Reduction or Supression of Plasma HIV Viral Load Increase in CD4 Count

Doltegravir/Abaravir/Lamividune (TRIUMEQ)
Criteria
Efficacy
#
1
Reduction or supression of plasma HIV viral load
Points
Increase in CD4 count
3
4
Resistance to the drug

Clinical trial evidence in ART nave patients with favorable
response
In the SINGLE trial, efficacy of DTG/ABC/3TC was compared with the

single table regimen of TDF/FTC/EFV IN 833 ART-nave patients. At 48 weeks,
88% of patients receiving DTG and 81% on EFV had plasma HIV-RA of <50
copies/mL (p=0.003). Patients in the DTG arm also experienced significantly
shorter median times to viral suppression (28 vs 84 days, p<0.0001), as well
as greater increases in CD4 counts (268 vs 208 cells/uL, respectively;
p<0.001). It is also noteworthy that none of the ART-nave patients receiving
DTG/ABC/3TC in the SINGLE trial developed resistance to DTG upon early
virologic failure. Given that ABC will be co-formulated with DTG, HLA-B*5701
genetic testing must be carried our before prescribing the STR in order to
identify patients at risk for developing ABC-associated hypersensitivity
reactions (Fernandez-Montero, et al, 2014)
Criteria
1
Safety
Points
Absent to minimal temporary/reversible side effects
Absent to minimal risk of organ toxicity or damage
3
4
No associated or rare life threatening ADRs

Minimal drug-drug interactions
+
-
When considering the use of DTG/ABC/3TC, data from the SINGLE trial
showed very reassuring results in ART-nave patients. Grade 3-4 adverse
effects events were reported in 10% of patients on DTG in comparison with
16% of subjects receiving EFV. DTG arm reported 43% versus the EFV arm
with 66% of all-grade drug-related side effects, with significantly lower
incidence of neuropsychiatric and skin adverse events. Most commonly
reported adverse events in DTG arm were diarrhea, insomnia,
nasopharyngitis and nausea (Fernandez-Montero, et al, 2014).
Drug interactions of this drug combination needs dosage adjustments
such drugs containing magnesium and aluminum, oral calcium and iron
supplements, and metformin. It is also not recommend with other retroviral
drugs such as etravine and nevirapine (Triumeq).
Criteria
Necessity
Points
1
Targets both HIV 1 and 2
2
High rate of adherence to the drug
3
4
Convenience of administration (dosing and schedule)

No contraindications to the host factors and conditions
+
+
DTG/ABC/3ATC is a drug available for HIV1 infection (Triumeq, 2015).

Overall, 2% of patients on DTG arm and 10% on EFV discontinued therapy
due to adverse effects. DTG has short absorption time, with a time to
maximum concentration (Tmax) of 1 hour. However, DTG has a longer serum
half-life of 15 hours, which makes possible one-daily dosing. Time to steadystate concentration was 7 days (Fernandez-Montero, et al, 2014). The drug
has no contraindications to the host factors and conditions because the
patient has no moderate and severe hepatic impairment, which is a
contraindication of use.
Criteria
1
Affordability
PHP 1- P34,999 per month
Points
++++
PHP 35,000 69,999 per month
3
4
PHP 70,000 139,999 per month

PHP >140,000 per month
+++
++
+
The cost of a month-treatment of DTG/ABC/3TC is approximately PHP

119,160 for 1 tablet intake once a day.
ESNA Score for
Doltegravir/Abaravir/Lamividune
Efficacy
Safety
Necessity
Affordability
Total
Score
3
3
3
2
11
Tenofovir/Emtricitabine (TRAVUDA)
Criteria
Efficacy
#
1
Reduction or supression of plasma viral load
Points
Maintenance of a higher CD4 count
3
4
Minimal resistance to the drug

response
+
+
A clinical trial by Amoroso et, al, tested the viral load decay in
antiretroviral-naive patients receiving once-daily tenofovir and emtricitabine
plus twice-daily nevirapine. All patients achieved viral decay with this
combination. Two patients discontinued prior to virologic suppression, one
with a viral load of 55 copies/mL. Virologic suppression (<50 copies/mL) was

achieved by Week 24 in the remaining 8 patients. An undetectable viral load
was maintained during > or =60 weeks follow-up. The clinical efficiency data
from a study conducted in United Kingdom compared the CD4 count levels of
TDF/FTC + ATV/r (from 206 cells to 324 cells) with ABC/3TC +ATV/r (from
198 cells to 305 cells) after 144 weeks of treatment.
In addition to Sax PE (2009), the time to virologic failure was
significantly shorter in the abacavir-lamivudine group than in the tenofovir
DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to
3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine
group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the
first adverse event was also shorter in the abacavir-lamivudine group
(P<0.001). There was no significant difference between the study groups in
the change from the baseline CD4 cell count at week 48.
Key NRTI resistance mutation M184V was significantly less common
among patients treated with emtricitabine/tenofovir (14.3%) compared with
those receiving either lamivudine/tenofovir (40.0%) or lamivudine plus
another NRTI (55.6%) (Svicher, 2010)
Criteria
1
Safety
Points
3
4

+
-
A randomized comparison of renal effects, efficacy, and safety with

once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered
with efavirenz, in antiretroviral-naive, HIV-1-infected adults revealed changes
in estimated glomerular filtration rate from baseline were similar between
arms [difference 0.953 mL.min.1.73 m (95% confidence interval: -1.445 to
3.351), P = 0.435]. Urinary excretion of retinol-binding protein and beta-2
microglobulin increased significantly more in the tenofovir/emtricitabine arm
(+50%; +24%) compared with the abacavir/lamivudine arm (no change;
-47%) (P < 0.0001). The study showed no difference in estimated glomerular
filtration rate between the arms, however, increases in markers of tubular
dysfunction were observed in the tenofovir/emtricitabine arm, the long-term
consequence of which is unclear (Post FA, 2010)
Tenofovor/Emtricibine can cause new onset of renal impairment such
as renal failure and Fanconis syndrome as well as Immune Reconstitution
Syndrome, changes in body fat, and bone promblems.
Drug to drug
interaction occurs with other antiretroviral drug such as
lamivudine,
didanosine, atazanavir, darunvair, and lopinavir (Gilead, 2013).
Criteria
1
Necessity
Points
3
4

No contraindications to host and risk factors
+
+
Emitricitabine/Tenofovir treatment is used for HIV-1 infection in

combination with other antiretroviral agents in adults and pediatric patients
12 years of age. Pre-exposure prophylaxis (PrEP) for prevention of HIV-1
infection in adults who are at high risk for acquiring HIV (DHHS, 2013)
Because of its long half-life (17 hours), it is administered once daily
with other antiretroviral drugs. In the study done by Magiolo, et al, the effect
of a fixed dose combination of emtricitabine, tenofovir, and efavarenz showed
promising treating adherence and treatment acceptability. The simple
reduction of the number of pills, induced a statistically significant (p = 0.014)
increment of self-reported adherence (number of doses assumed over the
previous month) from the mean baseline value o 96.1% (95% CI 94.397.9) to
97.7% (95% CI 97.098.4). Similarly the number of doses assumed fulfilling
scheduled timing (+/- 1 hour) increased from 92.9% (95% CI 90.495.4) to
96.0% (95% CI 94.897.2) (p = 0.033).
Criteria
1
Affordability
Points
++++
3
4
PHP 70,000 139,999 per month

+++
++
+
The cost of a month-treatment of TDF/FTC is approximately PHP 69,296

for 1 tablet intake once a day.
ESNA Score for
Tenofovir/Emitricitabine
Efficacy
Safety
Necessity
Affordability
Total
Score
4
3
3
3
13
Daranuvir/Ritonavir
Criteria
Efficacy
#
1
Reduction or supression of plasma viral load
2
Maintenance of a higher CD4 count
Points
+
+
3
4
Resistance to the drug

response
+
+
The MONET trial compared the efficacy, safety, and tolerability of

darunavir/ritonovir 800/100 mg once a day as a monotherapy with a triplecombination therapy containing 2 nucleosides and darunavir/ritonavir.
Darunavir/ritonavir monotherapy showed consistently noninferior efficacy
compared with triple-combination therapy at week 48. Of the total, 97.7%
achieved HIV-1 RNA below 50 copies/mL in the triple-combination-therapy
group, as did 97.6% in the darunavir/ritonavir monotherapy group (Hitt, E.,
2009)
With the combined results of POWER 1 and 2 trials, Daranuvir/ritonavir
boost provided superior suppression of HIV compared to comparator boosted
protease inhibitors in highly treatment experienced individuals. Attention was
then focused on the proportion of patients who achieved a fall in their viral
load to below 50 copies/ml. At week 48, 46% of the 110 individuals taking
darunavir/ritonavir had an undetectable viral load, compared to only 10% of
the 110 individuals taking a comparator drug, once again, this difference was
highly statistically significant (p = 0.003) (Karter & Alcorn, 2006)
The superior virological efficacy of daranuvir/ritonavir resulted in a
greater increase in CD4 cell count than that seen in the comparator arm.
Results were seen at week 48, the mean increase in CD4 cell count being 102
cells/mm3 in the daranuvir/ritonavir arm and 19 cells/mm3 in the comparator
arm (p = 0.005) (Karter & Alcorn, 2006).
In the ARTEMIS trial, virologic failure (HIV-1 RNA > 50 copies/ml) at any
time before the cutoff date was observed in 34 (10%) and 49 (14%) patients
in the DRV/r and LPV/r arms, respectively. In DRV/r virologic failures, no
patients developed an International AIDS Society (IAS-USA) protease inhibitor
resistance-associated mutation (RAM), while one patient developed an IASUSA nucleoside reverse transcriptase inhibitor (NRTI) RAM (M184I/V).
Emergence of drug resistance after changing a suppressive triple
antiretroviral therapy to DRV/r with or without nucleoside analogues is
uncommon. Overall, 36 of the 38 (95%) successfully genotyped patients
showed no International AIDS Society-USA major PI mutations, DRV mutations
or NRTI mutations (Pullido, 2011).
Criteria
1
Safety
Points
In the ARTEMIS trial, most adverse events were grade 1 or 2, and

discontinuations due to adverse events were infrequent; more LPV/r than
DRV/r patients discontinued due to an adverse event (LPV/r 7% and DRV/r
3%; post-hoc P < 0.05). The most common adverse events (regardless of
severity and causality) were diarrhea, nausea, headache, upper respiratory
tract infection, nasopharyngitis, abdominal pain, vomiting, and cough (Ortiz,
R, 2009).
In addition, serious adverse events (SAE) were reported in 7% of DRV/r
and 12% of LPV/r patients. The overall incidence of rash-related adverse
events (any grade, regardless of causality) was similar in the DRV/r (15%) and
LPV/r (13%) treatment groups, and led to permanent discontinuation in less
than 1% of patients for both arms. There was one case of Stevens-Johnson
syndrome (DRV/r arm).
Furthermore, it CYP3A4 inhibitors and substrates have potential drug
interactions.
Criteria
1
Necessity
Points
3
4

No contraidications to host factors and conditions
Darunavir, an HIV protease inhibitor, combined with a low dose of

ritonavir has been shown to be an effective therapeutic option for both
treatment-naive (800/100 mg once daily) and treatment-experienced
(600/100 mg twice daily) HIV-1-infected patients (McKeage, 2009)
In the ARTEMIS trial, the difference in virological response rates
between the adherent and suboptimally adherent participants was smaller
with
darunavir/ritonavir
(difference
of
6%)
(p=0.3312)
than
Lopinavir/ritonavir (difference of 25%) (P=<0.0001) (Ortiz, R, 2009).
Criteria
1
Affordability
3
4
PHP 70,000 139,999 per month

Points
++++
The cost of a month-treatment DRV/R is approximately PHP 69,296 for

1 tablet intake once a day.
+++
++
+
ESNA Score for

Daranuvir/Ritonavir
Efficacy
Safety
Necessity
Affordability
Total
Score
4
1
2
3
10
Bibliography
Amoroso. (2009, September). Viral load decay in antiretroviral-nave
patients receiving once-daily tenofovir and emtricitabine plus twicedaily nevirapine. Retrieved July 3, 2015, from
http://www.ncbi.nlm.nih.gov/pubmed/19906624
Carter, M., & Alcorn, K. (2006, August 2006). CHANGING TREATMENT
Darunavir/ritonavir superior virologically and immunologically to
comparator drugs over one year. Retrieved July 4, 2014, from
http://www.aidsmap.com/Darunavirritonavir-superior-virologically-andimmunologically-to-comparator-drugs-over-one-year/page/1424622/
FA, P. (2010, September 15). Randomized comparison of renal effects,
efficacy, and safety with once-daily abacavir/lamivudine versus
tenofovir/emtricitabine, administered with efavirenz, in antiretroviralnaive, HIV-1-infected adults: 48-week results from the ASSERT study.
Retrieved July 3, 2015, from NCBI:
http://www.ncbi.nlm.nih.gov/pubmed/20431394
Fernandez. (2014, April 28). Dolutegravir, abacavir, and lamivudine as
HIV therapy. Retrieved July 28, 3
Magiolo. (2008, January). Effect of a fixed-dose combination of
emtricitabine, tenofovir and efavirenz on adherence and treatment
acceptability (ADONE study). Retrieved july 4, 2015, from
http://www.researchgate.net/publication/225497604_Effect_of_a_fixeddose_combination_of_emtricitabine_tenofovir_and_efavirenz_on_adhere
nce_and_treatment_acceptability_(ADONE_study)
Ortiz, R. (2008, July 31). ARTEMIS Study: Efficacy and safety of oncedaily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive
HIV-1-infected patients at week 48. Retrieved July 3, 2015, from NATAP:
http://www.natap.org/2008/HIV/071108_02.htm
Pullido. (2011). Analysis of drug resistance during HIV RNA viraemia in
the MONET trial of darunavir/ritonavir monotherapy. Retrieved July 4,
2015, from http://www.ncbi.nlm.nih.gov/pubmed/21311109
PE, S. (2009, December 1). NCBI. Retrieved July 14 2015, 2015, from
Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1
therapy.: http://www.ncbi.nlm.nih.gov/pubmed/19952143
Triumeq. (2015). Retrieved July 3 2015
V Svicher, C Alteri, A Artese, and others. Different Evolution of

Genotypic Resistance Profiles to Emtricitabine Versus Lamivudine in
Tenofovir-Containing Regimens.Journal of Acquired Immune Deficiency
Syndromes (Abstract). August 24, 2010

Reduction or Supression of Plasma HIV Viral Load Increase in CD4 Count

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Reduction or Supression of Plasma HIV Viral Load Increase in CD4 Count

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Doltegravir/Abaravir/Lamividune (TRIUMEQ)

Increase in CD4 count

Resistance to the drug

In the SINGLE trial, efficacy of DTG/ABC/3TC was compared with the

Absent to minimal temporary/reversible side effects

Absent to minimal risk of organ toxicity or damage

No associated or rare life threatening ADRs

High rate of adherence to the drug

Convenience of administration (dosing and schedule)

DTG/ABC/3ATC is a drug available for HIV1 infection (Triumeq, 2015).

PHP 1- P34,999 per month

PHP 35,000 69,999 per month

PHP 70,000 139,999 per month

The cost of a month-treatment of DTG/ABC/3TC is approximately PHP

Maintenance of a higher CD4 count

Minimal resistance to the drug

with a viral load of 55 copies/mL. Virologic suppression (<50 copies/mL) was

Absent to minimal temporary/reversible side effects

Absent to minimal risk of organ toxicity or damage

No associated or rare life threatening ADRs

A randomized comparison of renal effects, efficacy, and safety with

Targets both HIV 1 and 2

High rate of adherence to the drug

Convenience of administration (dosing and schedule)

Emitricitabine/Tenofovir treatment is used for HIV-1 infection in

PHP 1- P34,999 per month

PHP 35,000 69,999 per month

PHP 70,000 139,999 per month

The cost of a month-treatment of TDF/FTC is approximately PHP 69,296

Maintenance of a higher CD4 count

Resistance to the drug

The MONET trial compared the efficacy, safety, and tolerability of

Absent to minimal temporary/reversible side effects

Absent to minimal risk of organ toxicity or damage

No associated or rare life threatening ADRs

Minimal drug-drug interactions

In the ARTEMIS trial, most adverse events were grade 1 or 2, and

Targets both HIV 1 and 2

High rate of adherence to the drug

Convenience of administration (dosing and schedule)

Darunavir, an HIV protease inhibitor, combined with a low dose of

PHP 1- P34,999 per month

PHP 35,000 69,999 per month

PHP 70,000 139,999 per month

The cost of a month-treatment DRV/R is approximately PHP 69,296 for

ESNA Score for

V Svicher, C Alteri, A Artese, and others. Different Evolution of

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