Conference Summaries of ICAAC 1999 and IDSA 1999: Part I
Conference Summaries of ICAAC 1999 and IDSA 1999: Part I
Conference coverage
Editor’s Note: The following summaries represent a selection of papers from those presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 26-29, 1999, in San Francisco and the 37th Annual Meeting of the Infectious Disease Society of America (IDSA), held November 18-21, 1999, in Philadelphia. It is important to recognize that many of these summaries are extracted only from the published abstract and it is possible that some of the material presented at the conference may have differed. The ICAAC abstracts are available on the American Society of Microbiology Web Site at: http://www.asmusa.org. The IDSA abstracts can be seen in Clin Infect Dis 1999;29:959-1112. —Stan Deresinski, MD, FACP
HIV Infection Antiretroviral Therapy
General Considerations. In further confirmation of the remarkable benefits of currently available antiretroviral therapy (ART), the extrapolated expected survival of a treated 38- to 39-year-old white HIV infected male in the United States was calculated to be 36 years—i.e., identical to that for the general white male population of that age. The news is not quite as good for those with more advanced disease; the expected survival for those with CD4 less than 200 cells/mm3 is 11 years. (ICAAC #1158.) Furthermore, an evaluation of 4168 patients followed for a mean of 17 months after the introduction of HAART found that fewer than 50% of deaths were purely HIV-related. (ICAAC #125.)
One of the factors affecting outcome of HIV infection is the genetic background of the patient. Genetic background also affects the response to therapy. Chemokine receptor gene polymorphisms correlated with the likelihood of a sustained viral response to HAART. Thus, for example, only 13% of CCR5 D 32 heterozygotes had viral rebound compared to 29% of CCR5 59029A homozygotes. (IDSA #356.) However, in contrast to previous observations, no gender difference in progression of disease could be detected in a large cohort of patients. (IDSA #375.)
Arguments continue over the intensity and virological goals necessary to ensure a favorable outcome of ART. An analysis of 4330 patients stratified by viral load found that, during a one-year follow-up, patients maintaining a viral load of 400-20,000 copies/mL were no more likely to develop a new AIDS-defining condition than those maintaining a viral load of less than 400 copies/mL. Those whose viral load was more than 20,000 copies/mL had a significantly higher number of events than the group with less than 400 copies/mL (P < 0.001). (IDSA #359.) It is likely, however, that further follow-up will demonstrate benefit to complete viral suppression. A separate study found that viral load was an independent risk factor for the risk of developing opportunistic diseases. (ICAAC #124.)
ART Naïve (or Mostly Naïve) Patients
A number of studies continue to examine various therapeutic approaches to the treatment-naïve patient, an increasingly scarce commodity for U.S. clinical researchers.
Protease Inhibitor Sparing Regimens
A series of trials examined the efficacy of regimens containing NRTIs alone or in combination with an NNRTI in the ART-naïve patient. Three component NRTI-only regimens had efficacy in this group. Sixty-seven ART-naïve patients were treated with didanosine/ lamivudine plus either zidovudine (49 patients) or stavudine (18 patients). At week 48, 45 of 51 (88.2%) evaluable patients had plasma HIV RNA less than 200 copies/mL; the mean increase in CD4 count was 236 cells/mm3. (ICAAC #1972.) One hundred seventy-three treatment-naïve patients with CD4 more than 100 cells/mm3 were given abacavir, lamivudine, and zidovudine. In an intent-to-treat analysis after 48 weeks, 60% had plasma HIV RNA less than 400 copies/mL with a mean increase in CD4 count of 150-183 cells/mL. (IDSA #341.) Five hundred sixty-two ART-naïve patients (CD4 > 100 cells/mm3) were randomized to receive Combivir together with either indinavir or abacavir. At week 24, approximately 60% of each group had a virological response, which did not depend on entry viral load. CD4 responses were approximately +100 cells/mm3 in each group. By week 48, however, better viral suppression was obtained with the indinavir-containing regimen in patients with viral loads more than 100,000 copies/mL at baseline. (ICAAC #505.)
Several studies demonstrated that an NNRTI can be substituted for a protease inhibitor in a multidrug regimen without loss of efficacy. Analysis of the 72-week data from Study 006 continues to show superiority of efavirenz over indinavir when combined with lamivudine and zidovudine. (IDSA #366; ICAAC #507.)
One hundred one ART-naïve patients treated with efavirenz plus stavudine plus either lamivudine or didanosine had a mean increase from baseline CD4 count of 289.6 cells/mL at 24 weeks. Some 68.9-88.9% had plasma HIV RNA less than 50 copies/mL. (IDSA #349.) Twenty of 33 (61%) originally ART-naïve patients on treatment for 52 weeks with stavudine/didanosine/nevirapine had plasma HIV RNA less than 50 copies/mL. (ICAAC #1978.)
Three hundred seventy-one ART-naïve patients were randomized to receive delavirdine/zidovudine/lamivudine, delavirdine/zidovudine, or zidovudine/lamivudine. At 52 weeks, 67% of the triple drug recipients had plasma HIV RNA less than 50 copies/mL, compared to 6% on the dual therapy regimens. (ICAAC #1979.) Similar results were obtained in a comparable study, although with only 40% of those on delavirdine/zidovudine plus a third NRTI having plasma HIV RNA less than 50 copies/mL at one year. (ICAAC #1980.) Thirty-one of 45 (68.9%) previously ART-naïve patients given stavudine/didanosine/efavirenz had plasma HIV RNA less than 50 copies at 24 weeks. (ICAAC #1982.)
Protease Inhibitor Containing Regimens
Two hundred four ART-naïve patients (CD4 > 200 cells/mm3) received lamivudine and indinavir plus either zidovudine or stavudine. After 48 weeks, approximately 50% in each group had plasma HIV RNA less than 50 copies/mL and had an approximately 200 cells/mm3 increase in CD4 count. (ICAAC #506.) Two hundred five lamivudine- and protease inhibitor-naïve patients with CD4 counts more than 200 cells/mm3 and viral loads less than 10,000 copies/mL were randomized to receive indinavir with either stavudine and didanosine or lamivudine and zidovudine. In a modified intent-to-treat analysis at 48 weeks, a viral load less than 500 copies/mL was present in 61% of the former and 45% of the latter group. Hypertriglyceridemia was more frequent in the stavudine/didanosine group. (IDSA #14.)
Protease inhibitor-naïve patients were randomized to receive either ritonavir/saquinavir/stavudine or indinavir/stavudine/lamivudine. By intent-to-treat analysis at 48 weeks, 68% of dual PI recipients and 89% of indinavir recipients had plasma HIV RNA less than 50 copies/mL. Dropouts were more frequent among the former than the latter group (P < 0.005). (ICAAC #1987.)
Examination of data from three clinical trials (INCAS, AVANTI 2 & 3) found that, among patients whose viral load nadir was 20-400 copies/mL, the duration that viral load was maintained below 500 copies/mL was greater for those assigned either zidovudine/lamivudine/indinavir or zidovudine/lamivudine/nelfinavir than in those assigned zidovudine/didanosine/nevirapine. (ICAAC #1992.)
Among previously ART-naïve patients randomly given Combivir/abacavir or Combivir/indinavir, 13% had a discordant response characterized by a fall in CD4 count (mean, -13 cells/mm3) together with a significant reduction in plasma HIV RNA. Predictors of discordancy at baseline included a high CD4 count and a low viral load. (ICAAC #1993.)
Forty-six zidovudine, didanosine, and/or zalcitabine experienced patients (but protease inhibitor- and NNRTI-naïve) were given lamivudine/stavudine/indinavir and, by randomization, either nevirapine or no adidanosinetional drug. No significant benefit from the addition of nevirapine to this three-drug regimen was detected. (ICAAC #1977.)
Pregnancy and Perinatal Infection
Newer regimens may be more efficient than use of zidovudine alone in prevention of perinatal transmission of HIV infection. HIV-1 infected women in Uganda were randomized to receive either nevirapine (200 mg orally) at onset of labor with 2 mg/kg to the infant within 72 hours of birth or the standard perinatal AZT regimen. Nearly all breast fed. The nevirapine regimen was associated with a 47% reduction in HIV infection of the infant at 14-16 weeks when compared to the AZT regimen. (IDSA #S98.)
The safety of many antiretrovirals during the early stages of pregnancy remains incompletely examined. Treatment of pregnant and lactating rats with indinavir or ritonavir was associated with developmental retardation and, in 2% of exposed fetuses, anophthalmia. (ICAAC #1762.)
Pharmacokinetics and Drug-Drug Interactions
Treatment failure in patients receiving an efavirenz- based regimen was approximately three times as frequent with a trough concentration of efavirenz less than 3.5 uM as compared to a concentration greater than this. (ICAAC #1201.)
Pharmacokinetic Interactions
The search for an effective once-a-day antiretroviral regimen continues. Efavirenz is administered once daily and evidence indicates that once daily didanosine is also effective. Now a study in 41 healthy volunteers found that once daily adminstration of 1600 mg saquinavir sgc together with 100 gm ritonavir qd appears to provide acceptable pharmacokinetics and tolerance and has been chosen for evaluation in a clinical trial. (ICAAC #330.)
Two adjunctive measures were shown to improve ART exposure. Coadministration of allopurinol resulted in markedly improved absorption of didanosine with a consequent more than 100% increase in its AUC. (ICAAC #662.) Ketoconazole coadministration increased the AUC ritonavir and saquinavir by approximately one-third each. The mean unbound CSF concentration was markedly increased (by 153%) out of proportion to serum levels, consistent with P-glycoprotein inhibition by ketoconazole, an effect possibly worthy of exploitation in the clinic. (ICAAC #658.) On the other hand, "double-strength" grapefruit juice increased gastric pH but had no effect on indinavir exposure. (ICAAC #660.)
One barrier to once-a-day regimens is the varying requirements with regard to the fed state and to the presence of gastric acid. Although concurrent administration of didanosine (which, of course, is formulated with an antacid) with indinavir reduces exposure of the latter by 80%, didanosine administration one hour before the protease inhibitor had little effect on indinavir exposure. (ICAAC #333.)
Drug-drug pharmacokinetic interactions continue to be a headache for the HIV caregiver and his or her patients. Ritonavir and saquinavir coadministration each caused significant increases in sildenafil (Viagra) Cmax via inhibition of first pass metabolism by CYP3A4; the kinetics of the protease inhibitors were not affected. (ICAAC #659.)
A patient receiving ritonavir and saquinavir developed severe ergotism after ergotamine was prescribed for bladder spasms. The ergot preparation was prescribed without the knowledge of the patient’s HIV treating physician. (IDSA #243.)
Coadministration of efavirenz and lorazepam, a drug metabolized via glucuronidation, was associated with an increased lorazepam Cmax by 16% and AUC by 7%. There was no effect on lorazepam elimination, indicating that efavirenz does not induce glucuronidation. (IDSA #323.) There was no significant pharmacokinetic interaction observed between nevirapine and rifabutin. (ICAAC #341.)
Which of the following is not correct?
a. Chemokine receptor gene polymorphisms correlate with the likelihood of a sustained response to HAART.
b. Some triple NRTI regimens are associated with inferior results, relative to protease inhibitor containing regimens, in patients with plasma HIV RNA more than 100,000 copies/mL at baseline.
c. Didanosine may be administered once daily without loss of efficacy.
d. Efavirenz must be administered twice daily.
Which of the following is not correct?
a. Coadministration of allopurinol results in a significant increase in the didanosine AUC.
b. Coadministration of the combination of ritonavir/saquinavir results in a significant decrease in sildenafil (Viagra) Cmax.
c. The dose of amprenavir may need to be decreased in patients with severe liver disease.
d. K103N is a key mutation in the reverse transcriptase gene determining resistance to NNRTIs such as efavirenz.
CSF Drug Penetration
Accumulating evidence indicates that CNS penetration of antiretroviral agents, as reflected in CSF concentration, is an important aspect of effective ART. Lamivudine Cmax in CSF is 8% of that achieved in plasma and Cmin is 39.7%; the AUC CSF:plasma ratio was 15.3%. (IDSA #330.) CSF penetration of stavudine is similar; the CSF:plasma Cmax and AUC ratios of stavudine in four patients were, respectively, 10.1% and 38.9%. (IDSA #340.)
The CSF:plasma Cmax, Cmin, and AUC ratios of indinavir in eight subjects were, respectively, 6.5%, 167.3%, and 17.0%. The estimated mean free (nonprotein-bound) level in CSF exceeded the IC95 of wild-type HIV-1 throughout the dosing interval. (IDSA #338.)
Pharmaceutical means to increase CSF drug levels could improve ART. Ketoconazole coadministration increased CSF concentrations of ritonavir by 153%, a value out of proportion to the increase in plasma levels achieved. These results were felt to be consistent with inhibition of P-glycoprotein inhibition by ketoconazole. (ICAAC #658.)
Liver Disease
Single-dose pharmacokinetics suggest that patients with cirrhosis and a Child-Pugh score of 5-8 should have their amprenavir dose reduced to 450 mg bid and those with scores of 9-12 should have their dose reduced to 300 mg bid. (ICAAC #326.)
Renal Insufficiency
A study of two patients undergoing continuous peritoneal dialysis and receiving 150 mg lamivudine daily found that peritoneal dialysis did not significantly affect the pharmacokinetics of the drug. Furthermore, the current recommendation of a dose of 25 mg daily appears too low. (IDSA #328.)
Therapy Simplification
The notion of maintenance/induction regimens has previously been dealt a near fatal blow by the results of several studies. In those trials, however, the maintenance regimens were clearly inferior in terms of sustainable antiretroviral activity to the induction regimens. The availability of new drugs requiring less frequent dosing than older HAART regimens has revived the issue with a subtly different concept—that of the simplification of HAART, while maintaining similar potency. Patients with plasma HIV RNA less than 50 copies/mL for at least six months and who had no RT codon 215 mutation at baseline were randomized to continue HAART or to change to abacavir plus Combivir. Evaluation of 69 patients with at least 12 weeks follow-up found no difference in maintenance of virolgical responses or CD4 counts, but did find a reduction in serum lipids in the group continued on NRTIs alone. (ICAAC #510.)
Thirty-three patients with no prior ART failure who had plasma HIV RNA less than 400 copies/mL changed from a protease inhibitor-based regimen to one based on efavirenz and/or abacavir (19 efavirenz, 7 abacavir, 7 efavirenz and abacavir). Baseline NRTIs were not altered (although in some, one was replaced by abacavir). Preliminary data from limited follow-up found that only one patient, whose therapy was abacavir plus two NRTIs, had viral rebound. (IDSA #316.)
Sixteen-week data were available for 30 of 78 patients with plasma HIV RNA less than 50 copies/mL while on two NRTI and a protease inhibitor who were randomized to no change or to replace the protease inhibitor with abacavir. There has been no case of viral rebound in either arm. (ICAAC #2194.)
Viral suppression was maintained for six months in 28 of 28 patients with plasma HIV RNA less than 20 copies/mL in whom efavirenz was substituted for their protease inhibitor. (ICAAC #2196.) Thus, therapy simplification, chosen appropriately, appears to be safe and effective.
Planned Therapy Interruption
"Auto-vaccination" by interruption of therapy in patients with undetectable plasma HIV continues to be explored. Thirteen patients, 10 of whom had received prior treatment with IL-2, had undetectable viral loads for at least one year while receiving HAART had planned discontinuation of their ART. Their viral loads increased to more than 50 copies/mL in each, most often two to three weeks after drug discontinuation; this was associated with a significant increase in CD4 T-cell production as determined by ex vivo labeling with BrDU. (ICAAC #689.)
Twenty-one subjects with acute primary HIV infection were started on HAART prior to full seroconversion with control of viremia. Therapy was associated with the generation of HIV-1 specific (p24) T helper response and this response was augmented by "structured treatment interruption." (IDSA #725.)
Intensification
Intensification appears to fly in the face of the admonition to never add a single agent to a failing regimen. However, the crux of the matter is the definition of failure. One hundred eighty-five patients with HIV plasma RNA between 400 and 50,000 copies/mL and no history of CD4 count less than 100/mm3 were randomized to have placebo or abacavir added to their stable background therapy. At week 48, 23 of 92 (25%) of abacavir recipients and six of 93 (6.5%) placebo recipients had viral loads less than 400 copies/mL (P < 0.001). This included 19 of 46 (41%) abacavir recipients with baseline viral loads of less than 5000 copies/mL vs. only four of 44 (9%) with viral loads more than 5000 copies/mL. Viral load did not predict response among placebo recipients. Three percent of abacavir recipients had hypersensitivity reactions. (ICAAC #1974.) Despite these favorable results, intensification would not be indicated in the presence of detectable resistance to the antiviral agents to be used.
Salvage Therapy
Seventy-nine patients who had viral rebound while receiving nelfinavir as their first protease inhibitor and then received ritonavir/saquinavir plus at least one NRTI were retrospectively evaluated. At three months, 65% (by intent-to-treat analysis) had plasma HIV RNA less than 500 copies/mL. (ICAAC #2065.) Ten patients failing a protease inhibitor-containing regimen who were naïve to nelfinavir, saquinavir, and efavirenz were given these three drugs together with one or two NRTIs. Eight (80%) had, after a mean follow-up of 8.4 months, undetectable viral loads and a mean CD4 increase of 165 cells/mm3. (ICAAC #2205.)
Twenty-two patients failing regimens containing indinavir or ritonavir (13 had previously also received saquinavir and 13 didanosine) were given didanosine/ hydroxyurea/efavirenz/nelfinavir. At 24 weeks, 12 (53%) patients had plasma HIV RNA less than 200 copies/mL and nine (41%) had less than 50 copies/mL. There was no increase in CD4 count. An undetectable viral load was associated with the presence of fewer than four protease gene mutations at baseline, but had no relation to RT gene mutations, previous didanosine use, initial viral load, or CD4 count. A viral load of more than 1000 copies/mL at 24 weeks was associated with the presence of K103N and L100I mutations seen with efavirenz resistance. (ICAAC #2206.)
Of 23 heavily pretreated patients with multiple protease gene mutations at baseline with three months of follow-up, only four had an undetectable viral load. Nine developed nephrolithiasis. (ICAAC #2209.)
Resistance to Antiretroviral Drugs
Resistance Testing. A comparison of DNA sequencing, the Affimetrix HIV GeneChip, and the line probe assay (LiPA) found that the three methods detected identical primary mutations (LiPA within the RT gene only) with discrepancies limited to secondary mutations. The LiPA may be more sensitive than the other two methods. (ICAAC #1590.)
A multilaboratory (33 sites) evaluation of HIV-1 drug resistance testing by gene sequencing was performed by submission of five coded plasma samples seeded with various proportions of two strains of HIV-1. One strain had defined mutations in the RT gene and the other in the protease gene. In 1:1 mixtures of mutant and wild-type virus, the five mutations were detected in 49% of laboratories for the protease gene and in 37% for the RT gene. There was no difference in results achieved by each of the three most commonly used sequencing methods. (ICAAC #1168.) There was 94.2% concordance of RT genotypic results when comparing the Affymetrix GeneChip and the Visible Genetics sequencer. Results were worse with HIV-1 clade C than clade B. (ICAAC #1174.) These results, while improved since this study was last performed, point to continued problems with current methods of genotypic analysis for detecting potential drug resistance.
The relative value of phenotypic and genotypic methods of resistance testing continues to be investigated. An extensive evaluation of phenotypic resistance testing using the ViroLogic method found that it appeared to provide more reproducible results than did genotypic methods, was readily performed on samples with viral loads as low as 500 copies/mL, and detected minority species making up as little as 10% of the viral population, especially if associated with high-level drug resistance. Results require 14 days. (ICAAC #418.)
Efavirenz and saquinavir naïve, but protease inhibitor experienced patients with plasma HIV RNA more than 5000 copies/mL were given, together with NRTIs, ritonavir (100 mg bid)/saquinavir (1000 mg bid)/efavirenz (600 mg qd). Twenty-one of 32 (67%) had plasma HIV RNA less than 500 copies/mL at 36 weeks. Although baseline genotypic resistance to saquinavir did not predict treatment failure, phenotypic resistance did. While 84% of those with virus phenotypically sensitive to saquinavir achieved a viral load less than 500 copies/mL, only 42% of those with resistance did so. (ICAAC #2068.)
Resistance Mutations. Analysis of the RT gene of HIV from 17 patients failing a regimen of efavirenz and nelfinavir found that K103N alone was the first NNRTI resistance mutation to appear in 11 (65%), while K103N appeared together with a second alteration in four (24%), with G190E/S alone in three (12%). The first protease gene mutation to appear was D30N alone in seven patients and L90M alone in four, while multiple primary mutations (including D30N + L90M) were observed in four. Two protease cleavage site mutations were identified at later time points, each in association with a D30M mutation. (IDSA #320.) Virus obtained from individuals following viral rebound during therapy with an NNRTI had an increase in IC50 from 1-2 nM to 43-49 nM, largely as the consequence of development of only a K103N mutation. Isolates that carried K103N or Y188L were cross-resistant to efavirenz, nevirapine, and delavirdine. Recombinant viruses containing Y188L with or without V106I or G190E mutations in the absence of detectable K103N had IC50s of more than 289 nM. (IDSA #322.)
Seven of 10 patients with the K103N mutation after nevirapine therapy had also been receiving zidovudine; the other three had used zidovudine prior to nevirapine therapy. None of 14 identified with only the Y181C mutation after nevirapine therapy had received concomitant zidovudine (P = 0.00035). These data suggest that the K103N mutation in patients receiving nevirapine may be dependent upon zidovudine use since, in contrast to K103N, virus with only Y181C may remain susceptible to efavirenz. (ICAAC #1171.)
No mutations in either the protease gene or the reverse transcriptase gene in HIV were initially detected in plasma shortly after loss of viral suppression in 20 of 26 patients receiving nelfinavir together with AZT and lamivudine. Virus from the other six contained the M184V mutation while three also contained D30N, but the appearance of the latter postdated that of the former. M41M/L or K219K/R was also detected in two of the six. Thus, initial breakthrough viremia in these patients appeared to be associated with genotypic evidence of lamivudine resistance, but not nelfinavir resistance. (IDSA #321.) This is a finding that has been seen with other regimens, including ones containing lamivudine and indinavir.
A phenotypic analysis of virus from patients failing their first protease inhibitor-containing regimen found that, compared to the other drugs of its class, the initial use of nelfinavir was associated with less cross resistance to other PIs. In particular, susceptibility to amprenavir and to saquinavir was frequently observed. (ICAAC #1167.)
Cross resistance to amprenavir was seen least frequently when compared to other available protease inhibitors in heavily pretreated patients. (ICAAC #442.)
Virus from three heavily treated patients had in frame three nucleotide mutations between RT codons 67 and 70, a region involved in positioning the template primer on the RT enzyme. (IDSA #365.) This is the same region in which insertions have been noted that are associated with stavudine and, often multiple NNRTI resistance.
Fitness and Other Changes in Mutated Virus
Viral constructs containing point mutations L74V, T215Y, Y188C, or G190E, which confer resistance to drugs acting against the RT, demonstrated reduced rates and extent of viral replication. Those with K103N exhibited reduced rate but not extent of replication. Constructs with Y181C, Y188H, or G190A grew slightly better than wild-type virus. (ICAAC #1169.)
Increased (2.5- to 10-fold) susceptibility to amprenavir was associated with the presence of an N88S mutation in HIV-1 protease. (ICAAC #1175.)
Post-Exposure Prophylaxis
Use of the HIV-1 Single Use Diagnostic System, which provides the results of HIV-1 antibody testing within two hours, in evaluating source patients in cases of parenteral exposure of health care workers resulted in significant cost savings by avoiding several days of prophylactic therapy when source cases prove seronegative. (IDSA #388.)
Fewer than one-fourth of health care workers completed the prescribed four weeks of PEP. (IDSA #389.)
Investigational Drugs
Coviracil (emtricitabine, FTC) is an oxathiolane nucleoside analog that also has activity against HBV.
Tenofovir (bis-POM-PMPA), a nucleotide analog RT inhibitor, is reported to maintain activity not only against virus with the mutation at codon 184 selected by lamivudine, but also against virus with the mutation at codon 151 asociated with multidrug resistance.
Emivirine (MKC-442) is an NNRTI with good CSF penetration: CSF levels were approximately 11% of plasma levels with concentrations 20-fold higher than the IC50 of wild strains. (IDSA #363.) Eighty-three percent of patients given emivirine plus lamivudine plus stavudine had viral loads less than 400 copies/mL, 84% of whom had viral loads less than 50 copies/mL. (IDSA #364.) Virus with K103N is resistant to emvirine. (ICAAC #1172.) Other investigational NNRTIs include lodenosine, DAPD, and UC781.
Protease inhibitors under investigation include UIC-94-003, tiprinavir, and VX-175/GW433908g, a prodrug of amprenavir. Progress on ABT-378, given with ritonavir, continues.
The fusion inhibitors T20 and T1249 remain under investigation, as are some chemokine receptor antagonists, such as TAK-779, a CCR5 receptor antagonist, and AMD3100, a CXCR4 receptor antagonist. The CXCR4 antagonists AMD-3100 and Met-SDF 1ß are antagonistic in vitro. (IDSA #369.)
A drug with a novel site of action is temacrizine, which selectively inhibits initiation of HIV-1 transcription. Didox is a ribonucleotide reductase inhibitor that shows promise in vitro. The immunosuppressive agent, mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, demonstrates significant in vitro synergy with abacavir against HIV-1. In contrast, antagonism is seen when this drug is combined with either zidovudine or stavudine, possibly due to inhibition of thymidine phosphorylation. (ICAAC #690; J Acquir Immune Defic Syndr 1999;21:362-370).
Which of the following is correct?
a. Less than 10% of health care workers discontinue post-exposure prophylaxis for HIV prior to completing four weeks.
b. Patients with lactic acidosis secondary to NRTI therapy invariably present with coma.
c. Humoral immunity may be enhanced by successful HAART.
d. Several protease inhibitors accelerate neutrophil apoptosis.
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