Are Anti-retroviral drugs effective at treating HIV?

1.1 The Problem

The human immunodeficiency virus (HIV) is a kind of retrovirus that causes a collective set of
life threatening conditions termed as Acquired Immunodeficiency Syndrome (AIDS) in humans.
It causes rapid and progressive collapse of the immune system which makes a person prone to
infections which usually are life threatening in the absence of immune system. HIV infection
occurs by transfusion and exchange of bodily fluids like blood, breast milk, semen, pre-ejaculate
and vaginal fluid. Without intervention, survival time after HIV infection is estimated to be 9 to
11 years.
HIV attacks the human immune system, targeting helper T cells and specifically CD4+ T cells,
Antigen presenting Dendritic cells and Macrophages. As the CD4+ T cell numbers go down
below critical levels, the body's immune system crumbles, and it becomes highly susceptible to a
wide range of infections which normally doesn't bother a healthy person.
1.2 The Management of Problem
We now know that there is no cure for AIDS and the term everybody uses is management. The
antiretroviral drugs are a cocktail of drugs that acts as a multipronged approach to contain the
disease. The use of combination of drugs that act on different Virus targets is called highly active
antiretroviral therapy (HAART). HAART fights the Virus and tries to cripple it, gives a chance to
the immune system to maintain itself and keeps life threatening infections at bay.
Antiretroviral treatment has been proven so successful that it has led to a sharp fall in the
mortality figures due to AIDS. Anthony Fauci, head of the US National Institute of Allergy and
Infectious Diseases notes that an estimated 700,000 lives were saved in 2010 alone due to
antiretroviral therapy.
In HAART, there are five classes of drugs, which are usually used in combination, to treat HIV
infection.

Entry inhibitors or fusion inhibitors disrupt binding, cell fusion and entry of HIV-1 to the
host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two drugs

in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper

T-cells.
At the molecular level, Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide
reverse transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which
prevent reverse transcription. HIV is a single strand RNA virus and in order to latch on to
the DNA in the nucleus of the human cell; it must be reverse transcribed into DNA. This
conversion of RNA to DNA is not done by human cell and is performed by a viral

protein which makes it a selective target for inhibition.

Non-Nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase
enzyme by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive

inhibitors of reverse transcriptase.

Integrase inhibitors disrupt the functioning of viral enzyme integrase, which is used by

virus for integration of viral DNA into the DNA of the infected cell.
Protease inhibitors block the viral protease enzyme essential to make new viruses by
budding from the host membrane.

Fig:1 Different modes of HIV invading a Cell

The reason HIV virus is untreatable lies in its genetic reproduction blueprint. HIV has a very
high rate of mutation when it changes its RNA into DNA via reverse transcription. This results
in a high genetic variability of HIV. As it has no fixed genetic pattern, this enables them to slip
past defenses such as the human immune system and antiretroviral drugs. The more the viruses
in the tissues, the greater is the danger of getting resistant to antiretroviral drugs.
Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number
of multiplication low and reduce the possibility of a superior mutation. If a mutation that conveys
resistance to one of the drugs being taken arises, the other drugs continue to suppress
reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been
demonstrated to suppress an HIV infection for long; these agents must be taken in combinations
in order to have a lasting effect. As a result, the standard of care is to use combinations of
antiretroviral drugs. Combinations usually comprise of three drugs from at least two different
classes. This three drug combination is commonly known as a triple cocktail. Combinations of
antiretrovirals are subject to positive and negative synergies, which limits the number of useful
combinations.
1.3 Benefits and Risks
Surprisingly a study from the US has found that some people with HIV, especially those treated
before their CD4 count falls below 350 cells/mm3, now have life expectancies equal to or even
higher than the US general population.
However, the study also finds that life expectancy for some other groups most notably women
and non-white people considerably below comparable members of the general population. A
second study, which looked at death rates among both HIV-positive and HIV-negative members
of two cohorts of people with or at risk of HIV, has found that the death rate from non-AIDSdefining illnesses among people with HIV who started ART above the 350 cells/mm3 threshold
was not, and never has been, any higher than among comparable HIV-negative people.
In other words, the sole contributor to the increased mortality in people who started ART early
was AIDS. This was not, however, the case for people who started ART later, who had raised
mortality due to non-AIDS-related causes as well as due to AIDS.

Evidence from trials indicates that ART can reduce the risk of transmitting HIV by as much as
96% (67,68), although the protective effect appears to be smaller in operational settings: for
example, an estimated 66% reduction in HIV incidence among a cohort of HIV discordant
couples in China. The trial findings have been confirmed by some longitudinal studies, including
in a rural part of South Africa, where the incidence of HIV infection fell by 17% for every 10%
increase in the number of people receiving ART. A 2011 modeling study estimated that a
combination of classical HIV prevention interventions and ART coverage of 80% (based on the
2010 WHO guidelines) could reduce the number of people acquiring HIV infection globally
from more than 3 million per year to 1.2 million by 2025 . Modeling in Vietnam suggests that a
combination prevention strategy centered on expanded HIV testing and early ART for key
populations could virtually eliminate HIV transmission in that country by 2025. This would
entail a series of The impact of ART on HIV transmission would be greatest if treatment is
initiated early during the course of infection, if strong adherence to treatment and viral
suppression is achieved and if ART is combined with other proven behavioural, biomedical and
structural prevention approaches such as condom use, harm reduction and voluntary medical
male circumcision. (WHO, 2014)
But Anti retroviral treatment is not all that easy, it's at best just management of the diseases, not
cure. Antiretroviral therapy of HIV infection has changed a uniformly fatal into a potentially
chronic disease. There are now 17 drugs in common use for HIV treatment. Patients who can
access and adhere to combination therapy should be able to achieve durable, potentially lifelong
suppression of HIV replication. Despite the unquestioned success of antiretroviral therapy,
limitations persist. Treatment success needs strict lifelong drug adherence. Although the widely
used drugs are generally well tolerated, most have some short-term toxic effects and all have the
potential for both known and unknown long-term toxic effects. Drug and administration costs
limit treatment in resource-poor regions, and are a growing concern even in resource rich
settings. Finally, complete or near complete control of viral replication does not fully restore
health. Long-term treated patients who are on an otherwise effective regimen often show
persistent immune dysfunction and have higher than expected risk for various non-AIDS-related
complications, including heart, bone, liver, kidney, and neurocognitive diseases. (Volberding,
Deeks, 2010)

Fig:2 Number of people on anti-retroviral medicine

1.4 Identifying applications and implications

Some 40 million people are living with HIV and it is estimated that 6 million of them in
developing countries are urgently in need of antiretroviral therapy (ART) in order to stay alive.
However, fewer than 8% of those who need antiretroviral drugs (ARVs) are receiving them.
Even with increased efforts to scale up the care and treatment of people living with HIV, such as
the 3 by 5 Initiative, not everyone in need can gain access to ART immediately. This situation
requires difficult choices in priority-setting, poses serious ethical issues and imposes on
governments the obligation to scale up programmes in ways that are ethically sound and as fair,
beneficial and sustainable as possible. These approaches to scaling-up must respond to local
needs, be locally legitimate and accord with human rights norms. The number of patients who,
according to WHO criteria, are in clinical need of ART and accompanying treatment greatly
exceeds current resources and capacity in many countries. Additional criteria and procedures
may be necessary in order to specify who should have priority in accessing the life-saving

treatment. Decision makers should establish clear policies on whether specific population groups
should be prioritized, so as to avoid decision-making based on subjective or arbitrary criteria that
may lead to discrimination. Special care has to be taken to ensure and monitor access for the
most vulnerable, poor and marginalized populations and for women. How should policymakers
in developing countries address the very difficult issue of purchasing antiretroviral (ARV) drugs?
ARVs are providing extraordinary results among people with AIDS (PWAs), in some cases
bringing patients back from the final stages of illness to again becoming active, productive
members of society. (Forsythe, 1998)
1.5 Alternative views or solutions
Developing a Vaccine for HIV is a utopia in which a person would walk in a hospital, get a shot
and be immune from infection. As of now, no effective HIV vaccine exists. Many HIV vaccines
have been tested in clinical trials since the discovery of HIV however, after over 20 years of
research, HIV vaccine still remains an enigma.
In 2003 a clinical trial in Thailand developed a HIV vaccine called RV 144 and in 2009, the
researchers reported that this vaccine showed some response in protecting recipients from HIV
infection. This is the first evidence of any vaccine effective at preventing HIV infection. Another
vaccine trial uses a gene therapy that changes the CCR5 co-receptor permanently, preventing
HIV from invading cells. But these are still in the early stages of testing.
Timothy Ray Brown, a 40-year-old HIV-positive man was given a stem cell transplant as part of
his treatment for acute myeloid leukemia (AML) in 2007. The donor was genetically compatible
and homozygous for a CCR5-32 mutation that was resistant to HIV infection. Without being on
antiretroviral drug treatment after 20 months it was detected that HIV levels in Brown's blood,
bone marrow, and bowel were below the limit f detection. After three years, the virus still
remained undetectable. Although the researchers this as a cure, skeptics suggest that the virus
may remain lodged in tissues such as the brain which acts as a viral reservoir. So stem cell
transplant remains a question mark and due to mortality risk associated with stem cell
transplants, prohibitive cost and the difficulty of finding suitable donors, it is far away from
being a cure for the masses.

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Evaluating two sources of the report

WHO's Global update on health sector response to HIV is a treatise on HIV conditions
particularly in developing world, the statistics and ART figures. It gives a detailed
account of measures to be taken or being taken for HIV prevention, care and support.
The data, reports and statistics are through because of the WHO branding and initiative of
Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS).

The research paper of Paul A Volberding, Steven G Deeks on Antiretroviral therapy and
management of HIV infection is a detailed account of Antiretroviral therapy. It talks
about various aspects of ART like C4D and Quantitative Viral Load testing. The
thoroughness of the paper can be gauged from carefully cited 146 sources.