1. Anthony D Harries Ministry of Health, Malawi
Cotrimoxazole and INH preventive therapies in the era of ART: are they necessary?
Anthony D Harries
Ministry of Health, Malawi

2. I DO NOT KNOW!

3. Cotrimoxazole

4. COTRIMOXAZOLE (CTX) PROPHYLAXIS
Useful against:-
Pneumocystis jiroveci (carinii) pneumonia
Toxoplasma encephalitis
Isospora belli diarrhoea
Some bacteria and enterobacteria
Nocardiosis
Falciparum malaria

5. CTX prophylaxis in HIV+ve persons in industrialised countries
Patients with CD4 counts < 200/mm3 to prevent PCP and other opportunistic infections
Patients who have had an episode of PCP or toxoplasma encephalitis
Children born to HIV-positive mothers

6. UNAIDS Recommendations for CTX prophylaxis in Africa
HIV positive adults with:-
WHO Stage II, III or IV disease
CD4 counts of 500/mm3 or less
HIV-exposed infants from six weeks of age (particularly any child born to an HIV-infected woman)

7. Advantages of CTX use Widely available, even in rural Africa
Easy to take
Relatively safe
Does not require laboratory monitoring
Effective during 2 year follow-up periods
Cheap [costs 6 – 12 USD per year]

8. CTX Prophylaxis Industrialised Countries Widely used
Main use to prevent PCP in adults with CD4 count < 200/mm3 and children born to HIV+ve mothers
Can be discontinued in those on ART if CD4 count rises to > 200/mm3
Sub-Saharan Africa
Infrequently used
Main effect is to prevent diarrhoea and malaria in adults and PCP in children
Reduces mortality, particularly in those with WHO Stage III and IV and patients with TB

9. CTX use in HIV-positive adults in Africa: before starting on HAART
Indications for CTX:
WHO Stage II disease
CD4 count > 350/mm3
TB patients on RH-regimens with R-NVP interactions
Eligible patients waiting to start ART
Comment:
Maybe less effective
May not be needed if NVP is replaced by EFV in ART regimen
Relieves anxiety and may prevent OIs

10. CTX use in HIV-positive adults in Africa: for patients on HAART
Advantages
Takes time for CD4 counts to rise, and may protect against infections in this interim period
May prevent malaria and diarrhoea even in those with good CD4 counts
Disadvantages
Adds to the number of pills and may compromise good adherence
Increases the risk of drug-induced toxicity
Increases expense
May increase risk of resistance to anti-malarial drugs (S-P)

11. CTX use in children born to HIV-positive mothers in Africa
Advantages:
From 6 weeks (up to when HIV infection can be ruled out) may prevent PCP
Difficult to diagnose HIV in infants
Difficult to determine if HIV-infected children are eligible for ART (need to measure CD4%)
Difficult to administer ART to infants
Question marks:
Duration of prophylaxis in children?
Will over-treat a considerable number of children, particularly if PMTCT programmes are operating well

12. The main question: “Is CTX necessary in patients taking ART in Africa
WE DO NOT KNOW
Therefore, the ways forward:-
Randomised controlled trial of CTX versus placebo in HIV-positive patients (TB and non-TB) commenced on HAART
In well run ARV programmes and TB programmes, assess use of CTX in the routine system against standardised outcomes

13. Isoniazid Preventive Therapy

14. Background: Isoniazid
HIV infection is strongest risk factor for reactivation of TB in persons with latent TB
[5 – 15% HIV+ve persons develop TB per year]
Isoniazid reduces risk of TB in HIV-positive persons:
[rate reduction of 0.4 in HIV+ve, PPD not determined]
[rate reduction of 0.6 in HIV +ve, PPD +ve]
Isoniazid reduces the risk of recurrent TB in HIV+ve TB patients who have completed a course of anti-TB treatment

15. Background: ART
ART improves cell mediated immunity and reduces the risk of TB in HIV-positive persons
ART reduces TB risk most in patients with WHO Stage III or IV disease and in those with CD4 counts < 200/mm3
ART may reduce risk of recurrent TB in HIV+ve patients completing TB treatment

16. Use of Isoniazid to prevent TB
Given as dose of 300 mg daily: 6-12 months
Relatively safe
Generally well tolerated
Does not promote INH drug resistance
Effect lasts 1 – 2 years and then risk of TB gradually returns
Need to be able to screen persons for TB before starting INH
INH preventive therapy not widely used in Africa because of difficult logistics

17. Value of Isoniazid
Useful as a measure to prevent TB for HIV-positive individuals, either first time TB or recurrent TB
Not useful as a measure to reduce the burden of TB in high HIV burden communities because:-
- need to have large numbers of people HIV tested
- small % of HIV+ve persons complete the course
- lack of structures to manage INH preventive therapy

18. Use of INH in era of ART: HIV-positive persons in WHO Stage I and II
ART is not indicated in such persons
INH therefore has potential benefit
One possible structure in which to introduce INH is the PMTCT programme
Risk of TB in Stage I and II may not be as high as in later stages, and therefore the cost-benefit of INH may be muted

19. Use of INH in era of ART: HIV-positive persons in Stage III and IV
Logistics and advantages:
ART is indicated in such patients
INH may be more useful to give in Stage III/ IV patients (with no TB)
For those on ART, there should be a regular structure for follow-up of patients and therefore INH adherence may be better
Problems:
May be difficult to exclude TB in these patients, especially stage III disease
INH may add to toxicity of ARV drugs, especially stavudine (d4T)
Extra pills to take and this may compromise adherence

20. Use of INH in era of ART: HIV+ve TB patients who completed TB treatment
ART is indicated in such patients
ART should reduce the risk of TB by increasing cell mediated immunity, although not to the extent of being HIV-negative: (in Cape Town, ART reduced incidence of new TB from 9.7% to 2.4% per annum)
INH may provide additional benefit

21. Research questions on INH
Does PMTCT provide a suitable structure for INH preventive therapy in HIV-positive persons in Stage I or II?
Does the addition of INH to ART further reduce the incidence of new TB and recurrent TB in HIV-positive patients in Stage III and IV?