Combination antiretroviral therapy for HIV infection

Author: Janine Maenza, Charles Flexner
Date: June, 1998

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.sup.+] 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.sup.+] 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.sup.+] 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.sup.+] count.[11,12] This comes as an addition to previous recommendations to institute therapy in symptomatic patients and in patients with [CD4.sup.+] counts of less than 500 per [mm.sup.3] (500 x [10.sup.6] 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.

TABLE 1 Antiretroviral Agents Used in the Treatment of HIV InfectionGeneric name Trade(abbreviation) name Standard dosageNUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORSDidanosine (ddl) Videx 200 mg twice daily (125 mg twice daily if patient weighs < 60 kg)Lamivudine (3TC) Epivir 150 mg twice dailyStavudine (d4T) Zerit 40 mg twice daily (30 mg twice daily if patient weighs < 60 kg)Zalcitabine (ddC) Hivid [is greater than or equal to 60 kg: 0.75 mg 3 times daily < 60 kg: 0.375 mg 3 times dailyZidovudine Retrovir 200 mg 3 times daily or (AZT, ZDV) 300 mg twice dailyNONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSDelavirdine Rescriptor 400 mg 3 times dailyNevirapine Viramune 200 mg once daily for 14 days, then 200 mg twice dailyPROTEASE INHIBITORSIndinavir Crixivan 800 mg every 8 hoursNelfinavir Viracept 750 mg 3 times dailyRitonavir Norvir 600 mg twice dailySaquinavir Invirase 600 mg 3 times daily Fortovase 1,200 mg 3 times dailyGeneric name(abbreviation) Common side effects Cost (generic)(*)NUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORSDidanosine (ddl) Peripheral neuropathy, $186 (116) pancreatitisLamivudine (3TC) Nausea 230Stavudine (d4T) Peripheral neuropathy, 243(234) pancreatitisZalcitabine (ddC) Peripheral neuropathy, 207 pancreatitis 165Zidovudine (AZT, ZDV) Anemia, neutropenia, 287 nausea,headacheNONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSDelavirdineNevirapine Rash 266 Rash 248PROTEASE INHIBITORSIndinavirNelfinavir Nephrolithiasis 450Ritonavir Diarrhea 559 Nausea, abdominal discomfort, 668 circumoral paresthesias, hypertriglyceridemiaSaquinavir Diarrhea, abdominal 572 discomfort, nausea Diarrhea, abdominal 588 discomfort, nausea

(*)--Estimated cost to the pharmacist for a 30-day supply based on average wholesale prices rounded to the nearest dollar in Red book. Montvale, N.J.: Medical Economics Data, 1998. Cost to the patient will be higher depending on prescription filling fee.

Zidovudine monotherapy was shown in initial clinical trials to decrease mortality, increase [CD4.sup.+] counts and lead to fewer opportunistic infections in patients with symptomatic HIV infection[13] and acquired immunodeficiency syndrome (AIDS).[14] Subsequent investigations revealed that progression to AIDS is slowed by zidovudine monotherapy in asymptomatic patients with [CD4.sup.+] counts of less than 500 per [mm.sup.3](500 x [10.sup.6] 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.sup.+] count is greater than 500 per [mm.sup.3] [500 x [10.sup.6] per L) does not prolong survival compared with delaying initiation of therapy (i.e., when the [CD4.sup.+] count is less than 500 per [mm.sup.3] [500 x [10.sup.6] 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.sup.+] 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

Address correspondence to Charles Flexner M.D., Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Osler 524, 600 N. Wolfe St., Baltimore, MD 21287. Reprints are not available from the authors.

COPYRIGHT 1998 American Academy of Family PhysiciansCOPYRIGHT 2000 Gale Group

© 2006,, All Rights Reserved.