HIV-infected children in
Tororo, Uganda, an area of high malaria transmission, on a lopinavir/ritonavir
(LPV/r, or Kaletra)-based antiretroviral (ART) regimen had a significantly lower risk of getting malaria,
compared to those on a non-nucleoside reverse transcriptase (NNRTI)-based
regimen, researchers reported at the 19th
Conference on Retroviruses and Opportunistic Infections in Seattle this
In this open-label randomised
trial comprising 170 children, all with a median age of three years, a LPV/r-based
regimen was associated with a 59% reduction in the risk of recurrent malaria
after treatment with artemether-lumefantrine (HR=0.41, 95% CI: 0.2-0.76, p=0.004).
Malaria and HIV, in sub-Saharan Africa in
particular, cause significant death and disease. In spite
of protective measures, including cotrimoxazole prophylaxis and
insecticide-treated nets, HIV-infected people in malaria endemic
areas continue to have higher rates of malaria. In areas of high prevalence,
additional protective measures may be of value.
presentation, researcher Jane Achan noted that both HIV and malaria parasites utilise aspartic class
proteases. In vitro studies have shown the antimalarial activity of some
protease inhibitors (PIs).
The increasing availability
of PIs in resource-poor settings suggests the potential for their strategic use
in high malaria-endemic areas, she noted.
Dr Achan and her
colleagues chose to examine the hypothesis that the incidence of malaria among
HIV-infected children receiving LPV/r-based ART would be significantly lower than
among children receiving an NNRTI-based ART regimen.
HIV-infected children aged
two months to five years of age, and already on an NNRTI-based regimen or eligible
for ART and with a viral load under 400 copies/ml, were randomised to get either LPV/r-based
ART (+ two NRTIs) or NNRTI-based ART (nevirapine or efavirenz + two NRTIs) and
were followed for two years.
All medical care was given at
the study clinic, which was open every day; all children received cotrimoxazole prophylaxis and
insecticide-treated nets, the standard of care in Uganda. Malaria was diagnosed according to
a history of fever and blood smear. Uncomplicated malaria was treated with artemether-lumefantrine (AL), the first-line
treatment for malaria in Uganda.
Following diagnosis of
malaria, children attended the clinic on days 1, 2, 3, 7, 14, 21 and 28.
Lumefantrine levels were measured on day 7. Day 7 lumefantrine levels have been
shown to be an independent predictor for malaria.
A total of 67% of the children enrolled
between September 2009 and July 2011 were ART-naive. There were no significant
differences in baseline characteristics between the two arms. Median CD4
percentages were between 14% (2 to 44%) and 16% (2 to 43%) for the LPV/r arm and the
NNRTI arm, respectively
Malaria incidence was
significantly higher in the NNRTI arm compared to the LPV/r arm: 2.25 compared
to 1.32 episodes per person-year (incidence rate ratio (IRR): 0.59, 95% CI:
0.36-0.97, p=0.04). LPV/r-based ART was therefore associated with a 41%
reduction in the incidence of malaria, compared to an NNRTI-based regimen.
In evaluating a possible
explanation for this outcome, Dr Achan and colleagues looked at the preventive effect
of LPV/r by measuring the incidence of first episodes of malaria. This measure
would rule out any drug-drug interaction that might influence outcomes. An
LPV/r-based regimen was linked with a 29% non-significant reduction in the risk
of a first episode of malaria (HR=0.71, 95% CI: 0.45-1.12, p=0.14).
However, after treatment with
AL, LPV/r had a significant effect on reducing the risk for recurrent malaria.
Ritonavir, Dr. Achan noted, is a known inhibitor of the CYP 3A4 pathway
involved in lumefantrine metabolism.
The median lumefantrine levels
in the blood on day 7 following treatment were significantly higher in the
LPV/r arm compared to the NNRTI arm: IQR: 926 (473-1910) and 200 (108-510),
p=<0.0001, respectively. The higher levels of lumefantrine appeared to be
driving the protective factor.
In the LPV/r arm alone, where
day 7 lumefantrine levels in the blood were over 300 ng/mL, there was a greater
than 85% reduction in the risk of recurrent malaria within 63 days of starting
treatment. The reduction in risk was dose-dependent, compared to levels under
300 ng/mL on day 7.
Levels of 280 ng/mL and above
are considered to provide better antimalarial protection.
There were no significant
differences in the risks for adverse events after antimalarial treatment in the
two arms. Temporary elevations in liver enzymes were more common in the NNRTI
arm, while itching was more common in the LPV/r arm. There was no evidence of
Dr Achan concluded that
children treated with LPV/r-based regimen had a significantly lower risk of
getting malaria compared to children on an NNRTI-based regimen as a result of
three potential mechanisms:
pharmacokinetic effect of LPV/r on lumefantrine leading to a prolonged
‘post-treatment’ prophylactic effect after treatment with AL, and as such is
the main driver of the outcome.
lesser extent the direct antimalarial effect of LPV/r; and
potential antiparasitic synergy between LPV/r and lumefantrine.
These findings, she noted,
suggest a role for ‘pharmaco-enhancement’ as a tool to help reduce the burden
of malaria in high endemic settings among HIV-infected individuals.