Dolutegravir was hailed as a game changer because resistance was expected to be rare. The new evidence challenges that assumption, at least in some settings.
Kenya could be safer than many countries when it comes to
HIV drug resistance, thanks to its reliance on tenofovir-based regimens.
A new study has found that resistance to dolutegravir (DTG),
the backbone of Kenya’s first-line HIV treatment, appears far less likely when
combined with tenofovir than with older drugs such as zidovudine or abacavir.
DTG has a high barrier to resistance, but if given on its
own, the virus can still adapt. That is why the World Health Organization recommends
that DTG always be combined with two other drugs of a different class.
The study looked at 660 patients in Kenya, South Africa, and
other regions. Among 183 patients with ongoing detectable virus, 11.5 per cent
showed dolutegravir resistance.
Patients taking zidovudine were almost 20 times more likely
to develop resistance compared to those on tenofovir. Those on abacavir were
more than five times more likely.
The study was published last week in the Clinical Infectious Diseases
journal, under the title “HIV resistance to dolutegravir varies with co-administered agents.”
The authors report: “Our multi-cohort analysis suggests that
HIV genotypic dolutegravir-resistance is more common when
dolutegravir+lamivudine is co-administered with either zidovudine or abacavir
compared to tenofovir.”
The science comes down to a drug’s “half-life”, or how long an
active drug stays in the body. Dolutegravir binds tightly to HIV for over
70 hours. Tenofovir’s active form also stays in cells for several days. But
abacavir and zidovudine fade much faster.
When patients miss doses, dolutegravir can end up working
alone, a situation that gives HIV a chance to adapt and develop resistance.
That is why the study found far more resistance in regimens built on abacavir
or zidovudine.
The authors explained: “We hypothesize that an NRTI (drugs
such as zidovudine and abacavir) increases the risk of dolutegravir-resistance
when its active metabolite’s intracellular half-life is relatively short.”
Kenya shifted to dolutegravir in 2019, introducing the TLD
combination (tenofovir + lamivudine+dolutegravir) as the national standard for
adults and adolescents. According to the Ministry of Health’s 2022 HIV
guidelines, TLD is the preferred first-line treatment for most patients.
But children are a different case. For those weighing under
30 kilogrammes, the guidelines recommend abacavir + lamivudine + dolutegravir
(ABC/3TC/DTG) as the preferred option. Tenofovir is not recommended in children
because it can damage bones and kidneys in young children. If a child reacts
badly to abacavir, zidovudine (another weak link) may be used as a substitute. This
leaves them more vulnerable to resistance.
This means that while most Kenyan adults are on the safer
tenofovir-based combination, thousands of children are still routinely given
abacavir or zidovudine with dolutegravir.
Globally, HIV drug resistance has undermined several
treatment strategies in the past. In the early 2000s, widespread resistance to
nevirapine and efavirenz forced African countries, including Kenya, to replace
entire treatment lines.
Dolutegravir was
hailed as a game changer because resistance was expected to be rare. The new
evidence challenges that assumption, at least in some settings.
Drug resistance has serious consequences for patients
because once the virus adapts, the standard regimen stops working. Patients
must be switched to second-line or third-line drugs that are more expensive,
harder to tolerate, and less widely available.
Children are especially vulnerable because if resistance
develops early, they may burn through the limited number of treatment options
available before reaching adulthood. That could put them on lifelong cycles of
drug changes and hospital visits.
A few nurses working in HIV clinics in Kenya told The Star that resistance
is rare. However, there are a few cases of patients with high viral load despite consistent
treatment.
“The problem is we still do not do Drug Susceptibility
Testing (DST) to check if the virus is resistant
to certain drugs. When we do a case summary for referral to Kemri, we are given a ‘Nat’
number but told there are no reagents for testing,” one said.