Page 114 - HIV/AIDS Guidelines

increased risk of HIV transmission, decline of CD4 count, HIV disease progression or death, development of
minor HIV-associated manifestations such as oral thrush, development of serious non-AIDS complications,
development of drug resistance, and the need for chemoprophylaxis against opportunistic infections
depending on the CD4 count. Treatment interruptions often result in rapid reductions in CD4 counts.
Prior to any planned treatment interruption, a number of ARV-specific issues should be taken into
consideration. These include:

• Discontinuation of efavirenz (EFV), etravirine (ETR), or nevirapine (NVP). The optimal interval
between stopping EFV, ETR, or NVP and other ARV drugs is not known. The duration of detectable
levels of EFV or NVP after discontinuation ranges from less than 1 week to more than 3 weeks. 17-18
Simultaneously stopping all drugs in a regimen containing these agents may result in functional
monotherapy with the NNRTIs because NNRTIs have much longer half-lives than other agents. This may
increase the risk of selection of NNRTI-resistant mutations. It is further complicated by evidence that
certain host genetic polymorphisms may result in slower rates of clearance. Such polymorphisms may be
more common among specific ethnic groups, such as African Americans and Hispanics. 18-19 Some experts
recommend stopping the NNRTI but continuing the other ARV drugs for a period of time. The optimal
time sequence for staggered component discontinuation has not been determined. A study in South Africa
demonstrated that giving 4 or 7 days of zidovudine (ZDV) + lamivudine (3TC) after a single dose of
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NVP reduced the risk of postnatal NVP resistance from 60% to 10%–12%. Use of nucleoside reverse
transcriptase inhibitors (NRTIs) with a longer half-life such as tenofovir (TDF) plus emtricitabine (FTC)
has also been shown to decrease NVP resistance after single-dose treatment. The findings may,
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however, differ in patients on chronic NVP treatment. An alternative strategy is to substitute a protease
inhibitor (PI) for the NNRTI and to continue the PI with dual NRTIs for a period of time. In a post-study
analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an
NNRTI- to a PI-based regimen prior to interruption had a lower rate of NNRTI-resistant mutation after
interruption and a greater chance of resuppression of HIV RNA after restarting therapy than those who
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stopped all the drugs simultaneously or stopped the NNRTI before the 2-NRTI. The optimal duration
needed to continue the PI-based regimen after stopping the NNRTI is not known. Given the potential of
prolonged detectable NNRTI concentrations for more than 3 weeks, some suggest that the PI-based
regimen may need to be continued for up to 4 weeks. Further research to determine the best approach to
discontinuing NNRTIs is needed. Clinical data on ETR and treatment interruption is lacking but its long
half-life of approximately 40 hours suggests that stopping ETR needs to be done carefully using the same
suggestions for NVP and EFV for the time being.
• Discontinuation and reintroduction of NVP. Because NVP is an inducer of the drug-metabolizing hepatic
enzymes, administration of full therapeutic doses of NVP without a 2-week, low-dose escalation phase will
result in excess plasma drug levels and potentially increase the risk of toxicity. Therefore, in a patient who
has interrupted treatment with NVP for more than 2 weeks, NVP should be reintroduced with a dose
escalation period of 200 mg once daily for 14 days and then a 200 mg twice-daily regimen (AII).
• Discontinuation of FTC, 3TC, or TDF in patients with hepatitis B virus (HBV) coinfection. Patients
with HBV coinfection (hepatitis B surface antigen [HbsAg] or hepatitis B e antigen [HBeAg] positive)
and receiving one or a combination of these NRTIs may experience an exacerbation of hepatitis upon
drug discontinuation. 23-24 (See Hepatitis B (HBV)/HIV Coinfection.)

References
1. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human
immunodeficiency virus. N Engl J Med. 2003;349(9):837-846.
2. Ruiz L, Ribera E, Bonjoch A, et al. Role of structured treatment interruption before a 5-drug salvage antiretroviral

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-21

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