Summaries of the Sixth Conference on Retroviruses and Opportunistic Infections:
March 15, 1999 22 minutes read
Summaries of the Sixth Conference on Retroviruses and Opportunistic Infections: Part I
conference coverage
Note: The following summaries represent a selection of papers from those presented at the 6th Conference on Retroviruses and Opportunistic Infections held on Jan. 31-Feb. 4, 1999, in Chicago, IL. It is important to recognize that some 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 abstracts and posters, as well as other information presented at the conference, are available on the internet at www.retroconference.org. —Stan Deresinski, MD, FACP
HIV Infection
Virology
Origin of HIV-1. It has been clear for some time that the primate reservoir of HIV-2 is the sooty mangabey. Although long suspected, proof of an African primate origin of HIV-1 has been lacking. There is now strong evidence implicating African chimpanzees as the source of this retrovirus.
The story of the index virus for this study, SIVcpzUS, is a fascinating one. Marilyn was one of a group of chimpanzees captured in West Africa and brought to a National Institutes of Health research facility. Having been selected to participate in HIV vaccine studies, she underwent screening studies and was found to be HIV-1 seropositive. Unfortunately, by the time this was discovered, Marilyn had died after childbirth (post-mortem examination was reported to show endometritis). Fortunately, her tissues were saved. These tissues were discovered some years later during the cleaning out of a freezer, and their potential importance was recognized. The virus, now called SIVcpzUS, was recovered from Marilyn's frozen tissue and fully sequenced for comparison with other relevant isolates.
Four SIV isolates (SIVcpz) obtained from chimpanzees were evaluated. One isolate, obtained from the chimp subspecies, Pan troglodytes schweinfurthii, was highly divergent from the others and from HIV-1. The other three isolates of SIVcpz, all isolated from the common subspecies Pan troglodytes troglodytes to which Marilyn belonged, were all closely related to each other and to all HIV-1 groups (M, N, O) known to infect humans.
Further analysis discovered that HIV-1 group N is a mosaic of SIVcpzUS and sequences related to those of HIV-1, evidence of an ancestral recombination event having occurred in a chimpanzee. Of further importance is the recognition that the natural range of P.t. trogolodytes coincides with those of HIV-1 endemicity in Africa. Thus, this chimp subspecies is the primate reservoir of HIV-1. Finally, there have been at least three independent introductions of SIVcpz into humans. Humans are likely to be at risk of such introductions as a consequence of their hunting and butchering of chimpanzees for food. Chimpanzees may also be kept as pets, providing additional potential means of transmission (Hahn. Keynote Address; Nature 1999;397:436).
Separately, another group of investigators detected SIVcpz in three of 29 wild chimps in Cameroon. (Abstract 76.)
Viral Replication Dynamics. CD45RO/CD45RA doubly-positive cells, which comprise less than 10% of CD4+ T lymphocytes, were reported to be the primary target cells for initial infection by HIV-1. (Abstract 66.) A reanalysis of HIV-1 dynamics suggested that viral clearance occurs with a half-life of 1.3-3.6 hours, a rate much faster than previously estimated, suggesting also that a much greater number of virions are produced and cleared each day. (Abstract 9.) The same group, using a method involving plasmapheresis, led to a half-life estimate of 39-109 minutes and daily viral turnover of 4-30 billion.
Any number of infections and other proinflammatory stimuli have been demonstrated to be associated with transiently increased plasma viral loads in HIV-infected patients. Supernatants from either lipopolysaccharide (endotoxin) stimulated macrophages, HSV-infected macrophages, or HTLV-1-infected CD4+ T cells induce in vitro activation of HIV from latently infected resting CD4+ T cells. Coculture with CD8+ T cells inhibits this reactivation, a finding consistent with the antiviral role played by these cells. (Abstract 164.) Allogeneic stimulation occurs during pregnancy, blood transfusion, and organ transplantation. Such stimulation of latently infected resting CD4+ T cells obtained from HIV-infected subjects induces HIV replication in vitro. (Abstract 153.)
Pathogenesis and Viral Phenotype. Longitudinal analysis of a large number of patients found that, among those with a more than 8.2% per year decline in CD4+ T cell count after the CD4+ T cell inflection point (the point at which the rate of CD4 count decrease changed from gradual to abrupt) has been reached, the majority had a viral phenotypic switch from nonsyncytium-inducing (NSI) to syncytium-inducing (SI). This switch was highly correlated with the timing of the inflection point, with the SI switch preceding the inflection point by a median 0.73 year; the inflection point, in turn, preceded the onset of AIDS by a median 1.4 years. This study confirms the important role of SI virus in progression to AIDS, as well as the concept of blind T cell homeostasis and its collapse leading to progression of disease. (Abstract 70.)
HIV Transmission
Many assume that patients who achieve undetectable viral loads in response to therapy are unlikely to transmit HIV infection. However, the concentration of HIV in semen may remain relatively high during the first year of infection in the face of low or undetectable levels in plasma. (Abstract 301.) In addition, HIV-1 proviral DNA could be detected in seminal cells of four of seven subjects despite prolonged suppression of virus in plasma (HIV RNA < 50 copies/mL). Replication competent virus was also detected from peripheral blood cells of three of seven and from seminal cells in two of the three subjects with proviral DNA detected. Analysis of the replicating virus from seminal cells of those two failed to detect evidence of resistance-associated mutations; the virus appeared to be M-tropic, the phenotype associated with sexual transmission. (Abstract 7.)
A case of heterosexual transmission of an NNRTI-resistant HIV-1 was reported. (Abstract 219.)
Review of 89 pregnancies during which PIs were administered found no transmissions and a prematurity rate that did not differ from prior results in HIV-infected women not receiving PIs. The 95% confidence interval for the transmission rate, based on 65 infants on whom complete information was available, was 0-6%. (Abstract 686.) Both PIs and nevirapine appeared to be safe and effective in a separate cohort of 64 pregnant women. (Abstract 687.)
A 52-year-old healthcare worker became HIV infected as the result of a needlestick injury despite initiation of post-exposure prophylaxis with AZT/3TC/ddI/indinavir within 40 minutes of injury. (Abstract 210.)
HIV Vaccines
Investigation into the development of a protective vaccine appears to have picked up. Work with a number of SIV-based vaccines was described including: D-Nef live attenuated SIV; SIV nucleocapsid mutant DNA; SIV gag/pol DNA; and SIV with inactivated (by disulfidation) nucleocapsid zinc fingers. (Abstracts 39-42.)
A DNA vaccine encoding HIV-1 env and rev is under evaluation in a Phase 1 study in adults. Preliminary data suggest that it is safe and, at the highest dose administered, leads to in vitro immune reactivity of peripheral blood mononuclear cells to cognate antigens. This was associated with secretion of IFN-gamma, MIP-1alpha, MIP-1beta and RANTES, but not IL-4. (Abstracts 41, 44.)
ALVAC-HIV vCP205, a recombinant HIV vaccine expressing gag p55-poly protein, p15 protein, anchoring region gp41 d HIV-1 LAI, and gp120 of HIV-1 MN is under evaluation in ACTG 326. Repeated doses (or placebo) are given to infants born to HIV-infected mothers, with the first dose given in the first 72 hours of life. Preliminary evaluation of the administration to 12 subjects suggests that this vaccine was safe and immunogenic in some of these neonates. (Abstract 43.)
Occult and Seronegative Infection
HIV-1 env, gag, and pol sequences were consistently detected in resting CD4+ T cells, but not plasma, of a cohort of 37 individuals who remained HIV-1 seronegative despite repeated high-risk sexual activity with HIV-1 infected partners. Genetic analysis of serially obtained isolates from individual subjects demonstrated sequence identity, suggesting no or little replication. In addition, there was no evidence of superinfection with other strains of HIV-1, suggesting the possibility of protection by this occult infection. (Abstract 8.)
Six HIV-21 infected, but persistently seronegative, patients were investigated. Analysis of their infecting virus detected no unusual characteristics. Four of the six patients had antibody against at least one other common pathogen. Despite mitogenic stimulation, no antibodies against HIV-1 were produced by their peripheral blood mononuclear cells in vitro. (Abstract 52.)
Primary Infection
Diagnosis. The value of a less sensitive ("detuned") EIA, together with standard EIA, in the diagnosis of primary HIV infection in patients undergoing recent seroconversion was confirmed. (Abstract 486.)
The use of HIV-1 RNA bDNA testing (Chiron 2.0; limit of quantitation, 500 copies/mL) was examined in the diagnosis of acute HIV infection. The true-positive rate was 100%, false-positive rates 2%; both false-positive cases gave results of less than 600 copies/mL. All true-positives yielded more than 2000 copies/mL. (Abstract 178.)
In a separate study, the same assay had a false-positive rate of 4.4%; with the Chiron 3.0 bDNA assay (limit of quantitation, 50 copies/mL), the rate of false-positives was 9.5% and ranged from 6.5% to 14.3% at different time points. The range of false-postive results with Chiron 2.0 was 501-9816 copies/mL and was 51-281 copies/mL with Chiron 3.0. The investigators conclude that "viral load screening in asymptomatic individuals yields a high false-positive rate and is not recommended as a diagnostic tool." (Abstract 179.)
Progression of Infection. Previous studies have found that the risk of progression to AIDS after seroconversion is associated with the magnitude of the initial stabilized plasma HIV-1 RNA concentration, often referred to as the set point. Examination of the MAC cohort has found that progression is also strongly associated with the rate of increase of viral load over the first three years of infection. (Abstract 273.)
Primary Drug Resistance. Examination of virus from recently infected patients in New York city and Los Angeles found that the incidence of primary drug resistance has remained stable and at a low level. (Abstract 277.) In Seattle, none of 24 recently infected subjects had evidence of genotypic resistance to PIs, but one had mutations associated with high-level resistance to RT inhibitors and two had evidence of low-level resistance to those drugs. (Abstract 217.) HIV isolates from seven (3.7%) of 189 ART-naïve subjects in British Columbia had mutations associated with significant resistance to RT inhibitors and two (1.4%) had genotypic evidence of resistance to PIs. (Abstract 218.)
Sixteen of 31 RT-gene sequences and 19 of 29 protease sequences from virus obtained from 34 recently infected subjects in the United States contained mutations associated with drug resistance. Four had two and one had three PI-associated mutations. (Abstract 216.)
Virus from plasma samples obtained a mean of 55 days after estimated seroconversion in 69 patients from San Diego, Los Angeles, Denver, Dallas, and Boston were susceptibility tested by the ViroLogic phenotypic assay. Mild-to-moderate resistance to at least one drug was present in 25%; 3% to an NRTI, 17% to an NNRTI, and 13% to a PI. High-level phenotypic resistance to at least one drug was seen in 4%. Reduced susceptibility to only one PI was seen with virus from seven subjects while that from two subjects was resistant to all PIs tested (ritonavir, saquinavir, indinavir, and nelfinavir). (Abstract LB10.)
The prevalence of primary resistance to nucleoside analog RTIs in Spain has remained constant at approximately 12% since 1993. (Abstract 125.) In Belgium, a study of 114 HIV-1 isolates from treatment-naïve patients infected within the last three years, found that the presence of genotypic or phenotypic (Virco) resistance was 21%. The prevalence of resistance to two different classes of drugs was 3.2% by genotype and 2.2% by phenotype; the prevalence of resistance to all three classes of drugs was 2.1% and 3.3%, respectively, by the two methods. (Abstract LB9.)
Therapy. Twenty patients with early HIV infection and 16 with recent (within 120 days) infection were treated with d4T/ddI/nelfinavir/hydroxyurea. After eight weeks, 95% with early and 88% with recent HIV infection had undetectable plasma HIV RNA (Chiron 2.0). While CD4% increased, the absolute number of CD4+ T cells remained unchanged. (Abstract 398.) Separately, 22 patients with primary HIV infection were randomized to receive d4T/ddI/nevirapine with or without hydroxyurea. Plasma viral load was less than 500 copies/mL in 18 of 19 at 12 weeks and 11 of 12 at 24 weeks. Thus, both regimens were effective in reducing viral load in this setting. (Abstract 399.)
Patients who receive HAART during primary infection appear to be able to preserve HIV-1 gag-specific T-helper responses. (Abstract S41.)
Ten patients received hydroxyurea, ddI, and a PI beginning within 1.7 months of becoming HIV infected. Plasma HIV RNA decreased to less than 50 copies/mL in each patient and was associated with return of naïve T cells and vigorous T-cell helper response. HIV was detected in quiescent T cells at a frequency of only 0.3 per 106 cells. (Abstract 401.)
A recently infected patient was started on therapy with ddI, indinavir, and hydroxyurea prior to his complete seroconversion with his plasma viral load decreasing to undetectable levels. Viral replication resumed after an initial therapy discontinuation, but not after a second, and plasma HIV RNA remained undetectable for 551 days after 176 days of treatment. Very small levels of HIV were, however, detected in lymph nodes (3 cells/4.4 ´ 107 cells) and in resting CD4+ T cells (< 0.1 cells/106 cells). The proportion of naïve T cells increased to normal. While no neutralizing antibody was detected, a vigorous CD8+ cytotoxic T lymphocyte response was present, possibly accounting for the continued suppression of viral replication in the presence of persistent infection but in the absence of antiretroviral therapy. (Abstract 351.)
Analysis of Antiretroviral Clinical Trial Results
A comparison of the two methods found that, in the evaluation antiretroviral therapy, determination of the "area about the change from baseline" was more robust than determination of the proportion of patients achieving undetectable viral loads. (Abstract 395.)
| Table |
| Study Analysis—Varied Methodologies_______________________________ |
Intention-to-treat vs. as-treated |
| The FDA requires an intent-to-treat analysis with missing data considered failure.
________________________________________________________________________ |
The method of analysis has profound effects on the reported results of clinical trials. A meta-analysis of 11 trials of HAART in antiretroviral naïve patients found that, using an assay with a lower limit of quantitation of 400 copies/mL and excluding missing data, the mean proportion of patients with undetectable viral loads was 81% (range 57-97%). At the other extreme, using a less than 50 copy assay and an intention-to-treat analysis with missing data counted as failure, the mean proportion of patients with undetectable viral load was only 52% (range, 30-78%). The mean difference between the most and least conservative analyses for the 11 trials was 29% (range, 15-46%). (Abstract 394.) The Table is a listing of variables to be considered in evaluating the reporting of clinical trial results.
Antiretroviral Therapy
In a survey performed at the end of 1997, more than one-fourth of patients were receiving ART regimens other than that recommended in the Department of Health and Human Services guidelines. (Abstract 104.) Separately, it was found that, also late in 1997, one-third of patients receiving medical care for HIV infection and eligible for antiretroviral therapy were not receiving HAART.
Adherence to Therapy. Clinicians tend to overestimate patient adherence to prescribed drug therapy; one-fourth of patients assessed as adherent by their caregivers actually took 80% or fewer of their PI doses. (Abstract 97.) In a study in which the "gold standard" for assessment of patient adherence to antiretroviral regimens used electronic detection of opening of medication bottles by use of the MEMS device, it was found that the accuracy of physicians' perception of adherence was extremely poor. Patient report was even worse. Modifiable variables associated with poor adherence included active depression (P = 0.002) and active alcholism (P = 0.069). With virological control defined as plasma HIV RNA less than 400 copies/mL, there was a strong association between adherence and virological control (P = 0.00001). Control was achieved in 81% of subjects with more than 95% adherence and in only 64% with 90-95% adherence. (Abstract 92.) In another study, only 22% of patients had perfect adherence as measured electronically. The sensitivity and specificity of detection of nonadherence self-report were only, respectively, 0.54 and 0.66. (Abstract 95.) Even some patients with an excellent initial viral load response to initiation of therapy may be nonadherent and are, therefore, at risk of subsequent failure. (Abstract 96.)
A high level of adherence, based upon measurement of plasma drug levels, to a PI-containing regimen in homeless patients has previously been reported. This same group has now reported that, in fact, the degree of adherence in these patients was not as great as they had previously reported. Median adherence, although 95% by self-report, was 77% by pill count and, most importantly, was only 59% by electronic monitoring. Of further note is that while adherence accounted for 60-70% of the observed variation in viral load during the eight weeks of this study, genotypic resistance was not predictive in subjects with virus susceptibility to at least one drug in their regimen. (Abstract 93.)
In what seems a paradoxical observation, treatment adherence increased with the number of antiretrovirals in a regimen as well as with the number of pills prescribed per day. Adherence was better if subjects reported that their regimen fit with their daily schedule and if they perceived therapy to be effective and that nonadherence would lead to viral resistance. (Abstract 98.) Limited literacy appears to be a more significant barrier to adherence than race. (Abstracts 108, 97.)
Usefulness of Genotypic Assessment of Drug Resistance. Genotypic sequence analysis with "expert advice" in patients failing HAART was associated with improved short-term (12 weeks) virological response when compared to a control group (-1.17 log10 vs 0.62 log10; P = 0.0001). However, there was evidence of rebounding viral load, and only 29% of the intervention group and 17% of controls had undetectable viral loads. The virologic response in both groups correlated with the number of active drugs prescribed. (Abstract LB8.) The insititution providing the analysis and advice charges in excess of $600 per result. At that cost, it is unclear that the modest benefit seen in this study warrants that cost. Furthermore, this study did not determine whether the drug history or the genotype was more important. Other methodologies are less expensive and require similar analysis.
Predictors of Response to Antiretroviral Therapy
The persistence of low-level viremia in the face of antiretroviral therapy has been puzzling and attempts to determine the presence or absence of resistant-associated mutations are often frustrated by an inability to amplify sufficient genome for analysis. Using a more effective extraction method, sequencing of virus obtained from five plasma samples with low levels of viremia (most < 1000 copies/mL) found a mean of 9.6 PI resistance-associated mutations and 11.4 RT resistance-associated mutations. (Abstract 144.)
Patients whose plasma HIV RNA was "detected, but less than 400 copies/mL" by the Amplicor assay were at four-fold risk of subsequent virological failure compared to those in whom it was undetectable. (Abstract 170.) Nearly one-half of clinic patients whose viral loads were less than 400 copies/mL had detectable virus when tested by an assay capable of quantitating as few as 20-50 copies/mL. However, this observation led to a change in therapy in only four (4.5%) of 86 patients with virus detectable but with less than 50 copies/mL. (Abstract 175.)
A comparison of RT gene sequencing and the line probe assay found discrepancies due to the presence of polymorphisms in the vicinity of resistance-associated codons, suggesting that the sequencing method is superior. (Abstract 143.) A comparison of the Affymetrix HIV PRT-440 (Gene Chip) with direct sequencing of the PI and RT genes of HIV-1 found little difference in detection of resistance-associated mutations although the version of the Gene Chip used did not detect codon 69 insertion mutants. (Abstract 142.)
Pretherapy RT gene sequences from baseline HIV-1 isolates in patients entering ACTG 241, a comparison of treatment with AZT/ddI with or without nevirapine, were analyzed. Regression analysis performed in order to determine predictors of response identified position 215 as the most important baseline variable at eight, but not at 48, weeks. Stepwise regression identified a predictive model incorporating baseline sequences at positions 215 as well as at 214, 202, and 60 (r2 = 0.35; P < 0.0002); in contrast to 215, mutations at the latter three positions were all associated with a better virological response. (Abstract 14.)
The initial RNA response to therapy with AZT/3TC/ABC is not affected by the presence or absence of M184V at baseline. (Abstract 132.)
The number of baseline RT- plus PI-resistance associated mutations was the only independent predictor of failure or response to salvage therapy with a nelfinavir-containing regimen. (Abstract 140.)
Some patients appear to reach a virological plateau during antiretroviral therapy in which their plasma viral loads remain stable. Evidence indicates that while the CD4 count may be preserved for a period of time in patients reaching such plateaus in the range of 500-10,000 copies/mL, their CD4 count eventually declines. By 72 weeks of therapy, the rise in CD4 cells of plateau responders (i.e., those whose viral load plateaus in response to treatment at 500-10,000 copies/mL) para-llels that of patients failing antiretroviral therapy. Nonetheless, these data suggest that maintenance of therapy in such patients is warranted in the absence of other effective therapies. (Abstract 168.)
Antiretroviral Resistance
NRTIs. Emergence of AZT-resistant HIV-1 from T cells, but not monocytes, was observed in two patients; only a minor population of plasma virus, detected by sequencing but not by gene chip analysis, contained AZT-resistance mutations. Thus, viruses within some compartments may differ from those in others. (Abstract 299.)
Virological failure in ACTG 175, a study of various NRTI regimens, was associated with the development of five or more RT resistance-associated mutations, including codon 68 mutations. (Abstract 138.)
Patients given AZT monotherapy continued on AZT alone or who had either ddI or ddI plus nevirapine added to their regimens as soon as the T215Y/F mutation was detected. There were no significant differences in CD4 cell decline or plasma viral load between the continued monotherapy or the combination therapy arms, indicating that the emergence of T215Y/F, even as a minority population, had an adverse effect on subsequent change in these changes in therapy. This negative effect appeared to be out of proportion to previously reported levels of cross-resistance. (Abstract 129.)
It has previously been demonstrated that, in the presence of additional RT mutations, the amino acid insertions S-A, S-S, or S-G between RT codons 69 and 70 are associated with resistance to multiple NRTIs. Sequencing of virus from 121 subjects who had received therapy with regimens containing either AZT or d4T found RT 69(S) insertion mutants in 3%. Maintenance of relatively low viral loads despite the presence of this mutation, however, suggest it may be associated with reduced replicative efficiency. (Abstract 123.) Such mutants are rapidly replaced by wild type strains when the selective pressure of the nucleoside analog therapy is discontinued, indicating reduced fitness of the mutant virus. (Abstract 122.)
A panel of 12 recombinant viruses expressing M184V together with K70R conferring low-level AZT resistance, T215Y/F plus other mutations conferring high-level AZT resistance, or Q151M plus others conferring multidrug resistance was constructed. In addition to the expected 3TC resistance (IC50 > 50-fold above wild-type virus), the fold increased IC50s for abacavir were, respectively, 4, 11, and more than 20. In contrast, the IC50s for adefovir and for PMPA remained within 2.5-fold that of the wild-type for all three groups of recombinants. Thus, both adefovir and PMPA appear to retain significant activity against strains resistant to AZT/3TC as well as to multi-nucleoside analog-resistant strains. (Abstract 124.)
The Q151M RT gene mutation, together with mutations at codons 62, 68, 75, 77, and 116 causes high-level cross-resistance to multiple NRTIs. A study of patients receiving ddI and d4T, each alone or in combination, confirmed previous findings that AZT-associated resistance mutations and the Q151M complex may occur in the absence of AZT exposure. (Abstract 116.) Studies with recombinant virus demonstrated that this multidrug resistance extends to abacavir. (Abstract 113.)
Abacavir was added to stable background therapy patients with viral loads more than 500 copies/ml. The majority of baseline strains resistant to 3TC were susceptible to abacavir and neither prior 3TC exposure nor the presence of the M184V mutation compromised the response to the addition of abacavir to baseline therapy. However, the presence of three or more AZT resistanceassociated mutations together with M184V significantly compromised the response to the addition of abacavir. (Abstract 114.)
In patients given the nucleotide, adefovir dipivoxil in addition to background therapy, the median decreases in viral load were 0.51, 0.75, and 0.94 log10 at week 24 in those with, respectively, high-level, low-level, or no resistance to AZT, each together with M184V. Lesser responses were seen in the absence of M184V, consistent with prior data indicating that this mutation sensitizes isolates to adefovir. In vitro phenotypic susceptibility results appeared to correlate with antiviral effect. No patients developed the adefovir-associated RT mutations K70E or K65R. (Abstract 137.)
NNRTIs. Initial rebound in viral load in patients receiving an efavirenz-containing regimen was usually associated with the emergence of virus containing the K103N mutation. With continued drug administration, many subsequently yielded virus with additional RT mutations, especially L100I, V108I, or P225H, and up to 20% developed a G190S/A/E mutation; mutations at position 181 were not observed. (Abstract 109.)
Studies with recombinant viruses revealed that, while those with single V108I or P225H amino acid substitution exhibited no increase in resistance to efavirenz, those with the K103N substitution had 18-fold and those with L100I had 24-fold increased resistance to this drug. Addition of either P225H or V108I to K103N increased resistance 100- to 120-fold, while the presence of L100I/K with K103N led to a more than 2300-fold increase. Similar results were obtained with nevirapine and with MKC442. On the other hand, P225H was associated with three-fold greater susceptibility to delavirdine. (Abstract 110.)
More than 70% of viral isolates from patients treated with delavirdine plus one or more NRTIs for 6-95 weeks were highly resistant to delavirdine, containing a mean of nine RT gene mutations, with the predominant one being K103N. The majority of these isolates, however, remained highly susceptible to efavirenz, as well as to the experimental NNRTI, PNU142721. (Abstract 111.)
PIs. In protease inhibitor-naïve patients who experienced virological failure while receiving AZT/3TC/amprenavir, RT resistance-associated mutations were present in 82.9%, but only 19.5% had PI resistance-associated mutations. Phenotypic resistance to NRTIs was present in 52.1%, while resistance to amprenavir was present in only 10.4%. Consistent with in vitro observations, I50V was the mutation most commonly associated with amprenavir resistance; I54V/L was also observed. I50V was not detected among 97 isolates containing five or more mutations obtained from patients who had received protease inhibitors other than amprenavir and, furthermore, the majority (55%) of these isolates remained susceptible to amprenavir. Among these patients, the most important genotypic predictor of amprenavir resistance was the presence of I84V together with a mutation at the L10 residue. (Abstract 118.)
UPDATES
By Carol A. Kemper, MD
Complement Deficiencies in Meningococcus
Source: Fijen CA, et al. Clin Infect Dis 1999;28:98-105.
In order to assess the frequency of complement deficiency in patients with meningococcal infection, Fijen and colleagues randomly selected from archived data a group of patients maintained during a period of 33 years who had meningococcal disease due to each of the different serogroups (A, B, C), as well as uncommon serogroups (W135, X, Y, and Z) and nontypeable strains. A total of 267 patients (and many of their family members) were willing to participate in the study.
Complement deficiency was found in 33% of patients with uncommon or nongroupable serotypes compared with only 2% of those with serogroup A disease and 7% of those with serogroup C disease. None of the patients with type B disease had deficiencies of complement. The most common abnormality was properdin deficiency which, although it occurred in 13 of 267 (4.9%) patients, was found only in patients with uncommon serotypes. Late complement component deficiencies (C5-C8) were found in 17 patients (6.7%) and C3 deficiency syndromes were found in six (2.2%)—all with a variety of different serotypes. Interestingly, although 34% of the patients were younger than 5 years of age at the time of their infection, only two (2%) had evidence of complement deficiency. In examining the age distribution for patients with uncommon serotypes, only one of 36 patients (3%) with complement deficiency was younger than 5 years old.
These intriguing differences may be, in part, explained by the more sporadic nature of meningococcal infection due to nontypeable and uncommon strains, whereas disease due to more common strains (i.e., A and B) tend to occur in outbreaks. However, Fijen et al discovered that by focusing on those individuals with meningococcal disease due to uncommon serogroups who were 5 years of age or older at the time of their infection, they were able to identify 30 of 33 families with complement-deficient members.
This information is helpful in identifying family members at risk who would benefit from meningococcal vaccination. Patients older than 5 years of age with disease due to uncommon serogroups should probably be screened for properdin or complement deficiencies (once they have recovered from their illness) and, if evidence of a bacteriocidal defect is found, family members could also be screened and vaccinated as necessary.
Hantavirus in the Channel Islands
Source: Polakovic G. Los Angeles Times, February 14, 1999:B3.
Hantavirus was first identified in the Channel Islands off the coast of California several years ago, but despite an ever increasing population of deer mice and rodents, and a vigorous camping scene, no human cases have been reported. More than 60,000 tourists visit the five channel islands each year, with the two most popular islands being Santa Rosa and Stan Cruz. At least seven of the 10 strains of rodents on these two islands are believed to be infected with hantavirus, including up to 58% of the deer mice on Santa Rosa Island. As a result of the El Niño rains last year, the rodent population has more than doubled (numbering about 300 mice per acre) and is especially problematic in campgrounds. Nevertheless, serological studies on about two dozen park employees a few years ago found no evidence of infection.
While some individuals have expressed concern for the potential for human infection, park officials question the risk and wonder whether the lack of evidence of human infection in the Channel Islands could indicate a less infectious strain of the virus. Although a few of the islands' campsites are posted with warnings and a fact sheet on hantavirus is apparently available at the mainland center, no warning is posted on the park's web page, and many visitors to the island are not aware of the potential risk. Although no human cases of infection have thus far been identified, tourists may wish to consider the potential risk before visiting the Channel Islands and take precautions to avoid camping in heavily rodent-infested areas.
Hematological Changes in Malaria
Source: Richards MW, et al. Am J Trop Med Hyg 1998;59:859.
Richards and colleagues examined hematological changes in 89 patients with imported Plasmodium falciparum malaria (4 of whom were co-infected with P. vivax). Nearly three-fourths of the patients had less than 1% parasitemia; only 1% had greater than 5% parasitemia. Anemia turned out to be fairly uncommon in these patients (< 15% of cases), although it's commonly reported in patients with malaria residing in malarious areas. In contrast, lymphopenia (< 1.5 ´ 109/L) and thrombocytopenia (< 150 ´ 109/L) occurred in about two-thirds of the patients, and at least one-third had platelet counts below 100 ´ 109/L. The degree of parasitemia was strongly related to the degree of thrombocytopenia. Lymphopenia and thrombocytopenia—but not anemia or leukopenia—were common in returning travelers with falciparum malaria.
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