Zidovudine: five years later.

Zidovudine: Five Years Later Gavin X. McLeod, MD, and Scott M. Hammer, MD

• Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.

Annals of Internal Medicine. 1992;117:487-501. From New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts. For current author addresses, see end of text.

Oince its approval in March 1987 by the Food and Drug Administration (FDA), zidovudine (ZDV, AZT, azidothymidine, 3'-azido-3'-deoxythymidine [Retrovir, Burroughs Wellcome Company, Research Triangle Park, North Carolina]) has been the primary treatment for human immunodeficiency virus type 1 (HIV-1) infection. The global pandemic of HIV-1 is entering its second decade, and zidovudine is the only drug that has been shown to prolong survival in persons with the acquired immunodeficiency syndrome (AIDS) (1). Further, recent studies have shown that zidovudine decreases the progression to AIDS in patients with asymptomatic and mildly symptomatic HIV-1 disease whose CD4+ lymphocyte counts are less than 500/mm3 (2-4). Because zidovudine was approved for use in patients only 2 years after the initial in-vitro study showed the drug's inhibition of HIV-1 (5), the initial pharmacologic data and clinical experience were limited. Since 1987, the results of further in-vitro studies, clinical trials, and single case studies have expanded the database on zidovudine's mechanism of action, efficacy, pharmacokinetics, and toxicity. Not unexpectedly, within the short period of its use, several reports of HIV-1 resistance to zidovudine have appeared, although the clinical significance of these findings remains to be fully determined (6-12). The development of zidovudine was an important first step in the treatment of HIV infection, but the drug is limited in its ability to reverse or slow the progressive loss of immune function in HIV-infected persons. Presently, zidovudine is being studied in combination with other antiretroviral agents and cytokines to determine whether immune function can be preserved more effectively, whether toxicity can be reduced, and whether the development of zidovudine resistance can be avoided. Our review summarizes the current information on zidovudine and explores the future role of the drug, including its use in combination therapy. Mechanism of Action Zidovudine is a dideoxynucleoside that is structurally related to thymidine but differs from the latter in having an azido (N3) group in place of the hydroxyl (OH) group at the 3' position of the ribose ring (Figure 1). Zidovudine enters the cell by passive diffusion (13) and is phosphorylated via three cellular kinases into its triphosphate form (zidovudine triphosphate). In the first

Drugs Generic Name didanosine zalcitabine zidovudine

Brand Name Videx Hivid Retrovir

© 1992 American College of Physicians

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step, the enzyme thymidine kinase phosphorylates zidovudine to azidothymidylate (zidovudine monophosphate) in an efficient manner (14). The second phosphorylation (zidovudine monophosphate to zidovudine diphosphate) is the rate-limiting step and involves the enzyme thymidylate kinase. The enzyme responsible for zidovudine triphosphate is believed to be pyrimidine nucleoside diphosphate kinase. The rate of phosphorylation of zidovudine to zidovudine triphosphate varies substantially from one cell type to another because of varying enzymatic activity in cells (15, 16). The ability of a cell to phosphorylate zidovudine and the intracellular ratio of zidovudine triphosphate to deoxythymidine triphosphate are the most important determinants of zidovudine's ability to inhibit HIV (5, 17, 18). Zidovudine triphosphate acts by competitively inhibiting the utilization of deoxythymidine triphosphate by the reverse transcriptase. In addition, zidovudine triphosphate terminates DNA synthesis when incorporated into the proviral DNA chain because the 3'-azido group does not allow for the 5' to 3' phosphodiester linkage that is required for chain growth. Tan and colleagues (19) recently reported that azidothymidylate (zidovudine monophosphate) may also decrease viral replication by inhibiting ribonuclease (RNase) H, an essential part of the reverse transcriptase encoded by the pol gene that functions as an endonuclease and a 3' to 5' exonuclease in transcriptional processing. Zidovudine is effective because it inhibits retroviral polymerases 50- to 100-fold more efficiently than the primary human DNA polymerases alpha and beta (14, 20). The human polymerase gamma that is found in mitochondria is inhibited by zidovudine at concentrations as low as 1 /tM, concentrations that are achieved in vivo (21).

virus, a murine type C retrovirus. In 1985, Mitsuya and colleagues (5) were the first to show that zidovudine inhibited HIV-1 replication in vitro. Depending on the assay and cell type used, zidovudine inhibits HIV-1 replication at concentrations of 0.01 to 10 /xM (5, 24, 25). Zidovudine is effective in inhibiting several other retroviruses in addition to HIV-1, including HIV-2, human T-cell fymphotropic virus type 1 (HTLV-1), animal lentiviruses, and murine retroviruses (16, 17, 24-27). The ability of zidovudine to inhibit a particular retrovirus depends on the cell system used and the affinity of zidovudine triphosphate for the reverse transcriptase of that virus. Although hepatitis B virus is a hepadnavirus virus and not a retrovirus, it uses a unique DNA polymerase that acts like reverse transcriptase to transcribe DNA from an RNA pregenome intermediate (28). Zidovudine can inhibit hepatitis B virus replication, but another nucleoside analog, 2',3'-dideoxyguanosine, is much more potent in a hepatoma cell line (29, 30). Although zidovudine has been effective in inhibiting Epstein-Barr virus, the drug has been ineffective in inhibiting other viruses, including herpes simplex virus types 1 and 2, varicella zoster virus, cytomegalovirus, vaccinia virus, influenza A virus, respiratory syncytial virus, measles virus, and adenovirus type 5 (24, 25, 31-33). Zidovudine also has shown in-vitro activity against bacteria of the family Enterobacteriaceae, including Shigella species, Salmonella species, Klebsiella species, Enterobacter species, Citrobacter species, and Escherichia coli, but the clinical significance of this antibacterial activity is unclear (34, 35).

Spectrum of Activity

Zidovudine is well absorbed after oral administration, with a 60% to 65% bioavailability (36-39). The drug reaches peak serum concentrations within 30 to 60 minutes after ingestion (40-44). After a 200-mg oral dose, the peak serum concentration ranges from 2.35 to 5.5 /LtM (41, 44-46). Zidovudine has been reported by most investigators to undergo biexponential decay kinetics, with a serum half-life of 1.0 to 1.5 hours. Morse and coworkers (42, 47), however, have reported a more prolonged elimination phase during multiple dosing; they found a terminal half-life of 4.1 hours for the drug, but this finding may be a reflection of their patient sample, which included hemophiliacs with some degree of hepatic dysfunction. The determination of intracellular levels of zidovudine and its phosphates is technically difficult to perform, but these measurements are important because they are probably a more reliable indicator of the drug's antiviral activity. The half-life of zidovudine triphosphate has been estimated to range from 3 to 4 hours in leukemic cell lines in vitro; however, zidovudine triphosphate could not be detected at 4 hours in human peripheral blood mononuclear cells (14, 48, 49). Zidovudine is well distributed throughout the body; the volume of distribution is 1.4 L/kg (38). Plasma protein-binding is low at 30% (43). The ratio of the cerebrospinal fluid concentration of zidovudine to the plasma concentration of zidovudine has ranged from 0.1 to 1.35 (37-39, 50, 51). This wide range probably reflects

Zidovudine was first synthesized in 1964 by Horwitz and colleagues (22) as a potential chemotherapeutic agent. The inhibition of retroviruses by zidovudine was first reported in 1974 by Ostertag and coworkers (23), who demonstrated inhibition of spleen-focus forming

Figure 1. Chemical structures of zidovudine and thymidine. 488

Pharmacokinetics

15 September 1992 • Annals of Internal Medicine • Volume 117 • Number 6


Table 1. Major Clinical Trials of Zidovudine Monotherapy in Adults* Study (Reference)

Patients

Stage

Zidovudine Dose

n NCI phase 1 (39)

19

Duration of Follow-up mo

AIDS (11 patients) Dose escalation to 30 mg/kg and AIDS-related body weight per day intracomplex (8 pavenously and 60 mg/d tients) orally

1.5

15 of 19 patients had an increase in the CD4 count; 2.2 kg average weight gain Increased survival in zidovudine group; decreased incidence of opportunistic infections in zidovudine group; increase in CD4 count and weight in zidovudine group Decrease in development of AIDS, AIDS-related complex, and death in the zidovudine group; increased CD4 count and decreased p24 antigen level in the zidovudine group Decrease in development of AIDS and AIDS-related complex in both zidovudine groups; increased CD4 count and decreased p24 antigen level in zidovudine groups Increased survival for lower dose; increased CD4 cells and decreased p24 antigen in both groups No difference in mortality; decrease in development of AIDS in early group; increased CD4 count and decreased p24 antigen level in early group Ongoing

BW 002 (1)

282

AIDS (160 patients) and AIDS-related complex (122 patients)

1500 mg/d (compared with placebo)

4

ACTG 016 (2)

711

AIDS-related complex


11

ACTG 019 (4)

1338

Asymptomatic

500 mg/d or 1500 mg/d (compared with placebo)

12.75

ACTG 002 (85)

524

AIDS

1500 mg/d or 1200 mg/d (then 600 mg/d after 4 weeks)t

25.6

VA study (3)

338

AIDS-related complex

"Early" therapy with 1500 mg/d compared with "late" therapy (1500 mg/d if CD4 count fell below 200/mm3 or AIDS event occurred)

27

Asymptomatic


Concorde 1 (62)

> 2000

Results

>30

* ACTG = AIDS Clinical Trials Group; AIDS = the acquired immunodeficiency syndrome; NCI = National Cancer Institute; VA = Veterans Affairs. t The 1200 mg/d dosage was reduced after 4 weeks; the 1500 mg/d dosage did not change.

the varied cerebrospinal fluid sampling times after administration as well as individual differences in bloodbrain barrier permeability in patients with AIDS and AIDS-related complex. The metabolism of zidovudine is primarily hepatic, with subsequent renal excretion. Zidovudine undergoes hepatic glucuronidation to 3'-azido-3'-deoxy-5'-beta-Dglucopyranosol thymidine, the only metabolite found in humans (36, 37, 44). Zidovudine undergoes extensive first-pass metabolism; 3'-azido-3'-deoxy-5'-beta-D-glucopyranosol rapidly appears in the plasma after administration. The concentration of this metabolite is much higher than that of zidovudine throughout steady-state conditions; this metabolite has no intrinsic antiviral activity, but its potential role in toxicity is unclear (36, 37, 41). After oral administration, 65% to 75% of the given dose is recovered in the urine as 3'-azido-3'-deoxy-5'beta-D-glucopyranosol and 8% to 15% as zidovudine. The remaining 15% to 20% of drug is excreted by an extrarenal mechanism, presumably via the intestinal or biliary system, but studies have not analyzed these pathways yet (38). The renal clearance of zidovudine and its metabolite is higher than the creatinine clearance, indicating that both glomerular filtration and tubular secretion occur (36, 38, 52).

In patients with cirrhosis, the oral clearance of zidovudine is reduced by 70%, resulting in two- to threefold increases in peak plasma levels and half-life (46). Although controlled clinical trials have not studied dosing and efficacy in patients with severe hepatic dysfunction, a reduced dose or dosing frequency (that is, every 8 hours) seems appropriate. In uremic patients, the peak concentration of zidovudine is increased by approximately 50% (43). One study found no significant increase in the half-life in 14 uremic patients, whereas another showed an increase to 2.9 hours in one patient on hemodialysis (43, 53). The metabolite 3'-azido-3'deoxy-5'-beta-D-glucopyranosol does have a markedly increased half-life in patients with renal insufficiency and is cleared by hemodialysis (43). Zidovudine dosing in patients with impaired renal function has not been established (43, 53, 54), but a recent report recommends a dosage of 100 mg three times daily (55). As zidovudine undergoes glucuronidation in the liver, other drugs undergoing hepatic metabolism would be expected to interact with it. Acetaminophen was found in the initial phase II Burroughs Wellcome trial (BW 002) to potentially increase the incidence of cases of anemia requiring transfusion by possibly inhibiting the metabolism of zidovudine. Further studies have shown,



489

however, that acetaminophen has no effect on glucuronidation or the metabolism of zidovudine (56, 57). Probenecid, however, does interfere with the metabolism of zidovudine, not by competing with hepatic enzymes but by decreasing renal excretion, resulting in increased serum levels and half-life (58, 59). Drugs that may interfere with zidovudine's glucuronidation include indomethacin, naproxen, phenytoin, chloramphenicol, and ethinylestradiol; further study is needed, however, to assess the effects of these drugs in vivo. As might be expected, drugs that are myelosuppressive (for example, ganciclovir) may have additive toxicity when administered with zidovudine, but such toxicity is not the result of pharmacokinetic interactions (60). Clinical Efficacy The beneficial effects of zidovudine have been shown clinically in several studies, but questions regarding the most effective dose and the ideal time to initiate therapy remain unanswered (Table 1) (61, 62). Yarchoan and colleagues (39) did the phase 1 study of zidovudine that first suggested clinical efficacy. This study, a dose-escalation trial in 19 patients with AIDS or AIDS-related complex, showed a significant increase in the CD4+ cell counts in 15 of the patients. The patients on average gained 2.2 kg. In addition, this trial showed that oral zidovudine administration resulted in adequate serum levels and tolerable side effects. In 1987, Fischl and colleagues (1) reported a multicenter, double-blind, placebo-controlled trial involving 282 patients (BW 002). This trial showed that zidovudine improved survival and reduced the incidence of opportunistic infections in patients with AIDS or advanced AIDS-related complex (1). In this study, which led to zidovudine's approval by the FDA, only 1 of 145 patients treated with zidovudine, 250 mg every 4 hours (1500 mg/d), died compared with 19 of 137 placebo recipients (P < 0.001). Opportunistic infections occurred in 24 zidovudine recipients and in 45 placebo recipients. Patients receiving zidovudine showed significant improvement in weight, Karnofsky score, and CD4+ cell count. Continued follow-up in 229 of these patients showed that the survival benefit of zidovudine extended to at least 21 months after the initiation of therapy; survival in the original treatment group was 68.1% at that time, whereas survival in the original placebo group at 9 months was 51.5% (63, 64). However, some of the improvement in survival may have been due to prophylaxis for Pneumocystis carinii pneumonia, which was instituted in the extended phase of the study. Several uncontrolled studies have also shown improved survival and a reduced frequency of opportunistic infections in patients with AIDS who were treated with zidovudine (65-70). Zidovudine has also been beneficial in HIV-infected children, who frequently have neurodevelopmental abnormalities (71-77). Both oral and continuous intravenous zidovudine have resulted in improved cognitive function, weight gain, and increased CD4+ cell counts in children. The benefit of zidovudine in patients with AIDS has been found to correlate with pretherapy status as de490

fined by hemoglobin concentration, Karnofsky score, and duration of disease after P. carinii pneumonia (65). The CD4-I- cell count and the serum HIV p24 antigen level have both been shown to initially respond after treatment with zidovudine (78-81). The mean CD4+ lymphocyte count has been shown to increase from 46 to 86 cells/mm3 in the first month of therapy (1, 80). However, this increase is transient; by the fourth to sixth month of therapy, the CD4 count returns to pretreatment levels and continues to decline thereafter (3, 80). Mean HIV p24 antigen levels have been shown to decrease by up to 90% after zidovudine treatment, but HIV antigen levels may subsequently increase (78, 82, 83). The ability to culture virus from peripheral blood mononuclear cells has not been affected by zidovudine therapy, although quantitative titers may decrease while patients are on therapy (50, 84). In 1990, lower-dose zidovudine therapy was found to be efficacious in patients with AIDS. In the AIDS Clinical Trials Group (ACTG) 002 protocol (85), zidovudine at a reduced dose, 200 mg orally every 4 hours (1200 mg/d) for 4 weeks followed by 100 mg every 4 hours (600 mg/d), was found to be as effective as and better tolerated than the previous standard dose of 250 mg every 4 hours (1500 mg/d). After 24 months, this study found estimated survival rates of 27% for the standardtreatment group and 34% for the low-dose group (P = 0.033). Both groups had the same incidence of opportunistic infections (82%) and similar increases in CD4+ lymphocyte counts. The demonstration of the efficacy of zidovudine in advanced HIV disease quickly led to studies to define the drug's role in early disease and to further define its optimal dosing (2-4, 86). The ACTG did a double-blind, placebo-controlled trial (ACTG 016) in 711 persons with mildly symptomatic HIV disease (2). This study used as clinical end points the development of AIDS, the development of advanced AIDS-related complex, or death. In the subgroup of patients with CD4+ cell counts between 200 and 500/mm3, 351 placebo recipients reached 34 clinical end points, whereas 360 patients treated with zidovudine, 200 mg every 4 hours (1200 mg/d) reached 12 clinical end points (P = 0.0002). The zidovudine-treated group also had significant increases in weight and CD4-I- cell count. No benefit could be detected in progression to a clinical end point in the subgroup of patients (n = 194) who had CD4-I- cell counts greater than 500/mm3. In this subgroup, however, zidovudine recipients showed a significant increase in the number of CD4+ cells that persisted for 8 weeks. An open-label study by Collier and colleagues (86) found that patients with AIDS-related complex and CD4+ counts between 200 and 500/mm3 benefited from even lower doses of zidovudine. In their study, patients received a low (300 mg/d), medium (600 mg/d), or high (1500 mg/d) dose of zidovudine, either with or without acyclovir (4.8 g/d). This study was initially designed to detect a possible synergistic effect between zidovudine and acyclovir, but the interesting finding was that lowdose zidovudine therapy appeared to have as beneficial an antiviral effect as the medium-dose and high-dose therapies. The low-dose group gained the most weight and had the greatest improvement in the mean CD4+



cell counts. No detectable differences among the three groups were found regarding change in HIV p24 antigen level. Acyclovir was well tolerated but was not shown to enhance any of zidovudine's antiviral effects. A double-blind Veterans Affairs (VA) Cooperative Study included a similar group of 338 patients with early symptomatic disease and CD4+ cell counts between 200 and 500/mm3, but patients were randomly assigned to either "early" or "late" therapy (3). "Early" therapy consisted of 250 mg of zidovudine orally every 4 hours (1500 mg/d), whereas "late" therapy consisted of placebo followed by the same dose of zidovudine when either CD4+ cell counts fell below 200/mm3 or an AIDS-defining event occurred. The patients were followed for a mean of 25.6 months as compared with 11 months in ACTG 016. In the study, 48 of 168 in the late-therapy group and 28 of 170 subjects in the earlytreatment group developed AIDS (P = 0.02). However, no survival benefit was found; there were 23 deaths in the early-therapy group and 20 deaths in the late-therapy group. Interpretation of this conclusion is hindered by the fact that 10 deaths in the early-therapy group and 8 deaths in the late-therapy group were "non-AIDSrelated" (3). Early therapy was also associated with a delay in the fall of CD4+ cell count to below 200/mm3, and a higher proportion of patients who received early therapy became serum p24 antigen negative (79% compared with 35% in the late-therapy group). In a subgroup analysis of the VA Cooperative study, the investigators noted an apparent racial difference in the response to zidovudine that has not been seen in other studies (3). The VA study found that white patients in the early-treatment group were less likely to progress to AIDS than white patients in the late-treatment group (P = 0.01). This benefit was not seen in black and Hispanic persons. No significant difference was seen in progression to death for any of the racial or ethnic subgroups, but a trend toward more deaths among the black and Hispanic subgroups receiving early zidovudine therapy was noted. Although not conclusive, the VA study emphasized the need to look at possible racial and gender differences in the response to zidovudine, especially because many of the ACTG study samples have been composed predominantly of white, homosexual men. In response to the VA report, a retrospective review of two large ACTG studies (016 and 019) was undertaken, but the review failed to detect any racial differences in response to zidovudine therapy (87). A separate multicenter, prospective, observational study noted that racial differences in survival and in the development of opportunistic infections were mainly attributable to the presence of more advanced disease in black patients when zidovudine was started and to the less frequent use of P. carinii prophylaxis (88). In addition, a longitudinal, observational study in Maryland noted that non-Hispanic white men were more likely to have received zidovudine therapy and other care such as P. carinii prophylaxis, accounting for a marked improvement in survival (70). Thus, access to care and late initiation of zidovudine therapy appear to be more important factors in the differential survival of minority patients than does a different response to zidovudine therapy.

The placebo-controlled ACTG 019 trial explored the use of two different doses of zidovudine: 500 mg/d (low dose) and 1500 mg/d (high dose) in asymptomatic patients (4). This randomized, double-blind trial enrolled 1338 patients, with 428 assigned to receive placebo, 453 to receive low-dose therapy, and 457 to receive high-dose therapy. After 55 weeks of follow-up, 33 placebo recipients had progressed to AIDS compared with 11 recipients of low-dose zidovudine therapy (P = 0.002) and 14 recipients of high-dose zidovudine therapy (P = 0.05). The zidovudine-treated patients also had significant increases in CD4+ cell counts and significant declines in p24 antigen levels. Patients receiving low-dose zidovudine had fewer adverse effects than those on high-dose therapy. These results, along with those of ACTG 016 and ACTG 002, led a National Institutes of Health (NIH) State-ofthe-Art Conference to recommend a zidovudine dose of 500 mg/d for persons with asymptomatic or symptomatic disease and CD4+ counts of less than 500/mm3 (89). The, effect of early therapy on survival and the optimal time to initiate therapy remain controversial (61, 62). The ACTG 019 trial failed to note any survival differences, and the VA Study remains the only doubleblind study to reach a conclusion on this issue. Important in this debate, however, are the recently reported data from the Multicenter AIDS Cohort Study (MACS), which found a survival benefit for patients receiving early zidovudine therapy, with the greatest benefit occurring in men with CD4 counts between 200 and 349 cells/mm3; data on study participants with CD4 counts greater than 350 cells/mm3 were too limited to draw conclusions (90). A major European trial, Concorde 1 (62), is a double-blind, placebo-controlled study that has enrolled over 2000 asymptomatic patients in the United Kingdom and France to compare zidovudine, 250 mg every 6 hours (1000 mg/d), with placebo. Because the study is still in progress and thus far has a mean follow-up of over 30 months, the effect of early zidovudine therapy on survival in asymptomatic patients may be defined more fully. Zidovudine has been found to be effective in the treatment of HIV-associated neurologic disease (51, 9195); peripheral neuropathy, subtle cognitive dysfunction, encephalopathy, dementia, and leukoencephalopathy in HIV-infected patients have responded to zidovudine. Zidovudine has also been shown to decrease the frequency of recovery of HIV-1 from cerebrospinal fluid (50, 72). In all adult studies of neurologic improvement, the patients received high-dose zidovudine ranging from 200 to 250 mg orally every 4 hours (1200 to 1500 mg/d). Thus, although recent studies have supported the use of lower zidovudine doses (500 to 600 mg/d), patients with severe HIV-induced neurologic disease should perhaps receive higher doses until further studies clarify this issue. Zidovudine has also proved to be the preferred treatment for HIV-related thrombocytopenia (96-101). The major toxicities of zidovudine are anemia and granulocytopenia; thrombocytopenia occurs infrequently, and patients with AIDS enrolled in BW 002 actually had a statistically significant increase in their platelet counts (102). Zidovudine has proved to be nearly 70% effective in patients given a prolonged therapeutic trial (100).



491

Table 2. Anemia and Zidovudine Therapy* Study (Reference)

Definition of Anemia

Stage

Zidovudine Dose

BW 002 (102)

Hemoglobin < 7.5 g/dL

1500 mg/d

ACTG 002 (85)

Hemoglobin < 8.0 g/dL

ACTG 016 (2) ACTG 019 (4)

Hemoglobin < 8.0 g/dL Hemoglobin < 8.0 g/dL

1500 mg/d 1200 mg/d for 4 weeks, followed by 600 mg/d 1200 mg/d 1500 mg/d 500 mg/d

Incidence of Anemia, % 31.3 15 39 29

AIDS AIDS-related complex AIDS AIDS Early AIDS-related complex Asymptomatic Asymptomatic

5 6.3 1.1

* ACTG = AIDS Clinical Trials Group; BW = Burroughs Wellcome.

Lower-dose zidovudine (600 mg/d) has been shown to increase the platelet count by 2.5-fold over baseline, whereas higher-dose zidovudine (1200 mg/d) has resulted in a 4.9-fold increase (96). The mechanism of action underlying the effect of zidovudine on HlV-related thrombocytopenia is unknown but may involve the inhibition of viral infection of megakaryocytes, platelets, and macrophages, thereby allowing for increased production and decreased reticuloendothelial system destruction. No effect on circulating immune complexes in patients who have responded to treatment has been noted (101). Zidovudine has no effect on the development of Kaposi sarcoma nor does it affect its clinical course when used alone {see the section on combination therapy) (1, 50). Zidovudine has been shown to have a beneficial effect on HIV-induced psoriasis, even in cases where the condition is unresponsive to other therapies (103105).

didanosine (500 mg/d) resulted in a statistically significant delay in time to first AIDS-defining event or death when compared with zidovudine (600 mg/d) (National Institutes of Allergy and Infectious Diseases, AIDS Division: ACTG 116B/117, Interim Summary for Study Investigators). Zalcitabine (dideoxycytidine) is a third dideoxynucleoside that was recently available in the United States through an expanded access program (111-115). Zidovudine has proved to be superior to zalcitabine in the treatment of patients with CD4+ cell counts of less than 200/mm3 and less than 3 months of previous zidovudine use (Salgo MP. Hoffman-La Roche Inc. Letter to physicians, 13 January 1992). Zalcitabine was recently approved for use in combination with zidovudine by the FDA (see section on combination therapy). This approval was based on the finding that combination therapy with zidovudine and zalcitabine results in a higher and more prolonged rise in CD4 cell count when compared with zidovudine monotherapy.

Alternative Dideoxynucleoside Agents Recently, two other dideoxynucleosides, didanosine (ddl) and zalcitabine (ddC, dideoxycytidine), have become available for clinical use. Didanosine, the second antiretroviral agent approved by the FDA, is currently indicated for the treatment of patients who are intolerant to or failing zidovudine therapy. Clinical trials have shown improvement in CD4 counts, HIV p24 antigenemia, and weight gain in patients treated with didanosine (106-110). An interim analysis of ACTG 116B/117, a phase III study that compared zidovudine and didanosine as monotherapy in patients who have received more than 16 weeks of zidovudine therapy, revealed that

Toxicity Although zidovudine proved to be the first clinically effective antiretroviral agent, the drug has substantial toxicities, especially at doses in the 1200 to 1500 mg/d range. These toxicities have led to reductions in dosing that have proved to be as effective with fewer side effects. Hematologic Effects The major toxicities of zidovudine are anemia and granulocytopenia, and their incidences in major clinical

Table 3. Neutropenia and Zidovudine Therapy* Study (Reference)

Zidovudine Dose

BW 002 (102)

1500 mg/d

ACTG 002 (85)

1500 mg/d 1200 mg/d for 4 weeks, followed by 600 mg/d 1200 mg/d 1500 mg/d 500 mg/d

ACTG 016 (2) ACTG 019 (4)

Stage

Incidence of Neutropenia, %

AIDS AIDS-related complex AIDS AIDS Early AIDS-related complex Asymptomatic Asymptomatic

31.3 11.7 51 37 4 6.3 1.8

* Neutropenia is defined as an absolute neutrophil count of less than 750 cells/mm3. ACTG = AIDS Clinical Trials Group; BW = Burroughs Wellcome. 492



trials are listed in Tables 2 and 3. Studies using lower doses have shown less severe hematologic toxicities. Myelosuppression has been associated with more advanced disease, lower CD4+ lymphocyte counts, decreased serum B 12 or folic acid levels, and baseline anemia or neutropenia (116). Macrocytosis occurs in more than 90% of patients treated with zidovudine but does not correlate with the development of anemia (2, 4). The mechanism of zidovudine myelosuppression is unclear. In vitro, zidovudine is known to inhibit both human granulocyte-macrophage colony-forming units and erythroid burst-forming units at concentrations of 1 to 2 fjM (117). The inhibition has been suggested to result from both the competitive inhibition of thymidine triphosphate and the incorporation of zidovudine triphosphate into the DNA of human bone marrow cells (14, 118). Heme synthesis, which occurs in the mitochondria of cells, also appears to be inhibited by zidovudine via its effect on DNA polymerase gamma (119). Zidovudine has been shown in vitro to inhibit peripheral blood mononuclear cell growth and responsiveness to mitogens (120). Thus, several mechanisms probably underlie bone marrow toxicity.

Myopathy Although myalgias were reported with increased frequency in the zidovudine-treated group of the BW 002 trial, clear-cut myopathy was not seen (102). Bessen and coworkers (121) first reported zidovudine-associated myopathy in 1988 in four patients on prolonged therapy. Myopathies associated with HIV-1 infection itself had been described before the use of zidovudine. Subsequently, the syndrome of zidovudine-associated myopathy and the underlying mitochondrial dysfunction were described in several reports (122-129). The syndrome is haracterized by the insidious onset of proximal muscle weakness and exercise-induced myalgias, usually occurring in patients after 6 to 12 months of therapy. Creatine kinase levels are often elevated, and electromyographic evaluation shows a myopathic pattern with fibrillations and positive sharp wave activity in proximal muscles. Light microscopy shows mild to moderate myonecrosis associated with ragged red fibers and mitochondrial excess. Inflammatory cell response with CD8+ lymphocytes has been reported to range from nonexistent to moderate. Electron microscopy confirms the mitochondrial abnormalities of enlargement and increased number. The mechanism of the myopathy may involve the inhibition of DNA polymerase gamma by zidovudine, which may result in impaired mitochondrial respiratory chain capacity in myocytes (127). Zidovudine-associated myopathy occurs in 6% to 18% of patients who receive therapy for more than 6 months (126, 129). In symptomatic patients, discontinuation of zidovudine therapy has resulted in a gradual resolution of symptoms over a 6- to 8-week period in 70% to 100% of patients (122, 129). Although most cases have been limited to skeletal muscle, a recent study suggested that zidovudine as well as didanosine and zalcitabine (dideoxycytidine) might cause cardiomyopathy (130).

Gastrointestinal Effects Nausea occurs more frequently in patients who receive zidovudine therapy; the incidence has ranged from 3.3% in asymptomatic patients on zidovudine, 500 mg/d (ACTG 019), to 68% in patients with AIDS-related complex on zidovudine, 1200 mg/d (ACTG 016), although this latter study showed a high incidence of nausea (46%) in placebo recipients as well (2, 4). The development of nausea does appear to correlate with higher zidovudine dose and later stage of disease. Vomiting, bloating, and dyspepsia have also been reported to occur more frequently in zidovudine-treated patients than in placebo-matched controls (2). However, these side effects less frequently result in discontinuation of therapy than do hematologic side effects. Elevations in liver transaminase levels have been as common in the treatment group as in the placebo group in each of the large double-blind studies (2-4, 102). However, one case of zidovudine-induced hepatitis has been reported (131), and four recent cases of severe liver dysfunction with three deaths in patients with early HIV disease have highlighted a cautionary note about the possibility of this rare adverse event (notification from Division of AIDS, National Institute of Allergy and Infectious Diseases, to ACTG investigators, 14 November 1991). Esophageal ulceration has reportedly occurred in patients who, while lying in bed, take zidovudine without a fluid bolus (132). Dermatological Effects Zidovudine may cause hyperpigmentation of the skin and nails (133-139). Melanonychia occurs in 40% of patients on therapy, with a much higher incidence occurring in blacks than in whites and Hispanics (67% to 81% compared with 20% to 31%, respectively). Miscellaneous Toxicities Malaise, fatigue, and insomnia also occur with increased frequency in zidovudine-treated patients (2, 3, 102). Zidovudine has reportedly caused seizures, macular edema, and the Stevens-Johnson syndrome (65, 80, 140). Rare cases of zidovudine-associated manic syndrome have also been described (141, 142). Patients on prolonged zidovudine therapy have been noted to have a higher incidence of non-Hodgkin lymphoma (143, 144). Although zidovudine can act as a weak mutagen (145), the increased incidence of non-Hodgkin lymphoma is believed to be due to the increased survival in the setting of severe immunodeficiency and not a direct effect of zidovudine (143, 144, 146). Resistance In 1989, Larder and colleagues (6) first reported that clinical isolates from patients on prolonged zidovudine therapy had developed in-vitro resistance. Using a HeLa cell line (HT4-6C) that expressed the human CD4 receptor on its surface, these investigators developed an assay that was able to assess the drug sensitivity of 30% of the clinical isolates of HIV-1. The assay showed that



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the 50% inhibitory dose (ID50) ranged between 0.01 and 0.05 /xM for 18 isolates from untreated patients. In contrast, the isolates of patients who had been treated with zidovudine for 6 months or more showed decreased sensitivity; five isolates had an ID50 ranging from 2.0 to 5.6 //M. This resistance reflected a greater than 100fold decrease in the in-vitro susceptibility. Using the HT4-6C cell assay, investigators have defined sensitivity as an ID50 of 0.01 to 0.05 /xM, partial resistance as an ID50 of 0.05 to 1.0 /iM, and high-level resistance as an ID50 of more than 1.0 /iM. Larder and coworkers (147-149) subsequently isolated and sequenced the complete reverse transcriptase gene from these isolates. Comparison of the genome from sensitive and resistant isolates yielded five frequent mutations. These mutations resulted in five distinct amino acid residue substitutions: Met41 to Leu, Asp67 to Asn, Lys70 to Arg, Thr215 to Phe or Tyr, and Lys219 to Gin. The degree of resistance appears to correlate with the number of mutations that are present. Mutations at codons 41, 70, and 215 appear to be most critical for the development of both partial and high-level zidovudine resistance with the additional mutations at codons 67, 219, or other sites playing a supplementary role (148151). Additional mutations have also been reported (for example, Leu125 to Trp, He142 to Val, Pro294 to Thr), but their importance has yet to be confirmed by sitedirected mutagenesis of molecular HIV clones (9, 152). Interestingly, the reverse transcriptase from resistant isolates has similar binding to and inhibition by zidovudine triphosphate as the reverse transcriptase from sensitive isolates (6). Thus, the precise mechanism of resistance at the molecular level remains unclear. Isolates from subjects with early-stage disease and higher CD4+ cell counts develop resistance at slower rates and to a lesser degree than do those from patients with AIDS or AIDS-related complex (153, 154). The likelihood of developing resistance would theoretically be expected to be higher in patients with AIDS because of a higher viral load (84, 155). The resistant isolates still retain their sensitivities to other dideoxynucleosides that do not contain a 3'-azido group, including didanosine and zalcitabine (dideoxycytidine), and to non-nucleoside agents such as nevirapine, alpha-interferon, soluble CD4, and foscarnet (156, 157). Recently, resistance to didanosine has been reported to occur after prolonged use in patients with previous zidovudine exposure (10, 158). In this circumstance, didanosine resistance is associated with the development of a Leu74-toVal mutation that occurs in the presence of the Thr to Tyr mutation at 215 (158). Interestingly the Leu74-to-Val mutation confers increased sensitivity to zidovudine in isolates containing the zidovudine-resistant mutations. The clinical significance of resistance has yet to be fully determined, but two recent reports indicate a correlation between decreased zidovudine sensitivity and poor clinical outcome. The investigators of the Multicentre Canadian AZT Trial have reported that patients with CD4-I- cell counts greater than 270/mm3 had a greater progression to AIDS if their isolates were resistant (159). In a study of 19 children, a highly significant correlation between in-vitro zidovudine sensitivity and clinical outcome was detected (12). Children who dete494

riorated or died had a median 50% inhibitory concentration (IC50) of 3.5 /iM, whereas those who remained stable had an IC50 of 0.57 /iM (P < 0.001). The ultimate relevance of zidovudine resistance will need to be determined in clinical studies that simultaneously evaluate resistance mutations, virus load, and virus phenotype (for example, syncytium-inducing ability) as each may contribute to clinical outcome. Prophylaxis and Primary HIV-1 Infection The use of zidovudine as prophylaxis after accidental needlestick exposure to HIV-1 infected blood is complex and controversial. Various murine and feline models of lentivirus infection have shown a benefit of prophylaxis (160-163). However, zidovudine prophylaxis has shown less efficacy in primate models, with evidence of failure in rhesus macaques after exposure to simian immunodeficiency virus (164, 165). Although the animal models are inconclusive, the studies in which a benefit has been shown demonstrate that the earlier prophylaxis is begun after exposure, the more effective is the prevention of subsequent infection. The issues of efficacy, cost effectiveness, and potential side effects contribute to the complicated issue of prophylaxis. Because of the low but definite risk (0.3% to 0.4%) of HIV seroconversion after needlestick exposures, the use of zidovudine in post-exposure prophylaxis has become the practice at many hospitals (166, 167). Zidovudine prophylaxis has generally been administered in a regimen of 200 mg every 4 hours (1200 mg/d) for 28 to 42 days (167, 168). However, three cases of failed zidovudine prophylaxis after HIV exposure have been reported (169-171). The efficacy of zidovudine in interrupting vertical transmission of HIV from mother to fetus is currently being evaluated. Zidovudine is known to cross the placenta and to reach adequate levels in the fetus (172). In a recent study of 43 women who received zidovudine during pregnancy, the drug was well tolerated and not associated with any fetal distress, premature births, or malformations in the newborns (173). A large, phase III, randomized, placebo-controlled trial (ACTG 076) is now under way to assess the efficacy and safety of zidovudine in preventing maternal-fetal transmission. One open-label study of zidovudine, 1000 mg/d, in the treatment of primary HIV-1 infection in 11 patients detected no significant adverse effects, no antiviral effect, and no clinical response (174). However, the patients in this study had only mild to moderate symptoms. In cases of meningoencephalitis or other severe manifestations occurring with primary infection, one should consider the use of zidovudine to possibly reduce symptoms and to shorten the duration of the illness, although further long-term, controlled studies are necessary to evaluate the utility of zidovudine in the treatment of primary HIV-1 infection. Combination Therapy Because of zidovudine's limited benefit, its toxicity profile, and the development of resistance, the use of multiple drugs to inhibit HIV-1 and to minimize toxicity



is currently an area of intense study. Several in-vitro studies have shown the synergistic effect of zidovudine combined with other drugs, including other nucleoside analogs, non-nucleoside agents, and cytokines. Many of the studies have used only the IIIB strain of HIV; studies using clinical isolates may yield different results (175). Zidovudine and didanosine have been found to work synergistically even when used against a zidovudine-resistant isolate (176, 177), similarly zidovudine and zalcitabine (dideoxycytidine) have synergistic activity against HIV-1 in vitro (178). Alternating zidovudine and zalcitabine in cultures in vitro every 3 days was more effective at inhibiting HIV-1 infection than using either agent alone (179). Alpha-interferon has also proved to work synergistically with zidovudine (180), and the combination of both with didanosine is more effective than two-drug regimens (177). Other studies have found that zidovudine has at least an additive effect with acyclovir (181) and works synergistically with soluble CD4 (182). Not all antiretroviral drug combinations have additive or synergistic effects, however; ribavirin and zidovudine have antagonistic effects in vitro, apparently because ribavirin inhibits the phosphorylation of zidovudine (183). Results of preliminary phase I/II studies have been reported for the use of zidovudine in combination therapy with dideoxycytidine, alpha-interferon, acyclovir, foscarnet, and cytokines, and studies of zidovudine in combination with other drugs are under way. Combination therapy with zidovudine and dideoxycytidine currently appears to be one of the most promising regimens. Yarchoan and colleagues (184) first reported the alternating regimen of oral zidovudine, 200 mg every 4 hours for 7 days, and oral dideoxycytidine, 0.03 mg/kg every 4 hours for 7 days. In this phase I study, the five patients who completed 9 weeks of therapy had a mean increase in their CD4+ lymphocyte count of 48 cells/ mm3 and in their weight of 1.6 kg. The toxicity was limited to neuropathy in two patients, one of whom had received dideoxycytidine alone before the alternating regimen. The results of the ACTG 106 trial, a phase I/II study of six different combinations of zidovudine and dideoxycytidine, were recently published (185). This study analyzed 56 patients with AIDS or advanced AIDSrelated complex and CD4+ counts of less than 200 cells/mm3 who had not been previously exposed to zidovudine. Patients received zidovudine at doses of 50 mg, 100 mg, and 200 mg alone or in combination with dideoxycytidine at either 0.005 mg/kg or 0.01 mg/kg, with both drugs being given every 8 hours. Neither drug altered the pharmacokinetics of the other, nor were toxicities increased. The patients who received the high-dose combination therapy had a mean maximal CD4+ count increase of 109 cells/mm3 and the CD4+ counts remained elevated for at least 10 months. Compared with either drug alone, the mean maximal increase seen with combination therapy was higher (109 cells/mm3 compared with 45 to 70 cells/mm3) and longer (10 months compared with 4 to 5 months) than previously reported. Reductions in HIV p24 antigenemia occurred with all regimens but were significant for the group that was taking zidovudine, 200 mg, and dideoxy-

cytidine, 0.01 mg/kg, every 8 hours. Interestingly, patients receiving only zidovudine, 150 mg/d, had the smallest increase in CD4+ counts when compared with the other groups, which shows the beneficial effect of combined dideoxycytidine and zidovudine therapy. However, this study also provided evidence that the daily dose of zidovudine should probably be at least 300 mg/d (186). One of the concerns raised in interpreting this study was that a control arm of zidovudine at 600 mg/d (that is, "standard" therapy) was not included in the study design. The data from this ACTG study and an ongoing Burroughs Wellcome trial (BW 34,225-02) recently led the FDA to approve dideoxycytidine in combination with zidovudine for patients with advanced HIV disease. More definitive results about combination therapy with zidovudine and dideoxycytidine in patients who have received zidovudine previously should be provided by ACTG 155, a large, three-arm study that is currently examining the relative efficacy and safety of zidovudine alone at 600 mg/d, dideoxycytidine alone at 2.25 mg/d, and the combination of zidovudine and dideoxycytidine in patients with CD4+ cell counts of less than 300/mm3 and at least 6 months of previous zidovudine exposure. Zidovudine and acyclovir have been studied in combination in a number of clinical trials. Two open-label, phase I studies of zidovudine and acyclovir showed no significant pharmacokinetic interactions between the two drugs; however, the studies did not have control groups, and therefore definitive conclusions could not be reached about efficacy (187, 188). In another study, 18 asymptomatic patients received oral zidovudine, 1000 mg/d, with or without acyclovir, 3200 mg/d, for 8 weeks; those receiving acyclovir showed no significant change in p24 antigen levels and CD4-I- counts (189). Collier and colleagues (86) also failed to detect any benefit from acyclovir when added to zidovudine in their phase II dose-escalation study. The EuropeanAustralian collaborative group did a double-blind, placebo-controlled study of zidovudine, 250 mg every 6 hours (1000 mg/d), with or without acyclovir 800 mg every 6 hours (3200 mg/d) (190). After 6 months of follow-up, this study found no difference in efficacy when combination therapy was compared with zidovudine alone. Additional data are forthcoming from another European-Australian trial and from ACTG 063, an ongoing multicenter, double-blind study comparing zidovudine alone with zidovudine and acyclovir in the treatment of patients with CD4+ counts of less than 200/mm3. In a 2-week study of six patients, combination therapy with zidovudine and foscarnet was tolerated, and an additive in-vivo antiretroviral effect was noted (191). The recent finding that patients with cytomegalovirus retinitis had decreased mortality when treated with foscarnet compared with those treated with ganciclovir may possibly be due to foscarnet's activity against HIV-1 or to synergism between zidovudine and foscarnet (192). The use of zidovudine and interferon-alpha in combination has been examined in asymptomatic patients, persons with advanced disease, and patients with Kaposi sarcoma (193-197). The combination of the two



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agents, both of which have been shown to have antiviral activity, has unfortunately caused significant adverse effects, in particular neutropenia and anemia. One study reported a 57% incidence of neutropenia (neutrophils < 1.25 x 109 [1250/mm3]) (194). Therapeutic effects on the underlying HIV disease have been variable (193197), but a 42% to 46% response in Kaposi sarcoma lesions has occurred at interferon doses (5 to 10 x 106 U/d) that are much lower than those needed to obtain a similar response when used alone (> 20 x 106 U/d) (194, 195). The surrogate marker effect has been largely limited to a reduction in p24 antigen as interferon produces a lymphopenia that is reflected in decreased CD4+ cell counts. Nevertheless, the CD4 percent and the CD4+/ CD8+ cell ratio, which may be a more accurate assessment of immune status, do not change significantly when this regimen is used (194). Studies continue to evaluate the combination of zidovudine and alpha-interferon; for example, ACTG 068, a phase I/II open-label study of symptomatic patients with CD4+ cell counts of more than 200/mm3 is currently under way (198). Cytokines with hematopoietic stimulatory activity have been studied in combination with zidovudine to reduce the hematologic toxicity of zidovudine. Erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) have all been used in trials with zidovudine. Recombinant human erythropoietin was found to reduce the transfusion requirement of patients with AIDS who were receiving zidovudine and whose baseline endogenous erythropoietin levels were less than 500 IU/L. Erythropoietin had virtually no side effects in this double-blind, placebo-controlled study (199, 200). The neutropenia associated with zidovudine therapy has been successfully treated in combination studies with recombinant human G-CSF and GM-CSF, with the former appearing to be better tolerated (201-206). The use of GM-CSF alone was associated with increases in HIV p24 antigenemia in two studies, but such an association was not seen in two other studies nor when GM-CSF was given in combination with zidovudine (203-206). Zidovudine has also been used in combination with bone marrow transplantation with little success. The possible eradication of HIV-1 infection in a patient with non-Hodgkin lymphoma who was treated with allogeneic bone marrow transplantation and high-dose zidovudine was encouraging (207). However, 16 patients receiving such therapy at the National Institutes of Health showed only transient improvement in CD4 cell percent and had persistently positive HIV cultures (208). The use of zidovudine as the core of combination therapy is evident in multiple ongoing studies (209). A phase I/II, open-label study (ACTG 143) to evaluate the combination of zidovudine and didanosine in the treatment of 125 asymptomatic patients is currently under way. A randomized, double-blind phase II/III trial (ACTG 175) of monotherapy and combination therapy with zidovudine and didanosine or dideoxycytidine is enrolling patients with CD4+ cell counts between 200/ mm3 and 500/mm3. Other studies of dideoxynucleoside combinations (zidovudine with didanosine or zalcitabine [dideoxycytidine]) include the European Delta trial, the Burroughs Wellcome-sponsored study (BW 34,225-02), 496

and the Community Program Clinical Research Association study (CPCRA 007). Non-nucleoside reverse transcriptase inhibitors, including nevirapine; L 697,661 and (a pyridinone compound); and R82913 (a "TIBO" compound) are currently being tested in combination with zidovudine (210-212). Conclusions Although much has been learned about zidovudine during the past 5 years, many areas of promise and uncertainty remain that need to be further explored. Currently, the optimal zidovudine dose is 500 to 600 mg/d, but additional studies are needed to assess precisely which dose is best for particular patient populations (for example, adults with HIV-related neurologic disease and children). Further, if the patient develops anemia or granulocytopenia while receiving zidovudine therapy, the decision to reduce the dose of zidovudine, change therapy to another dideoxynucleoside (didanosine or zalcitabine [dideoxycytidine]), or to initiate combination therapy with cytokines (erythropoietin, G-CSF, or GM-CSF) is an issue confronting physicians. Perhaps most pressing is the need to define the clinical significance of zidovudine resistance and the efficacy and safety of combination therapies in patients with both advanced- and early-stage HIV disease. Zidovudine, in its first 5 years of licensure, has been the mainstay of antiretroviral therapy and will likely continue in this role for the foreseeable future; however, based on the promise of current research developments, we hope to move well beyond this first but important step in the treatment of HIV-infected persons in the next 5 years. Grant Support: In part by Public Health Service grants AI27659 and HL43510 from the National Institutes of Health and Defense Department contract DAMD-17-90-C-0106. Requests for Reprints: Gavin X. McLeod, MD, Division of Infectious Diseases, New England Deaconess Hospital, 185 Pilgrim Road, Boston MA 02215. Current Author Addresses: Drs. McLeod and Hammer: Division of Infectious Diseases, New England Deaconess Hospital, 185 Pilgrim Road, Boston MA 02215. References 1. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med. 1987;317:185-91. 2. Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Para MF, et al. The safety and efficacy of zidovudine (AZT) in the treatment of patients with mildly symptomatic HIV infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group. Ann Intern Med. 1990;112:727-37. 3. Hamilton JD, Hartigan PM, Simberkoff MS, Day PL, Diamond GR, Dickinson GM, et al. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study. N Engl J Med. 1992;326:437-43. 4. Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, et al. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. N Engl J Med. 1990;322:941-9. 5. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, NusinoffLehrman SN, Gallo RC, et al. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectrvity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA. 1985;82: 7096-100.



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A Dream of Retarded Children That afternoon I had been fishing alone, Strong wind, some water slopping in the back of the boat. I was far from home. Later I woke several times hearing geese. I dreamt I saw retarded children playing, and one came near, And her teacher, face open, hair light. For the first time I forgot my distance; I took her in my arms and held her. Waking up, I felt how alone I was. I walked on the dock. Fishing alone in the far north. Robert Bly Selected Poems New York: Harper & Row; 1986: p. 51

Submissions from readers are welcomed. If the quotation is published, the sender's name will be acknowledged. Please include a complete citation, as done for any reference.—The Editors

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The Copeland intraocular lens: five to ten years later.

An undergraduate program in anesthesia and medicine: five years later.

Medicine and health care in South Africa--five years later.

CBCD: 25 years later!

Irisin, two years later.

Sixty years later.

Ten years later.

Meddoc three years later.

Polyelectrolytes, thirty years later.

10 years later

Thirty-five years later, the first assisted reproductive technology program opens in Cambodia.

The Affordable Care Act, Five Years Later: Policies, Progress, and Politics.

The Alzheimer's Study Group's recommendations five years later: planning has advanced, but agenda remains unfinished.

The Darwinian Revolution, as seen in 1979 and as seen Twenty-Five Years Later in 2004.

Adolescent's respiratory sinus arrhythmia is associated with smoking rate five years later.

Mummy days: ten years later.

Exxon Valdez: 25 years later.

Pickwickian syndrome, 20 years later.

DIGAMI 1: 20 years later.

[Rüti-study - 5 years later].

Frustration theory--many years later.

Five years of translation.

Twenty-five years.

The Zollinger-Ellison syndrome--23 years later.