Clinical management is intended to decrease viral load, increase CD4 cell count, provide prophylaxis against OIs as appropriate, treat OIs when present, and decrease morbidity and mortality. New knowledge about the life cycle of HIV and the advent of different classes of antiretroviral medications have altered the state-of-the-art of treatment, which now requires combination antiretroviral therapies and the prophylaxis of OIs according to guidelines based on the prevalence of each OI at various stages of immunodeficiency. Except in cases of HIV primary infection, pregnancy in an HIV-infected woman, or symptomatic HIV disease, antiretroviral therapy in asymptomatic patients known to be HIV positive is usually initiated when the CD4 cell count is between 200 and 350.

Part of instituting antiretroviral therapy involves ensuring that patients recognize their HIV infection, have access to health care, develop ongoing provider relationships, and are motivated to adhere to complicated treatments, even during an asymptomatic phase of infection. Taking a combination of at least three antiretroviral medications is currently the best way to accomplish this objective.

If a patient is not ready to adhere to antiretroviral therapy (e.g., because of chaotic life due to psychiatric instability, substance use, and/or homelessness; lack of motivation; or insufficient social supports), it is important to first address barriers to adherence. Evidence demonstrates that 95% adherence is necessary to suppress fully the replication of virus that is sensitive to the regimen being administered. Even though 80%­95% adherence decreases morbidity and mortality, long-term implications are unclear (e.g., resistant strains, neuropsychiatric sequelae). Mental health professionals often have important roles in promoting adherence.

Antiretroviral therapies are classified according to the specific step inhibited in the HIV life cycle within the CD4 lymphocyte. Individually, these agents are not very potent in inhibiting viral replication, but combining classes enables different replication steps to be “attacked,” enhancing the possibility of interrupting viral reproduction.

The four major classes of therapies currently available are
1) nucleoside reverse transcriptase inhibitors (NRTIs), which act by incorporating themselves into the DNA of the virus through the reverse transcriptase enzyme, resulting in DNA that is incomplete and incapable of creating new virus (didanosine, lamivudine, stavudine, zalcitabine, zidovudine [AZT], abacavir);
2) nonnucleoside reverse transcriptase inhibitors (NNRTIs), which stop HIV production by binding directly to reverse transcriptase and preventing the conversion of viral RNA to DNA (delavirdine, efavirenz, nevirapine);
3) nucleotide reverse transcriptase inhibitors, which have a mechanism of action similar to that of NRTIs (tenofovir); and
4) protease inhibitors (PIs), which affect the last stage of viral reproduction by inhibiting the viral protease enzyme from cleaving the viral protein chains into smaller infectious virions (amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir).

The PIs are often potent inhibitors of one or more cytochrome P450 enzymes, which may have implications for interactions with psychiatric and other medications. A new category of antiretrovirals, called fusion inhibitors, is being developed and acts by inhibiting HIV from binding to CD4 cells.

Milton L. Wainberg, M.D.
Francine Cournos, M.D.
Karen McKinnon, M.A.
Alan Berkman, M.D.

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