Note: The following summaries represent a selection of papers from among those presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28-October 1, 1997, in Toronto and the 35th Annual Meeting of the Infectious Disease Society of America (IDSA), held September 13-16, 1997, in San Francisco. Although these two meetings were held separately for the first time, my contrary nature causes me to combine them here. The abstract designations which begin with "IDSA" indicate that they were presented at that meeting; the remainder were presented at ICAAC. It is important to recognize that many of these summaries are extracted only from the published abstracts, and it is possible that some of the material presented at the conference may have differed. SD
Epidemiology: HIV-2
HIV-2 infection may not be reliably detected by all HIV tests. Two patients born in India and having HIV risk factors while living there, but currently residing in the United States, were found to be infected with HIV-2. Neither had epidemiological ties to West Africa. HIV-2 infection should be considered in India-born individuals since that country is the first outside Africa to be widely afflicted by this virus (Dietrich U, et al. Trends Microbiol 1995;3:17-21). (IDSA-468.)
Post-exposure prophylaxis
At least two studies indicated that currently recommended post-HIV exposure prophylaxis regimens are poorly tolerated. Of 148 health care workers in Boston with occupational HIV exposure, 46 (31%) initiated post-exposure prophylaxis according to CDC guidelines. Eleven (24%) prematurely discontinued prophylaxis at a mean of 8.5 days because of toxicity. One was hospitalized because of pancytopenia, and two others missed more than a week of work. Ten (22%) reported emotional distress. (IDSA-480.)
In Iowa, one-third of the participants discontinued prophylaxis prematurely because of toxicity (IDSA-481). Similarly, in a nationwide registry (call 1-888-HIV-4PEP to register subjects), 31% discontinued prophylaxis because of toxicity. (IDSA-482.)
These data suggest that we need to take a close look at current recommendations for post-exposure prophylaxis in HIV-exposed health care workers, and that currently planned studies of similar prophylaxis after sexual exposure may prove difficult.
Viral load and Durability of Response
In patients given ZDV, ddI, or nevirapine in varying combinations, plasma viral load nadir reached after institution of therapy was predictive, in a multivariate analysis, of the durability of suppression (defined as remaining within 0.5log of the nadir) of viral replication. Baseline viral load or CD4 count or change in CD4 count were not. The median duration of suppression for individuals whose nadir was less than 20 copies/mL was 154 days, while it was only seven days for those who did not achieve this nadir (P = 0.0001). (A-14.)
Failure of Antiretroviral Therapy
Of 137 patients receiving either indinavir or ritonavir at a university-based public health clinic, 53% evidenced failure of antiretroviral therapy as defined by the presence of plasma HIV RNA levels of more than 500 copies/mL on two consecutive measures obtained after at least 24 weeks of therapy. Late-stage disease and suboptimal prior therapy were independent predictors of failure. (LB-2.)
The disposition of protease inhibitors is quite variable among HIV-infected patients, and this variability may explain the lack of adequate response to therapy in some. Indinavir administration to 13 antiretroviral naïve patients resulted in plasma HIV RNA concentrations of less than 500 copies/mL in seven, while the level remained above 500 copies/mL in the remainder. Patients whose viral load was undetectable by this assay had a median minimum (trough) indinavir plasma concentration of 0.14 mg/mL and area under the curve of 20.2 mg•hr/L, while the respective values for those whose virus remained detectable were 0.02 mg/mL (P = 0.05) and 11.5 mg•hr/L (P = 0.06) (A-15). The association of treatment failure with low trough serum concentrations of indinavir was confirmed in a study in which this protease inhibitor was administered with nevirapine. (I-173.)
In another study, the mean extrapolated trough plasma concentration of indinavir of responders (< 500 copies/mL) was 0.133 mg/mL, while that of compliant non-responders was 0.023 mg/mL. All 11 responders had plasma indinavir concentrations above the IC50 (0.075 mg/mL) for at least 90% of the dosing interval, while this was true for only 58% of the non-responders. The authors conclude that trough levels above 0.075 mg/mL should be maintained for at least 90% of the dosing interval. (A-19.)
A significant proportion of the interpatient variability in disposition of protease inhibitors may be the result of varying levels of activity of the enzyme largely responsible for their metabolism, P450 (CYP) 3A4. The erythromycin breath test may be useful in characterizing this activity (A-55).
Dosing
Administration of indinavir in a dose of 1200 mg every 12 hours appears to be as effective and tolerated as the standard dose of 800 mg every eight hours (IDSA-225). The antiviral activity and the safety profile of q 12-hour administration of indinavir was comparable to that of q eight-hour administration in patients also receiving 3TC. (I-91.)
The administration of ddI as a single daily dose of 400 mg may be as effective and well-tolerated as the standard 200 mg bid dosing regimen. (IDSA-210, 211.)
Protease Inhibitors in Combination
Coadministration, in various q12h doses, of ritonavir increased the indinavir area under the curve by as much as 480% and increased its maximum concentration by up to 110%. There was no significant effect on ritonavir disposition. It was estimated that a regimen of 400 mg each of indinavir and ritonavir q12h will lead to areas under the curve of each drug being similar to that seen with currently used regimens. (A-57.)
CNS Penetration and Antiviral Activity
Twelve of 13 patients with baseline CD4 counts of 50-350 cells/mm3, a median viral load of 57,000 copies/mL, and who had been largely antiretroviral naïve were given ritonavir and saquinavir and found to have less than 400 HIV RNA copies/mL in their CSF after a median of 60 weeks of treatment. (LB-3.)
CSF indinavir concentrations in 10 patients receiving 800 mg every eight hours were 51-149 nM with median CSF: plasma ratios ranging from 2.2% to 76%, with the highest ratios seen at the end of the dosing interval. CSF HIV RNA was less than 200 copies/mL in nine of the 10 subjects. (IDSA-22.)
Salvage Therapy
Patients with an L90M and G48V mutation after saquinavir monotherapy failed to respond to treatment with the combination of ritonavir and saquinavir. Patients with a L90M mutation alone had a transient response. (I-193.)
Twenty-two patients, previously protease inhibitor therapy naïve, who had failed treatment for at least 12 weeks with a nelfinavir-based regimen received either indinavir or saquinavir plus ritonavir in place of nelfinavir. In most, the subsequent change in viral load was minimal, indicating failure (LB-5). On the other hand, seven of nine patients given a ritonavir plus saquinavir based regimen after failing nelfinavir had a reduction of viral load to less than 500 copies/mL after a median of 2.2 months. (I-204.)
Nelfinavir was largely ineffective as salvage therapy in most patients with CD4 less than 100 cells/mm3 who had failed prior therapy with indinavir or ritonavir. (I-192.)
Treatment of patients who had failed indinavir therapy with saquinavir plus ritonavir led to a greater than 1 log10 reduction in viral load to less than 2000 copies/mL at 12 weeks in four of 11 (I-201). However, in another study, only four of 16 patients failing indinavir who were managed in this way had a durable response (> 1.0 log10 below baseline) beyond 12 weeks (I-205). Even more limited benefit was seen in a group of patients who had failed indinavir or ritonavir prior to being given the combination. (I-206.)
These results suggest that only a minority of patients who fail protease inhibitor therapy will have a durable response to another drug or combinations of drugs from this class, even when combined with RT inhibitors. Genotypic analyses of the protease and RT genes have become available and may prove useful in selecting appropriate drugs for salvage therapy. In addition, a phenotypic assay for resistance of a patient’s HIV-1 isolates to antiretroviral drugs, which provides results within only 8-10 days, was described. The system consists of replication defective pseudotyped virions into which the protease and reverse transcriptase genes of the HIV isolate being examined drive a firefly luciferase reporter system. (LB-1.)
Adverse Effects
Twelve (6.9%) of 174 patients receiving indinavir developed nephrolithiasis at a mean of four months (range, 3 days-10 months) after institution of therapy with this drug. Eight of the 12 with a first episode continued indinavir therapy, and five (62.5%) had a second episode of nephrolithiasis (I-183). In contrast, a clinic in Dusseldorf found that 19 (12%) of 158 patients developed sonographically confirmed nephrolithiasis, while another 11% had flank pain without documented stones. (I-184.)
Metabolic Effects
The administration of indinavir to 10 antiretroviral naïve patients for four weeks resulted in an increase in serum cholesterol from 145 + 24.9 to 172 + 36.0 mg/dL (P = 0.018), while triglycerides increased from 95.5 + 39.2 to 142.1 + 54.4 mg/dL (P = 0.0067). (IDSA-233.)
Protease inhibitor therapy is associated with increases in body weight, body mass index, fat free mass, total body water, and fat (IDSA-549). Administration of oxandrolone and L-glutamine was associated with significant weight gainincreased body cell mass without gain in body fat. (IDSA-548.)
Six (5.7%) of 105 patients given protease inhibitor therapy (mostly indinavir or saquinavir) developed symptomatic diabetes mellitus; two each were managed with insulin, oral agents, or diet alone. (LB-8.)
Efavirenz (DMP 266)
The most common mutation in the HIV-1 reverse transcriptase gene associated with failure of therapy with the new non-nucleoside reverse transcriptase inhibitor (NNRTI)efavirenzwas K103N. Changes at amino acid positions 188, 106, 190, and 100 were also seen, but changes at 101 or 181 (which are associated with resistance to other NNRTIs) were not. (I-172.)
Coadministration of efavirenz with nelfinavir results in an approximately 15% increase in the area under the curve of nelfinavir; no significant change in efavirenz pharmacokinetics was observed. (I-174.)
Efavirenz appeared in the CSF of three patients after administration of 200 mg daily, with CSF concentrations varying from 26.4 nM 1.2 hours after a dose to 16.9 nM at 22 hours, representing 1.19-0.65% of simultaneous plasma concentration, reflecting the proportion of non-protein bound drug in plasma. These concentrations are above the IC95 for most HIV-1 isolates. (A-12.)
Co-administration of efavirenz to healthy volunteers did not affect the pharmacokinetics of fluconazole. (A-4.)
Cryptococcus neoformans
A total of three cases of clinical and laboratory resistant Cryptococcus neoformans infections were reported, all after prolonged use of fluconazole as maintenance therapy for cryptococcal disease (IDSA-528, 529). Fortunately, this problem remains infrequently encountered.
Cytomegalovirus
Three hundred seventy-seven patients with CMV retinitis were randomized to receive either an intravitreal ganciclovir implant plus oral ganciclovir (4.5 g daily), an implant plus placebo, or IV ganciclovir alone. The subsequent incidences of extraocular CMV or contralateral retinitis were, respectively, 22.4%, 37.8%, and 17.9%; both therapies with systemic ganciclovir were significantly superior to implant therapy alone. Rates of new CMV disease in a subset receiving HIV-1 protease inhibitors were low in all treatment groups. The use of oral ganciclovir was associated with a reduced risk of new AIDS-associated conditions, particularly Kaposi’s sarcoma (P = 0.008), suggesting possible in vivo activity of this drug against the Kaposi’s sarcoma herpes virus (KSHV). (LB-9.)
Maintenance therapy for healed CMV retinitis was discontinued in eight patients after a mean of 398 days of HAART which had resulted in an increase in CD4 count to a mean of 172 cells/mm3 (range 63-404 cells/mm3). No cases of CMV progression occurred after a mean follow-up of 146 days (range, 72-205 days), despite detectable plasma HIV RNA in six of the eight (I-33). A similar evaluation involving seven patients also failed to observe any CMV relapses after discontinuation of maintenance therapy. (I-36; IDSA-512.)
Leishmania
Eighty-one HIV-infected patients with visceral leishmaniasis were randomized to treatment with either amphotericin B or stilbamidine, with a cure rate of 57% in the amphotericin B recipients and 66% in the stilbamidine group. Relapse rates were high but similar in the two treatment groups.
Measles
Vaccination of 58 HIV-infected adults with a median CD4 with MMR count of 179 cells/mm3 (range, 0-875) was safe but infrequently resulted in measles seroconversion, irrespective of CD4 count. (I-48.)
Microsporidiosis
Patients with intestinal microsporidiosis due to Encephalitozoon intestinalis were randomized to receive albendazole (400 mg bid for 3 weeks) or placebo. Clinical improvement occurred in the albendazole group, among whom GI clearance of the organism was observed in four of four patients; none of the four placebo recipients had clearance. The four placebo recipients subsequently received albendazole and exhibited intestinal clearance of the coccidian parasite. All eight patients were then randomized to prolonged administration of albendazole or no treatment. Three of five on no treatment relapsed, while none of three receiving albendazole did so (I-148). These results tend to confirm uncontrolled studies suggesting efficacy of albendazole in the treatment of intestinal microsporidiosis.
A dose escalation study of fumagillin administration demonstrated evidence of efficacy in the treatment of intestinal microsporidiosis due to Encephalitozoon intestinalis. (I-149.)
Mycobacterium avium Complex
Further analysis of previous studies of clarithromycin prophylaxis of MAC infection found that the associated survival benefit was the result of a reduction in incidence of a wide variety of opportunistic infections, not just MAC. These include PCP, giardiasis, community-acquired pneumonia, and HIV-related neoplastic disease (I-213).
An emerging problem is the management of macrolide-resistant MAC infection. Eight patients who relapsed with macrolide-resistant MAC bacteremia during treatment with clarithromycin plus clofazimine ± ethambutol were maintained on macrolide therapy and were given additional antimicrobials, including various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. Five of the eight had a more than 1log10 decrease in colony counts in blood, and negative blood cultures were achieved in two of these. (I-218.)
A retrospective analysis found that reduced-dose (500 mg daily) clarithromycin may be as effective as rifabutin (300 mg daily) in the prevention of MAC bacteremia. (I-223.)
Pneumocystis carinii
All the reviewed studies dealt with issues of prophylaxis of Pneumocystis carinii pneumonia (PCP). Since trimethoprim-sulfamethoxazole (TS) is the preferred prophylactic agent, it is generally recommended that patients intolerant to this drug combination be "desensitized" so that it can be safely administered in the appropriate dose. There is, however, much confusion concerning the safety of this approach and myriad regimens have been used for this purpose. For the first time, a large, randomized trial has addressed this issue.
Patients with non-life-threatening intolerance (rash or fever) to TS were randomized to either a six-day incremental dose escalation reaching one single-strength TS daily or direct rechallenge with this dose. All were also given an antihistamine. No serious or life-threatening reactions were observed. The study was discontinued after 191 patients were enrolled because it became apparent that the dose escalating regimen was superior, with 80% being successfully maintained on TS for at least six months compared to 55% in the comparator arm (P = 0.0038).
The safety of discontinuation of PCP prophylaxis in patients with marked increases in CD4 counts after institution of highly active antiretroviral therapy (HAART) was addressed. Fifty patients whose mean CD4 nadir had been 77 cells/mm3 but whose CD4 count had risen to more than 200 cells/mm3, (mean, 370 cells/mm3) after institution of HAART, discontinued PCP prophylaxis (prophylaxis was primary in 45). At the time of discontinuation, plasma HIV RNA levels were "non-detectable" in 40 and did not exceed 15,000 copies/mL in the other 10. No cases of PCP were observed after a mean follow-up of 6.4 months (median, 4.8; range, 0.4-30.5 months). (LB-11.)
Although thrice weekly TS appears to be effective PCP prophylaxis, concern has been raised about its adequacy in preventing toxoplasmosis in seropositive patients. A case-control study found that low-dose TS (< 4 DS tablets weekly) was inferior to high-dose S (> 4 DS weekly) in the primary prophylaxis of toxoplasmic encephalitis. In addition, rifampin appeared to diminish the efficacy of TS prophylaxis. (I-140.)
In addition, a randomized trial of PCP prophylaxis with TS (DS) in 2625 patients with a median CD4 count of 120 cells/mm3 and 5310 person years of follow-up found a trend toward superior effects, especially when used for secondary prophylaxis, when given daily rather than thrice weekly. (I-146.)
Four hundred seventy-six patients were randomized to receive, as either primary or secondary PCP prophylaxis, low-dose (750 mg daily) or high-dose (1500 mg daily) atovaquone suspension or aerosolized pentamidine 300 mg monthly. The incidences of PCP were, respectively, 22%, 20%, and 17% (P = NS) (IDSA-518). Thus, prophylaxis of PCP with either dose of atovaquone suspension appears to have efficacy similar to that of aerosolized pentamidine.
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) stabilized or improved in two patients coincident with administration of cidofovir (I-5). A retrospective analysis suggests that HAART prolongs survival in patients with PML (I-34).
Sinusitis
Patients with paranasal sinusitis were randomized to receive cefuroxime axetil with or without Flonase. Failures were significantly more common in the group not receiving Flonase. Of the total group, 43% had recurrence of sinusitis at a mean of 10 weeks after completion of therapy. (IDSA-541.)
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