Co-administration of
dolutegravir-based antiretroviral therapy and short course (12 weeks) of rifapentine/isoniazid
(3HP) for people living with HIV needing preventative treatment for latent
tuberculosis (TB) infection was well tolerated with no adverse reactions, the
Conference on Retroviruses and Opportunistic Infections (CROI 2019) heard last
week in Seattle.

Dr Kelly Dooley, presenting
on behalf of the DOLPHIN study team, said that all 60 participants maintained
viral suppression throughout 3HP/dolutegravir treatment in this single-arm
phase I/II safety and pharmacokinetics (PK: drug absorption, distribution,
metabolism and elimination from the body) study, conducted in South Africa.

In Summer 2018 the World
Health Organization (WHO) recommended dolutegravir as the preferred
first-line treatment for treatment-naïve people living with HIV. 

WHO
has also given updated guidance
for preventative therapy of latent
TB infection.Twelve once-weekly doses of 3HP are now recommended as
an alternative to six months of isoniazid for TB prevention in countries with
high TB incidence.

This could transform the
prevention of TB. However, drug interactions with antiretrovirals could make
implementation difficult, as dolutegravir is metabolised by CYP3A and UGT1a1.
These are enzymes induced by rifamycin antibiotics including rifapentine. This
means when used together effective concentrations of dolutegravir may be
reduced.

A previous trial to see how dolutegravir should be dosed involving four healthy HIV-negative volunteers showed, unsurprisingly,
a slight reduction in dolutegravir concentrations. However, two experienced
adverse events including high fever, hypertension and increased liver function enzymes
so the study was stopped early.

Both dolutegravir-based
antiretroviral therapy and 3HP have advantages. The question, Dr Dooley said,
is can they be given together safely in people living with HIV needing latent
TB treatment? If so, what is the right dolutegravir dose?

Sixty HIV-positive adults
with undetectable viral load on an efavirenz-based regimen were enrolled. At
the time of enrolment all were switched from efavirenz to dolutegravir + tenofovir/emtricitabine
(Truvada) for a period of eight weeks
to allow for efavirenz to washout.

They then received
dolutegravir (50mg once a day) + tenofovir/emtricitabine (Truvada) plus a weekly dose of 3HP (900mg/900mg) for 12 weeks.
After 3HP completion all participants were followed for four more weeks. All
had access to dolutegravir for 12 months after treatment.

Viral loads were measured at
baseline (dolutegravir alone), week 11 (dolutegravir+3HP) and week 24 (one month after 3HP completion).

Thirty participants had semi-intensive
PK sampling: dolutegravir alone (week 8), dolutegravir after the third 3HP dose (week 11) and dolutegravir
after the eighth 3HP dose (week 16). Three interim analyses looking at PK and
safety and to decide doses to be used were performed. The other thirty
participants had sparse PK sampling.

The primary objectives were
to look at the effect of rifapentine and isoniazid at doses of 900mg once
weekly on the PK of dolutegravir, and to evaluate the safety of dolutegravir
taken with 3HP. Secondary objectives included viral load suppression.

Of the 60 participants 70%
were female with a median age of 40 years. All were of black ethnicity having a
baseline median CD4 cell count of 683 cells/mm3. Fifty-four per cent tested positive
with the QuantiFERON Gold in Tube test (a test to detect latent TB infection
and TB disease).

The drugs were well tolerated
with no grade 3 or higher clinical or laboratory adverse events that were
related to 3HP.

All participants completed
all 12 doses of 3HP.

HIV viral loads remained
40 copies/ml throughout for all participants. Although one participant had
a viral load of 2300 copies/ml at week 24 (four weeks after 3HP completion), following
adherence counselling viral load returned to 40 copies/ml.

One woman taking oral
contraceptives became pregnant at week 24. Dr Dooley suggested barrier
contraception for women taking rifampicin-containing TB prophylaxis, because of
possible harm to foetal development.

Dolutegravir trough
concentrations (the lowest concentration of the drug in the blood measured
after a dose) were reduced by approximately 50%. The area under the curve (AUC:
the overall amount of drug in the bloodstream after a dose) was reduced by
approximately 30% with 3HP. However, median values were above the target value
of 300 ng/ml at all time points.

According to
pharmacokinetic/pharmacodynamic analysis (how PK/PD together influence dosing,
benefits and adverse effects) the average trough concentration with a 10mg once
daily dose given as monotherapy is 300 ng/ml, which is equivalent to a once-daily dose of 50mg as part of combination therapy.

Dr Dooley concluded the
findings reassuring, highlighting the importance of testing tolerability and
safety in patients in whom clinicians hope to use the therapy.