# GlaxoSmithKline PLC ViiV switch study shows 2DR as effective as 3DR

- Link: https://www.directorstalkinterviews.com/glaxosmithkline-plc-viiv-switch-study-shows-2dr-as-effective-as-3dr/412787439
- Published: 2019-07-10T07:25:09+01:00
- Author: Giles Arbor

ViiV Healthcare, the global specialist HIV company majority-owned by **[GlaxoSmithKline](https://www.directorstalkinterviews.com/ftse-company/glaxosmithkline-plc/gsk.l)
plc** ([LON: GSK](https://www.directorstalkinterviews.com/ftse-company/glaxosmithkline-plc/gsk.l)),
with **Pfizer Inc.** (NYSE: PFE) and Shionogi Limited as shareholders, today announced
positive Week 48 results from its phase III TANGO study. The TANGO study was conducted
to assess whether adults living with HIV-1 who had maintained viral suppression 
for at least six months on a tenofovir alafenamide fumarate (TAF)-containing regimen
of at least three drugs, were able to maintain similar rates of viral suppression
after switching to the 2-drug regimen (2DR) of dolutegravir plus lamivudine in a
fixed dose combination, compared to continuing the TAF-containing regimen.

The study met its primary endpoint for non-inferiority, based on the proportion 
of participants with plasma HIV-1 RNA ≥50 copies per millilitre (c/mL) using the
FDA Snapshot algorithm at Week 48. No patients met confirmed virologic withdrawal
criteria or developed treatment resistance in the dolutegravir plus lamivudine arm
of the study. The safety results for the 2DR of dolutegravir plus lamivudine were
consistent with the product labelling for the medicines.[1]

Full results from the study will be presented at the 10th International AIDS Society
Conference on HIV Science (IAS 2019), to be held from 21-24 July in Mexico City.

**Kimberly Smith, M.D., Head of Global Research & Medical Strategy at ViiV Healthcare,
said:**

> “When we developed the TANGO study, we asked if virally suppressed people living
> with HIV could reduce the number of medicines in their HIV treatment regimen while
> maintaining viral suppression. These Week 48 data clearly indicate that they can–
> individuals who are already on treatment can maintain viral suppression if they
> switch from a 3-drug, TAF-containing regimen to a 2-drug regimen of dolutegravir
> plus lamivudine.”

The single-pill, 2DR of dolutegravir plus lamivudine, was authorised in the United
States earlier this year for the treatment of HIV-1 infection in adults with no 
antiretroviral treatment (ARV) history and with no known resistance to either dolutegravir
or lamivudine.[2] It was also authorised in Europe in July 2019 for the treatment
of HIV-1 infection in adults and adolescents above 12 years of age weighing at least
40 kg, with no known or suspected resistance to the integrase inhibitor (INI) class,
or lamivudine.[3]

**About TANGO**

TANGO is a phase III, randomised, open-label, active-controlled, multicentre study
to assess the antiviral efficacy and safety of switching to a 2DR consisting of 
dolutegravir plus lamivudine in HIV-infected adults who are virally suppressed and
stable on a TAF-containing regimen. [4]

Study participants were HIV-1 infected adults on a TAF-containing regimen with HIV-
1 RNA<50c/mL for at least six months, without prior virologic failure, no historical
nucleoside reverse transcriptase inhibitors (NRTI) or INI major resistance mutation,
and no evidence of hepatitis B infection. Participants were randomised to switch
to dolutegravir plus lamivudine or continue on the TAF-containing regimen through
Week 148. The primary endpoint was the proportion of participants with a viral load
of >50 c/mL at Week 48 (FDA Snapshot algorithm) for the Intention To Treat-Exposed(
ITT-E) population.4

**About dolutegravir and lamivudine**

Dolutegravir is an INI for use in combination with other antiretroviral agents for
the treatment of HIV.[5] INIs block HIV replication by preventing the viral DNA 
from integrating into the genetic material of human immune cells (T-cells). This
step is essential in the HIV replication cycle and is also responsible for establishing
chronic infection. Dolutegravir is authorised in over 100 countries across North
America, Europe, Asia, Australia, Africa and Latin America.

Lamivudine, commonly known as 3TC, is a nucleoside analogue used in combination 
with other antiretroviral agents for the treatment of HIV infection. Lamivudine 
is available in branded (Epivir®) and generic forms.[6]

Dolutegravir plus lamivudine is a once-daily, single-pill, 2-drug regimen that combines
the INI dolutegravir (Tivicay, 50 mg) with the NRTI lamivudine (Epivir, 300 mg).
2 The fixed dose combination of dolutegravir plus lamivudine is authorised in the
EU for the treatment of HIV-1 infection in adults and adolescents above 12 years
of age weighing at least 40 kg, with no known or suspected resistance to the INI
class, or lamivudine,3 and in the US for the treatment of HIV-1 infection in adults
with no antiretroviral (ARV) treatment history and with no known resistance to either
dolutegravir or lamivudine.2

Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

Important Safety Information for 50mg dolutegravir/300mg lamivudine tablets in the
EU

The following Important Safety Information is based on the Summary of Product Characteristics
for dolutegravir plus lamivudine. Please consult the full Summary of Product Characteristics
for all the safety information.

Dolutegravir plus lamivudine (50mg dolutegravir/300mg lamivudine)

Dolutegravir plus lamivudine is indicated for the treatment of Human Immunodeficiency
Virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing
at least 40 kg, with no known or suspected resistance to the integrase inhibitor
class, or lamivudine.

The recommended dose of dolutegravir plus lamivudine in adults and adolescents is
one 50 mg/300 mg tablet once daily.

**Method of administration**

Oral use. Dolutegravir plus lamivudine can be taken with or without food.

**Contraindications**

Hypersensitivity to the active substances or to any of the excipients listed in 
section 6.1.

**Dose adjustments**

A separate preparation of dolutegravir is available where a dose adjustment is indicated
due to drug-drug interactions (e.g. rifampicin, carbamazepine, oxcarbazepine, phenytoin,
phenobarbital, St. John’s wort, etravirine (without boosted protease inhibitors),
efavirenz, nevirapine, or tipranavir/ritonavir. In these cases the physician should
refer to the individual product information for dolutegravir.

**Missed doses**

If the patient misses a dose of dolutegravir plus lamivudine, the patient should
take dolutegravir plus lamivudine as soon as possible, providing the next dose is
not due within 4 hours. If the next dose is due within 4 hours, the patient should
not take the missed dose and simply resume the usual dosing schedule.

Special warnings and precautions for use

**Transmission of HIV**

While effective viral suppression with antiretroviral therapy has been proven to
substantially reduce the risk of sexual transmission, a residual risk cannot be 
excluded. Precautions to prevent transmission should be taken in accordance with
national guidelines.

**Hypersensitivity reactions**

Hypersensitivity reactions have been reported with dolutegravir, and were characterized
by rash, constitutional findings, and sometimes, organ dysfunction, including severe
liver reactions. Dolutegravir plus lamivudine and other suspect medicinal products
should be discontinued immediately if signs or symptoms of hypersensitivity reactions
develop (including, but not limited to, severe rash or rash accompanied by raised
liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters,
oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical
status including liver aminotransferases and bilirubin should be monitored. Delay
in stopping treatment with dolutegravir plus lamivudine or other suspect active 
substances after the onset of hypersensitivity may result in a life-threatening 
allergic reaction.

**Weight and metabolic parameters**

An increase in weight and in levels of blood lipids and glucose may occur during
antiretroviral therapy. Such changes may in part be linked to disease control and
life style. For lipids, there is in some cases evidence for a treatment effect, 
while for weight gain there is no strong evidence relating this to any particular
treatment. For monitoring of blood lipids and glucose reference is made to established
HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

**Liver disease**

Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at an increased risk of severe and potentially fatal hepatic adverse
reactions. In case of concomitant antiviral therapy for hepatitis B or C, please
refer also to the relevant product information for these medicinal products.

Dolutegravir plus lamivudine includes lamivudine, which is active against hepatitis
B. Dolutegravir lacks such activity. Lamivudine monotherapy is generally not considered
an adequate treatment for hepatitis B, since the risk for hepatitis B resistance
development is high. If dolutegravir plus lamivudine is used in patients co-infected
with hepatitis B an additional antiviral is therefore generally needed. Reference
should be made to treatment guidelines.

If dolutegravir plus lamivudine is discontinued in patients co-infected with hepatitis
B virus, periodic monitoring of both liver function tests and markers of HBV replication
is recommended, as withdrawal of lamivudine may result in an acute exacerbation 
of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis
have an increased frequency of liver function abnormalities during combination antiretroviral
therapy, and should be monitored according to standard practice. If there is evidence
of worsening liver disease in such patients, interruption or discontinuation of 
treatment must be considered.

**Immune Reactivation Syndrome**

In HIV-infected patients with severe immune deficiency at the time of institution
of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic
or residual opportunistic pathogens may arise and cause serious clinical conditions,
or aggravation of symptoms. Typically, such reactions have been observed within 
the first few weeks or months of initiation of CART. Relevant examples are Cytomegalovirus
retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii
pneumonia (often referred to as PCP). Any inflammatory symptoms should be evaluated
and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease
and autoimmune hepatitis) have also been reported to occur in the setting of immune
reactivation; however, the reported time to onset is more variable and these events
can occur many months after initiation of treatment.

Liver chemistry elevations consistent with immune reconstitution syndrome were observed
in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy.
Monitoring of liver chemistries is recommended in patients with hepatitis B and/
or C co-infection.

**Osteonecrosis**

Although the aetiology is considered to be multifactorial (including corticosteroid
use, biphosphonates, alcohol consumption, severe immunosuppression, higher body 
mass index), cases of osteonecrosis have been reported in patients with advanced
HIV-disease and/or long-term exposure to CART. Patients should be advised to seek
medical advice if they experience joint aches and pain, joint stiffness or difficulty
in movement.

**Opportunistic infections**

Patients should be advised that dolutegravir, lamivudine or any other antiretroviral
therapy does not cure HIV infection and that they may still develop opportunistic
infections and other complications of HIV infection. Therefore, patients should 
remain under close clinical observation by physicians experienced in the treatment
of these associated HIV diseases.

**Undesirable effects**

The most frequently reported adverse reactions are headache (3%), diarrhoea (2%),
nausea (2%) and insomnia (2%).

The most severe adverse reaction reported with dolutegravir was a hypersensitivity
reaction that included rash and severe liver effects.

Tabulated list of adverse reactions is available in the full information leaflet.

**Changes in laboratory biochemistries**

Dolutegravir has been associated with an increase in serum creatinine occuring in
the first week of treatment when administered with other antiretroviral medicinal
products. Increases in serum creatinine occurred within the first four weeks of 
treatment with dolutegravir plus lamivudine and remained stable through 48 weeks.
These changes are linked to the inhibiting effect of dolutegravir on renal tubular
transporters of creatinine. The changes are not considered to be clinically relevant
and do not reflect a change in glomerular filtration rate.

**Co-infection with Hepatitis B or C**

In the Phase III studies for the dolutegravir single agent, patients with hepatitis
B and/or C co-infection were permitted to enrol provided that baseline liver chemistry
tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety
profile in patients co-infected with hepatitis B and/or C was similar to that observed
in patients without hepatitis B or C co-infection, although the rates of AST and
ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection
for all treatment groups. Liver chemistry elevations consistent with immune reconstitution
syndrome were observed in some subjects with hepatitis B and/or C co-infection at
the start of dolutegravir therapy, particularly in those whose anti-hepatitis B 
therapy was withdrawn.

**Drug interactions**

No drug interaction studies have been conducted using dolutegravir plus lamivudine.
Dolutegravir plus lamivudine contains dolutegravir and lamivudine, therefore any
interactions identified for these individually are relevant to dolutegravir plus
lamivudine. No clinically significant drug interactions are expected between dolutegravir
and lamivudine.

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with
rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John’s wort,
etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/
ritonavir.

dolutegravir plus lamivudine should not be co-administered with polyvalent cation-
containing antacids. Polyvalent cation-containing antacids are recommended to be
taken 2 hours after or 6 hours before dolutegravir plus lamivudine.

When taken with food, dolutegravir plus lamivudine and supplements or multivitamins
containing calcium, iron or magnesium can be taken at the same time. If dolutegravir
plus lamivudine is administered under fasting conditions, supplements or multivitamins
containing calcium, iron or magnesium are recommended to be taken 2 hours after 
or 6 hours before dolutegravir plus lamivudine.

Dolutegravir increased metformin concentrations. A dose adjustment of metformin 
should be considered when starting and stopping coadministration of dolutegravir
plus lamivudine with metformin, to maintain glycaemic control. Metformin is eliminated
renally and, therefore, it is of importance to monitor renal function when co-treated
with dolutegravir plus lamivudine. This combination may increase the risk for lactic
acidosis in patients with moderate renal impairment (stage 3a creatinine clearance
45- 59 mL/min) and a cautious approach is recommended. Reduction of the metformin
dose should be highly considered.

The combination of dolutegravir plus lamivudine with cladribine is not recommended.

Dolutegravir plus lamivudine should not be taken with any other medicinal product
containing dolutegravir or lamivudine, except where a dose adjustment of dolutegravir
is indicated due to drug-drug interactions.

Other established and theoretical interactions with selected antiretrovirals and
non-antiretroviral medicinal products are listed in the full information leaflet.

**Fertility, pregnancy and lactation**

**Women of childbearing potential**

Women of childbearing potential (WOCBP) should undergo pregnancy testing before 
initiation of dolutegravir plus lamivudine. WOCBP who are taking dolutegravir plus
lamivudine should use effective contraception throughout treatment.

**Pregnancy**

The safety and efficacy of a dual regimen has not been studied in pregnancy. Preliminary
data from a surveillance study has suggested an increased incidence of neural tube
defects (0.9%) in mothers exposed to dolutegravir (a component of dolutegravir plus
lamivudine) at the time of conception compared with mothers exposed to non-dolutegravir
containing regimens (0.1%).

The incidence of neural tube defects in the general population ranges from 0.5-1
case per 1,000 live births (0.05-0.1%). As neural tube defects occur within the 
first 4 weeks of foetal development (at which time the neural tubes are sealed) 
this potential risk would concern women exposed to dolutegravir at the time of conception
and in early pregnancy. Due to the potential risk of neural tube defects with dolutegravir,
dolutegravir plus lamivudine should not be used during the first trimester unless
there is no alternative.

More than 1000 outcomes from second and third trimester exposure to dolutegravir
in pregnant women indicate no evidence of increased risk of malformities and foeto/
neonatal negative effects. However, as the mechanism by which dolutegravir may interfere
in human pregnancy is unknown, the safety in use during the second and third trimester
cannot be confirmed. Dolutegravir plus lamivudine should be used during pregnancy
only if the expected benefit justifies the potential risk to the foetus.

In animal reproductive toxicology studies with dolutegravir, no adverse development
outcomes, including neural tube defects, were identified. Dolutegravir was shown
to cross the placenta in animals.

A large amount of data on the use of lamivudine in pregnant women (more than 3000
outcomes from first trimester) indicates no malformative toxicity.

Animal studies showed lamivudine may inhibit cellular DNA replication (see section
5.3). The clinical relevance of these findings is unknown.

**Mitochondrial dysfunction**

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo 
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside
analogues, these have predominantly concerned treatment with regimens containing
zidovudine. The main adverse reactions reported are haematological disorders (anaemia,
neutropenia), and metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions
have often been transitory. These findings do not affect current national recommendations
to use antiretroviral therapy in pregnant women to prevent vertical transmission
of HIV.

**Breast-feeding**

It is unknown whether dolutegravir is excreted in human milk. Available toxicological
data in animals has shown excretion of dolutegravir in milk. In lactating rats that
received a single oral dose of 50 mg/kg at 10 days postpartum, dolutegravir was 
detected in milk at concentrations typically higher than blood.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations 
of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4%
of maternal serum concentrations) and progressively decrease to undetectable levels
when breastfed infants reach 24 weeks of age. There are no data available on the
safety of lamivudine when administered to babies less than three months old.

It is recommended that HIV infected women do not breast-feed their infants under
any circumstances in order to avoid transmission of HIV.

**Fertility**

There are no data on the effects of dolutegravir or lamivudine on human male or 
female fertility. Animal studies indicate no effects of dolutegravir or lamivudine
on male or female fertility.

**Effects on ability to drive and use machines**

Dolutegravir plus lamivudine has no or negligible influence on the ability to drive
and use machines. Patients should be informed that dizziness and somnolence has 
been reported during treatment with dolutegravir. The clinical status of the patient
and the adverse reaction profile of Dolutegravir plus lamivudine should be borne
in mind when considering the patient’s ability to drive or operate machinery.

Please refer to the full European Summary of Product Characteristics for Dolutegravir/
lamivudine

for full prescribing information, including contraindications, special warnings 
and precautions for use. For the US, please refer to the US Prescribing Information.

**About ViiV Healthcare**

ViiV Healthcare is a global specialist HIV company established in November 2009 
by **GlaxoSmithKline** (LON: GSK) and **Pfizer** (NYSE: PFE) dedicated to delivering
advances in treatment and care for people living with HIV and for people who are
at risk of becoming infected with HIV. Shionogi joined in October 2012. The company’s
aims to take a deeper and broader interest in HIV/AIDS than any company has done
before and take a new approach to deliver effective and innovative medicines for
HIV treatment and prevention, as well as support communities affected by HIV.

**References**

[1] ViiV Healthcare: TANGO headline results. Data on file.

[2] Dolutegravir plus lamivudine Prescribing Information. U.S. Approval 8 April 
2019. Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/
US/en/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF Accessed July 2019

[3] Dovato EU Summary of Product Characteristics. July 2019. Available at: https://
www.medicines.org.uk/emc/product/10446/smpc Accessed July 2019.

[4] Clinical trials.gov. Switch Study to Evaluate Dolutegravir Plus Lamivudine in
Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO).
Available at: https://clinicaltrials.gov/ct2/show/NCT03446573?term=TANGO+dolutegravir&
rank=1. Accessed July 2019

[5] Tivicay (dolutegravir) European Summary of Product Characteristics. Available
at: https://www.ema.europa.eu/en/documents/product-information/tivicay-epar-product-
information_en.pdf. Accessed July 2019.

[6] European Medicines Agency. Epivir (lamivudine) European Summary of Product Characteristics.
Available at: https://www.ema.europa.eu/en/documents/product-information/epivir-
epar-product-information_en.pdf Accessed June 2019.

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