HIV infection by CCR5Δ32/ Δ32 stem cell transplantation. Blood, 2011 (accessed on 5/02/2015) 21. Veterans Affairs San Diego Healthcare System and University of California San Diego, Departments of Pathology and Medicine 0679, La Jolla, California 92093-0679, USA. HIV chemotherapy available at http://www.ncbi.nlm.nih.gov/pubmed/11309630 (accessed on 5/02/2015) 22. http://www.nhs.uk/conditions/hiv/pages/introduction.aspx(accessed on 5/02/2015) 23. http://sfaf.org/hiv-info/basics/is-there-a-cure-for-hiv-aids.html(accessed on 5/02/2015) 24. http://www.who.int/bulletin/volumes/88/7/09-068015/en/(accessed on 5/02/2015) 25. http://en.wikipedia.org/wiki/Elvitegravir(accessed on 5/02/2015) 26. http://en.wikipedia.org/wiki/Emtricitabine/tenofovir/efavirenz(accessed on 5/02/2015) 27. http://en.wikipedia.org/wiki/Cobicistat(accessed on 5/02/2015)s

Evaluation of sources: I used the Advanced Biology by Michael Kent textbook to get information about the symptoms of HIV virus and how it is treated and also why it is difficult to treat. I also got some information about the use chemotherapy to treat HIV.It explained the mechanism of the viral infection very well to, though it wasn’t very detailed. I think I was one of the most reliable sources I used because it has been published so all the information in it would be thoroughly checked and proof read. Many highly educated people contributed to the writing of the book, making the book even more reliable as they would presumable be very knowledgeable in their subject. It’s a published resource which means there has to be a third party that has reviewed it and made sure the information is right. Furthermore, Oxford University Press (its publisher) has published many other respected and reliable books such as the Oxford English dictionaries. It is also a good source for medical claims as it is a reliable, third-party, published source because it is a widely recognized standard textbooks written by experts in a field. There is also no reason for these authors to be bias as textbooks are mostly purely factual. Having said that it is written for A level students so some of the information might have been simplified to make it easier for school students to understand. It is a little out of date as it was written in 2000, but the information appeared to be fairly accurate and up to date as I cross-referenced with other sources, such as source 13, on the internet and they agreed with each other in various aspects. For example both sources had the same information about T helper cells and their role vital roles in the immune system and I also cross referenced the information about the use of chemotherapy in treating HIV and both agreed on facts such as chemotherapy is only used if cancer is also present in an HIV infected patient. The source I used the most would be the official Stribild website. This gave me information about the design of the studies and extra information about Stribild such the side effects and prescription regulations etc. I also found information about the design of the experiment, for example the proportion of men and women used in the study. This was quite a reliable source at it was the official website but it may have been bias and left out some bad details about the study. For example, after cross referencing with other websites that reported the two studies, I found that there were some deaths related to the studies, which is information I couldn’t find on the website. I think cross-referencing increased the reliability of both of my sources. The author of both these sources was not stated so I cannot assess their reliability. Also the information on the website was taken from a published source which means the information would have been reviewed thoroughly, so bias should be minimised. The researchers writing these papers were part of the double blind trial so they shouldn’t have been bias either. These documents were also used to decide if Stribild should be approved as a HIV treatment by the FDA, which is a highly regulated organisation, which adds more weight made to the claims made by the researchers and therefore the claims on the website. Furthermore, the accounts of two different researchers were used,so the facts on the website should be reliable and both of these researchers agreed with each other on the outcomes of investigation. Although this was an internet based source produced with a slightly bias motive, the sources used to compile the information together was published and unbiased, improving its reliability. Cross –referencing also showed that most of the claims and valid, however some information was filtered out, as a marketing strategy which could imply that it doesn’t show the full picture. However, I used other sources to fill these gaps.

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