1. Protease Inhibitors, Integrase Inhibitors, and
Reverse Transcriptase Inhibitors Effectiveness on
Combating HIV
Dusek
Erin Ladd, Gage Moreno, Alex
Dusek
2. Background/Abstract
• Currently 37 million individuals worldwide living with HIV
• We analyzed which treatment is most successful in treating individuals
• Success was determined by suppression in both viral load count and resistance mutations.
• Researched Reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and
“cocktail approach”
• ANOVA statistical test: p-value .027782, F-ratio=3.74- indicates a significant difference
between the 4 types of treatments and a rejection of the null hypothesis
• Protease and reverse transcriptase inhibitors were most successful in suppressing viral
load
• Research suggested that in order to effectively combat HIV, one must be on a mixture of
treatments so the viral life cycle can be stopped at each virus specific location.
3. Introduction
• Spread of Human Immunodeficiency Virus (HIV) was first recognized in the United States in the 1980’s as a
pandemic (Avert, May 2015)
• HIV virus is thought to have originated in Western Africa in apes
• High mortality rate of those infected is a result of the life cycle of HIV
• When a person is infected with HIV, viral loads increase and CD4 T cell counts decrease.
• When a person is initially infected, the virus recognizes CCR5 on a CD4T cell, attaches to the cell membrane
of these cells, and then inserts itself to the cell
• Here it undergoes reverse transcription which turns viral RNA into DNA
• The process of integration then occurs where the enzyme integrase inserts the viral DNA into the host’s DNA
• Once the cell has budded off, the enzyme protease organizes the viral proteins in the necessary order and
these become a mature viral HIV virus.
5. Intro Cont.
• Once the immune system of the host catches up and tries to fight back (asymptomatic phase), viral load
decreases but remains constant at a rate of 30,000 copies per milliliter.(Shelby O’Connor (9/14/2015)
6.
7. Methods/Criteria
• Main criteria chosen from various articles and studies included the percentage of individuals
who were “successful” in viral suppression (metric)
• In most studies, successful viral suppression was indicated by <400 copies/mL
• Baseline data included that these patients had not yet undergone first-line antiretroviral therapy,
or had failed first-line antiretroviral therapy.
• ANOVA statistical test
• Successfulness is identified as the percentage of HIV patients whose viral load was suppressed.
• The magnitude of viral load decrease seen as significant varied within studies
evaluated the percentage of treatment success for each individual study and compared these
success percentages
8. Results
Effects of Reverse Transcriptase Inhibitors on Viral Load (Gage)
• 5 out of the 6 found reverse transcriptase inhibitors to have a success rate of 80% or more
• These studies defined success as achieving viral load levels ranging from >10,000 copies/mL (Bock et al.,
2012) to >50 copies/mL (Seang et al., 2014)
• Outlier study found 65.9% of people on a reverse transcriptase based ART to reach viral load levels of >50
copies/mL (Nachenga et al., 2007).
o This number is still relatively high considering that 22.1% of patients had viral load levels of >400
copies/mL, and 11.9% as between 50 and 400 copies/mL (Nachenga et al., 2007)
o The difference between this study and the other 5 could do to the fact that the subject had to have completed
at least 1 month of NNRTI-based HAART in order to become eligible for the study
9. Results
Effects of Integrase Inhibitors on Viral Loads (Alex)
After 24 weeks of treatment 88% of patients on dolutegravir and 85% of patients on reltegravir achieved viral loads of <50
copies/mL catagorizing this as a success.
After 48 weeks of treatment only 78% of patients achieved viral loads of <400 copies/mL
Of 506 patients who developed resistance to integrase inhibitors, 38.6% were considered resistant to dolutegravir, 34.9%
resistant to elvitegravire, and 13.9% resistant to raltegravir. Totalling 87.4% of poeple in the study developing resistance
to integrase inhibitors.
The studies agreed that up to 7% of all people develop mutations after 48 weeks on integrase inhibitor treatment.
Overall, integrase inhibitors are effective in the short term, however when taking integrase inhibitors for a long period of time it is
common to develop mutations.
10. Results
Effects of Protease Inhibitors on Virological Failure, Resistance Mutations and Viral Load (Erin)
• 4 out of 5 studies showed success in viral load suppression/resistance mutation suppression.
• Protease inhibitor darunavir or darunavir-ritonavir treatments-most viral load decrease
• 82% of patients using darunavir suppressed viral load to <200 copies/mL (Mata-Marin et. al., 2015)
• 73% of patients on darunavir-ritonavir regimen- viral loads of <50 copies/mL (Biscione, F. et al,
2013).
• Both these studies involved second-line therapy to adults
• Further studies should compare the effectiveness in both treatment-naive individuals and those who
have already undergone first-line ART
• Study that didn’t show successful viral load/mutation suppression-majority of patients who
experienced virological failure because they developed drug resistance
(only 17.6% of patients experienced virological failure (Aghokeng et al, 2013).
results of studies differed based on the age of patients and whether they had received ART treatment
prior to the study.
11. Results
Cocktail Approach on Viral Load (Group Effort)
• 4 studies involving the combination of treatments resulted in virological success rates of 70% or higher
• Treatment-naive patients- viral load suppression of <200 copies/mL when using 1 protease inhibitor and 2
reverse transcriptase inhibitor combo (see table)
12. Discussion
• Using a single drug to combat the HIV virus is less effective than using a combination treatment
• Cocktail approach had the highest mean percentage of success and the lowest standard error
• These results were expected because of the fact that HIV has such a rapid mutation rate
• With only a single ART, the HIV virus would mutate to become immune to the treatment type
• For ex. if only reverse transcriptase inhibitors were used, the HIV virus would be able to mutate in order to
recognize the inhibitor and avoid it
• Each class specifically targets a virus-specific function
• 5 classes of antiretroviral drugs
• Each class of ART had a different effect on the life-cycle
• RTI’s work best as first line treatments-it is one of the first steps in the life-cycle of HIV.
• Integrase/Protease inhibitors are most effective as second line therapy/post-exposure prophylaxis because
integration comes later in the HIV lifecycle- polyprotein made early in HIV life cycle, then HIV-1 protease
cuts this polyprotein into smaller protein pieces later into the life cycle (Goodsell, 2000).
14. Conclusions/Implications for Future Studies
➢ Problems with our studies:
○ 1) Number of participants was relatively low (averaged 20-300 participants) meaning the results are more likely
to be due to random chance/ do not accurately portray the inhibitors effectiveness
○ 2) Studies were held over 48 week-period, which isn’t long enough to determine long-term results
■ patients can forget to take their medication- results in ART resistance and creates different HIV strains in
the body
● 3) Our studies excluded people that were currently in successful treatment (only analyzed treatment-naive or
those who failed first-line treatment)
Future studies should:
be performed over a longer period of time-more realistic situation of how people take their
medication
include larger, diverse sample sizes from different areas
compare the use of single class ART’s over a long period of time versus the multi-class drugs
shows that single class ART’s eventually will develop resistances and the multi-class drugs are
most effective
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