1. HIV-TB Model: The Botswana experience By E.M. Lungu (UB) M. Kgosimore (BCA) F. Nyabadza (UB) Modeling Disease in Africa Workshop 25 – 27 June 2007, Stellenbosch, S.A.

2. Botswana implemented 100% coverage of DOTS in 1986. Since 1986 all individuals who tested positive were enrolled for the anti-TB program. For new patients: Treatment consists of 2 months of isoniazid [H], rifampicin [R], pyrazinamide [Z], and ethambutol [E] [2HRZE] followed by 4 months of isoniazid and rifampicin [4HR] Re-treatment Patients: The re-treatment regimen is [2HRZES/1HRZE/5HRE] Both treatments for new or recurrent TB are the best standard regimens recommended. Despite this the number of TB cases increased by 120% between 1986 1nd 1989.

3. In the first drug-resistance survey in 1995, of the 44% of patients with tuberculosis, 49% were HIV infected. In 2002, the case detection rate in Botswana was 88%, of which 78% of patients completed treatment and 6% interrupted treatment. In 2002, a third survey was undertaken to determine trends in anti-tuberculosis drug resistance in patients with tuberculosis and to provide a nationwide estimate of HIV infection in such patients.

4. PATIENT DISTRIBUTION 2002 survey PATIENTS 2425 NEW PATIENTS 1990 (82%) RETREAMENT PATIENTS 429 (17.2%) UKNOWN STATUS 6 (0.2%) SMEAR POSITIVE 210 (49%) SMEAR NEGATIVE 219 (51%) HIV POSITIVE 1457(60%)

5. PATIENTS TB STATUS Sample Size 2425 POSITIVE FOR MYCOBACTER IA 1481 (61%) NEGATIVE MYCOBACTERIA 944 (39%) POSITIVE M TUBERCULOSIS 1288 ( 87%) LATENT M TB 193 (13%)

6. Drug resistance results For new patients: 1995 1999 2002 n=430 n=638 n=1182 Any Drug Res16(3.7%) 40(6.3%) 123(10.4%) Isoniazid7(1.6%) 28(4.4%) 53(4.5%) Rifampicin 4(0.9%) 4(0.6%) 24(2.0%) Ethambutol0 1(0.2%) 15(1.3%) Streptomycin 6(1.5%) 14(2.2%) 82(6.9%)

7. Monores 15(3.5%) 34(5.3%) 86(7.3%) Isoniazid6(1.4%) 23(3.6%) 22(1.9%) Rifampicin 3(0.7%) 1(0.2%) 10(0.8%) Ethambutol0 0 2(0.2%) Streptomycin 6(1.5%) 10(1.6%) 52(6.9%) Multidrugres1(0.7%) 3(0.5%) 10(0.8%)

8. Prev treated cases: – 1995-96 1999 2002 n=121 n=145 n=106 Drug Res 18(15%) 33(23%) 24(23%) Isoniazid12(10%) 24(27%) 15(14%) Rifampicin 10(8%) 19(24%) 13(12%) Ethambutol6(5.3%) 4(3%) 9(9%) Streptomycin 10(9%) 7(5%) 17(16%)

9. Monoresistance – Mono Res 9(7.4%) 18(12.4%) 7(6.6%) Isoniazid4(3.3%) 9(6.2%)0 Rifampicin 2(1.7%) 6(4.1%) 0 Ethambutol0 0 2(1.9%) Streptomycin 3(2.5%) 3(2.1%) 5(4.7%) Multidrugres 7(6.1%)13(9.0%)11(10.4%)

10. Significant increases were recorded for resistance to any drug and for resistance to isoniazid, streptomycin, ethambutol, or rifampicin in new patients. The proportion of tuberculosis multidrug resistance in new patients remained low, although results from the three surveys suggest an increasing trend. The reports (1995, 1999, 2002) show a trend of rising resistance to at least one drug in new patients from 3.7% in 1995 to 10.4% in 2002 and an HIV prevalence of 60% in patients with TB.

11. The increasing trend to TB drugs has implications for TB control and HIV treatment. We illustrate this with the following examples:

12. The American report on incidence in Sub-Sahara Africa

13. Poor absorption of both TB and HIV medication may be causing mutations in the HIV virus. The following examples illustrate this point.

14. A study of 23 patients in Botswana on one of the baseline regimen and who met the requirement for a drug resistance test Either (a) DDI + 3TC + Nevirapine NRTI +NRTI + Nevirapine Or (b) D4T + 3TC + Nevirapine NRTI +NRTI + Nevirapine 14. Of 15 patients who discontinued treatment Seven patients were found to possess the mutant virus K65R

15. Study by Gallant et el (2006) comparing two regimens involving 35 patients: Regimen 1. TDF + emtricitabine + efavirenz NRTI + NRTI + NNRTI (12 Patients) Regimen 2. AZT + 3TC + efavirenz NRTI + NRTI + NNRTI (23 Patients) On Regimen 1: 2 developed M184V/I mutations On Regimen 2. 7 developed M184V/I mutations

16. We believe that 100% coverage of DOTS may be contributing to the problem. Careful screening must be implemented before DOTS. We develop a model to evaluate the advantages of screening.

17. MODEL DIAGRAM S I1I1 I2I2 I3I3 I4I4 I5I5 I6I6 A1A1 A2A2

26. Plots of Susceptibles/Infectives over time

27. Phase portraits

28. Plots of New Infections vs Prevalence

29. Tragectories for Infectives and AIDS Populations

30. Discussion and Conclusions