The majority of patients presenting for care in resource limited countries have symptomatic HIV infection and so, in addition to antiretroviral agents, they are likely to be taking other medications:
• for the control of HIV/AIDS related symptoms
• for prophylaxis of opportunistic infections
• for treatment of opportunistic infections and tumours
• for treatment of other coincident infections
Successful ART results in amelioration of many HIV/AIDS related symptoms and a decreased likelihood of opportunistic infections. It may even be possible, once immune competence has been restored, to discontinue primary prophylaxis for some of the opportunistic infections. There are nevertheless, numerous possibilities for drug interactions of which clinicians need to be aware. Drug interactions are of clinical importance if they increase the likelihood of drug toxicity or if they decrease the therapeutic effectiveness of an administered drug. The longer the duration of any drug therapy the more significant this becomes. In the context of ART clinically important interactions are likely:
• between the different antiretroviral drugs that are prescribed
• between prescribed drugs and alternative or non-prescription medications,
• between drugs and food (see section 3.2.2)
• with certain “recreational” drugs
A detailed synopsis of all possible drug interactions is beyond the scope of this publication and only a few important examples are cited on the following pages.
There exist several sources of information on potential drug interactions, particularly where access to the Internet is available and these are well worth referring to.*
* Some sources of comprehensive drug interaction information available through the Internet:
American Foundation for AIDS Research (AMFAR) Treatment Directory: http://www.amfar.org
Medscape HIV/AIDS Resources: http://www.medscape.com
3.6.1. ANTIRETROVIRAL DRUGS AND THE TREATMENT OF TUBERCULOSIS
The Rifamycin antibiotics (rifampin & rifabutin) stimulate the activity of the enzyme system in the liver (cytochrome P450) that metabolises Protease Inhibitors (PIs) and Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). This can lead to a reduction in the blood levels of the PIs and the NNRTIs. Conversely, PIs and NNRTIs may also enhance or inhibit this same enzyme system, although to individually different extents, and can lead to altered blood levels of the Rifamycin antibiotics. The potential drug to drug interactions may result in ineffectiveness of the antiretroviral drugs, to innefective treatment of tuberculosis or to an increased risk of drug toxicity.
It is worth noting that:
• Rifabutin, can be used with all PIs (except saquinavir) and with all NNRTIs (except delavirdine), although dosage adjustments are sometimes necessary.
• Isoniazid, which is recommended for the preventive therapy of tuberculosis, is free from any interactive effect with PIs and NNRTIs.
• The Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are not metabolised by the cytochrome P450 enzyme system and are free from interaction with either of the Rifamycin antibiotics.
Tuberculosis is an important public health problem in many resource-limited countries and also a common “opportunistic infection” in HIV infected individuals.
With time, as the use of antiretroviral drugs increases, it is likely that the concurrent treatment of these two infections will become more frequent.
It has been suggested that in resource limited settings, patients with active tuberculosis should not commence ART until chemotherapy for tuberculosis has been completed. While this would greatly simplify treatment regimens and enhance adherence, the effects of this approach on the overall outcomes of treatment have not been fully evaluated and further research is needed.
In general, the treatment of tuberculosis should be in accordance with the recommendations of the National Tuberculosis Programme in each country.1
1Treatment of Tuberculosis: Guidelines for National Programmes. World Health Organisation. 2nd Edition 1997.
Since rifabutin is often not available in resource limited countries, the following are possible options for the treatment of tuberculosis in patients receiving ART, which are drawn from published guidelines.2,3
2Safe and effective use of antiretrovirals. Module 4, Guidance Modules on Antiretroviral Treatments. World Health Organisation. WHO/ASD/98.1
3Updated Guidelines for the Use of Rifabutin or Rifampin for the Treatment and Prevention of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors. MMWR March 10, 2000/49 (9); 185-9
Possible options for ART in patients with active Tuberculosis (TB)
• Defer ART until TB treatment is completed
• Defer ART until ‘the continuation phase’ of treatment for TB and use ethambutol + isoniazid as continuation.
• Treat TB with rifampin containing regimen and use ritonavir + 2 NRTIs*
• Treat TB with rifampin containing regimen and use ritonavir/saquinavir + 2 NRTIs*
• Treat TB with rifampin containing regimen and use efavirenz + 2 NRTIs*
• Treat TB with rifampin containing regimen and use a 2 NRTIs regimen, then change to maximally suppressive ART once TB treatment is completed.
* Clinical experience and pharmacokinetic data on these combinations are still limited.
3.6.2. INTERACTIONS WITH DRUGS COMMONLY USED FOR THE PREVENTION AND TREATMENT OF OIs
Trimethoprim/sulfamethoxazole, ganciclovir and hydroxyurea can potentially cause additive haematologic toxicity when given together with zidovudine. In these situations, careful monitoring of haematologic indices is necessary.
Dapsone, may lead to additive neurotoxicity when used together with stavudine, zalcitabine, and didanosine.
The antifungal agents ketoconazole and fluconazole may inhibit the metabolism of Protease Inhibitors and the resultant increase in the serum levels of PIs, increases the risk of toxicity.