Recommended regimens

Since publication of the APA practice guideline in 2000, changes have occurred in the U.S. Department of Health and Human Services (DHHS) guidelines on antiretroviral therapy for the management of HIV infection (available online at http://aidsinfo.nih.gov). According to the DHHS guidelines, as of October 2005 there were 21 approved antiretroviral agents, belonging to four classes (6). A new class of antiretroviral medications, the fusion/entry inhibitors, is engineered to work by preventing the virus from fusing with a cell membrane and entering the cell, thus preventing infection of cells. Antiretroviral agents are prescribed in combination regimens that are also known as combination antiretroviral therapy (CART) (previously termed highly active antiretroviral therapy [HAART]) (6). The timing of CART initiation has been debated and may depend on assessment of viral load, CD4 count, and history of associated symptoms. There has been consensus to recommend the following as first-line regimens: 1) efavirenz + (lamivudine or emtricitabine) + (zidovudine or tenofovir) or 2) lopinavir + (lamivudine or emtricitabine) + zidovudine.

Notably, three nonnucleoside reverse transcriptase inhibitors (NNRTIs) (namely, delavirdine, efavirenz, and nevirapine) are currently marketed for use. The NNRTI-based regimens are commonly prescribed as initial therapy for treatment-naive patients. These regimens have the advantage of lower pill burden compared with most protease inhibitor–based regimens. Use of NNRTI-based regimens as initial therapy spares the protease inhibitors for later use, reducing or delaying patient exposure to some of the treatment-limiting adverse effects more commonly associated with the protease inhibitors. The major disadvantage of these regimens is their low genetic barrier for resistance. Only a single mutation need exist to confer resistance to these agents. Moreover, resistance often develops across the entire class. As a result, patients who do not respond to this initial regimen may lose the utility of other NNRTIs and/or may transmit NNRTI-resistant virus to others. Efavirenz is recommended, on the basis of safety data, as the preferred NNRTI in initial therapy. Exceptions are pregnant women (especially during the first trimester), women who are planning to conceive, and women who are not using effective and consistent contraception. For such patients, nevirapine is recommended as the alternative to efavirenz. Delavirdine has the least potent antiviral activity in this class and is not recommended for initial treatment.

Because of the association of the protease inhibitor class of antiretrovirals with the development of metabolic syndrome (see "Metabolic Syndrome and Lipodystrophy" below), regimens are structured to reserve this class of antiretrovirals for future use in case of treatment failure.

Many new medications to manage HIV infection are in development.



In patients receiving antiretroviral treatment, lack of almost perfect adherence to daily regimens continues to be the greatest barrier to sustaining a clinically effective response. Within the community, lack of adherence can also lead to the development of HIV strains resistant to the available antiretrovirals. The prevalence of HIV isolates that demonstrate resistance to antiretroviral agents is increasing, and such isolates can develop despite stable low-level viremia (7). Resistance testing, genotypic or phenotypic, is indicated when patients experience virologic failure (failure to achieve or maintain virologic suppression below 400 HIV RNA copies/mL plasma at 24 weeks or 50 copies/mL plasma at 48 weeks or >400 copies/mL plasma after viral suppression [6, 8]).

Directly observed therapy (DOT), originally used to improve cure rates of tuberculosis in hard-to-reach populations, has been adapted for individuals receiving treatment for HIV to decrease long-term morbidity and mortality. In treatment-experienced HIV-infected substance-using patients, DOT has been successfully used to promote adherence. A study of 69 HIV-infected individuals enrolled in a community-based modified DOT program showed a median decrease of 2.7 log in HIV viral load (9). DOT also provides a way to offer psychosocial support as well as connections to addiction, psychiatric, and social services (10).

Adherence to antiretroviral therapy improves in depressed patients treated with antidepressants. Untreated depression has been associated with medication nonadherence (11).


Drug-drug interactions between new antiretroviral agents and psychotropic medications

Interactions between psychotropic and antiretroviral medications are common in the HIV-infected patient. Drug-drug interactions are too numerous to be listed here in full. Most medications used in the treatment of psychiatric disorders are metabolized by the cytochrome P450 (CYP) enzymes, especially the subgroups 3A4 and 2D6. Of the antiretrovirals, the protease inhibitors tend to pose the greatest risk for changes in drug levels that are significant in the HIV patient. Ritonavir is the most potent of the protease inhibitors, with the greatest impact on the inhibition of 3A4 and to a lesser extent 2D6. Enfuvirtide, the fusion inhibitor, is not an inhibitor of CYP enzymes and does not alter the metabolism of CYP 3A4, CYP 2D6, CYP 2C19, or CYP 2E1 substrates. Thus, it has no significant impact on blood levels of psychiatric medications or other antiretrovirals (12).

Efavirenz has been shown in vivo to induce CYP 3A4 (12). Other compounds that are substrates of CYP 3A4 may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isoenzymes in the range of observed efavirenz plasma concentrations (13). Coadministration of efavirenz with drugs primarily metabolized by these isoenzymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs that induce CYP 3A4 activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations (http://www.rxlist.com/cgi/generic/efaviren_ad.htm).

Antiretrovirals that inhibit or induce the CYP enzymes may increase or decrease methadone levels, leading to acute withdrawal symptoms or excessive dosing in otherwise stabilized methadone maintenance patients, which may lead to unfounded assumptions about opioid relapse (14–16).

It is important for psychiatrists to remain in contact with other medical providers, maintain updated lists of all medications and substances of abuse, and frequently consult updated web-based information sites regarding potential drug-drug interactions (17). Web sites (Table 1) provide the most up-to-date information about specific drug-drug interactions.


Central nervous system (CNS) side effects

Efavirenz has been reported to produce side effects including sleep disturbances and a transient neurovestibular symptom complex (18–20). Such side effects are common but generally short-term.

One randomized, controlled study of 100 patients supported the addition of efavirenz rather than a second drug from other classes of antiretrovirals for improved quality of life, despite a greater incidence of side effects; the study authors recommended, however, that patients with prior histories of emotional disturbances be monitored carefully over the long term (21). A cross-sectional study of 828 patients determined that factors independently associated with discontinuation of efavirenz were female gender, unemployment, a steady sexual partner, and multiple episodes of depression (22). Another cross-sectional study of 60 patients on regimens that included efavirenz and 60 patients on regimens that included a protease inhibitor found that mild and clinically tolerable neuropsychiatric disorders could persist after 2 years in patients receiving efavirenz; quality of life and psychological status remained good in both study groups (23).

In a study conducted by the AIDS Clinical Trials Group (24), efavirenz was associated not only with having vivid dreams but also with being off balance, having the sensation of falling over, feeling that the room is spinning, being unsteady in walking, feeling lightheaded, and being drowsy. Neuropsychological performance improved with initiation of therapy in an efavirenz-treated group compared with an NRTI-treated control group. Nevertheless, small negative significant correlations between efavirenz levels and neuropsychological performance persisted over time (24). Efavirenz causes subjective symptoms during the first week of treatment that are most consistently described as a vestibular disorder. Overall, sleep quality was not impaired by efavirenz and was improved at week 4 compared with the control group. Transient increases in vivid dreams associated with efavirenz use resolved by week 4 of therapy. No differences in changes of depressed mood or anxiety were detected. Overall, efavirenz-associated toxicities resolved without treatment by week 4 (24).


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