The Expert Committee recommended the addition of the fixed-dose combination
formulation of dolutegravir + lamivudine + tenofovir disoproxil fumarate to the
core list of the EML for treatment of HIV infection in adults and adolescents.
The Committee noted the demonstrated efficacy and safety of DTG-based
regimens in treatment-naive patients, and that DTG-based regimens are now
recommended as preferred first-line therapy in WHO Guidelines for adults and
adolescents initiating antiretroviral treatment.
The Committee also considered that the availability of fixed-dose
combinations of antiretroviral therapies provides benefits to patients in terms
of ease of administration and reduced pill burden, which can contribute to
improved therapeutic adherence.
The application requested the addition of a fixed-dose combination formulation of dolutegravir, lamivudine and tenofovir disoproxil fumarate (TLD) to the core list of the EML for treatment of HIV infection in adults and adolescents.
This fixed-dose combination (FDC) had been previously considered by the Expert Committee for addition to the EML. The component medicines are all included individually on the EML.
Public health relevance
In 2017, UNAIDS reported there were 36.9 million people living with HIV/
AIDS globally, 1.8 million new HIV-1 infections, and 940 000 thousand HIV-
related deaths (1). Over 95% of infected people live in low- and middleincome
countries (LMICs) with inadequate resources to effectively combat the
epidemic. While some countries have achieved declines in new HIV infections
among adults of 50% or more, global data show that many others have not
made measurable progress and others have experienced worrying increases in
new HIV infections. Overall, approximately 21.7 million people were receiving
antiretroviral therapy (ART) in 2017, but this is estimated to represent only 59%
of people living with HIV.
Early and effective ART not only significantly improves the health
of those people living with HIV, but also reduces transmission of the disease
as shown in the recently reported START study (2). For this reason, WHO
released guidelines in 2015 calling for treatment for all people with HIV. Easy to
administer, highly effective, safe treatment options remain desperately needed
in many areas of the world to meet the UNAIDS ‘90-90-90’ targets, which call
for 90% of people living with HIV to know their status, 90% of those with known
infection to be on ART, and 90% of those on ART to be virally suppressed (i.e.
on successful therapy) by the year 2020 (3).
The efficacy of dolutegravir (DTG) has been demonstrated in ART-naive subjects
in three randomized, controlled, multinational, Phase III studies: SPRING-2 (4),
SINGLE (5) and FLAMINGO (6). The findings of these studies were evaluated
in the 2017 consideration of dolutegravir by the Expert Committee and are not
The safety, tolerability and efficacy of a dolutegravir-based regimen was
evaluated in a prospectively-enrolled, open-label cohort of 564 Indian adults
receiving dolutegravir in combination with other ARVs (primarily tenofovir
disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC)) as
either first- or second-line therapy. Among the treatment naive patients initiating
DTG plus TDF/3TC or TDF/FTC, all had viral suppression at the 6 month
follow‑up, and overall, viral suppression occurred in 82.9% at six months (7).
The NAMSAL ANRS study randomized HIV-infected adults in
Cameroon to receive either a dolutegravir-based regimen (TLD) (n=310) or
an efavirenz-containing regimen (TLE-400) (n=303) for first-line treatment.
Preliminary efficacy results at 48 weeks on treatment indicate the proportion
of patients with HIV RNA <50 copies/mL was 74.5% in the TLD arm and
69% in the TLE-400 arm. Fewer patients with initial HIV RNA levels >100 000
copies/mL had virologic suppression to <50 copies/mL: 66.2% in the TLD arm
and 61.5% in the TLE-400 arm. In this study, viral suppression with TLD was
numerically higher but not statistically superior to TLE-400; NNRTI resistance
was an important determinant of TLE-400 failure (8).
In the clinical studies to date, dolutegravir-based regimens were
either non-inferior or superior in efficacy to comparator regimens containing
other integrase inhibitors, boosted protease inhibitors and NNRTIs regardless
of patient population. In patients initiating first-line treatment, successful
virologic suppression occurred in more patients receiving dolutegravir than the
comparators. A systematic review and meta-analysis conducted by WHO in 2016
concluded that among treatment-naive patients, treatment with an integrase
inhibitor (particularly DTG) plus two NRTIs, had superior efficacy and tolerance
to the current standard of care regimens of efavirenz plus two NRTIs (9).
The overall safety profile of dolutegravir in adults compared favourably to other
ARVs included in the clinical trials reported previously.
There have been multiple reports of neuropsychiatric events among
patients receiving dolutegravir-based treatment since its approval. Although
dolutegravir appears to result in fewer of these events compared to efavirenz in
comparative clinical trials (5), some patients receiving dolutegravir experience
episodes of insomnia or depression. Causality for these events has been difficult
to determine as many patients are reported to have a previous history of
In the South Indian cohort of first- and second-line patients, dolutegravirbased
regimens were well tolerated. Mean alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) decreased slightly in the cohort during the
6-month evaluation period, mean haemoglobin increased slightly, and kidney
function remained stable. In this cohort, sleep disturbances and neuropsychiatric
symptoms were not reported. The frequency of opportunistic infections
decreased from 7.4% prior to starting DTG to 3.3% after six months follow up.
None of the patients in this cohort discontinued DTG during the evaluation
period. Four deaths were reported (two sepsis and two cytomegalovirus (CMV)
encephalitis, considered unrelated to ARVs) (7).
A nationwide birth outcomes surveillance programme conducted in
Botswana began collecting data in women initiating dolutegravir in 2014.
An initial report of pregnant women who began taking either a dolutegravir-
(n=1729) or efavirenz-based (n=4593) treatment regimen identified no difference
in risk for adverse birth outcomes, even among those beginning treatment
during the first trimester (i.e. post-conception ART) (10). However, an interim
analysis of a second surveillance study of women becoming pregnant while
already receiving ART (i.e. pre-conception ART) identified an excess number
of neural tube defects among infants of women receiving a dolutegravir-based
regimen. Neural tube defects were observed in 4 of 426 (0.94%) infants born to
women receiving dolutegravir compared to 14 of 11 300 (0.12%) infants born
to women receiving any other ART regimen and 61 of 66 057 (0.09%) infants
born to HIV-uninfected women. Although none of the affected women were
receiving folate supplements, no other risk factors for neural tube defects have
been identified (11). This study is ongoing and expects to have a final analysis
in 2019. While awaiting the final study results and data from other sources,
WHO recommends counselling for women of childbearing potential and access
to effective contraception in those receiving dolutegravir. However, they also
suggest that an efavirenz-based regimen remains safe and effective in women
who plan to become pregnant (12).
The NRTI backbone of TDF/3TC has an extensive history of use in ART
globally and has accumulated a favourable safety and tolerability profile. Initial
concerns regarding potentially serious renal and bone toxicity due to the TDF
component have not been borne out over years of clinical experience although it
requires dose adjustment in patients with significant renal impairment and so is
not generally used in this sub-group.
In addition, the potential risks and benefits of wide implementation
of TLD were evaluated in a 2018 modelling exercise conducted by a group
of independent researchers. The group used existing data to estimate HIV
transmission and disease progression (taking into account drug resistance,
drug potency, differential viral suppression and clinical outcomes) to compare
outcomes of different ART regimens in various scenarios. In their model, the
greatest number of disability-adjusted life-years was averted in the scenario
providing TLD to all adult patients without restrictions over 20 years compared
to adults based on intent to have children and/or dependent on documentation
of viral suppression (13).
Cost / cost effectiveness
Various sources indicate an average price per patient per year for the FDC of US$ 74.00. This price is comparable to other first-line regimens.
A pricing agreement was announced in July 2017 by the governments
of South Africa and Kenya, together with UNAIDS, CHAI, the Bill & Melinda
Gates Foundation, Unitaid, the UK Department for International Development,
PEPFAR, USAID, and the Global Fund, with Aurobindo and Mylan.
Under the agreement, Aurobindo and Mylan agreed to offer TLD
at approximately US$ 75 PPPY. This lower price is accessible to public sector
purchasers in over 92 LMICs worldwide.
The 2016 WHO Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing HIV infection recommended TDF plus 3TC as a
preferred nucleoside/tide backbone in first-line therapy and dolutegravir 50 mg
in combination with TDF and 3TC as an alternative first-line regimen (14). In
addition, these guidelines reiterate the WHO conclusion that FDCs and oncedaily
regimens are most preferred. At that time, TLD was not available as an
FDC. In the most recent WHO treatment guidelines update (July 2018), a DTGbased
regimen is recommended as a preferred first-line regimen for adults and
adolescents living with HIV who are initiating antiretroviral therapy (12).
This product is currently available for procurement from multiple suppliers (including WHO prequalified manufacturers).
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dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study. Lancet
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