1. The emergence of HIV resistance to HAART in a Barbadian cohort; Implications for the treatment programme.
N. Adomakoh, S Branch , S Critchlow, T Roach, D Babb, A Best.
 Ladymeade Reference Unit,
Ministry of Health, Barbados

2. Trends in Leading Causes of Death Among Persons 25-44 Years Old: USA, 1982-1998

4. Statistical Update

5. M98-863 established the superiority of boosted PI regimens
Intent To Treat
100 80 60 40 20 † † † † *
Lopinavir/r 400/100 mg bid, n = 326
75%
63%
Nelfinavir 750 mg tid, n = 327
HIV RNA <400 copies/ml (%)
Abbott M was a randomized placebo-controlled trial that compared lopinavir/ritonavir
SGC with nelfinavir both on a backbone of stavudine and lamivudine in 653 antiretroviralnaive
patients. Lopinavir/ritonavir was found to be superior to nelfinavir (the previous
standard-of-care PI) in maintaining HIV-1 RNA < 400 copies/mL through Week 48 (75% vs
63% by intent-to-treat (ITT) analysis, respectively, [P < .001] with persistent virologic
response at Week 48).[3] Overall adverse event rates and study discontinuation rates because
of adverse events were similar between the 2 groups. Lopinavir/ritonavir was also found to be
superior to nelfinavir in protecting future treatment options: no evidence of genotypic or
phenotypic resistance to PIs was detected in any of the 51 lopinavir/ritonavir-treated patients
with HIV-1 RNA > 400 copies/mL at up to 48 weeks’ follow-up. By contrast, D30N and/or
L90M mutations were detected in 45% of the nelfinavir-treated patients with viral loads > 400
copies/mL.[4]
Between-group comparisons:
* p < 0.05
† p < 0.001
Week
Walmsley et al. N Engl J Med 2002;346:

6. Clinical outcomes
At the time of the study patients were registered on the database
M:F = 1.1:1, median age of 40years.
610 persons were on HAART supported by an intensive adherence programme.
virologic success (VL <400 copies / ml at last test) observed in 535 patients ( 87%) over an average duration of therapy of 31 months.

7. Treatment Effects on CD4 and
Viral Load
Telenti, et al. In: Program and abstracts from the 2nd International Workshop on HIV Drug Resistance and Treatment Strategies ; Fleury, et al.; Kaufmann, et al.; Fessel, et al. All from: 12th World AIDS Conference ; Geneva, Switzerland.

9. How does HIV Develop Resistance to Antiretrovirals?
HIV Reverse Transcriptase is a low fidelity enzyme, i.e. transcription mistakes are common
Mistakes lead to mutant strains of HIV, a/k/a quasispecies
Most mutations generate incompetent strains of HIV, but certain mutations confer resistance to currently available antiretroviral drugs
Administration of antiretrovirals in an insufficiently potent manner exerts reproductive pressure that selects for resistance-bearing strains

10. Resistance Accumulation
Time after failure
Number of mutations
Response to second regimen

11. How Drug Resistance Arises
I like this graphic because it illustrates the population dynamics of drug-resistant strains of HIV within an individual on therapy. The slide starts with the depiction of several different strains, or quasispecies, of HIV, here, which accurately reflects the wide diversity of HIV within an HIV-infected person. In this model of drug monotherapy, we see how the drug, here, effectively blocks the replication of most of the HIV quasispecies, but not this bottom one, here. Over time, this strain of HIV, which was initially a minority strain, proliferates and becomes the dominant strain.
How drug resistance arises. Richman, DD. Scientific American , July 1998

12. The emergence of HIV resistance to HAART in a Barbadian cohort; Implications for the treatment programme.
N. Adomakoh, S Branch , S Critchlow, T Roach, D Babb, A Best.
 Ladymeade Reference Unit,
Ministry of Health, Barbados

13. Results for genotypic resistance testing
Available for 45patients (29 males, 16 females)
42/ 45 were exposed to non-nucleoside reverse transcriptase inhibitors (NNRTIs) (32 initiating therapy with an NNRTI based regimen).
38/45 clients had been on 2 or more regimens at the time of testing. The median time from commencement of HAART to a positive resistance test was 26 months (n = 41).
No. of regimens 1 2 3 4
No. of clients 6 17 19

14. Results
Resistance testing revealed ; NNRTI resistant strains in 36 of the 45 clients; Protease inhibitor (PI) resistance in 8 of 45 clients, of which 2 cases involved cross PI class resistance.

20. Cost effectiveness of Viral resistance testing; Cost of AZT/3TC/NFV vs ABC/d4T/Lop/r

21. Programme Implications
Rx outcomes
Cost
Sustainability

23. Cost of regimens
KALETRA+COMBIVIR-$ $137.62=$ (LPV/R+AZT+3TC)
STOCRIN+DUOVIR-$ =$ (EFV+AZT+3TC)
VIRAMUNE+DUOVIR-$ =$ (NVP+AZT+3TC)
CRIXIVAN+COMBIVIR-$ =$ (IDV+AZT+3TC)

24. Approved Antiretrovirals
Between ’87 and ’95, 4 antiretrovials were launched.
Since ’95, 19 new products have been introduced.
Combivir
Epivir
Viread
Rescriptor
Hivid
Ziagen
Emtriva
Viramune
Sustiva
Zerit
Trizivir
Retrovir
Videx
’87
’88
’89
’90
’91
’92
’93
’94
’95
’96
’97
’98
’99
‘00
’01
‘02
‘03
‘04
RTI
Up until 1995, there were only 4 drugs approved for the treatment of HIV infection. Since that time, 12 new drugs have entered the marke, with introductions of new classes of agents that interfere with different viral targets.
Today,combination therapy that uses several drugs with complementary mechanisms of action have produced the most effective means of controlling HIV replication, thereby slowing disease progression.
Invirase
Viracept
Kaletra
Reyataz
NNRTI
Fortovase
Agenerase
Fuzeon PI
Norvir
Lexiva
Crixivan

25. Time Trends in Primary HIV-1 Genotypic Drug Resistance Among Recently Infected Persons
% of resistant isolates
JAMA Jul 10;288(2):181-8.

26. Prevalence of drug resistance in treatment-naive patients
France5 12%
UK7 9%
Canada2 10%
US (33 States)4
13%
Germany1 11%
Switzerland3 8%
Mexico9 ~4%
Brazil6 7%
Australia8 (Victoria) 13%
Botswana10 (estimated)
< 5%
National Canadian cohort treatment-naïve, newly diagnosed: 10%
Rates cannot be cross-compared. Duration of infection prior to resistance testing varies by study. Definition of resistance may vary by study
1. Oette M, et al. J Acquir Immune Defic Syndr 2006; 41:573–581.
2. Brooks JI, et al. Antivir Ther 2006; 11 (suppl 1):S119 (abstract 106)
3. Yerly S, et al. Antivir Ther 2006; 11 (suppl 1):S118 (abstract 105)
4. Ross LL, et al. Antivir Ther 2006; 11 (suppl 1):S120 (abstract 107)
5. Chaiz ML, et al. Antivir Ther 2006; 11 (suppl 1):S123 (abstract 110)
6. Brindeiro RM, et al. AIDS 2003; 17:1063–1069
7. Health Protection Agency. CDR Weekly 2006; 16
8. Middleton T, et al. Antivir Ther 2004; 9:S110
9. Escoto-Delqadillo M, et al. XV International AIDS Conference 2004; abst B11496
10. Vardavas R & Blower S. Antivir Ther 2005; 10 (suppl 1):S154 (abstract 141)

27. Resistance Variables Universal access to ARVs
CSME – wider movement of caribbean nationals within the region
Time
Prevention interventions

28. Viral Resistance Laboratory