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Title: Do we still need new drugs to treat HIV?
Background: The first documented case of Acquired Immunodeficiency Syndrome (AIDS) was in Los Angles (US) 1981 and the Human Immunodeficiency Virus (HIV) was identified as the causative agent of AIDS by Dr Robert Gallo and Dr Luc Montagnier in 1984. After 28 years, 33.4 million people are living with HIV, 2.7 million new cases and 2 million AIDS related death were reported in 2008. With the introduction of High Active Antiretroviral Therapy (HAART) in 1996, there was a decline in AIDS related mortality rate. Currently the FDA and EMEA had approved over 20 types of HIV drugs to tackle the HIV/AIDS epidemic.
Objectives: This dissertation examines whether is there a need to create new HIV drugs in the context of high income countries (Gross National Income (GNI) per capita of US$11,906 or more) versus middle (GNI per capita between US$ 975 to US$ 11906) and poor income countries (GNI per capita of US$975 or less).
Methods: Literature search was conducted on World Health Organization, UNAIDS, FDA, EMEA websites and major journals. The most badly affected country in their regions was selected for statistical analysis. Selected countries gross national income per capita and it mortality rate from 1990 to 2007 were analyzed using Pearson Bivariate Correlation 2-tailed tests by SPSS software at 0.01 level of significance.
Results: Three high income countries Australia, Italy and United States of America had negative correlation and seven countries middle and poor income countries South Africa, China, Myanmar, Russian federation, Sudan, Haiti and Brazil had positive correlation.
Discussion: There is indeed a correlation between wealth and death rate. However beside wealth, there are other reasons that will effect mortality rate such as the cost of HIV drugs, insufficient funding toward HIV/AIDS epidemic, insufficient HAART coverage in middle and poor income countries and the failure of WHO 3 by 5 initiatives, such reasons do not support the creation of new HIV drugs. Reasons that supported the creation of new HIV drugs are, due to wide spread of mutations in all HIV drugs and by introduction a new HIV drug, many lives can be saved.
Conclusion: If there is no sufficient research and development begin put into new HIV drugs development, there maybe a time when all of the HIV drugs are useless again HIV and all the efforts in the fight against HIV/AIDS epidemic will be wide off. So the creation of new HIV drugs is indeed vital.
Do we still need new drugs to treat HIV?
1.1 First documented case of AIDS
On June 5th 1981 the Morbidity and Mortality Weekly Report had published an article under the title of "Pneumocystis pneumonia - Los Angles." (Morbidity and Mortality Weekly Report, 1981, Sepkowitz, 2001 and Merson, 2006) That article reported Pneumocystis pneumonia with other unusual infections were found in five young homosexual men. (Morbidity and Mortality Weekly Report, 1981, Sepkowitz, 2001 and Merson, 2006) This was the first case of Acquired ImmunoDeficiency Syndrome (AIDS) documented in the world. (Morbidity and Mortality Weekly Report, 1981, Sepkowitz, 2001, Merson, 2006 and Hall et al., 2009) During the early years of AIDS, scientists were trying to find the causative agents for AIDS and by 1984 the Human Immunodeficiency Virus (HIV) was identified as the causative agent by Dr Robert Gallo and Dr Luc Montagnier. (Watts 2008 and Nobel Foundation, 2008) In 2008, Dr Luc Montagnier and his assistance Françoise Barré-Sinoussi were awarded half of the Nobel Prize in Physiology or Medicine for their discovery and contribution to the understanding of HIV and its treatment. (Watts 2008 and Nobel Foundation, 2008)
WHO, UNICEF and UNAIDS had regularly monitor the global HIV/AIDS epidemic. (UNAIDS, 2009) After 28 years since the first AIDS case, the estimated numbers of people living with HIV was about 33.4 million in 2008 (UNAIDS, 2009) While the HIV/AIDS epidemic had stabilized since year 2000 and the infection rate had declined from 3.0 million in 2001 to 2.7 million in 2008 yet the mortality rate had increased from 1.7 million in 2001 to 2 million in 2008. (UNAIDS, 2009) Each day there were over 6800 new cases of HIV infection diagnosed and over 5700 deaths related to AIDS. (UNAIDS, 2009) Hence for every 1 new case of HIV, there was about 0.83 deaths. (UNAIDS, 2009) Globally 25 million AIDS related deaths had occurred since 1981. (UNAIDS, 2009)
The HIV/AIDS epidemic had moved from a single report of an infection cluster into a worldwide epidemic with two broad epidemiologic patterns of global distribution had been observed. (Sepkowitz, 2001, Cohen et al., 2008 and UNAIDS, 2008) In most countries, the HIV/AIDS epidemic is concentrated among high risk groups such as: homosexual man, drug addicts sharing injection, commercial sex workers and partners of such persons. (Cohen et al., 2008 and UNAIDS, 2008) However in sub-Saharan countries, the HIV/AIDS epidemic is generalized and self sustaining within the population. (Cohen et al., 2008 and UNAIDS, 2008) HIV/AIDS epidemic also had an unequal spread among the countries in the world, majority of the HIV patients (67%) were coming from sub-Saharan region. (Sheri et al., 2003, Sepkowitz, 2001, Cohen et al., 2008 and UNAIDS, 2008) In recent years, Asia countries had shown a rising trend in HIV infection particularly in South East Asia countries like Thailand and Myanmar. (UNAIDS, 2008) For the rest of countries, there were either show slight increases or decreases in the number of HIV infected patients. (UNAIDS 2008) Table 1 shows the global spread of HIV infection as the end of 2008.
Adults and children
living with HIV
Adults and children
newly infected with HIV
Adult and child deaths
due to AIDS
South & South East Asia
Eastern Europe & Central Asia
Western and Central Europe
Middle East & North Africa
Global HIV epidemics spread, people living with HIV, newly infected cases and death due to HIV/AIDS as of 2008 (UNAIDS, 2009)
1.3 Treatment for HIV
The first HIV drug was zidovudine and it was approved back in 1987 by the US FDA but zidovudine alone was insufficient to control HIV. (Sepkowitz, 2001, Stevens et al., 2004 and Hogg et al., 2006) Only in 1996, HAART (Highly Active Antiretroviral Therapy) was introduced and for the first time the world saw a decline in HIV mortality rate especially in high income countries like United States, France, Germany, Spain, Italy and Australia. (Sepkowitz, 2001, Frieden et al., 2005, Deeks, 2006, Sackoff et al., 2006 and Grinsztejn et al., 2007) HIV positive had used to be equal to an instant death sentence associated with rapid progressive disease and life expectancy often measured in months. (Hogg et al., 2006 and Nijhuis et al., 2007) Now with HAART the mortality rate among HIV patients had greatly reduced and may no be higher than other chronic diseases. (Sepkowitz, 2001, Sackoff et al., 2006, Hogg et al., 2006 and Lohse et al., 2007)
HAART is made up of a cocktail of different HIV drugs, normally 3 to 4 different types of HIV drugs from different classes. (DHHS, 2009) These different classes of drugs which will inhibit the HIV viral replication life cycle at different critical points and prevent it from replication. (Hogg et al., 2006) Currently the FDA (US) and EMEA (EU) had approved over 20 HIV drugs and are separated into six classes. (FDA and EMEA) Depending on indivdual responses, toxcity, side effects and economic status, HAART can effectively suppress HIV viral for many years and HIV patients can have a good prognosis of a median survival of 35 yrs. (Lohse et al., 2007) Table 2 is the list of HIV drug approved for use in US and EU.
Multi-class combination products - 2 NRTIS plus 1 NNTRIs
Efavirenz, emtricitabine and tenofovir
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - competitive inhibitors of HIV reverse transcriptase
No longer market in US
Lamivudine and zidovudine
Enteric coated didanosine
Abacavir, zidovudine, and lamivudine
Abacavir and lamivudine
Marketed as kivexa in Europe
Tenofovir and emtricitabine
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) - non competitive antagonist that directly bind and inhibit HIV reverse transcriptase
Protease Inhibitors (PIs) - inhibitors of HIV protease enzymes needed for viral maturation
Lopinavir and ritonavir,
Marketed as Telzir in Europe
Fusion Inhibitors - prevent HIV from entering CD4 cell
Entry Inhibitors - CCR5 co-receptor antagonist - prevent HIV from entering CD4 cell
Marketed as CelsentriÂ in Europe
HIV integrase strand transfer inhibitors - interfere with integrase enzymes
Antiretroviral drugs used in the treatment of HIV infection approved by FDA and EMEA (2009)
Current guidelines recommended by theÂ US Department of Health and Human Services (DHHS) considered of 2 NRTIs plus either a NNRTIs or a PIs for HIV naÃ¯ve patient. (Deeks, 2006 and DHHS, 2009) DHHS also recommended when an asymptomatic HIV patient's CD4+ cells count drop to a range between 350cells/ÂµL to 200cells/ÂµL treatment should begin. (Deeks, 2006 and DHHS, 2009) For symptomatic HIV patients, they should begin treatment regardless of CD+4 cells count. (Deeks, 2006, DHHS, 2009 and Kitahata et al., 2009)
2.1 Do we still need new drugs to treat HIV?
The main purpose of HIV drugs is to reduce mortality rate and prolong life of a HIV infected person. With our current drugs the HIV viral load can be reduced to a level which is beyond detection so is there still a need to create new HIV drug? The objective of this dissertation is to find out how critical is the creation of new HIV drugs in the context of high income countries (Gross National Income (GNI) per capita of US$11,906 or more) versus middle (GNI per capita between US$ 975 to US$ 11906) and poor income countries (GNI per capita of US$975 or less). Below are some factors that about the no versus the yes to the creation of new HIV drugs.
Why we do not need new HIV drug?
Why we need new HIV drug?
The high cost of HAART
Mutations of HIV which render current HIV drugs less effective
Insufficient funding to deal with the HIV/AIDS epidemic
The potential that new HIV drug can save more lives
Failure of WHO 3 by 5 initiatives
Insufficient HAART coverage for HIV patient
Inaccessibility of Indinavir
3.1 Data sources
Internet websites like UN, WHO, UNAIDS, FDA and EMEA had provided the latest update on the current HIV/AIDS epidemic, latest statistic, efforts by the global communities to control HIV spread, and types of drugs approved for treatment of HIV. Athens account by University of Bradford provide reputable journals and articles sources like British Medical Journal, Journal of Virology, New England journal of Medicine, Lancet, etc. Such journals and articles provided the information on HIV mutations, drug resistance, current global HIV epidemic, etc. Key words uses are "HIV, mutation, drug resistance by HIV, FDA, EMEA, WHO HIV initiatives, UNAIDS report, global HIV and World wealth."
3.2 Countries selection and study period
Ten countries from ten different regions in the world were chosen, they were South Africa, China, Australia, Myanmar, Russian Federation, Italy, Sudan, US, Haiti and Brazil. These countries are the most badly affected countries in their regions according to statistic figures by UNAIDS. Each country gross national income per capita and it AIDS related death rate from 1990 to 2007 were studied.
3.3 Statistical Analysis
Each country GNI per capital and AIDS related death were analyze using Pearson Bivariate Correlation 2-tailed tests by SPSS software at 0.01 level of significance. The objective of this statistical analysis is to find out what type of correlation ship (negative or positive) and how strong is the correlation between the individual countries wealth and their death rate. The hypothesis of this statistical analysis is: the higher the income of the country will result in lower the death rate.
Correlation of mortality rate
and GNI per capital
Average GNI per capital (1990 to 2007)
South & South East Asia
Eastern Europe & Central Asia
Western and Central Europe
Middle East & North Africa
United States of America
Table 3 *India has a HIV population of 2.5 million but was excluded due to in-sufficient data.
Table 3 show the result from the SPSS analyze, three countries, Australia (-0.495), Italy (-0.585) and United States of America (-0.491) had negative correlation between their GNI per capital and death rate. The other countries, South Africa (0.653), China (0.979), Myanmar (0.611), Russian Federation (0.921), Sudan (0.622), Haiti (0.622) and Brazil (0.664) had positive correlation. Beside the correlation, the average GNI per capital of each country were also tabulated.
5.1 Correlation between GNI per capital and mortality rate
From the results, the richer countries like Italy, Australia and US had negative correlation between it GNI per capital and it death rate. With increasing wealth, these countries experience a lower death rate. For the rest of the seven countries, they all had a positive correlation. Their wealth and death rate are on the raise together. So when the wealth of the country had increase to a certain level, it will cause a decrease in mortality rate. The three richer countries had an average GNI per capital are above US$20 000 and the other seven countries range from US$192 to US$3960. There is indeed a correlation between wealth and death rate. However wealth is only part of the factors that will affect the death rate, there are still many more factors to consider. Some of these factors discussed below debate whether we still need to create new HIV drugs.
5.2 Reasons why we do not need new drugs
Despite the success of HAART in reducing AIDS related mortality, it does not cure HIV/AIDS completely, it only suppress the HIV viral from replication and only about one in five HIV patients in middle and poor income countries is fortunate enough to receive treatment. (Merson, 2006, Ford et al., 2009) The following reasons are why new HIV drugs are no needed : inaccessibility of new HIV drug: Indinavir, the high cost of HAART, insufficient funding to deal with the HIV/AIDS epidemic, insufficient HAART coverage for HIV patients, failure of WHO 3 by 5 initiatives and the accessibility of new HIV drugs.
5.2.1 Inaccessibility of new HIV drug: Indinavir
In 1996, Merck had launched it first protease inhibitor, Indinavir (Crixivan) and bring new hope to the HIV population worldwide. (Tanouye, 1996) When Indinavir was launched, it only took seven months and it outsells all other HIV drugs during that time. (Tanouye, 1996) But there was a problem with Indinavir, the demand was so high that it exceeds it supply. (Tanouye, 1996) Merck did not forecast such strong demand and was unwilling to invest heavily in the beginning. (Tanouye, 1996) It was only producing enough for 90,000 HIV patients and this resulted in higher price, inaccessible and HIV patients who are on Indinavir may have to discontinue Indinavir due to stock out in local hospitals. (Tanouye, 1996) Even HIV patients in United States may not have access to Indinavir due to it scarceness and high price. (Tanouye, 1996) For those who are already on Indinavir, they may have to stop Indinavir and might developed resistance; therefore it maybe better for the HIV patient not to take Indinavir at all. (Tanouye, 1996) No doubt the new HIV drugs can help to save more lives but stock out is not an option and the pharmaceutical companies will need to guarantee the output is able to match the demand and not just only interested in making profit.
5.2.2 The high cost of HAART
The cost of treatment is too expensive for an average worker. The HAART regiment recommended by DHHS consist of two NRTIs plus either a PIs or a NNRTIs. (DHHS, 2009) The prefer NRTIs are tenofovir and emtricitabine with fosamprenavir (PIs) boosted with ritonavir (PIs) or efavirenz (NNRTIs). (DHHS, 2009) The alternate regiment two NRTIs are abacavir and lamivudine with atazanavir (PIs) unboosted or nevirapine (NNRTIs). (DHHS, 2009) The average cost of these HIV drugs inHIVH the western countries range from US$10,000 to US$15,000 per year. In order to carter to the poor and middle income countries, many pharmaceutical companies were asked to relax or give up their existing patent rights to create generic version of HIV drugs for such countries.
Cost of the commonly prescribed HIV drugs from 2004 to 2008. (UNAIDS, 2009)
In the recent years from 2004 to 2008, the cost of HAART in poor and middle income countries had declined by about 48%. Figure 1 show the decline of various HIV drugs combinations from 2004 to 2008. Such decline in price can be credited to the sustained scaling up of treatment programmes, growing transaction volumes and predictability of demand, competition between a growing number of products prequalified by WHO and favourable pricing policies by pharmaceutical companies. (Gutierrez et al., 2004, Hogan et al., 2005, Ford et al., 2009) In 2008 the cost of HAART in the low income countries ranges between US$88 to US$261 per year. (UNAIDS, 2008) The weighted average median price of first-line treatment was US$143 per person per year in 2008, which was 16% lower compare to the price in 2007. (UNAIDS, 2008) The cost of second line treatment had also declined but is still significantly more expensive than first line treatment, the cost range from US$819 to US$1105. (UNAIDS, 2008) However these prices can be as high as US$2634 in upper-middle-income countries. (UNAIDS, 2008) In addition the prices mention above does not include freight, storage, insurance, labour or other essential handling fees. Even with the sharp cost decline of HIV drug is still too pricey for the majority HIV infected patients. (Sepkowitz, 2001) New HIV drugs are simply priced too high for the average citizens of such middle and poor income countries. New HIV drugs like Raltegravir can cost up to US$1000 per month in United States. Therefore what these people are not new HIV drugs but affordable basic HIV treatment.
5.2.3 Insufficient funding to deal with the HIV/AIDS epidemic
The amount of funding available for HIV/AIDS epidemic from 1986 to 2007. (UNAIDS, 2008)
HIV/ADIS epidemic is a global threat to the world security and stability. (UNAIDS, 2008) Many rich countries and rich corporations had donated generously to fight the HIV/AIDS epidemic. Figure 2 show the amount of fund available for HIV/AIDS epidemic from 1986 to 2007. The global funding of HIV/AIDS in 2008 had reach US$13.8 billion which was about 40%, increase from 2007. (UNAIDS, 2008) Domestic expenditure (52%) accounted for the largest source of fund follow by direct bilateral cooperation (31%), multilateral institutions (12%) and philanthropic sector (5%). (UNAIDS, 2008) The two major international sources of funding are the Global Fund to Fight AIDS, Tuberculosis and Malaria and the United States President's Emergency Plan for AIDS Relief. (Kim et al., 2004, Kim et al., 2005, Merson, 2006) Even thought there have been a significant increase in HIV/AIDS funding since 1990s, but it is still insufficient to tackle the global HIV/AIDS epidemic. (Dyer, 2009) Expenditure for year 2009 and 2010 are estimate to US$19.8 and US$25.1 billion respectively. Meeting the require amount will be a big challenge to the donors especially after the recent financial crisis. (Dyer, 2009 and UNAIDS, 2008) If there is insufficient funding for the coming year, many HIV patients who need treatment may not be able to receive treatment in time and worst if some HIV patients may forced to be dropped off the treatment programme and developed drug resistance. New HIV drugs normally cost much more than generic HIV drug, now there is already a lack of funding and if more money is channelled into purchasing new HIV drugs, that will deprived many other HIV patients who only need a basic and cheap HIV drugs.
5.2.4 Insufficient HAART coverage for HIV patients
The number of HIV patients on treatment from 2002 to 2008. (UNAIDS, 2009)
When HAART was introduced in 1996, most of the poor and middle income countries do not benefit from it and their mortality rate continue to soar to new levels. (UNAIDS, 2009) However with the political commitments, efforts by various non-government organizations and local communities, there are massive increases in the number of HIV patients receiving treatment in the poor and middle income countries by end of 2008. (UNAIDS, 2009) Figure 3 show the increase in the number of HIV patients receiving treatment from end of 2002 to end of 2008. By the end of 2008, WHO, UNICEF and UNAIDS had estimated that the HAART coverage had increase from 33% in 2007 to 42% in 2008. (UNAIDS, 2008) The greatest increase in HIV patient receiving HAART come from Sub-Saharan region which was the most badly affect area on Earth. (UNAIDS, 2008) The HIV population receiving treatment was less than half a million in 2003 but in 2008 there were about 4 million patients receiving treatment. (UNAIDS, 2008) Nevertheless, the global HIV population stands at 33.4 million at the end of 2008. About 9.5 million HIV patients needs treatment but only about 4 million (42%) are fortunate enough to receiving HAART either through free or subsidize channels. (UNAIDS, 2008) The rest of the 52% of the HIV patients are left without even the most basic first line treatment which is widely available in most developed countries. New HIV drugs are patented drugs and are too expensive to use as a recommended drugs in these middle and poor countries. Therefore in order to achieve universal access in 2010, the only way is to turn to older, generic version HIV drugs. New HIV drugs will remain exclusive to the rich during these present times.
5.2.5 Failure of WHO 3 by 5 initiatives
In Dec 2003, WHO launched a programme known as 3 by 5 initiatives. (Kim et al., 2004, Kim et al., 2005, Bate, 2006) It was an international effort to provide HAART to 3 millions HIV infected patients in poor and middle income countries by 2005. (Kim et al., 2004, Kim et al., 2005, Bate, 2006) However problems started to arise even before the programme was officially launched. WHO had set the numbers to be treated in each country too high and unsustainable. (Bate, 2006) For example South Africa, before the 3 by 5 initiatives, it already had a HIV treatment programme and has over 85 000 patients on treatment. (Bate, 2006) This number maybe small compare to it 5 million HIV populations but is sustainable in the long run. (Bate, 2006) However WHO required South Africa to expand it HIV treatment to 375 000 people by the end of 2005 without provide the necessary resources and this number was not even in consultation with South Africa government. (Bate, 2006)
During the 2 years programme, many problems had surfaced which resulted in the failure to reach the target set by WHO. Such problems can be categorized as: political, drug quality issues, management, infrastructure, logistical and manpower. (Bate, 2006) First, when the programme was launched in 2003 it was not officially presented to each country for endorsement which is necessary for political support for implementation. (Bate, 2006) Second, the quality of the drugs administered in this programme was sub standard resulting in thousands of patients developing drug resistance. (Bate, 2006) In order to achieve the target, WHO come out with a simplified drug regimen and relaxed approval requirements. (Bate, 2006) It uses a non-FDA approved generic triple-drug therapies which is not used in most developed countries. (Bate, 2006 Ford et al., 2009) Normally generics manufacturers are required to submit documentation to the WHO to prove the bioequivalence of their drugs. (Bate, 2006) However countries such as India do not require such data for exported drugs, and WHO just assumed that the Indian drugs would be bioequivalent to their branded counterpart. (Bate, 2006) Third, countries who received the drug had poor management of HIV treatment using this drug. (Bate, 2006) Hence many patients did not adhere to the therapy regiment and thousands of HIV patients become resistance to the first line drugs. (Stevens et al., 2004 Bate, 2006) Fourth, these poor countries that received the drug did not have the infrastructure such as a modern lab to conduct the blood test for the CD4 cell count prior to commencement of the treatment, and to check the patient's viral load. (Stevens et al., 2004, Kim et al., 2005, Bate, 2006) Fifth, according to WHO guidelines, treatment for HIV patient will begin when patient reach stage 3 or 4 of the disease or simply wait until symptoms of AIDS started to appear which maybe too late for any effective treatment. (Ford et al., 2009)
Soon technical problems start to arise, from over-work health care staffs, logistic problem, and infrastructure problems especially in rural areas, drug quality issues and management. (Kim et al., 2004, Kim et al., 2005, Bate, 2006) In the end of 2005, only 1 million HIV patients were receiving treatment and WHO HIV/AIDS department Director Jim, Yong Kim had to apologize for the organization failure to meet the goal of its 3 by 5 initiative. (Medical News today, 2005, Merson, 2006)
5.2.6 Why new HIV drugs are not needed?
Due to the inaccessibility to new HIV drugs, high cost of HAART, insufficient funding to deal with HIV/AIDS epidemic, insufficient HAART coverage for HIV patients to the failure of WHO 3 by 5 initiatives. Majority of the HIV patients do not need new HIV drugs, what they need urgently is the availability and affordability for the current first and second line HIV. And such needs can be met if the global communities are willingly to come together and bring a ray of hope to these HIV patients from middle and poor income countries.
5.3 Reasons why we need new drugs:
HIV drug Resistance
The rise of drug-resistant HIV is a major problem which responsible for treatment failure in a substantial proportion of the global HIV population. (Nijhuis et al., 2007) Drug-resistant HIV can be divided into two categories: primary resistance or secondary resistance. (Taylor et al., 2008) In primary resistance, the uninfected person got infected by a HIV patient who has a drug resistant strain and in secondary resistance, the virus acquired resistance over a period of HIV drug treatment. (Stevens et al., 2004 Taylor et al., 2008) Resistance to at least one HIV drug has appeared in over 50% of HIV patients currently undergoes HAART and about 10-20% of HAART naÑ-ve patients. (Deeks, 2006, Alteri et al., 2009, Menéndez-Arias 2009) Presently drug resistance has been observed in all HIV drug classes. (Alteri et al., 2009, Menéndez-Arias 2009)
Mutations of amino acids along the HIV's DNA which affect different classes of HIV drugs (Johnson, et al., 2008)
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Resistance to NRTIs occurs through 2 different mechanisms: the first is mutation of the residues which interfere with corporation of the NRTI into the growing DNA chain (Zdanowicz, 2006, Cases-González et al., 2007, Menendez-Arias 2008 and Cihlar et al., 2009) Second mechanism is by increasing phosphorolytic activities which enhance the removal of the HIV drug from its binding site at the end of the DNA chain. (Zdanowicz, 2006, Cases-González et al., 2007, Menendez-Arias 2008 and Cihlar et al., 2009)
Major mutations in HIV's DNA which confer resistance to NRTIs (Johnson, et al., 2008)
Mutation of the K65R is the most commonly observed mutation within the NRTIs class. (Johnson, et al., 2008) Most HIV patients who were treated with emtricitabine, lamivudine tenofovir, didanosine and abacavir have K65R mutation from lysine(K) to arginine(R) at amino acid position 65. (Delaugerre et al., 2005, Kagan et al., 2007, Menendez-Arias 2008, Kisic et al., 2008 and Theys et al., 2009) Emtricitabine and lamivudine also had M184V/I mutation from methionine(M) to valine(V) or isoleucine(I) at position 184. (Delaugerre et al., 2005, Menendez-Arias 2008, Kisic et al., 2008 and Cihlar et al., 2009) Beside K65R, tenofovir had K70E mutation lysine(K) to glutamate(E) at position 70. (Kagan et al., 2007and Menendez-Arias 2008) This mutation primarily affects tenofovir but K70E presence has been observed in patient when tenofovir was administered with didanosine, lamivudine and abacavir. (Kagan et al., 2007and Menendez-Arias 2008) L74V mutation from leucine (L) to valine(V) at position 74 has been reported primarily in didanosine and abacavir only. (Kagan et al., 2007and Menendez-Arias 2008) Beside the K65R and L74V mutations observed in abacavir, Y115F mutation from tyrosine(T) to phenylalanine(F) at position 115 and M184V mutation from methionine(M) to valine(V) at position 184 are observed in patients treated heavily with abacavir. (Menendez-Arias 2008) Both stavudine and zidovudine shaped similar mutations. (González et al., 2007, Menendez-Arias 2008 and Kisic et al., 2008) Both drugs have M41L mutation from methionine(M) to leucine(L) at positon 41, D67N mutation from aspartate(D) to asparagine(N) at position 67, K70R mutation from lysine(K) to leucine(R) at position 70, L210W mutation from leucine(L) to tryptophan(W) at position 210, T215Y/F mutation from threonine(T) to tyrosine(Y) or phenylalanine(F) at position 215 and K219Q/E mutation from lysine(K) to glutamine(Q) or glutamate(E) at position 219. (González et al., 2007, Menendez-Arias 2008 and Kisic et al., 2008)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
The hydrophobic binding region of NNRTIs consist of amino acids position from 100 to 110, 180 to 190 and 220 to 240 and a single mutation along this region can cause high level of resistance to all drugs within the NNRTIs class. (Paolucci et al., 2007 and Ren et al., 2008) Therefore the NNRTIs have a low genetic barrier (Schiller et al., 2008, Pauwels, 2004 and Ren et al., 2008)
Major mutations in HIV's DNA which confer resistance to NNRTIs (Johnson, et al., 2008)
Currently there are over 40 amino acid mutations that have been identified to be associated with NNRTIs resistance (De Béthune, 2009) and the most commonly observed NNRTIs mutations are L100I mutation from leucine(L) to isoleucine(I) at position 100 and Y181C/I mutation from tyrosine(Y) to cysteine(C) or isoleucine(I) at position 181. (Pauwels, 2004 Smith et al., 2008 Ren et al., 2008 Sarafianos et al., 2009 and De Béthune, 2009) These two mutations can even affect the new NNRTIs, etravirine. (Schiller et al., 2008 and De Béthune, 2009) Other common mutations such as K103N from lysine(K) to asparagine(N) at position 103, V106M from valine(V) to methionine(M) at position 106, V108I from valine(V) to isoleucine(I) at position 108, Y188L from tyrosine(Y) to leucine(L) at position 188 and G190A from glycine(G) to alanine(A) at position 190 are normally observed in older NNRTIs. (Pauwels, 2004 Smith et al., 2008 Ren et al., 2008 Sarafianos et al., 2009 and De Béthune, 2009)
Proteases Inhibitors (PIs)
Resistance to PIs occurs as a result of amino acid mutations within or proximal to the catalytic binding site which leads to conformational changes thus reduced PIs incorporation onto the catalytic site. (Freire, 2006, Zdanowicz, 2006, Nijhuis et al., 2007, Menendez-Arias, 2008 and Wensing et al., 2009)
Major mutations in HIV's DNA which confer resistance to PIs (Johnson, et al., 2008)
Older PIs such as saquinavir and nelfinavir had G48V mutation from glycine (G) to valine(V) at position 48 and D30N mutation from aspartate(D) to asparagine(N) at position 30 respectively. (Sa-Filho et al., 2003, Martinez-Cajas et al., 2007, Wensing et al., 2009 and Bihani et al., 2009) And they both have the distinct L90M mutation from leucine(L) to methionine(M) at position 90 which affect no other PIs. (Sa-Filho et al., 2003, Martinez-Cajas et al., 2007, Wensing et al., 2009 and Bihani et al., 2009) I50L mutation from isoleucine(I) to leucine(L) at position 50 and this mutation was commonly observed in atazanavir, darunavir and fosamprenavir when boosted with ritonavir. (Martinez-Cajas et al., 2007 and Wensing et al., 2009) Another more commonly observed mutation between these three drugs was I84V, mutation from isoleucine(I) to valine(V) at position 84. V82T mutation from valine(V) to threonine(T) at position 82 is fairly common in patients undergoes indinavir, lopinavir and tipranavir when boosted with ritonavir. (Martinez-Cajas et al., 2007)
Major mutations in HIV's DNA which confer resistance to enfuvirtide (Johnson, et al., 2008)
Mutations in the heptad repeat (HR) 1 region involving amino acids position 36 to 45 have been associated with a increase resistance to enfuvirtide. (Fung et al., 2004, Miller et al., 2004, Poveda et al., 2005, Menéndez-Arias 2009 and Covens et al., 2009) An average of a 21 folds increase of enfuvirtide resistance had been documented in HIV patient with enfuvirtide resistance. (Carmona et al., 2005) A G36D/S mutation from glycine(G) to aspartate(D) or serine(S) at position 36 and L44M mutation from leucine(L) to methionine(M) can confer 5 to 10 folds of enfuvirtide resistance but when G36S and L44M mutation occurred simultaneously, the degree of resistance can be increase to about 100 folds. (Carmona et al., 2005 and Menéndez-Arias 2009)
Major mutations in HIV's DNA which confer resistance to maraviroc (Johnson, et al., 2008)
Amino acid mutations in the V3 loop of gp120 seem to be the key for maraviroc treatmen failure, when amino acid mutation at A316T from alanine(A) to threonine(T) at position 316 and I323V mutation from isoleucine(I) to valine(V) at position 323 within the V3 loop of gp120 there is a significant increase of maraviroc resistance. (Esté et al., 2007, Lieberman-Blum et al., 2008, (Menéndez-Arias 2009 and Hughes et al., 2008) Mutation of T163K from threonine(T) to lysine(K) and S405A from serine(S) to alanine(A) at position 405 at V2 and V4 loop and the mutation of C3 domain N355Y from asparagine(N) to tyrosine(Y) all confer resistance to maraviroc. (Menéndez-Arias 2009) Maraviroc resistance can also develop by mutations which allow HIV-1 to use CXCR4 coreceptors instead of CCR5 receptors to gain entry into CD4. (Menéndez-Arias 2009)
Major mutations in HIV's DNA which confer resistance to raltegravir (Johnson, et al., 2008)
Raltegravir is a new HIV drug under a new class integrase inhibitor, it has a low genetic barrier and drug resistance only requires a single point mutation. (Havlir 2008 and Cocohoba et al., 2008) Resistance to raltegravir mainly occurred at Y143R/H/C mutation from tyrosine(Y) to arginine(R), histidine(H) or cysteine(C), Q148H/K/R mutation from glutamine to histidine(H), lysine(K) or arginine(R) at position 148 or N155H mutation from asparagine(N) to histidine(H) at position 155. (Cooper et al 2008 and McColl et al., 2009) Mutations of Q148H were found to increase raltegravir resistance by 7 to 8 folds and mutation of N155H caused an increase of 14-folds resistance to raltegravir. (Cocohoba et al., 2008 Cooper et al 2008, McColl et al., 2009 and McColl et al., 2009) In Phase III clinical trials, mutations associated with raltegravir was N155H accounted for 39% to 42% and Q148K/R/H accounted for 27% to 31%. (Cocohoba et al., 2008)
New drugs can save life
The three high income countries use in the statistical analysis United States of American, Australia and Italy had shown a significant decrease in AIDS related death from 1995 to 1997. (The light blue region represent the year from 1995 to 1997) Beside these three countries, countries such as United Kingdom, Canada, Japan and many other high income countries all show such a trend. So what is the cause for such a decline? Let go back to the early years when HIV was discovered as the causative agent for HIV.
The number of AIDS related deaths from 1990 to 2007 for US, Australia and Italy (UNAIDS)
Types of HIV drugs that were approved by FDA and EMEA from 1995 to 1997. (FDA and EMEA)
From 1981 to 1986, there was no practically no drugs or cure for HIV, only in 1987 the first HIV drug zidovudine was introduce, however zidovudine was not enough to control HIV. In 1995, the first time protease inhibitors (PIs) saquinavir was approved by the FDA and the EMEA in 1996. Follow by 1996, the first non-nucleoside reverse transcriptase inhibitor (NNRTIs), nevirapine was approved with two new PIs, ritonavir and indinavir. (FDA) In 1997, two more new drugs from the NNRTIs class delavirdine and nelfinavir was approved. (FDA).
When these new HIV drugs was introduced between 1995 to 1997, a new way of treating HIV was also introduced, doctors begin to use a combination of these HIV drugs in dual or triple threapy rather than monotherapy. This was the beginning of the HAART era and many HIV patients begin to life longer and had a better quality of life. Now the current guidelines recommend to begin treatment is two NRTIs plus either a NNRTIs or a PIs as first line treatment. As of 2010, the FDA had aproved 3 more classes of HIV drugs: the fusion inhibitor class: enfuvirtide in 2003, the entry inhibitor class: maraviroc and the integrase strand transfer inhibitor class: raltegravir both in 2007. These new HIV drugs were use as a salvage threapy for heavily treated patient who had experienced multi-drug resistant. Unfortunately resistant to these new classes of HIV drugs also had emerged over a period of treatment.
Figure number and title ??
In 2005 the G8 (France, United States, Britain, Germany, Japan, Italy, Canada, and Russia) with many other rich countries and private organizations such as Gates foundation and World Bank had launched a goal to provide universal access of HIV drugs to all who need it by 2010 and that was a direct response to deal with the poverty issues of middle and poor countries. Countries like Brazil (Okie, 2006), Botswana and Namiba had been providing free treatment to it HIV population and other countries are heavily subsidize their HIV treatment programme. So in the future, the accessibility and availability of HIV drugs will not be an issue. However as in all HIV patients who will require to undergo life long treatment, mutation of the HIV is inevitable and is going to happen. The second and third line therapy must be already in place to deal with such mutations which confer resistant to the first line therapy. As HIV virus is ever evolving and without an effective vaccine on the horizon, new HIV drug is a necessity to combat HIV and save as many life as possible If there is no sufficient research and development begin put into new HIV drugs development, there may be a time when all of the HIV drugs are useless again HIV and all the efforts in the fight against HIV/AIDS epidemic will be wide off. So the conclusive message for this dissertation is that indeed we need new HIV drugs so that we can effective counter the HIV/AIDS epidemic in the near future.