Conference Feedback

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Conference Feedback

• For 6th UK-CAB
• 8th August 2003
• Simon Collins
• HIV i-Base

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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.p
  df
• Require Adobe Acrobat Reader (free software) from
  http//www.adobe.com
• Or follow link from i-Base home page
  http//www.i-Base.info

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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 isnt so good
• Every scientist presents a paper and every
  paper is very interesting
• The next studies were all new, and relevant to
  clinical care

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Clinical Studies

• 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

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Primary Resistance (CATCH)

• 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 lt .001)

Mexico, Abstract 17
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UK transmission

• Data from UK HIV Drug Resistance Database
  (community initiated collaboration)
• 9,800 tests from 7000 patients. Collected 1996 -
  Mar 03
• yr PI NNRTI Key mutations in naive
• 96-98 26 20 10
• 99-01 32 40 16
• 01-03 27 48 17
• BHIVA
• Resistance test before treatment
• Resistance test on diagnosis

Pillay et al Abstract 124
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Implications of transmitted Rx

• Doesnt 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)

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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 doesnt 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

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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)

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Phylogenetic tree (RTI)

• Example of
• Phylogentic tree
• For RTI sequence

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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

Mexico, Abstract 78, 79
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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)

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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

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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 AZT-based (but IAS Abs
  42 - TZVTDF included AZT with K65R)

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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)

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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

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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 gt AZT use gt HIV naïve gt HIV-negative

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Morphology of adiposetissue

• 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).
• Normal adipose tissue histology.
• Typical histology associated with
• subcutaneous fat wasting.
• Line arrows indicate blood vessels.
• Block arrow indicates a lipogranuloma.

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Lipoatrophic tissue
Lipo workshop Summary, J Cappeau, IAS, Paris
20
Comparison of adipocyte mtDNA copy number
HIV-neg, HIV negative HIVART-, HIV positive,
antiretroviral therapy naive ZDV, zidovudine
d4T, stavudine. Nolan, Mallal et al AIDS
2003 17(9)1329-1338
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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)

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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 (p0.024) and
  shorter use of d4T on-study (p0.004)

Carr et al Abstract 16
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Reduced BMD in women

• Dexa in 84 HIV vs 63 HIV-
• Oesteopenia in 54 vs 30 (p0.004)
• Osteoporosis in 10 vs 5 (p0.27)
• BMD correlated with body mass and total fat
  (plt0.001)
• Markers of bone metabolism showed increased
  resorbtion
• Monitoring important for HIV women

Grinspoon et al Abstract 24
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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

Allin et al Abstract 129
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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

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Most important IAS study?

• SIMBA Trial (Stopping Infection from
  Mother-to-child via Breastfeeding in Africa)
• 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

IAS. Abstract LB7.
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UK-CAB.6

• 8th August 2003
• Training sessions
• Conference Feedback Sessions
• Afternoon
• GSK