Download the mcc are mixing up issues

The MCC are mixing up issues
On the 12th July 2004, the Medicines Control Council recommended that nevirapine
should not be used as monotherapy for the prevention of mother to child transmission
(PMTCT) because of the dangers of drug resistance.
Let’s unpack this
 The MCC statement implies that monotherapy is the reason there is drug
resistance. The published data shows that any nevirapine- containing regime
(whether single, dual or triple) given as a single dose can cause drug resistance in
some women.
 Occurrence of resistant mutations after a single dose of nevirapine was identified
several years ago.
 To date no work has been completed on the clinical significance of drug
resistance in HIV infected women who have taken a single dose of nevirapine. By
clinical significance I mean whether it is very harmful to a significant proportion
of women or their babies. Or that the harm outweighs the benefits in terms of an
individual or group’s health.
 New, good quality evidence has however arisen, that drug regimes containing
more than one drug are more effective, than nevirapine alone. This has led some
authorities (the Western Cape Health Authority, the Thai Ministry for Health) to
recommend them for PMTCT. Not because of the dangers of drug resistance but
because they work better. Resistance has not been deemed by them to be an area
where new data has arisen that requires urgent and dramatic responses.
In short, nevirapine works as a single dose and has saved the lives of many thousands
of babies in SA. It works better in combination. We do not yet know the clinical
significance of the resistance a single dose causes in women.
Since there seems to be no science and no logical reasoning behind the MCC statement,
one is left to wonder what are the intentions behind making this statement.
Improving a protocol recommendation is to be welcomed. It is very different from the
irresponsible act of NOT recommending the current protocol, with omitting to
recommend another more appropriate protocol.
The probable effects are to cause confusion amongst the women who are offered
nevirapine,sow distrust of the health care workers by women and lead many to believe
that nevirapine alone is “bad” for one’s health.
The issue in greater depth
 Triple ARV therapy containing NNRTI’s (nevirapine is a NNRTI class drug)
taken by the women after delivery, for their own health (i.e. as treatment rather
than prevention of HIV for the baby) ,or by a baby (in whom the prevention
measures failed) may not work at all, or may work for a short time, or work well
in people with nevirapine resistance after a single dose. We simply do not yet
know the answer to this question.
 Rates of nevirapine resistance reduces with time in a person. After a single dose
of nevirapine given for PMTCT, published studies have shown that resistance
levels decrease from higher levels after 10 days to virtual disappearance after 1824 months. Although some drug resistant virus is stored in the lymph tissue. We
do not yet know if this is a problem.
 Some women who are exposed to single dose nevirapine get resistant mutations.
These are mainly women with high viral loads who should perhaps be on life long
triple ARV therapy.
 A recent study in Thailand has shown that not all women who have nevirapine
drug resistance, get virologic failure after starting triple ARV soon after
delivery.
 And not all women who have nevirapine drug resistance have lower CD4 counts
on triple ARV therapy. In fact after 6 months the increase in Cd4 counts were the
same in women who had NEVIRAPINE exposure and women who do not have
NEVIRAPINE exposure.
I would like to see
A clear and unequivocal statement by our Government that
 Where possible, to decrease rates of transmission, AZT from 28 weeks will be
added to the single dose nevirapine
 nevirapine as currently recommended, should be available in all clinics and
hospitals in SA, that are waiting to get AZT
 nevirapine as currently recommended, should be offered to all women who are
HIV infected who book later in pregnancy
 HAART roll-out be accelerated and expanded to all areas of SA
 Research funded to examine HAART in pregnancy, clinical implications of drug
resistance, dual or triple therapy for a few weeks post – partum for that sub- set of
women in whom resistance may be a clinical problem.
 Once, high grade published scientific work is available, review of the treatment
protocols occurs. Until then we follow WHO recommendations
 Either free formula feeds or exclusive breast feeding should be offered as a choice
to women. The problems of increased transmission with mixed feeding should be
emphasized.
 Increase pressure to lower drug prices (especially of the drug class of protease
inhibitors), make available WHO pre-qualified generics.
What is drug resistance in HIV?
 HIV has a very fast mutation rate. Mutations can occur in the parts of HIV which
are targeted by anti-HIV drugs.
 This can, but not always result in strains of HIV that have reduced sensitivity to
these drugs.
 These HIV strains are called drug resistant.
 When an anti-HIV drug is started, HIV that is fully susceptible to that drug
disappears rapidly, leaving behind drug resistant viruses.
 These viruses continue to reproduce themselves despite the drugs presence.
Resistance and NEVIRAPINE
 We have known for several years that NEVIRAPINE causes “a lot” of drug
resistance, because it stays in the blood for a long time. Yet still have
recommended it. To date there is no NEW CONVINCING evidence that
resistance has become a pressing and urgent problem, demanding changes in
protocols.
Resistance tests are a complex new development in HIV care. Results should be
interpreted by someone who is experienced in their use. Drug resistance is not the only
reason HIV treatment can fail. Resistance tests may be unreliable if the viral load is
below 1000 copies.
Interpretation of drug resistance depends on whether genotypic or phenotypic tests were
done, the subtype of HIV, choice of assay, the choice of mutations you choose to study.
This means that studies are not always comparable, and often produce differing and
conflicting results.
If resistance is a problem, do we know if it would be a large one?
Of pregnant HIV infected women in South Africa
About 20% will be immune-compromised, i.e. have a CD4 count of less than 200, or
and ADI (AIDS defining illness). Under current guidelines these women should be
offered HAART both to prevent MTCT and for life for their own health and treatment.
About 80% will have CD4 >200
of them some will have booked early enough to have been counseled and tested and had
results returned before 28 weeks. These can be offered the more EFFECTIVE treatment
of AZT from 28 weeks plus NEVIRAPINE
This will work better in reducing the chances of transmission to baby but still will
produces NEVIRAPINE resistance in some women.
The rest will book later and can be offered single dose NEVIRAPINE as the next best
PMTCT intervention.
This 80% of women will require HAART at some point in the future, from 6 weeks to 10
years later. No-one knows whether the NEVIRAPINE, or AZT plus NEVIRAPINE they
took during pregnancy and at delivery will cause treatment failure. But if there is
treatment failure, alternative regimes should be offered.
So if nevirapine resistance is a problem it is more likely to be a problem in a minority of
women who are offered PMTCT drug interventions.
if nevirapine does not cause clinically significant resistance in women, by denying it to
thousands we are killing hundreds of babies.
NEVIRAPINE in treatment and prevention. Nevirapine is provided for two reasons ;
1. for treatment - as part of a ARV package of three drugs
2. for prevention of HIV. Especially prevention of mother to child infection.
 When given as part of a treatment package it is only given to people with CD4
count of less than 200 cells/mm3.
 When given as prevention it is given to all HIV infected women and their babies,
to prevent infection in their babies, irrespective of their CD4 count.
 Women who are pregnant and need triple ARV therapy (CD4 <200) should be
offered ARV package of three drugs, which can do both jobs (treat her and
prevent the baby from infection)
 For women who are pregnant and HIV infected (CD4>200) current thinking is to
prevent infection with ARV/c/s, formula feeding and other interventions.
 Then when the time comes that their CD4 count has fallen they should be offered
triple ARV therapy. This can be anytime from 6 weeks after delivery to 10 years
or more.
 We give triple ARV therapy as opposed to mono or dual therapy for treatment to
prevent drug resistance. It works well, and has reduced TB rates and deaths from
TB, other opportunistic infection, and prevented death from AIDS in many
people.
Dr Natalya Dinat MD, FCOG(SA), Specialist obstetrician-gynaecologist, Johannesburg
July 13, 2004