Treatment: HIV Infection (See Also Chap. 226, HPIM-19)

General principles of pt management include counseling, psychosocial support, and screening for infections and other conditions and require comprehensive knowledge of the disease processes associated with HIV infection.

ANTIRETROVIRAL THERAPY (See TABLE 105-2) The cornerstone of medical management of HIV infection is combination antiretroviral therapy, or cART. Suppression of HIV replication is an important component in prolonging life as well as in improving the quality of life of pts with HIV infection. Data from observational studies and randomized controlled trials have demonstrated that cART is of benefit to the pt at any stage of HIV infection and is also associated with a decreased risk of transmitting infection to an uninfected partner. However, several important questions related to the treatment of HIV disease lack definitive answers. Among them are what is the best initial cART regimen, when should a given regimen be changed, and which drugs in a regimen should be changed when a change is made. The drugs that are currently licensed for the treatment of HIV infection are listed in Table 105-2. These drugs fall into four main categories: those that inhibit the viral reverse transcriptase enzyme, those that inhibit the viral protease enzyme, those that inhibit viral entry, and those that inhibit the viral integrase. In addition, more than a dozen combination drugs that combine 2 or more agents have been licensed (Table 105-2A). There are numerous drug-drug interactions that must be taken into consideration when using antiretroviral medications.

Nucleoside/Nucleotide Analogues These agents act by causing premature DNA-chain termination during the reverse transcription of viral RNA to proviral DNA and should be used in combination with other antiretroviral agents. The most common usage is together with another nucleoside/nucleotide analogue and a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor (see below).

Nonnucleoside Reverse Transcriptase Inhibitors These agents interfere with the function of HIV-1 reverse transcriptase by binding to regions outside the active site and causing conformational changes in the enzyme that render it inactive. These agents are very potent; however, when they are used as monotherapy, they result in the rapid emergence of drug-resistant mutants. Five members of this class, nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine are currently available for clinical use. These drugs are licensed for use in combination with other antiretrovirals.

Protease Inhibitors These drugs are potent and selective inhibitors of the HIV-1 protease enzyme and are active in the nanomolar range. Unfortunately, as in the case of the nonnucleoside reverse transcriptase inhibitors, this potency is accompanied by the rapid emergence of resistant isolates when these drugs are used as monotherapy. Thus, the protease inhibitors should be used only in combination with other antiretroviral drugs.

HIV Entry Inhibitors These agents act by interfering with the binding of HIV to its receptor or co-receptor or by interfering with the process of fusion. A variety of small molecules that bind to HIV-1 co-receptors are currently in clinical trials. The first drugs in this class to be licensed are the fusion inhibitor enfuvirtide and the entry inhibitor maraviroc.

HIV Integrase Inhibitors These drugs interfere with the integration of proviral DNA into the host cell genome. The first agent in this class, raltegravir, was approved in 2007 for use in treatment-experienced pts. Two other integrase inhibitors, dolutegravir and elvitegravir, are also licensed.

Choice of Antiretroviral Treatment Strategy The large number of available antiretroviral agents makes the subject of antiretroviral therapy one of the more complicated in the management of HIV-infected pts.

The principles of therapy for HIV infection have been articulated by a panel sponsored by the U.S. Department of Health and Human Services (Table 105-3). Treatment decisions must take into account the fact that one is dealing with a chronic infection and that complete eradication of HIV infection has not been achieved with currently available cART regimens. Thus, therapeutic decisions must take into account the balance between risks and benefits. At present most guidelines recommend cART for anyone with a diagnosis of HIV infection. In addition, one may wish to administer a 4-week course of therapy to uninfected individuals immediately following a high-risk exposure to HIV (see below).

When the decision to initiate therapy is made, the physician must decide which drugs to use in the initial regimen. The options for initial therapy most commonly in use today are (1) two nucleoside/nucleotide analogues (one of which is usually tenofovir or abacavir, and the other of which is usually lamivudine or emtricitabine) combined with an integrase inhibitor; (2) two nucleoside/nucleotide analogues and a protease inhibitor; or (3) two nucleoside/nucleotide analogues and a nonnucleoside reverse transcriptase inhibitor. There are no clear data at present on which to base a distinction between these approaches.

Following the initiation of therapy, one should expect a 1-log (tenfold) reduction in plasma HIV RNA within 1-2 months; eventually a decline in plasma HIV RNA to <50 copies/mL; and a rise in CD4+ T cell count of 100-150/µL during the first year. Failure to achieve and maintain an HIV RNA level <50 copies/mL is an indication to consider a change in therapy. Other reasons for changing therapy are listed in Table 105-4. When changing therapy because of treatment failure, it is important to attempt to provide a regimen with at least two new drugs. In the pt in whom a change is made for reasons of drug toxicity, a simple replacement of one drug is reasonable.

Treatment of Secondary Infections and Neoplasms Specific for each infection and neoplasm (see Chap. 226, in HPIM-19).