Pharmacological interactions can reduce the efficacy of ART and/or increase ART-related toxicities. Major ARV drug interactions are summarized in Table 4.14 and described in more detail in Annex 13. Providers should be aware of all drugs that people are taking when ART is initiated, including alternative medicine products such as herbal remedies and dietary supplements as well as new drugs that are added during treatment maintenance.
WHO Treatment of tuberculosis guidelines include key considerations for managing concomitant TB and HIV therapy (452). A key contraindicated drug combination is rifampicin with PIs. When people with HIV-related TB are receiving a boosted PI, rifampicin may need to be substituted with rifabutin. If rifabutin is not available, LPV/r can be used for the duration of TB treatment by doubling the standard dose of LPV/r or increasing the boosting dose of RTV (see section 4.8.1 “Second-line ART for adults and adolescents”). For children, using a triple NRTI regimen (such as AZT + 3TC + ABC) should also be considered. For patients who are coinfected with HIV and extensively drug-resistant or multidrug-resistant (XDR/MDR) TB, there is limited information on the drug interactions of ARV drugs with new drugs such as bedaquiline and delamanid. As bedaquiline is primarily metabolized by CYP3A4, concomitant use with EFV and PIs can interfere with drug concentrations and should be undertaken with extreme caution and close clinical monitoring; alternative ARV options should be considered (453). Rifampicin is known to significantly lower plasma concentrations of DTG, and increasing the dose to a twice-daily schedule may be necessary, but there are very few studies and limited clinical experience with this combination, particularly in individuals living with HIV and active TB (see section 4.4.1 “First-line ART for adults”).
Drugs for hepatitis C
Potential drug interactions should be considered when using ARV drugs and DAAs for HCV infection. Simeprevir and the combination of ombitasvir + paritaprevir + ritionavir plus dasabuvir should not be co-administered with any PI or NNRTI. Daclatasvir is associated with significant drug interactions with many NNRTIs and PIs, and its concomitant use requires caution, dose adjustments or consideration of alternative DAAs. Ledipasvir and sofosbuvir have shown reduced potential for drug interactions with ARV drugs due to their use of different metabolic pathways (454,455). Although access to DAAs is still limited in many settings, ribavirin and pegylated interferon alpha-2a are being less frequently used to treat HCV infection. Administration of both agents with AZT has been associated with an increased risk of anaemia and hepatic decompensation. People coinfected with HCV and HIV who are using AZT may need to be switched to TDF. A complete list of drug–drug interactions is available at www.hep-druginteractions.org.
Itraconazole and ketoconazole are often used to treat fungal infections. Studies have shown that NVP may decrease the concentrations of these antifungal agents to subtherapeutic levels. Alternative antifungal agents (such as flucytosine and fluconazole) could be used to ensure adequate treatment of fungal infections among people with HIV.
WHO recommends artemisinin-based combination therapies for treating uncomplicated Plasmodium falciparum malaria (456). One such recommended artemisinin-based combination therapy is artesunate and amodiaquine. EFV increases the concentrations of amodiaquine and has been associated with significant increase in liver transaminases. Halofantrine and lumefantrine should not be used with PIs. Alternative artemisinin-based combination therapies (such as artestunate plus mefloquine or artesunate plus sulfadoxine-pyrimethamine) could be used to prevent severe toxicity in people with HIV.
Opioid substitution therapy
WHO recommends methadone and buprenorphine for treating opioid dependence (457). Co-administering EFV decreases methadone concentrations. This could subsequently cause withdrawal symptoms and increase the risk of relapse to opioid use. People taking methadone and NNRTIs should be monitored closely, and those experiencing opioid withdrawal may need to adjust their methadone dose.
ARV drugs have the potential to either decrease or increase the levels of steroid hormones in hormonal contraceptives (458). There may be drug interactions between some NNRTIs and RTV-boosted PIs with hormonal contraceptives, which can reduce the effectiveness of both the hormonal contraceptive and the ARV drug. There are generally fewer concerns regarding interactions of hormonal contraceptives with NRTIs and newer NNRTIs (see Annex 13). The contraceptive efficacy of injectable formulations of either intramuscular or subcutaneous depot medroxyprogesterone acetate (DMPA) is unaffected by ARV drugs and can be used without restriction (459). There is a potential for reduced efficacy of longacting progestogen-only implants when a women is also on ART containing EFV. If women receiving ART decide to initiate or continue using hormonal contraceptives, consistently using condoms and other contraceptive methods is recommended both to prevent HIV transmission and unintended pregnancy. WHO recommendations released in 2014 on the use of hormonal contraception by women receiving ART are available at www.who.int/ reproductivehealth/publications/family_planning/MEC-5/en.
Concomitant use of boosted PIs and NNRTIs with some antihistamine agents (such as astemizole and terfenadine) has been associated with severe and life-threatening reactions, such as cardiac arrhythmia. Alternative antihistamine agents include loratidine and cetirizine.
WHO recommends statins for people with a 10-year cardiovascular risk exceeding 30% (460). Boosted PIs may lead to increased concentrations of lovastatin and simvastatin,which may increase the risk of serious adverse events such as myopathy, including rhabdomyolysis. Alternative cholesterol-lowering agents should be used to prevent severe toxicity in people with HIV.
DTG should not be simultaneously administered with cation-containing antacids, laxatives and multivitamin or mineral supplements because of the risk of chelation. If combined, DTG should be administered two hours before or six hours after taking medications containing polyvalent cations (445).