The Dolutegravir Antiretroviral Mono-Therapy for HIV Trial

Dolutegravir (DTG) is an integrase inhibitor (INI) with in vitro activity
against HIV-1 and has recently been approved by the European Medicines Agency
for the use in combination antiretroviral therapy (cART) for ART experienced
and naïve HIV patients.[1] INI inhibit HIV-1 DNA transfer into host DNA, which
is a pivotal step in lasting forward HIV-1 transmission and disease
progression. DTG is a second generation INI and its molecular structure allows
for greater binding activity leading to a potential for more potent activity
and a higher barrier to resistance in wild type and ART and INI resistant HIV-1
compared to the first generation INI raltegravir (RAL) and elvitegravir (EVG)
in vitro.[2, 3] Available data also indicate that most RAL and EVG resistant
strains with double or more INI mutations remain susceptible to DTG with only 2
mutant viruses (Q138K/Q148K and Q148R/N155H) leading to a >10 fold chance in
EC50 against HIV-1 in vitro.[4] In contrast to RAL or EVG, 112 days of DTG
monotherapy in vitro selects for only T124A, S153Y, T124A/S153Y,
L101I/T124A/S153F, all associated with <5 fold resistance compared to wild-type
HIV. Furthermore, DTG exhibits broad potency across HIV types in different cell
types.
Phase I and Phase IIa trials results show that DTG at a dose of 50mg once-daily
(QD) has a 14 hour half-life, maintains concentrations above in vitro IC90 for
over 30 hours following a single dose, reaches steady-state after 5 days and
has lower intra-subject variability compared to first-generation INI.[5, 6]
Cerebrospinal fluid (CSF) concentrations of DTG are similar to plasma
concentrations exceeding IC50 for wild-type HIV-1 (0.2ng/mL) with similar
HIV-RNA reduction in CSF and plasma, indicating therapeutic concentrations in
the central nervous system.[7] DTG is predominantly metabolized by hepatic
uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and cytochrome P450
(CYP)3A4. In contrast to EVG, DTG does not need a PK booster. Excretion of DTG
is in part renally where DTG can inhibit tubular OCT-2 creatinine transport,
which results in a non-pathological creatinine increase and therefore a
decrease in creatinine-based eGFR measurements but not the real GFR (when
measured with exact eGFR measurements like inuline). DTG can be administered
with or without food. It cannot be taken with antacids as they can lower DTG
plasma exposure when taken within an 8 hour window of DTG administration. DTG
does not induce or inhibit CYP isoenzymes or UGT and has therefore a low
potential for drug-drug interactions.
DTG*s safety, good clinical efficacy against HIV-1 and absent potential for
acquiring resistance have been demonstrated in 1 phase IIb and 3 large phase
III randomized clinical trials in a total of 2344 ART naïve patients. The phase
II dose finding partially blinded trial SPRING-1 randomized 205 naïve HIV-1
patients to DTG 10, 25 and 50mg and efavirenz 600mg with abacavir/lamivudine
(ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) as nucleoside reverse
transcriptase inhibitor (NRTI) backbones and found sustained and comparable
virological efficacy over 96 weeks of DTG and EFV.[8] These results were
confirmed in the randomized phase III double blind double dummy SINGLE on 833
naïve HIV-1 patients on QD DTG + ABC/3TC versus co-formulated EFV/TDF/FTC over
96 weeks with superior DTG activity by intention to treat (ITT) analysis due to
more adverse events (AE) related discontinuation in the EFV group.[9] DTG was
well tolerated with only 2% discontinuations due to AE compared to 10% on EFV.
Reported AE in >10% of DTG patients were diarrhea (17%), insomnia (15%),
nasopharyngitis (15%), nausea (14%), headache (13%) and fatigue (13%). More
subjects in the EFV group (4%) experienced ALT>3x ULN compared to DTG (1%) and
renal safety was similar.
SPRING-2 and FLAMINGO were both double blind double dummy trials on 822 HIV-1
naïve HIV-1 patients randomized to DTG 50mg QD or RAL 400mg BID and 484 naïve
HIV-1 patients randomized to DTG or ritonavir boosted darunavir (DRV/r)
800/100mg QD respectively, both with NRTI backbones. In SPRING2, DTG 50mg QD
showed equal virological efficacy to RAL 400mg BID over 96 weeks of
follow-up.[10] Both groups had good tolerability with 2% withdrawal to AE, 6%
grade 2-4 related AE and only 3/29 serious AE (SAE) were considered DTG
related. Reported AE occurring in >10% of DTG group were similar to SINGLE
although insomnia and fatigue were not reported over 10%. Hepatic safety and
fasting lipid profiles were good and similar in both groups. In FLAMINGO, DTG
50mg QD demonstrated superior virological efficacy at week 48 in achieving
HIV-RNA <50c/mL by intention to treat analysis.[11] The HIV-RNA in the week 48
window were not <50c/mL in 2% of DTG group versus 5% of DRV/r group.
Discontinuations for AE were infrequent on DTG (1%) and DRV/r (4%).
In summary, the trials of DTG use in ART naïve HIV-1 patients showed that DTG
had similar or superior virological efficacy regardless of baseline HIV-RNA to
comparators* arms as high as 90% at week 48. Importantly, DTG*s safety and
tolerability were equal or superior, had comparable CD4 count increases and
there has not been a single case of acquired resistance INI/NRTI or protease
inhibitors (PI); all patients had wild-type HIV-1 strains upon virological
failure.
These data combined indicate that DTG is a valuable addition to the
antiretroviral drugs repertoire because of its efficacy and safety profile. The
current standard of care, as stated in international guidelines, includes the
use of an INI, NNRTI or boosted PI with FTC/TDF or ABC/3TC for ART naïve
patients.[16-18] Although currently 4 single tablet regimens are available, all
consist of at least 3 antiretroviral drugs. These drugs have their specific
mild to sometimes serious side effects, drug-drug interactions and other
contra-indications. As HIV-1 treatment is lifelong and discontinuation of
therapy would result in virological rebound with immunological decay, AIDS and
ultimately death, the long-term side-effects of cART are becoming increasingly
important. As it is as yet impossible to predict which patient will experience
side-effects they often have to switch drugs at some time during treatment. A
recent study on 21.801 ART naïve HIV patients from 18 European and
North-American cohorts that started HAART after the year 2002 showed a 60%
switch rate of one or more drugs within 3 years and mostly for drug
toxicity.[19, 20] Furthermore, the increased focus on cost-containment in HIV-1
care could result in the need for more cost-effective treatments.[21] Reducing
the drug burden in cART to dual or antiretroviral monotherapy could be a
preferable option for a considerable number of patients who have to switch cART
for various reasons, especially if virological suppression can be maintained.
Studies have been undertaken to evaluate this potential strategy with 1
specific group of antiretrovirals, namely boosted PI. The OK pilot study was
followed by the first randomized open-label trial to evaluate the efficacy of
boosted lopinavir (LPV/r) monotherapy in 205 HIV suppressed patients and found
comparable efficacy in mono and triple-therapy without development of
significant drug resistance >2.7 fold change in IC50 on monotherapy or
differences in AE and CD4 cell counts.[22, 23] The 96 week KAIMO randomized
pilot trial on 60 HIV suppressed patients reported equal efficacy, no drug
resistance, CD4 counts, AE and HIV-RNA in semen remained undetectable in 93%
of patients on LPV/r monotherapy.[24] The MONARK trial was a randomized trial
in 2008 comparing LPV/r monotherapy with LPV/r plus zidovudine and lamivudine
in 136 ART naïve patients and demonstrated week 48 HIV-RNA <400c/mL in 64% and
75% of patients respectively without differences in CD4 cell count change or
tolerance.[25] Three patients on monotherapy developed minor genotypic
mutations to PI resulting in a maximum 2.7 fold change in phenotypic
sensitivity. Darunavir/ritonavir (DRV/r) monotherapy, another more recent PI
was associated with 94% virological efficacy at week 48 compared to 99% with
triple therapy in 225 randomized HIV-1 suppressed patients of the open-label
MONO-ANRS136 trial.[26] No genotypic resistance to PI emerged and no
differences in CD4 counts or AE were observed. Of 256 HIV-1 suppressed patients
randomized to DRV/r 800/100mg QD or triple therapy in the open-label MONET
trial, non-inferiority of monotherapy was shown without differences in CD4 cell
count, AE or significant emerging drug resistance to PI.[27] DRV monotherapy
was not shown to be non-inferior to DRV+2NRTI triple therapy in the subset of
enrolled HIV suppressed patients with CD4<200 (N=66) of the open-label PROTEA
trial (N=273).[28]
In the GARDEL trial, 217 ART naïve patients were randomized to LPV/r with 2
NRTI (triple therapy) or LPV/r with 3TC (dual therapy) and demonstrated
non-inferiority of the latter in achieving HIV-RNA <50 c/mL at week 48 with
comparable CD4 increases and significantly fewer side-effects in the dual
therapy arm.[29] The open-label MODAT trial randomized 103 HIV-1 suppressed
patients to continuing boosted atazanavir (ATV/r) 300/100mg with 2 NRTI or
ATV/r monotherapy. By week 48, 73% of patients on monotherapy and 85% triple
therapy had continued virological suppression. In patients with virological
rebound (2 consecutive HIV-RNA >50c/mL), no acquired resistance was detected
and all were re-suppressed with the introduction of their previous NRTI
backbone. CD4 count changes did not differ between groups. Grade 3/4 AE were
observed less often and estimated glomerular filtration rate improved with
monotherapy.
Although the studies described above have shown that PI monotherapy can be a
valid treatment option to maintain virological suppression, it has not been
widely adopted because the pill-burden and size of the PI pills much higher (2
to 4 large-size pills per day). Also, all drugs of the PI class have to be
combined with ritonavir as a CYP450 3A4 pharmacological booster. The
coadministration of ritonavir poses patiens at risk for other, sometimes
dangerous, drug-drug interactions.
As DTG therapy consists of a small single tablet and has very little drug-drug
interactions it would be an attractive monotherapy drug. However, no
DTGmonotherapy trial has been undertaken in ART naïve or ART experienced
patients. A small pilot study with DTG/3TC dual therapy trial (PADDLE) is
ongoing.[30] In conclusion, the use of ART monotherapy has only been evaluated
with boosted PI monotherapy and seems associated with non-inferior virological
responses to comparators* arms, absent rates of significant treatment emerging
resistance, equal CD4 counts and less AE in the trials of HIV-1 suppressed
patients.
This study will expand the experience with the monotherapy treatment strategy
and evaluate the efficacy and safety of DTG monotherapy in HIV-1 suppressed
patients in an open-label randomized clinical trial with patients continuing
their original cART as controls. The studies mentioned above show that reducing
the pill burden could result in ongoing virological efficacy, improve safety
and without detrimental effects on immunological function. Because DTG has been
shown to be superior to boosted PI cART regimens, this regimen has the
potential to be as effective as monotherapy as DRV/r monotherapy in HIV-1
suppressed patients. The insight that this study will generate on DTG potential
as monotherapy will be valuable for future patients with difficult to manage
HIV-1 infections.
An important secondary virological endpoint in this study is the effect of DTG
monotherapy on the cellular HIV reservoir. The effect of DTG on the viral
reservoir is unknown. Furthermore, there is no study assessing the effect of
ART monotherapy on viral reservoir kinetics. All included patients will be
chronically infected HIV-1 patients on long-term cART. However, cART is not
able to clear the virus and in patients with no detectable plasma vireamia, a
latent (pro)viral reservoir persists. Interruption of cART in these patients
usually results in rapid viral rebound.[31] The pro-viral reservoir*s decay
rate with cART follows a linear pattern with a half-life estimated up to 44
months, dependent partially on the timing of cART initiation.[32, 33] In
perspective of potential future treatment strategies to diminish or eradicate
HIV reservoir size, data on the impact of DTG monotherapy on the viral
reservoir are needed and will be collected.

OT population excludes patients lost to follow-up, or that discontinued DTG for
reasons of intolerance or toxicity. ITT = all patients that took at least 1 DTG
tablet

Primary objective:
* To evaluate the efficacy of DTG monotherapy in maintaining virological
suppression with HIV-RNA <200 c/mL at week 24 by OT analysis.

Secondary objectives:
* To evaluate the time to loss of virological response (TLOVR) in the OT
population defined as the first of two confirmed HIV-RNA >50c/mL at least 1
week apart.
* To evaluate the efficacy of DTG monotherapy in maintaining virological
suppression with HIV-RNA <200 c/mL at week 24 by OT analysis in the entire
study population (n=104) which consists of the immediate switchers group (n=52)
and the delayed switchers from the control arm (n=52).
* To evaluate the efficacy of DTG monotherapy in maintaining virological
suppression with HIV-RNA <50 and <200 at week 24 and 48 by OT and ITT analysis.
* To evaluate the safety (acquired resistance, and AE according to CTC 4.0) of
DTG monotherapy
* To evaluate the evolution of CD4 associated HIV-1 reservoir (total/integrated
HIV-DNA and 2LTR) at baseline and during DTG monotherapy.
* To evaluate the number and type of INI resistance mutation in patients with
confirmed HIV-RNA >200 c/mL.
* To evaluate the CD4 cell count change at week 48.
* To evaluate blood-pressure, weight, BMI, fasting serum lipids, Framingham
risk score, ATP-III treatment goals, inflammatory markers, renal function,
urinalysis, bone mineral density at week 24 and 48.
* To evaluate the cost effectiveness of DTG monotherapy.

Randomized open-label phase IV intervention study (figure below). HIV-1
infected patients on suppressive cART with HIV-RNA <50 c/mL for >24weeks, a CD4
nadir >200 cells/mm3, and a HIV-RNA plasma load before cART initiation <100.000
c/ml will be randomized 1:1 to immediate switch to DTG monotherapy or to
continue current cART till delayed switch at week 24 to DTG monotherapy.
Patients will be assessed at screening, day 1 (baseline) and weeks 4, 8, 12,
18, 24, 36 and 48. Patients will return to their previous cART regimen when
criteria of treatment failure are met.

Patients on current standard cART will switch to dolutegravir, an INI active
against wild-type, *2 ART classes including or excluding INI resistant HIV-1
will be given as a single tablet 50mg QD. The branded name for DTG is Tivicay®
and DTG is produced by ViiV Healthcare.

Burden: 5 extra visits for a total of 8 visits. Extra blood sampling (190mL in
48 weeks). DEXA scan will be done at week 0 and 24 on DTG monotherapy.

Risks: Risks associated with the study are the side effects of DTG as observed
in the phase III clinical trials. In these studies DTG was well tolerated and
DTG discontinuation were less frequent compared to frequently used comparators
arms at 96 weeks of follow-up. No life threatening drug-related AE were
observed.

The virological properties of DTG and absent treatment emergent DTG resistance
in the clinical trials are reassuring and show that DTG is a potent drug with a
high genetic barrier to resistance. However, although patients will be
carefully monitored and cART will be reinitiated promptly at the time of
virological rebound, there is a chance that DTG monotherapy will fail in a
small subset of patients. Because, none of the study participants have
experienced virological failure in the past, these patients can restart their
previous cART regimen if DTG monotherapy fails. As only patients with a high
CD4 count are included, the restart of their previous cART regimen will be
possible before a clinically relevant decrease in CD4 cell count is observed.

The risks associated with blood sampling are small. Severe adverse events are
very infrequent with these procedures.

Benefits: In some patients: decrease in pill count from 3 or 2 medicines to 1
pill per day. Decrease in pill volume (in all). Decrease in antiretroviral
compounds from 3 to 1 and therefore the risk of side effects due to these
discontinued antiretroviral compounds.