Strategies for the treatment of human immunodeficiency virus (HIV) infection began changing with the recognition that viral replication occurs during the years preceding the development of clinical disease.^1,2 Between the time of the initial infection and the development of clinical disease, T-lymphocyte CD4⁺ counts progressively decline as immune function becomes impaired. Viral replication is so rapid that the half-life of HIV in plasma is calculated to be less than 48 hours.^3,4 These observations have important implications for antiretroviral treatment strategies. Combination antiretroviral therapy is now used to maintain viral suppression and prevent the emergence of viral resistance to antiretroviral agents. Such a treatment strategy translates into clinical benefit: multiple studies have shown that combination antiretroviral therapy reduces the risk of HIV disease progression and death.^5–8

Viral load, a measure of the plasma HIV RNA concentration, correlates both with changes in the CD4⁺ count and with prognosis.^9,10 HIV clinical trials have traditionally assessed clinical end points (e.g., disease progression, death) and have used changes in the CD4⁺ count as surrogate markers for clinical response. Now, however, clinical trials rely more on a decrease in the viral load as the marker of an effective response to therapy than on clinical end points. These observations also translate into clinical practice: current recommendations for initiating antiretroviral treatment suggest that antiretroviral therapy be considered in any patient with a viral load higher than 5,000 to 20,000 copies per mL, regardless of the CD4⁺ count.^11,12 This comes as an addition to previous recommendations to institute therapy in symptomatic patients and in patients with CD4⁺ counts of less than 500 per mm³ (500 × 10⁶ per L). Effective combination therapy should decrease a patient's viral load by at least 1 log (10-fold) after three to four weeks of treatment. The current therapeutic goal is to decrease viral load as much as possible, ideally to undetectable levels, four to six months after initiation of a new regimen.^11,12

A variety of combinations of antiretroviral agents have been evaluated. The specific combination selected must account for the patient's prior history of antiretroviral use, including current treatment failure or suboptimal therapy, and for the side effects and drug–drug interactions that occur with these agents. In addition, patients may have a preference for one of a number of equivalent regimens based on their own knowledge and beliefs about these medications.

Nucleoside Analog Reverse Transcriptase Inhibitors

Nucleoside analog reverse transcriptase inhibitors were the first group of agents shown to be effective in the treatment of HIV infection. The first of these agents, zidovudine (AZT, ZDV; Retrovir), became available in 1987. Since that time, four additional agents have been licensed for this purpose, as follows: didanosine (ddI; Videx), zalcitabine (ddC; Hivid), stavudine (d4T; Zerit) and lamivudine (3TC; Epivir). The viral target for this class of drugs is HIV reverse transcriptase, an RNA-dependent DNA polymerase. Standard dosing regimens and common side effects of these agents are summarized in Table 1.

Zidovudine monotherapy was shown in initial clinical trials to decrease mortality, increase CD4⁺ counts and lead to fewer opportunistic infections in patients with symptomatic HIV infection¹³ and acquired immunodeficiency syndrome (AIDS).¹⁴ Subsequent investigations revealed that progression to AIDS is slowed by zidovudine monotherapy in asymptomatic patients with CD4⁺ counts of less than 500 per mm³ (500 × 10⁶ per L).¹⁵

Limitations of monotherapy have also been demonstrated, however. Several studies showed that the benefits of zidovudine therapy are only of one to two years' duration,^16,17 and that beginning antiretroviral therapy with one drug early in the course of infection (i.e., when the CD4⁺ count is greater than 500 per mm³ [500 × 10⁶ per L]) does not prolong survival compared with delaying initiation of therapy (i.e., when the CD4⁺ count is less than 500 per mm³ [500 × 10⁶ per L]).^6,18 These observations may apply to single-drug therapy with certain other agents as well: drug-resistant virus can develop in the face of single-drug therapy with other agents, such as didanosine, lamivudine, nevirapine, ritonavir and indinavir.^19–23

Two nucleoside analogs constituted the first combination antiretroviral regimen. Compared with zidovudine monotherapy, combination therapy with zidovudine and zalcitabine,^5,6,24 zidovudine and didanosine,^5,6,25 or zidovudine and lamivudine^26–28 has been shown to be more effective clinically or more effective in producing an increase in the CD4⁺ count or a decrease in the viral load. Although combination therapy that includes a protease inhibitor has recently been found to be more effective than a combination of two nucleoside analogs in reducing the viral load, the principle of combination therapy remains the same: the use of multiple agents may prevent or delay the development of drug resistance. Given the availability of complex antiretroviral regimens, however, medications with different side effects must be combined in a way to avoid additive toxicity.

Nonnucleoside Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors noncompetitively inhibit HIV reverse transcriptase by binding to a site distant from the active site involved in genomic replication. Two nonnucleoside reverse transcriptase inhibitors have been approved by the U.S. Food and Drug Administration (FDA): nevirapine (Viramune) became available in 1996 and delavirdine (Rescriptor) was licensed in early 1997 (Table 1). Table 2 summarizes the drug interactions that have been noted with these two agents.

These agents should only be used in combination regimens, because monotherapy is associated with the rapid development of resistance.²¹ The combination of nonnucleoside reverse transcriptase inhibitors and nucleoside analogs has been evaluated in several studies. A triple-drug combination of zidovudine, didanosine and nevirapine has been found to outperform combination therapy with two nucleosides as demonstrated by changes in the viral load and the CD4⁺ count.^29,30 Combination therapy with a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor is also currently under investigation.

Protease Inhibitors

The four protease inhibitors currently approved for the treatment of HIV infection are saquinavir (Fortovase, Invirase), ritonavir (Novir), indinavir (Crixivan) and nelfinavir (Viracept). The standard dosages and common side effects of these agents are summarized in Table 1. These agents all share a common mechanism of action: they prevent maturation of virus protein by competitively inhibiting HIV protease, an enzyme essential for viral protein cleavage. When this protein cleavage is blocked, immature noninfectious virus particles are produced.³¹ The HIV protease inhibitors all share a number of other properties: they are difficult to synthesize, they have little effect on mammalian proteases, they are metabolized by hepatic and intestinal cytochrome P₄₅₀ enzymes, they have multiple important pharmacokinetic interactions with other medications and they have limited central nervous system penetration.³¹

After one or two months of use, protease inhibitor monotherapy leads to a 2 to 3 log (100- to 1,000-fold) decrease in plasma HIV RNA.^32,33 This decline in viral load is associated with an increase in the CD4⁺ count of 100 to 150 per mm³ (100 to 150 × 10⁶ per L).^32,34 Monotherapy with a protease inhibitor, however, is associated with the development of viral resistance to the agent. Single-drug treatment with ritonavir or indinavir, for example, leads to the accumulation of resistance mutations in a stepwise fashion.^22,23 Many of these mutations also confer resistance to other protease inhibitors.^22,23 Once a patient develops resistant virus, that virus may be retained for a long period, even after protease inhibitor therapy is discontinued.³⁵

Although protease inhibitors were used as single-agent therapy in early studies, it is now recognized that these agents should only be used as part of a combination regimen. Dosage regimens of protease inhibitors are designed to maintain plasma concentrations that keep the virus suppressed. If plasma drug levels become too low, resistant virus may emerge.^32–34 Thus, a dosage reduction because of medication intolerance, for example, should be avoided because such a change may promote drug-resistant virus. Strict adherence to the prescribed therapy must be stressed to all patients.

Table 3 summarizes the most common drug interactions observed with the four protease inhibitors.

Saquinavir

Initially available in 1995, saquinavir was the first protease inhibitor to be licensed by the FDA for use in combination with nucleoside analogs. The clinical activity of saquinavir is limited by its low bioavailability (less than 4 percent with the original formulation). Saquinavir remains useful, however, because it is well tolerated and has been shown to improve surrogate markers of HIV disease^36,37 and clinical outcome³⁸ in combination with nucleoside analogs.

Few toxicities are associated with saquinavir. The most common side effects are diarrhea, abdominal discomfort and nausea, but these side effects are each reported in fewer than 5 percent of patients. A new formulation of soft-gel capsules (Fortovase) has been shown to increase oral bioavailability two- to threefold.

Ritonavir

Ritonavir and indinavir both became available in early 1996. In a trial in which ritonavir was added to an existing regimen of nucleoside analogs in patients with advanced HIV disease, the addition of ritonavir produced a significant reduction in disease progression and mortality.³⁹ Although most commonly used in combination with nucleoside analogs, ritonavir is also being studied in combination with saquinavir. Ritonavir inhibits saquinavir metabolism, leading to increased saquinavir levels and increased antiviral activity.⁴⁰

Toxicities associated with ritonavir include significant nausea, abdominal discomfort, diarrhea, hypertriglyceridemia and circum-oral paresthesias. These effects may be minimized by using a schedule of dosage escalation over 10 to 14 days. Treatment may be initiated with 300 mg two times daily for two days, followed by 400 mg two times daily for three days, then 500 mg two times daily for three days and, finally, 600 mg two times daily. Drug–drug interactions are extremely important to consider when using any protease inhibitor but are most extensive with ritonavir because it is the most potent inhibitor of the cytochrome P₄₅₀ system.⁴¹ These interactions are listed in Table 3. Ritonavir is also a modest inducer of hepatic drug-metabolizing enzymes.⁴²

Indinavir

Indinavir was approved by the FDA for use in HIV infection based on its effects on viral load. Indinavir-containing regimens—the combination of zidovudine, lamivudine and indinavir or of stavudine, lamivudine and indinavir—have recently been shown to be superior to double nucleoside therapy with zidovudine and lamivudine or stavudine and lamivudine with regard to clinical outcome (HIV disease progression, death).⁴³ Because indinavir monotherapy and subtherapeutic levels of indinavir are both associated with the development of resistant virus, the drug should always be used at full dosage, with adherence to the dosing schedule of every eight hours.

Indinavir use is frequently associated with elevation of unconjugated bilirubin, although in most cases this occurs without any apparent clinical harm or change in other liver function tests.⁴⁴ The major clinical toxicity of indinavir is nephrolithiasis, which occurs in approximately 5 to 6 percent of patients.⁴⁴ The risk of renal stones may be diminished through adequate hydration. Patients should be instructed to drink 48 oz of additional fluid each day while they are taking indinavir.

Nelfinavir

Introduced in March 1997, nelfinavir is the most recent protease inhibitor to be approved. It has potent antiviral activity as monotherapy but, like the other protease inhibitors, has an even greater effect on viral load when used in combination with nucleoside analogs.⁴⁵ Watery diarrhea is the major side effect of nelfinavir.⁴⁶ Nelfinavir is a modest cytochrome P₄₅₀ inhibitor, like indinavir, and a modest hepatic enzyme inducer, like ritonavir (Table 3).

Treatment Guidelines

Guidelines for specific drug regimens may be found in the recently formulated recommendations of the U.S. Public Health Service and the International AIDS Society.^11,12 An adapted summary of these guidelines is presented in Table 4. In utilizing these guidelines, it is crucial to consider the patient's willingness to accept therapy and the patient's understanding of the need for strict adherence to such therapy.

Changing therapy may be as important as initiating it. Therefore, application of treatment guidelines includes the need to make adjustments in response to treatment failure, as evidenced by an increase in viral load, a decrease in CD4⁺ counts or worsening symptoms.