Human Immunodeficiency Virus

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?

1.0 Introduction

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)

1.2 Epidemiology

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.

Regions

Adults and children

living with HIV

Adults and children

newly infected with HIV

Adult and child deaths

due to AIDS

Sub-Saharan Africa

22.4 million

1.9 million

1.4 million

East Asia

850 000

75 000

59 000

Oceania

59 000

3900

2000

South & South East Asia

3.8 million

280 000

270 000

Eastern Europe & Central Asia

1.5 million

110 000

87 000

Western and Central Europe

850 000

30 000

13 000

Middle East & North Africa

310 000

35 000

20 000

North America

1.4 million

55 000

25 000

Caribbean

240 000

20 000

12 000

Latin America

2.0 million

170 000

77 000

Total

33.4 million

2.7 million

2.0 million

Table 1

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.

Brand

Name

Generic Name

FDA Approval

Date

EMEA Approval

Date

Remarks

Multi-class combination products – 2 NRTIS plus 1 NNTRIs

Atripla

Efavirenz, emtricitabine and tenofovir

July 06

Dec 07

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) – competitive inhibitors of HIV reverse transcriptase

Retrovir

Zidovudine

Mar 87

NA

Videx

Didanosine

Oct 91

NA

Hivid

Zalcitabine,

Jun 92

NA

No longer market in US

Zerit

Stavudine

Jun 94

May 96

Epivir

Lamivudine,

Nov 95

Aug 96

Combivir

Lamivudine and zidovudine

Sep 97

Mar 98

Ziagen

Abacavir

Dec 98

July 99

Videx EC

Enteric coated didanosine

Oct 00

NA

Trizivir

Abacavir, zidovudine, and lamivudine

Nov 00

Nov 00

Viread

Tenofovir

Oct 01

Feb 02

Epzicom

Abacavir and lamivudine

Aug 02

Dec 04

Marketed as kivexa in Europe

Emtriva

Emtricitabine,

Jul 03

Oct 03

Truvada

Tenofovir and emtricitabine

Aug 04

Feb 05

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) – non competitive antagonist that directly bind and inhibit HIV reverse transcriptase

Viramune

Nevirapine

Jun 96

Feb 98

Rescriptor

Delavirdine

Apr 97

NA

Sustiva

Efavirenz

Sep 98

May 99

Intelence

Etravirine

Jan 08

Aug 08

Protease Inhibitors (PIs) – inhibitors of HIV protease enzymes needed for viral maturation

Invirase

Saquinavir

Dec 95

Oct 96

Norvir

Ritonavir

Mar 96

Aug 96

Crixivan

Indinavir,

Mar 96

Oct 96

Viracept

Nelfinavir

Mar 97

Jan 98

Agenerase

Amprenavir

Apr 99

Oct 00

Kaletra

Lopinavir and ritonavir,

Sep 00

Mar 01

Reyataz

Atazanavir

Jun 03

Mar 04

Lexiva

Fosamprenavir

Oct 03

Jul 04

Marketed as Telzir in Europe

Aptivus

Tipranavir

Jun 05

Oct 05

Prezista

Darunavir

Jun 06

Feb 07

Fusion Inhibitors – prevent HIV from entering CD4 cell

Fuzeon

enfuvirtide,

Mar 03

May 03

Entry Inhibitors - CCR5 co-receptor antagonist – prevent HIV from entering CD4 cell

Selzentry

maraviroc

Aug 07

Sep 07

Marketed as Celsentri in Europe

HIV integrase strand transfer inhibitors – interfere with integrase enzymes

Isentress

raltegravir

Oct 07

Dec 07

Table 2 Antiretroviral drugs used in the treatment of HIV infection approved by FDA and EMEA (2009)

Current guidelines recommended by theUS Department of Health and Human Services (DHHS) considered of 2 NRTIs plus either a NNRTIs or a PIs for HIV naïve patient. (Deeks, 2006 and DHHS, 2009) DHHS also recommended when an asymptomatic HIV patient's CD4+ cells count drop to a range between 350cells/µL to 200cells/µL 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)

2.0 Objective:

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?

1

The high cost of HAART

Mutations of HIV which render current HIV drugs less effective

2

Insufficient funding to deal with the HIV/AIDS epidemic

The potential that new HIV drug can save more lives

3

Failure of WHO 3 by 5 initiatives

4

Insufficient HAART coverage for HIV patient

5

Inaccessibility of Indinavir

3.0 Methods

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 s 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.

4.0 Results

Regions

Countries

Correlation of mortality rate

and GNI per capital

Average GNI per capital (1990 to 2007)

Sub-Saharan Africa

South Africa

0.653

3525

East Asia

China

0.979

1007

Oceania

Australia

-0.495

23886

South & South East Asia

Myanmar

0.611

192

Eastern Europe & Central Asia

Russian Federation

0.921

3392

Western and Central Europe

Italy

-0.585

22931

Middle East & North Africa

Sudan

0.622

538

North America

United States of America

-0.491

32374

Caribbean

Haiti

0.622

370

Latin America

Brazil

0.664

3960

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.

5.0 Discussion

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.

In the recent years from 2004 to 2008, the cost of HAART in poor and middle income countries had declined by about 48%. 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. 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) 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 naїve 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)

Fusion inhibitor

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)

Entry inhibitor

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)

Integrase inhibitor

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.

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.

6.0 Conclusion

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.

References:

1. AIDS epidemic update. (2009). UNAIDS.

2. Alteri Claudia, Svicher Valentina, Gori Caterina, D'Arrigo Roberta, Ciccozzi Massimo, Ceccherini-Silberstein Francesca, Selleri Marina, Bardacci Stefano Aviani, Giuliani Massimo, Elia Paola, Scognamiglio Paola, Balzano Roberta, Orchi Nicoletta, Girardi Enrico, Perno Carlo Federico and SENDIH Study Group. (2009). Characterization of the patterns of drug-resistance mutations in newly diagnosed HIV-1 infected patients naïve to the antiretroviral drugs. BMC Infectious Diseases. Vol: 9,111.

3. Antiretroviral drugs used in the treatment of HIV infection. (2009). Available on:[http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm]. assessed on 18th Sep 2009.

4. Bate Roger. (2006). WHO's AIDS Target: An Inevitable Failure. American Enterprise Institute for public policy research. 3, pp: 1-5.

5. Bihani Subhash C., Das Amit, Prashar Vishal, Ferrer J.-L and M.V. Hosur. (2009). Resistance mechanism revealed by crystal structures of unliganded nelfinavir-resistant HIV-1 protease non-active site mutants N88D and N88S. Biochemical and Biophysical Research Communications. 389, 295–300.

6. Carmona R., Perez-Alvarez L., Munoz M., Casado G., Delgado E., Sierra M., Thomson M., Vega Y., E. Parga Vazquez de, Contreras G., Medrano L. and Najera R. (2005). Natural resistance-associated mutations to Enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients. Journal of Clinical Virology. 32, 248–253.

7. Cases-González Clara E., Franco Sandra, Martínez Miguel Ángel and Menéndez-Arias Luis. (2007). Mutational Patterns Associated with the 69 Insertion Complex in Multi-drug-resistant HIV-1 Reverse Transcriptase that Confer Increased Excision Activity and High-level Resistance to Zidovudine. J. Mol. Biol.365, 298–309.

8. Cihlar, T. and Ray, A.S. (2009). Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. doi:10.1016/j.antiviral.2009.09.014.

9. Cocohoba Jennifer and Dong Betty J. (2008) Raltegravir: The First HIV Integrase Inhibitor. Clinical Therapeutics. Vol 30, No 10, 1747-1765. Cohen Myron S., Hellmann Nick, Levy Jay A, DeCock Kevin and Lange Joep. (2008) The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. The Journal of Clinical Investigation. Vol: 118, 4, pp: 1244 – 1254.

10. Cooper David A (2008). Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection. N Eng J Med. 359. 4. 355-365.

11. Covens Kris, Kabeya Kabamba, Schrooten Yoeri, Dekeersmaeker Nathalie, Wijngaerden Eric Van, Vandamme Anne-Mieke, Wit Stéphane De and Laethem Kristel Van. (2009).Evolution of genotypic resistance to enfuvirtide in HIV-1 isolates from different group M subtypes. Journal of Clinical Virology. 44, 325–328.

12. Deeks Steven G. (2006). Antiretroviral treatment of HIV infected adults. BMJ, vol, 332, 24, pp 1489 – 1493.

13. Delaugerre Constance,, Roudiere Laurent, Peytavin Gilles, Rouzioux Christine, Viard Jean-Paul and Chaix Marie-Laure. (2005).Selection of a rare resistance profile in an HIV-1-infected patient exhibiting a failure to an antiretroviral regimen including tenofovir DF. Journal of Clinical Virology. 32, 241–244.

14. De Béthune, M.-P. (2009). Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989–2009). Antiviral Res. doi:10.1016/j.antiviral.2009.09.008.

15. Drugs approved for HIV treatment. European Medicine agency. Available on: [http://www.emea.europa.eu/]. Accessed on 26th Dec 2009.

16. Dyer Clare. (2009). Funding for HIV/AIDS needs to double to ensure universal access to drugs. BMJ;338:b583.

17. Emery Sean, Winston Alan. (2009). Raltegravir: a new choice in HIV and new chances for research. Lancet. 374.5, 764-765.

18. Esté José A and Telenti Amalio. (2007) HIV entry inhibitors. Lancet, Vol 370. 81-8.

19. Ford Nathan, Mills Edward and Calmy Alexandra. (2009). Rationing Antiretroviral Therapy in Africa -Treating Too Few, Too Late. N Eng J Med. Vol: 360, 18, pp: 1808 – 1810.

20. Freire Ernesto. (2006). Overcoming HIV-1 resistance to protease inhibitors. Drug Discovery Today: Disease Mechanisms Vol. 3, 281-286.

21. Frieden Thomas R, Das-Douglas Moupali, Kellerman Scott E, and Henning Kelly J. (2005). Applying Public Health Principles to the HIV Epidemic. N Engl J Med, Vol. 353, No. 22, pp 2397 - 2402.

22. Fung Horatio B. and Guo Yi. (2004). Enfuvirtide: A Fusion Inhibitor for the Treatment of HIV Infection. CLINICAL THERAPEUTICS. VOL. 26, NO. 3, 352-378.

23. Grinsztejn Beatriz, Veloso Valdilea G, Jose´ Pilotto Henrique, Campos Dayse Pereira, Keruly Jeanne C and Richard D. Moore. (2007). Comparison of Clinical Response to Initial Highly Active Antiretroviral Therapy in the Patients in Clinical Care in the United States and Brazil. J Acquir Immune Defic Syndr. Vol: 45, pp 515–520.

24. Gulick Roy M, Lalezari Jacob, Goodrich James, Clumeck Nathan, DeJesus Edwin, Horban Andrzej, Nadler Jeffrey, Clotet Bonaventura, Karlsson Anders, Wohlfeiler Michael, Montana John B, McHale Mary, Sullivan John, Ridgway Caroline, Felstead Steve, M, Dunne Michael W, Ryst Elna van der and Mayer Howard. (2008). Maraviroc for Previously Treated Patients with R5 HIV-1 Infection. N Eng J Med. 359, 14, 1429-1441.

25. Gutierrez Juan Pablo, Johns Benjamin, Adam Taghreed, Bertozzi Stefano M, Edejer Tessa Tan-Torres, Greener Robert, Hankins Catherine and Evans David B. (2004). Achieving the WHO/UNAIDS antiretroviral treatment 3 by 5 goal: what will it cost? Lancet. Vol: 364, pp 63–64.

26. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. (2009). DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. (2009). Available on: [http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf]. Assessed on 27th Dec 2009.

27. Hachiya Atsuko, Gatanaga Hiroyuki, Kodama Eiichi, Ikeuchi Mieko, Matsuoka Masao, Harada Shigeyoshi, Mitsuya Hiroaki, Kimura Satoshi and Oka Shinichi. (2004). Novel patterns of nevirapine resistance-associated mutations of human immunodeficiency virus type 1 in treatment-naive patients. Virology.327, 215– 224.

28. Hall H. Irene, Geduld Jennifer, Boulos David, Rhodes Philip, An Qian, Mastro Timothy D, Janssen Robert S and Archibald Chris P. (2009). Epidemiology of HIV in the United States and Canada: Current Status and Ongoing Challenges. J Acquir Immune Defic Syndr. Vol: 51:S13–S20.

29. Havlir Diane V. (2008). HIV Integrase Inhibitors — Out of the Pipeline and into the Clinic. N Eng J Med. 359, 4, 416-418.

30. HIV Drug Resistance Mutations by Drug Class (2009). Stanford HIV resistance database. Available on: [http://hivdb.stanford.edu]. Accessed on 26th Dec 2009.

31. Hogan Daniel R, Baltussen Rob, Hayashi Chika, Lauer Jeremy A and Salomon Joshua A. (2005). Cost effectiveness analysis of strategies to combat HIV/AIDS in developing countries. BMJ, doi:10.1136/bmj.38643.368692.68.

32. Hogg RS, Bangsberg DR, Lima VD, Alexander C, Bonner S, et al. (2006) Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med 3(9): e356. DOI: 10.1371/journal. pmed.0030356.

33. Hughes Amelia, Barber Tristan, Nelson Mark. (2008). New treatment options for HIV salvage patients: An overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists. Journal of Infection. 57, 1-10.

34. Johnson Victoria A. (2008). Update of the Drug Resistance Mutations in HIV-1:December. Topics in HIV Medicine.138-145.

35. Kagan R.M., Lee T.-S., Ross L., Lloyd Jr R.M., Lewinski M.A. and Potts S.J. (2007). Molecular basis of antagonism between K70E and K65R tenofovir-associated mutations in HIV-1 reverse transcriptase. Antiviral Research. 75, 210–218.

36. Kim Jim Yong and Ammann Arthur. (2004). Is the “3 by 5” Initiative the Best Approach to Tackling the HIV Pandemic? PLoS Medicine. Volume 1, Issue 2 ,e37, pp: 97- 100.

37. Kim Jim Yong and Charlie Gilks (2005). Scaling Up Treatment - Why We Can't Wait. N Eng J Med. 353;22, pp: 2392 -2394.

38. Kisic Mónica, Mendieta Jesús, Puertas María C., Parera Mariona, Martínez Miguel A., Martinez-Picado Javier and Menéndez-Arias Luis. (2008). Mechanistic Basis of Zidovudine Hypersusceptibility and Lamivudine Resistance Conferred by the Deletion of Codon 69 in the HIV-1 Reverse Transcriptase Coding Region. J. Mol. Biol. 382, 327–341.

39. Kitahata Mari M, Gange Stephen J, Abraham Alison G, Merriman Barry, Saag Michael S, Justice Amy, Hogg Robert, Deeks Steven G, Eron Joseph J, Brooks John T, Rourke Sean B, Gill M. John, Bosch Ronald J, Martin Jeffrey N, Klein Marina B, Jacobson Lisa P, Rodriguez Benigno, Sterling Timothy R, Kirk Gregory D, Napravnik Sonia, Rachlis Anita R, Calzavara Liviana M, Horberg Michael A, Silverberg Michael J, Gebo Kelly A, Goedert James J, Benson Constance A, Collier Ann C, Rompaey Stephen E. Van, Crane Heidi M, Rosemary G. McKaig, Lau Bryan, Freeman Aimee M. and Moore Richard D. (2009). Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival. N Engl J Med .Vol: 360, pp:1815-26.

40. Lieberman-Blum Sharon S., Fung Horatio B and Bandres Juan C. (2008). Maraviroc: A CCR5-Receptor Antagonist for the Treatment of HIV-1 Infection. Clinical Therapeutics. Volume 30, Number 7, 1228-1250.

41. Liu Fengling, Kovalevsky Andrey Y., Tie Yunfeng, Ghosh Arun K., Harrison Robert W., and Weber Irene T. (2008). Effect of Flap Mutations on Structure of HIV-1 Protease and Inhibition by Saquinavir and Darunavir. J. Mol. Biol. 381, 102–115.

42. Lohse Nicolai, Hansen Ann-Brit Eg, Pedersen Gitte, Kronborg Gitte, Gerstoft Jan, Sørensen Henrik Toft, Væth Michael and Obel Niels. (2007). Survival of Persons with and without HIV Infection in Denmark, 1995–2005. Ann Intern Med. Vol: 146, pp: 87-95.

43. Martinez-Cajas Jorge L and Wainberg Mark A. (2007). Protease inhibitor resistance in HIV-infected patients: Molecular and clinical perspectives. Antiviral Research. 76, 203–221.

44. McColl, D.J and Chen, X. (2009). Strand transfer inhibitors of HIV-1 integrase: Bringing IN a new era of antiretroviral therapy. Antiviral Res. doi:10.1016/j.antiviral.2009.11.004

45. Menendez-Arias Luis. (2008).Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Research. 134. 124–146.

46. Menéndez-Arias Luis. (2009). Molecular basis of human immunodeficiency virus drug resistance: An update. Antiviral Res. doi:10.1016/j.antiviral.2009.07.006.

47. Merson Michael H. (2006). The HIV–AIDS Pandemic at 25 - The Global Response. N Eng J Med.354; 23, pp: 2414 – 2417.

48. Miller Michael D. and Hazuda Daria J. (2004). HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. Drug Resistance Updates 7, 89–95.

49. Murri Rita. (2005). Highly active antiretroviral therapy, Exhaustion of treatment options is a challenge that can be delayed. BMJ. 330:681–2.

50. National Accounts Main Aggregates Database. (2009). United Nation Statistic Division. Available on:[ http://unstats.un.org/unsd/snaama/dnllist.asp]. Accessed on 26th Dec 2009.

51. Nijhuis Monique, Maarseveen Noortje M. van, Lastere Stephane, Schipper Pauline, Coakley Eoin, Glass Barbel, Rovenska Mirka, Jong Dorien de, Chappey Colombe, Irma W. Goedegebuure, Snyder Gabrielle Heilek, Dulude Dominic, Cammack Nick, Brakier-Gingras Lea, Konvalinka Jan, Parkin Neil, Krausslich Hans-Georg, Brun-Vezinet Francoise and Boucher Charles A. B. (2007). A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism. PLoS MEDICINE. Volume 4, Issue 1, e36, pp 152 – 163.

52. Okie Susan. (2006). Fighting HIV - Lessons from Brazil. N Engl J Med. Vol: 354, 19, pp: 1977 – 1981.

53. Paolucci Stefania, Baldanti Fausto, Campanini Giulia, Cancio Reynel, Belfiore Amalia, Maga Giovanni and Gerna Giuseppe. (2007). NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine. Antiviral Research. 76, 99–103.

54. Pauwels Rudi. (2004). New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Current Opinion in Pharmacology. 4, 437–446.

55. Poveda Eva, Rodes Berta, Lebel-Binay Sophie, Faudon Jean-Louis, Jimenez Victoria and Soriano Vincent. (2005).Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. Journal of Clinical Virology. 34, 295–301.

56. Pneumocystis Pneumonia --- Los Angeles. (1981). Morbidity and Mortality Weekly Report. 30(21);1-3.

57. Re M.C., Monari P., Bon I., Borderi M., Gibellini D., Schiavone P., Vitone F., Furlini G and Placa M. La. (2002). Development of drug resistance in HIV-1 patients receiving a combination of stavudine, lamivudine and efavirenz. International Journal of Antimicrobial Agents. 20, 223-/226.

58. Ren Jingshan and Stammers David K. (2008). Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Research. 134, 157–170.

59. Report on the global AIDS epidemic. (2008). UNAIDS

60. Sabin Caroline A, Hill Teresa, Lampe Fiona, Matthias Ryanne, Bhagani Sanjay, Gilson Richard, Youle Mike S, Johnson Margaret A, Fisher Martin, Scullard George, Easterbrook Philippa, Gazzard Brian and Phillips Andrew N. (2005). Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study. BMJ. doi:10.1136/bmj.38369.669850.8F.

61. Sackoff Judith E, Hanna David B, Pfeiffer Melissa R and Torian Lucia V. (2006). Causes of Death among Persons with AIDS in the Era of Highly Active Antiretroviral Therapy: New York City. Ann Intern Med. Vol: 145, pp: 397-406.

62. Sa-Filho Dercy J., Costa Luciana J., de Oliveira Carlos F., Guimara˜es Ana Paula C., Accetturi Conceic¸a˜o A., Tanuri Amilcar and Diaz Ricardo S. (2003). Analysis of the protease sequences of HIV-1 infected individuals after Indinavir monotherapy. Journal of Clinical Virology. 28, 186-202.

63. Sluis-Cremer Nicolas and Tachedjian Gilda. (2008). Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Research. 134, 147–156.

64. Sarafianos Stefan G., Marchand Bruno, Das Kalyan, Himmel Daniel M., Parniak Michael A., Hughes Stephen H. and Arnold Eddy. (2009).Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition. J. Mol. Biol. 385, 693–713.

65. Schiller Daryl S and Youssef-Bessler Manal. (2009). Etravirine: A Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Active Against NNRTI-Resistant Strains of HIV. Clinical Therapeutics. Volume 31, Number 4, 692-704.

66. Steigbigel Roy T., (2008). Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection. N Eng J Med. 359. 4.339-354.

67. Sepkowitz Kent A. (2001). AIDS — THE FIRST 20 YEARS. N Engl J Med, Vol. 344, No. 23, pp 1764 – 1772.

68. Sheri Weiser, Wolfe William, Bangsberg David, Thior Ibou, Peter Gilbert, Makhema Joseph, Kebaabetswe Poloko, Dickenson Dianne, Mompati Kgosidialwa, Essex Max and Marlink Richard. (2003). Barriers to Antiretroviral Adherence for Patients Living with HIV Infection and AIDS in Botswana. J Acquir Immune Defic Syndr.vol:34, pp 281–288.

69. Smith Marilyn B. Kroeger, Rader Lenea H., Franklin Amanda M., Taylor Emily V., Smith Katie D., Smith Richard H. Jr., Tirado-Rives Julian and Jorgensen William L. (2008).Energetic effects for observed and unobserved HIV-1 reverse transcriptase mutations of residues L100, V106, and Y181 in the presence of nevirapine and efavirenz. Bioorganic & Medicinal Chemistry Letters. 18, 969–972.

70. Stevens Warren, Kaye Steve and Corrah Tumani. (2004). Antiretroviral therapy in Africa. BMJ VOLUME 328, 31, pp 280 – 282.

71. Taylor Barbara S., Sobieszczyk Magdalena E., McCutchan Francine E and Hammer Scott M. (2008). The Challenge of HIV-1 Subtype Diversity. N Engl J Med. 2008 April 10; 358(15): 1590–1602.

72. The Nobel Prize in Physiology or Medicine. (2008). Nobel Assembly at Karolinska Institutet. Stockholm. Nobel Foundation. Available on [http://nobelprize.org/nobel_prizes/medicine/laureates/

2008/press.html]. Accessed on 26th Sep 2009.

73. Theys Kristof, Vercauteren Jurgen, Abecasis Ana B., Libin Pieter, Deforche Koen, Vandamme Anne-Mieke andCamacho Ricardo. (2009). The rise and fall of K65R in a Portuguese HIV-1 Drug Resistance database, despite continuously increasing use of tenofovir. Infection. Genetics and Evolution. 9, 683–688.

74. Vaclavıkova Jana, Machala Ladislav, Stankova Marie, Linka Marek, Bruckova Marie, Vandasovac Jana and Konvalinka Jan. (2005). Response of HIV positive patients to the long-term salvage therapy by lopinavir/ritonavir. Journal of Clinical Virology. 33, 319–323.

75. Vallejo Alejandro, Olivera Mercedes, Rubio Amalia, Sánchez-Quijano Armando, Lissen Eduardo and Leal Manuel. (2004). Genotypic resistance profile in treatment-experienced HIV-infected individuals after abacavir and efavirenz salvage regimen Antiviral Research .61, 129–132.

76. Vergani Barbara, Cicero Mirko Lo, Vigano' Ottavia, Sirianni Francesca, Ferramosca Stefania, Vitiello Paola, Vincenzo Paola Di, Pasquale Maria Pia De, Galli Massimo and Rusconi Stefano. (2008). Evolution of the HIV-1 protease region in heavily pretreated HIV-1 infected patients receiving Atazanavir . Journal of Clinical Virology. 41,154–159.

77. Watts Geoff. (2008). Three Europeans win Nobel medicine prize for discovering HIV and HPV. BMJ 2008;337:a2023

78. Wensing Annemarie M.J., Maarseveen Noortje M. van, Nijhuis Monique. (2009). Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance. Antiviral Res. doi:10.1016/j.antiviral.2009.10.003.

79. WHO HIV/AIDS Director Apologizes for Missing 3 By 5 Initiative's End-of-Year Goal. (2005). Medical News today. Available on: [http://www.medicalnewstoday.com/articles/34257.php]. Assessed on 211th Sep 2009.

80. Zdanowicz Martin M. (2006) The Pharmacology of HIV Drug Resistance American Journal of Pharmaceutical Education. 70 (5) Article 100.

What are the tables which follow- number them and give them a title.

Countries

Year

Death

GNI ($US)

Countries

Year

Death

GNI ($US)

South Africa

(Sub-Saharan Africa)

1990

2600

2946

China

(East Asia)

1990

<500

347

1991

4200

3121

1991

<1000

359

1992

6800

3315

1992

<1000

422

1993

11 000

3232

1993

1300

524

1994

17 000

3290

1994

1800

473

1995

26 000

3572

1995

2500

601

1996

39 000

3316

1996

3500

701

1997

56 000

3367

1997

4800

775

1998

79 000

2980

1998

6600

817

1999

110 000

2906

1999

8800

864

2000

140 000

2857

2000

12 000

949

2001

180 000

2493

2001

15 000

1039

2002

220 000

2320

2002

17 000

1137

2003

270 000

3441

2003

23 000

1282

2004

310 000

4453

2004

27 000

1504

2005

330 000

4961

2005

31 000

1741

2006

320 000

5232

2006

34 000

2059

2007

350 000

5655

2007

39 000

2532

Countries

Year

Death

GNI ($US)

Countries

Year

Death

GNI ($US)

Australia

(Oceania)

1990

<200

17578

Myanmar (South East Asia)

1990

1500

129

1991

<500

17782

1991

2400

130

1992

<500

17416

1992

3800

144

1993

<500

17276

1993

5500

154

1994

<500

19196

1994

7600

167

1995

<500

20452

1995

9900

180

1996

<500

22527

1996

12 000

193

1997

<200

22435

1997

15 000

204

1998

<100

19788

1998

18 000

128

1999

<100

21374

1999

20 000

145

2000

<100

20312

2000

22 000

159

2001

<100

19122

2001

24 000

165

2002

<100

21049

2002

26 000

222

2003

<100

26718

2003

27 000

212

2004

<100

31654

2004

27 000

216

2005

<100

34960

2005

27 000

249

2006

<100

36670

2006

26 000

284

2007

<100

43634

2007

25 000

378

Countries

Year

Death

GNI ($US)

Countries

Year

Death

GNI ($US)

Russian Federation (Eastern Europe & Central Asia)

1990


3830

Italy

(Western and Central Europe)

1990

7500

19667

1991


3754

1991

8900

20675

1992


3212

1992

10 000

21823

1993


3014

1993

11 000

17588

1994


2706

1994

12 000

18084

1995


2647

1995

12 000

19349

1996


2595

1996

12 000

21674

1997

<100

2665

1997

4900

20624

1998

<200

1747

1998

3300

21023

1999

<500

1272

1999

2800

20765

2000

<1000

1716

2000

3000

18878

2001

1900

2059

2001

3100

19186

2002

3800

2319

2002

2900

20833

2003

7300

2877

2003

2100

25652

2004

12 000

4001

2004

1500

29378

2005

20 000

5177

2005

1600

30217

2006

29 000

6679

2006

1700

31647

2007

40 000

8782

2007

1900

35687

Countries

Year

Death

GNI ($US)

Countries

Year

Death

GNI ($US)

Sudan

(Middle East & North Africa)

1990

1300

537

United States of America

(North America)

1990

17 000

22358

1991

2300

245

1991

24 000

22811

1992

3500

290

1992

32 000

23748

1993

5100

317

1993

41 000

24563

1994

7000

444

1994

50 000

25812

1995

9200

467

1995

59 000

26927

1996

12 000

272

1996

38 000

28204

1997

14 000

330

1997

22 000

29753

1998

16 000

343

1998

18 000

31296

1999

18 000

377

1999

18 000

32940

2000

19 000

325

2000

17 000

34863

2001

21 000

445

2001

17 000

35469

2002

21 000

505

2002

18 000

35997

2003

22 000

602

2003

18 000

37150

2004

23 000

706

2004

18 000

39374

2005

24 000

917

2005

19 000

41782

2006

24 000

1134

2006

21 000

44108

2007

25 000

1420

2007

22 000

45534

Countries

Year

Death

GNI ($US)

Countries

Year

Death

GNI ($US)

Haiti (Caribbean)

1990

<500

364

Brazil

(Latin America)

1990

8100

3239

1991

<1000

319

1991

9300

2808

1992

1200

206

1992

11 000

2714

1993

1800

204

1993

12 000

2979

1994

2500

266

1994

14 000

3688

1995

3300

294

1995

15 000

4689

1996

4100

344

1996

16 000

5044

1997

5000

381

1997

10 000

5133

1998

5800

427

1998

11 000

4882

1999

6500

465

1999

9400

3311

2000

7100

411

2000

11 000

3600

2001

7500

386

2001

9400

3027

2002

7900

346

2002

11 000

2724

2003

7900

305

2003

9600

2940

2004

7900

391

2004

8800

3493

2005

7400

436

2005

9600

4586

2006

7300

504

2006

12 000

5612

2007

7200

612

2007

15 000

6809

21

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