The Cost of Treatment: A Discussion of the Adverse Effect of Combination

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LOGO HERE Antiretroviral Therapy in Patients Suffering from Human Immunodeficiency Virus OPTIONAL
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A Study of Disease Progression and Effects of Oxidative Stress in Human Immunodeficiency Virus Patients Treated with Antiretroviral Drugs
Original Paper: “Altered oxidative stress indexes related to disease progression marker in human immunodeficiency virus infected patients with antiretroviral therapy” Gil L, et al.
Lauren McGuire

INTRODUCTION TREATMENT BACKGROUND DATA COLLECTION and RESULTS

• The methods, data, results and conclusions of a study comparing the disease progression and
HIV and AIDS have been described as a mirror that selectively reflects and exposes the
induced oxidative stress related to two different Highly Active Antiretroviral Therapies (HAART)
worst of human nature and its deepest weaknesses. Arising from a chance genetic mishap,
used to treat Human Immunodeficiency Virus will be discussed.
HIV has a unique ability to evade modern medical science and wreck havoc human
• Adverse effects of treatment with NARTIs
populations. HIV and its associated diseases are seemingly avoidable yet tenaciously
• Loss of serum HIV suppression and development of drug-resistant HIV strains
resistant to medical intervention, making their treatment and control one of the greatest
• Increased probability of illness progression
medical mysteries to doctors, scientists, virologists, epidemiologists and public health
• Lactic Acidosis
officials.
• Hyperlipidemia
What is HIV?
• Glucose intolerance/Diabetes mellitis
HIV belongs to a group of retroviruses
• Atherosclerosis
called lentiviruses, characterized by slow rates
• Mechanism of adverse side effects is dominated by the formation of highly reactive oxygen
of growth and propogation. HIV is comprised
species leading to oxidative stress
of a viral capsid that binds to CD4 proteins on
• Other effects are due to mitochondrial toxicity caused by phosphorylated NARTI
T4 lymphocytes, the target immune cells of HIV.
Once bound, the virus injects its RNA and EXPERIMENTAL DESIGN AND METHODS
other transcription machinery into the host
Table 1: Antiretroviral drugs used in the study
cell. The virus replicates by reverse • 84 HIV+ and 84 HIV- individuals Name Type
transcription using reverse transcriptase. Viral participated in the study.
RNA is transcribed into DNA and incorporated AZT Zidovudin NARTI
https://www.msu.edu/course/isb/202/ebertmay/images/HIV • HIV- patients acted as control subjects
into the host cell’s DNA, where it is used to 3TC Lamivudine NARTI
%20virus.png of the study
create more viruses. Figure 1: HIV Virus structure • Of the 84 HIV+ individuals
D4T Stavudine NARTI
How is HIV Treated? • 26 acted as a control group and NEV Nevirapine NNRTI
Development of the treatment and control of the disease has bewildered scientists for received no antiretroviral treatment IND Investigational New
many reasons. As a retrovirus, the disease proves difficult to vaccinate against, largely due • 26 were treated with AZT, 3TC and
Drug
to the extended period of dormancy characteristic of HIV. The virus can theoretically “hide IND combination therapy (Group I) Contain Nucleoside Analog Reverse Transcriptase
out” in the host cell’s DNA, avoiding antiviral treatments until later proliferation. Another • 26 were treated with D4T, 3TC and Inhibitors (NARTI) or Non-Nucleoside Reverse
reason is its extraordinarily high mutation rate. This rapid rate of mutation makes HIV an Transcriptase Inhibitors (NNRTI)
NEV combination therapy (Group
incredibly adaptive virus that can quickly become resistant to even the most promising II) Table 2: Experimental Groups
treatments. Finally, the fact that HIV invades and macrophages and T4 cells, central • The drugs used for treatment were n Status Treatment
components of the immune system, makes it almost impossible to kill off. common antiretroviral compounds Control 26 HIV+ Naïve (no HAART)
Azidothymidine (AZT) • Subjects had no opportunistic infection Group I 26 HIV+ AZT, 3TC, IND
New possibilities came in 1985 with the development of AZT, or azidothymidine, an • Study time period was 6 months Group II 26 HIV+ D4T, 3TC, NEV
antiretroviral drug sold as Retrovir that showed promise in treating HIV. It acts as a thymidine
analog that inhibits reverse transcriptase, thus preventing the formation of viral DNA. This 84 HIV+ individuals distributed evenly into one of three
groups: Control (no HAART), Group I (AZT, 3TC, IND)
new treatment reduces viral load and slows the rate of CD4 cell decline caused by the virus. and Group II (D4T, 3TC, NEV)
However, the drug’s effects seemed to decline over time and a large portion of patients
suffered from terrible side effects and drug toxicity from the treatment. DATA COLLECTION and RESULTS
Table 3: Redox marker data
• Laboratory Analyses: Blood and serum Indicator Time (mo) Mean
samples were taken and processed. HIV PP (uM) Control 7.32
Figure 4 (A-H): Biochemical Serum Measurements of redox and oxidative stress markers evaluated in 28
0 10.43
positiveness was tested with ELISA 6 12.33 HIV+ naïve treatment subjects (Control), 28 HIV+ Group I subjects (AZT, 3TC, IND) and 28 HIV+ Group II
testing and confirmed with Western Blot subjects (D4T, 3TC, NEV) at day 0 and 6 months after treatment. Data show significant increase in OS
CAT Control 2.3
Testing. (U/mg Hb min) 0 3.8 markers in HAART subjects (Groups I and II) when compared to the control group at both times.
• Flow Cytometry Analysis: Study of T 6 4.6

Lymphocytes by elimination of interfering SOD Control 2.1 CONCLUSIONS

(U/mg Hb min) 0 4.2
cells (Erythrocytes) with a lysing solution. 6 5.33
• Viral Load: Determined with PCR-NASBA HPO (uM) Control 103.7
• The data display higher levels of oxidative stress (Table 3) and slowed
Figure 2: Structure of AZT. Figure 3: Mechanism of AZT action in the inhibition of reverse transcription by measuring the levels of HIV RNA. 0 173.66
disease progression (Table 4) in HIV+ subjects undergoing HAART
• Biochemical Measurements 6 201.19
http://ntp.niehs.nih.gov/index.cfm? http://www.mcld.co.uk/hiv/images/aztAction.gif
objectid=071DB495-BA03-B4F0-
• GSH (Glutathione concentration): GSH MDA Control 2.74 treatment compared to HIV+ control subjects.
470794F78211A098
Combination Therapy suppresses viral replication, aids
(nmol/g Hb) 0
6
7.61
9.95
• During apparently successful HAART treatment (Table 4), increased
Given AZT’s toxic effects and somewhat inconsistent results in long-term HIV treatment, immune system, prevents oxidation by GSH Control 786.06 oxidative stress occurs additionally to persistent redox imbalance
scientists began to develop other antiretroviral drugs that, when used in conjunction with acting as a cellular redox potential (uM/g Hb) 0 413.96
associated with HIV infection.
6 320.79
AZT, proved more effective in HIV treatment. This combination therapy was meant to regulator.
• MDA (Malondialdehyde concentration): AOPP (uM) Control 12.36 • Data show higher oxidative stress in HIV+ subjects treated with D4T,
reinforce the effects of AZT while evading the virus’ ability to mutate to an AZT-tolerant form. 0 22.85
Despite its effectiveness, its unpleasant and severe side effects along with its inconvenient Marker for oxidative stress. 6 29.69 3TC and NEV (Group II) when compared to HIV+ subjects treated with
and expensive application still presented a significant challenge for scientists and doctors. • PP (Peroxidation potential): Oxidative FDNA Control 6.30 AZT, 3TC and IND (Group I) (Figure 4 A-H)
Despite this, the impact of combination therapy continued to be profound. degeneration of lipids (by free radicals) (% fragmented) 0 7.89
6 9.16 • The data show the underlying HAART associated toxicity.
Though no single drug seemed to thwart all of HIV’s defenses, a number of drugs were that results in cell damage.
developed in the 1990s that seemed to combat many of the virus’ effects. These fell into one • HOP (Total hydroperoxide): Oxidizing Control are HIV- subjects. Values at time 0 and
agent, oxidizes ferric ions to ferrous 6 months are serum levels from HIV+ subjects. In treating HIV with HAART (Highly Active Antiretroviral Therapies), successful
of two categories: Nucleoside Analog Reverse Transcriptase Inhibitors (NARTIs) and Non- Data show increased levels of oxidative stress in
Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). NARTIs are analogs to naturally ions under acidic conditions. treatment not only involves slowing disease progression as shown by decreased viral
HIV+ patients treated with antiretroviral drugs as
occurring deoxynucleotides andlack a 3’-hydroxyl group. Following their incorporation into a • DNA Fragmentation: shown by various redox markers. load and increased T4 cell count, but also involves overcoming the severe metabolic
growing DNA strand, they prevent the incorporation of the next nucleotide and thus prevent Mutation/Destruction of DNA and immune dysfunctions caused by the virus itself, as well as enduring oxidative
Table 4: HIV progression marker data
reverse transcription. NNRTIs act as non-competitive inhibitors of reverse transcriptase and determined by colorimetric stress associated with the use of antiretroviral drugs to gain the aforementioned
Indicator Time (mo) Mean
are not incorporated into the viral DNA. diphenylamine assay and quantified results. The combination of the adverse effects of the virus itself and those of the
Complications with Treatment spectrophotometrically. CD3+/CD4+ 0 334.0
treatment intended to combat it, scientists have gained insight into reasons for the
(cel/mm3) 6 557.6
This miracle of combination therapy did not come without complications. Not only was the • SOD (Superoxide Dismutase): Enzyme difficulty in HIV treatment.
regimen hugely expensive and nearly impossible to conform to as it required taking over 30 that acts as an antioxidant; catalyzes CD8+/CD38+ 0 1200.12
the dismutation of superoxide into O2 (cel/mm3) 6 1006.1
different medications throughout the day, but a myriad of side effects came with the REFERENCES
treatment, some severe enough that many patients admitted preferring death over the and H2O2. CD4+/CD95+ 0 1561.28
suffering caused by AZT combination therapy. Though these antiretroviral therapies are • Catalase (CAT): Enzyme that catalyzes (cel/mm3) 6 1407.6 REFERENCES
•"Reverse Transcriptase Inhibitor." Wikipedia. 2010. Web.
shown to decrease viral load, improve immune function in patients, and display overall global the decomposition of H2O2 to O2 and Viral load (U) 0 28408.7
<http://en.wikipedia.org/wiki/Reverse_transcriptase_inhibitor>.
clinical improvement, the physical cost of the treatment is not insignificant. This prompted H2O, thus preventing cell damage by 6 5695
•Engel, Jonathan. The Epidemic: A Global History of AIDS. New York: HarperCollins
doctors, scientists, public health officials and members of the FDC to investigate these side H2O2. Values of each index at time 0 and 6 months are Publishers Inc., 2006. Print.
• AOPP (Advanced Oxidation Protein •GilL,etal.Alteredoxidativestressindexesrelatedtodiseaseprogressionmarkerinhuman
effects, their mechanisms and possible solutions that would not only improve the different from HIV+ subjects. Data show an increase in
immunodeficiencyvirusinfectedpatientswithantiretroviraltherapy.Biomedicine&Pharmacotherap
drugs’ effects in disease progression, but would also diminish the often unbearable side Products): Marker for protein oxidation both CD4+ and CD8+ T cell count. HIV-RNA y(2010),doi:10.1016/ j.biopha.2010.09.009
and other forms of oxidative stress. copies showed significant decrease in HIV+
effects of the treatment itself. Understanding how different combinations of drugs effect patients treated with antiretroviral drugs.
these two issues has become the main focus of many HIV treatment studies.
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