TAP Program Mozambique MOH World Bank HAART and resistance viral mutations monitoring in Mozambique

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TAP ProgramMozambique MOH World BankHAART
and resistance viral mutations monitoring in
Mozambique
Leonardo Palombi
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(No Transcript)
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Enrolled patients by year in Mozambique Total
15,385
March 2006
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Patients received HAART in Mozambique by
year TOTAL 7,869
March 2006
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Major limitations with an exclusively preventive
approach - MTCT

• High refusal and drop out rates
• Severe limitations caused by the low access rate
  to health centers
• Unsafe breastfeeding
• Increased number of viral resistance mutations
• Not protecting the mothers

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Viral load in breast milk comparison in the
HAART (A) and non-HAART (B) Groups at delivery
and after 1 week
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The new approach Month 1
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The new approach Month 6
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HIV status by parity at 1 month
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Malnourished and anemic children in the breastfed
cohort
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Resistances
42 unselected women that completed the protocol
were assessed for genotypic resistance, in a time
period between 2-6 months after therapy
interruption All carried a subtype C strain
(more prone to resistance to nevirapine respect
to subtype A and B) 37 (88.1) showed no
mutations associated with resistance 5 (11.9)
carried mutations associated with resistance to
nevirapine 3 K103N 2 G190S Resistance to
3TC and AZT-D4T was not detectable
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Children in DREAM

• A major problem

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HIV Children attending the DREAM centerstotal
1,286
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Survival Outcome (150 deaths)
Median Observation Time (MOT) 352 days (IQR
135-689) Dead patients MOT 91 days (IQR
27-196)
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Viral load decrease more than 1.5 log after six
months of HAART or more than 3.0 log after one
year of HAART (698 children)
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Percentage of children with increased Z-score
increased according to lenght of HAART (698
children)
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Percentage of children with increased CD4
according to length of HAART (698 children)
HAART
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Cox proportional hazard risk of death(1,286
children)
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Survival according to pre-HAART Viral Load
Adjusted for HAART, CD4 percentage , Hemoglobin,
age and Z-score
1,0
,9
Cumulative Survival
,8
CV
gt100,000
lt100,000
,7
lt10,000
1000
800
600
400
200
0
Days of observation
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Survival according to age
Adjusted for HAART, CV, CD4 percentage, Hemoglobin
1,0
,9
Age (years)
Cu,ulative survival
,8
gt 10
5 - 9
2 - 5
1 - 2
,7
0 - 1
1000
800
600
400
200
0
Days of observation
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Survival according to pre-HAART CD4 percentage
Adjusted for HAART, Viral Load, age, Z-score ed
hemoglobin
1,0
Cumulative Survival
,9
CD4
gt25
15-25
lt15
,8
1000
800
600
400
200
0
Days of observation
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Survival according to pre-HAART Z - score
Adjusted for HAART, CV, CD4 percentage, Age,
Z-score and hemoglobin
1,0
,9
Cumulative survival
Z- SCORE
gt-2,00
,8
lt-2,00
1000
800
600
400
200
0
Days of observation
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Opportunistic/concomitant infections in patients
with CD4 percentage lower than 15(329 children)
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Children not in HAART (393 children)
Death OR 2.7 0.8-9.1
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Children not in HAART (393 children)
Death OR 3.2 1.4-7.3
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HIV -1 pol GENE DIVERSITY IN MOZAMBIQUE

• This study aimed to assess the following
• Genetic polymorphisms of HIV in Mozambique
• Prevalence of mutations conferring resistance to
  antivirals in pregnant women undergoing antiviral
  therapy because of their disease and/or for the
  prevention of mother-to-child transmission
• Development of mutations conferring resistance
  to antiviral drugs in patients failing antiviral
  therapy
• Viral pol gene diversity was investigated by
  direct sequencing in 177 infected patients

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NAIVE PATIENTS

• Objectives of the study
• Assess whether virus strains circulating in
  Mozambique are naturally resistant to antiviral
  therapy.
• Define clade specificity of viral strains

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NAIVE PATIENTS

• Results
• Sequencing of pol gene from 58 treatment-naive
  HIV-1 infected patients shows that all virus
  strains cluster within clade C, with the
  exception of a single patient carrying a G-
  subtype virus.
• Relevant mutations (per se conferring minimal
  resistance) in Reverse Transcriptase (RT) are
  rare
• 118A/I/L/G (four patients)
• 179E/D/I (three patients)
• 333E/D (two patients)
• 101R and 210F (one patient each)
• Relevant mutations in Protease (PR)
• V82I (six patients) is the only relevant mutation
• 20R, 36I/L, 60E, 63P and 93L are natural
  polymorphisms/secondary mutation

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NAIVE PATIENTS

• Conclusions
• HIV-virus strains circulating in Mozambique
  belong to clade C (the most common in the world)
• Primary mutations affecting the efficacy of
  antiviral drugs are absent in this cohort of
  patients, thus suggesting that (in principle)
  antiviral therapy is effective
• Clinical results confirm the great activity of
  antiviral regimens used so far
• Nevertheless, the presence of a substantial
  number of polymorphisms (typical of subtype C
  virus) suggests the importance of carefully
  monitoring long-term efficacy of antivirals, that
  may somewhat be different than that found in
  Europe and America where subtype B is prevalent.
• Monitoring resistance to antivirals in patients
  failing therapy remains crucial also in Africa

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PREGNANT WOMEN

• Sequencing of pol gene from 42 pregnant women
  HIV-1 infected with combination therapy based on
  two nucleosides and one nonnucleosides, after the
  end of therapy (post-partum) shows
• Relevant mutations in Reverse Transcriptase (RT)
  are rare
• NRTI
• 118I/G (two patients)
• 333E/D (six patients)
• None of them related to therapy (see natural
  polymorphisms in naive patients)
• NNRTI
• K103N (two patients)
• G190A (three patients)
• Potentially related to therapy
• Relevant mutations in Protease (PR)
• V82I (four patients) and L33F (one patient) are
  the only relevant mutations

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PREGNANT WOMEN

• CONCLUSIONS
• - Development of resistance to antiviral drugs is
  limited in pregnant women treated with triple
  therapy, lower than the prevalence reported for
  treatment with nevirapine alone.

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PATIENTS FAILING ANTIRETROVIRAL DRUG THERAPY

• Sequencing of pol gene from 87 HIV-1 infected
  with combination therapy based on
• Two nucleosides one nonnucleoside (NNRTI)
• Two nucleosides or a non-ritonavir boosted
  protease inhibitor (a small minority of patients
  respect to the total)

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Patients distribution by HAART Regimen5,576
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Distribution by HAART line

• First line 4,855 (87,08)
• First line Tox.mod 316 (5,66)
• Second line 405 (7,26)
• 92,74 of the patients is still in first line
  with a median time of more than 2 years

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PATIENTS FAILING ANTIRETROVIRAL DRUG THERAPY

• Relevant mutations in Reverse Transcriptase (RT)
  75
• NRTI
• K65R (4 patients) 3TC,ABC,DDI T69D (1 patient)
  AZT
• M184V (61 patients) 3TC T215F/Y (5 patients) AZT
• K219E (1 patient) AZT,DDI Other TAMs (3
  patients) AZT
• Thymidine associated mutations

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NNRTI 60/87

• K103N (19 patients) NVP V106M (4 patients) NVP
• V108I (6 patients) NVP Y181C (25 patients) NVP
• Y188L/C (3 patients)EFV/NVP G190A/S (23
  patients) NVP

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Protease (PR) 7

• V82I/A (3 patients) L90M (2 patients)
• M46I (2 patients)
• 20R, 36I/L, 60E, 63P/V V77I and 93L are natural
  polymorphisms-secondary mutations (see naive
  patients)

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PATIENTS FAILING ANTIRETROVIRAL DRUG THERAPY

• CONCLUSIONS
• Resistance to antiviral drug is relatively common
  at the time of failure
• Resistance is mainly confined to drugs with low
  genetic barrier (3TC and NNRTI), that do not
  compromise the efficacy of the second therapeutic
  regimen.
• Thimidine associated mutations (TAMS) that confer
  cross resistance to many antiviral drugs are rare
  at the time of failure
• Protease mutations conferring resistance to
  antiviral drugs are also rare, and related to the
  use of protease inhibitors not-boosted with
  ritonavir. Conceivably, the introduction of
  boosted protease inhibitors will increase
  efficacy and further decrease the rate of
  resistance
• Salvage therapies can be foreseen as effective in
  african settings where therapies are properly
  given and followed-up