Cotrimoxazole and INH preventive therapies in the era

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

I DO NOT KNOW!

Cotrimoxazole

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

CTX prophylaxis in HIV+ve persons in industrialised countries • Patients with CD 4 counts < 200/mm 3 to prevent PCP and other opportunistic infections • Patients who have had an episode of PCP or toxoplasma encephalitis • Children born to HIV-positive mothers

UNAIDS Recommendations for CTX prophylaxis in Africa • HIV positive adults with: WHO Stage II, III or IV disease CD 4 counts of 500/mm 3 or less • HIV-exposed infants from six weeks of age (particularly any child born to an HIVinfected woman)

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]

CTX Prophylaxis Industrialised Countries • Widely used • Main use to prevent PCP in adults with CD 4 count < 200/mm 3 and children born to HIV+ve mothers • Can be discontinued in those on ART if CD 4 count rises to > 200/mm 3 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

CTX use in HIV-positive adults in Africa: before starting on HAART Indications for CTX: • WHO Stage II disease • CD 4 count > 350/mm 3 • TB patients on RHregimens 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

CTX use in HIV-positive adults in Africa: for patients on HAART Advantages • Takes time for CD 4 counts to rise, and may protect against infections in this interim period • May prevent malaria and diarrhoea even in those with good CD 4 counts Disadvantages • Adds to the number of pills and may compromise good adherence • Increases the risk of druginduced toxicity • Increases expense • May increase risk of resistance to anti-malarial drugs (S-P)

CTX use in children born to HIVpositive 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 CD 4%) • 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

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

Isoniazid Preventive Therapy

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

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 CD 4 counts < 200/mm 3 • ART may reduce risk of recurrent TB in HIV+ve patients completing TB treatment

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

Value of Isoniazid • Useful as a measure to prevent TB for HIVpositive 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

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

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 (d 4 T) • Extra pills to take and this may compromise adherence

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

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?