Transcript Document

Conference Feedback
For 6th UK-CAB
8th August 2003
Simon Collins
HIV i-Base
UK-CAB August 2003
Online abstracts
• XII Resistance Workshop, Mexico
http://www.mediscover.net/journals.cfm
• 5th Lipodystrophy Workshop, Paris
http://www.intmedpress.com
• 2nd IAS Conference, Paris
http://ww2.aegis.org/conferences/2ndIASHIVPT/ias.pdf
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UK-CAB August 2003
XII Resistance Meeting
• Resistance meeting usually based on research
more than clinical studies, but an indication of
the importance of research is that most
discoveries that lead to changes in treatment
practice were first presented as early data to
these annual meetings.
• Only around 120 scientists attend [+ very few
community – this isn’t so good…]
• Every scientist presents a paper – and every
paper is very interesting
• The next studies were all new, and relevant to
clinical care
UK-CAB August 2003
Clinical Studies
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Transmission of drug resistance
Co-infection, reinfection, superinfection
Single dose nevirapine (75% MTCT)
Effectiveness of resistance tests
Cross resistance between NNRTIs
Resisdual activity of drugs
Tenofovir resistance
UK-CAB August 2003
Primary Resistance (CATCH)
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Evaluated primary drug resistance in Europe and Israel
Isolates from over 1600 patients were genotyped
Overall rate of genotypic resistance was 9.6%
NRTIs had the highest rate (6.9%), followed by NNRTIs (2.6%)
and PIs (2.2%); 1.7% of isolates with multiclass resistance
• 11% seroconvertors and 8% chronic infection
• The most common mutations are significant in conferring
reduced susceptibility to agents such as:
– Zidovudine and stavudine (M41V, T215F/Y)
– NNRTIs (K103N)
– PIs (M46I, G48V, I84V)
• Higher rate of primary resistance in subtype B vs non-B isolates
(11.3% vs 3.3%, P < .001)
UK-CAB August 2003
Mexico, Abstract 17
UK transmission
• Data from UK HIV Drug Resistance Database (community
initiated collaboration)
• 9,800 tests from 7000 patients. Collected 1996 - Mar 03
yr
• 96-98
• 99-01
• 01-03
PI
26%
32%
27%
NNRTI
20%
40%
48%
Key mutations in naive
10%
16%
17%
• BHIVA:
– Resistance test before treatment
– Resistance test on diagnosis
UK-CAB August 2003
Pillay et al Abstract 124
Implications of transmitted Rx
• Doesn’t revert to wild type
- Little et al, K103N to K median 196 days (95CI: 153-238
No reversion of PI in 64, 191, 342 days
only 1/10 revert at 1019dy (Abs 115)
- Delauguerre et al - 2 cases sexual transmission out to 2 years in
cellular reservoirs (Abs 80)
- Coral - 9/46 seroconvertors with resistance progressed at similar
rates - therefore NOT less fit (Abs81)
UK-CAB August 2003
Co-infection, reinfection and superinfection
• important to recognise that all occur, and the differences
between them
• Co-infection = either infected with two different viruses at
the same time
OR infected with a second virus before your immune
system reacts to the first infection (ie prior to
seroconversion - this may be re-infection
(re-infection usually requires clearing of a first infection,
which doesn’t happen with HIV)
• Superinfection = second infection AFTER first infection is
established
• Frequency is unknown, BUT effect of drug resistance is
likely as in other cases
UK-CAB August 2003
Example of superinfection
• Daar et al, SubB MDR, vl to 1000 at mo 2, then
superinfected with WT
[Phylogenetic analysis and viral diversity]
• Burger et al, Kenyan woman, SubA 1986, Sub A/C
1997 (IAS, Abs 71)
• Manigart et al, 2/147 women, Burkino Faso both
showed evidence of second separate infection at
time of viral increase (IAS 72)
UK-CAB August 2003
Phylogenetic tree (RTI)
• Example of
Phylogentic tree
For RTI sequence
UK-CAB August 2003
Single-dose nevirapine
• HIVNET 012 - single dose of NVP to
mother at onset of labour and single dose
to infant - 21/111 (19%) Rx at 6-8 wks
• Now 25/33 (76%) Rx at wk 2
• Reversed to WT by wk 8 in 12/27 (44%)
• Highlights limitations of Rx testing, that
reversion occurs, but also likely to be
archived in pro-viral DNA
• Implications for future treatment
UK-CAB August 2003
Mexico, Abstract 78, 79
NNRTI X-resistance
• Sometimes hear of people cycling NNRTIs even
though not recommended
• Resistance tests can show 181 and not 103
• Mellors et al, 50/216 NNRTI-exp but without
resistance has same response to those with
evidence of NNRTI resistance (Abs 134)
• Lecossier et al, with selective PCR found 103N in
5/16 samples with previously only 181 by regular
tests (Abs 143)
UK-CAB August 2003
Resisdual activity of drugs
• NNRTIs have no activity with 103 etc
• RTIs may continue activity (d4T) (Abs
133)
• 3TC withdrawal in small study lead to
increased viremia (Abs 140)
• Also see Deeks, 10th CROI Abs 188
• CAUTION: sanctuary compartments
UK-CAB August 2003
Tenofovir
• New drug, few failures in trials
• K65R in 8/36 failures (20%)
• X-Rx with abacavir and some
pipeline
• May occur less with d4T or AZTbased (but IAS Abs 42 - TZV+TDF included AZT
with K65R)
UK-CAB August 2003
5th Lipodystrophy Workshop
• Annual meeting - this year 350 delegates
• Includes community places and press
registrations
• Often at least half is basic science including in
vitro and animal studies
• Posters usually include clinical research
including other side effects (LA, bone, diarrhoea etc)
• Six key lectures online: (in next few weeks) - including
atherosclerosis, role of adipose tissue and adipocytokines
in insulin resistance, pharmacogenomics)
UK-CAB August 2003
5th Lipodystrophy Workshop
• Link between adipocytes, mitochondrial
depletion, HIV and AZT/d4T treatment now clear
• Reversal of fat loss with switch of d4T or AZT to
abacavir, and benefits continue out to 2 yrs
• Intima Media Thickness (IMT) and heart disease
• Reduced BMD in women - increased monitoring
recommended
• Rosigliatazone reverses lipoatrophy in people
with HIV and insulin resistance
• Fat transfer of broen fat led to swollen cheeks
• Treatment interruption - option used in practice
UK-CAB August 2003
Morphology of adipose tissue
• Several groups are reporting very exciting and important
work looking closely at fat cells and comparing HIV-negative,
HIV-positive untreated, and by exposure to different
treatment (ie d4T, AZT and other nukes or PI)
Caron, Bastard et al, Lancet 2003]
Nolan, Mallal et al, AIDS 2003; 17(9):1329-1338
• The Australian group (Nolan et al) also reported looking at
mitochondrial differences in fat cells form these different
groups, and showed correlation of damage to treatment:
d4T use > AZT use > HIV+ naïve > HIV-negative
UK-CAB August 2003
Morphology
of adipose
tissue
Fat cells from HIV-positive and
nucleoside-exposed patients
are not plump full cells differences include that they
are smaller and shorter-lived.
Nolan, Malal et al,
AIDS 2003; 17(9):1329-1338
Adipose tissue morphology (light microscopy).
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Normal adipose tissue histology.
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Typical histology associated with
subcutaneous fat wasting.
Line arrows indicate blood vessels.
Block arrow indicates a lipogranuloma.
UK-CAB August 2003
Lipoatrophic tissue
UK-CAB August 2003
Lipo workshop Summary, J Cappeau, IAS, Paris
Comparison of adipocyte mtDNA copy number
HIV-neg, HIV negative; HIV+ART-, HIV positive, antiretroviral therapy naive ZDV, zidovudine; d4T,
stavudine.
Nolan, Mallal et al AIDS 2003; 17(9):1329-1338
UK-CAB August 2003
Switch d4T to abacavir
Continued increase in limb fat out to 2 years following switch from
AZTor d4T to abacavir (Carr et al for MITOX Study, IAS LB18)
UK-CAB August 2003
MITOX study
• Serial DEXA and CT showed +0.39kg
limb fat at 24 wks
• Mean f/u 102 wks with 74/111 with
imaging to wk 104: +1.26kg
• Greater increases associated with
lower BMD, shorter duration of AZT
pre-study (p=0.024) and shorter use
of d4T on-study (p=0.004)
UK-CAB August 2003
Carr et al Abstract 16
Reduced BMD in women
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Dexa in 84 HIV+ vs 63 HIVOesteopenia in 54% vs 30% (p=0.004)
Osteoporosis in 10% vs 5% (p=0.27)
BMD correlated with body mass and total
fat (p<0.001)
• Markers of bone metabolism showed
increased resorbtion
• Monitoring important for HIV+ women
UK-CAB August 2003
Grinspoon et al Abstract 24
Severe efavirenz side effects
• Small study - 6/200 pts from Kings referred to
specialist unit
• Included suicide ideation and severe depression,
homicide ideation in one case, suicide attempted
in two cases
• Symptoms resolved when EFV stopped
• 2/6 with no previous psychiatric history
• As first line UK therapy, awareness of 2-3% risk is
important for this small group of people
UK-CAB August 2003
Allin et al Abstract 129
Further Reading
Reports by Mark Mascolini:
(Each approx 30 pages)
• XII Resistance Workshop, Mexico
http://www.ias.se/pdf/625.pdf
• 2nd IAS Meeting
http://www.ias.se/pdf/632.pdf
UK-CAB August 2003
Most important IAS study…?
SIMBA Trial (Stopping Infection from Mother-to-child
via Breastfeeding in Africa)
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HIV-infected pregnant women received zidovudine (ZDV) +didanosine
(ddI) from the 36th week of gestation until 1 week after delivery
397 infants were randomized to receive once-daily lamivudine (3TC) or
nevirapine (NVP) until 1 month after breastfeeding was stopped;
breast milk was the only source of nutrition to the infant
Overall, there were 30 cases of HIV infection (7.6% transmission); 24
cases resulted from intrauterine transmission; 3 cases were probably
due to transmission during delivery
Of the remaining 370 infants at risk of becoming infected, only 3
(0.8%) became HIV-positive
3TC and NVP were effective (Gd 3/4 toxicty apprx 15% & 20% resp.)
Potential to protect 250,000+ infants from HIV each year
UK-CAB August 2003
IAS. Abstract LB7.
UK-CAB.6
• 8th August 2003
• Training sessions:
Conference Feedback Sessions
• Afternoon:
GSK
UK-CAB August 2003