1. HIV AND HIV MUTANTS E. Chigidi and E. Lungu University of Botswana Private Bag 0022 Gaborone, Botswana

2. 1. HAART has transformed HIV infection into a chronic manageable disease. 2. However, Although many regimens lower plasma viral load to below the limit of detection in most patients, maintaining a durable response remains challenging because of (I) Adverse effects (II) Long term toxicity (III) Drug resistance

3. 4. Adverse effects + Metabolic toxicity associated with Protease Inhibitor use have resulted in increasing use of regimens containing NNRTIs 5. Even NRTIs have also been associated with long term toxicity 6. Mutations of virus can occur before anti- HIV therapy is started

4. 7. Mutations can occur in two ways (a) Natural selection (b) Transmission of drug-resistant virus 8.Natural selection (a) HIV makes mistakes during copying and produces variants (b) Some variants have mutations that allow the virus to partly or even full resist an anti-HIV drug

5. 9. Many HIV-positive people now take anti-HIV drugs. 10. Some have already developed resistance to one or more of these drugs 11. If they have unprotected sex with another individual they can pass on this strain. 12. The individual infected with this strain might have a problem controlling their viral load.

6. Is there evidence of HIV mutations 13. A study of 23 patients in Botswana on Either (a) DDI + 3TC + Nevirapine NRTI +NRTI + Nevirapine Or D4T + 3TC + Nevirapine NRTI +NRTI + Nevirapine 14. Of 15 patients who discontinued treatment Seven patients were found to possess the mutant virus K65R

7. 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

8. The mutant virus K65R was not detected in both groups However, exposure to NNRTI efavirenz resulted in the development of mutation K103N in 21 out of 35 patients Other mutations were detected such as K101E, K103E, V108I/M V179D, Y188H, G190A/S/E, P225H, M230L

9. In western countries where choice for anti-HIV drugs is greater and financial constraints are not so acute, the rate of evolution of drug resistant strains has, to a large extent, been matched by the rate of development of new drugs. Sub-Sahara Africa is affected by several barriers namely, financial, organizational, physical and social. Drug resistant strains will cause high levels of transmitted HIV resistance and possibly lead to a reduction in the effectiveness of control efforts.

10. We investigate the following scenario: Drug- resistant strains are less well transmitted than the wild-type strain. However, the drug resistant strain will evolve and its transmission characteristics will improve. Can this compound the current epidemic? How soon? We formulate a mathematical model in which we vary the probability of transmission and the proportions and the rate at which individuals start treatment in order to predict the spread of the disease.

11. Model diagram: Model without treatment

12. Model equations

13. Model diagram: Model with treatment

14. Model equations incorporating treatment

15. Endemic equilibrium point

20. Model without treatment (left) and with treatment (right) for a constant population model

22. Model without treatment (left) and with treatment (right) for a varying population model

24. Model without treatment (left) and with treatment (right) for a constant population model

25. Model without treatment (left) and with treatment (right) for a varying population model