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Rapid change in the use of antiretroviral agents and improvement in a population of HIV-infected patients: France, 1995-1997. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA).

PURPOSE: To describe the recent evolution of antiretroviral prescriptions and to look for clinical and biological changes among a population of HIV-infected patients. SUBJECTS: Patients received follow-up in the hospital-based information system of the Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA), Southwestern France, from 1995 to 1997. METHODS: Quarterly evolution of the prescriptions of antiretroviral treatments and of the population clinical and biological indicators were studied in this observational survey of computerized records obtained after each hospital contact. RESULTS: Overall numbers of patients who received follow-up and of hospital contacts remained stable. The proportion of untreated patients decreased from 38.5% to 10.5%. Monotherapies were progressively abandoned. Double combination therapies with two nucleoside analogues were used for 55% of the patients by early 1996 and then decreased, whereas triple combination therapies with one protease inhibitor (PI) rapidly increased to comprise up to 40% of the prescriptions in 1997. PIs were prescribed earlier and earlier in the course of HIV infection. Overall incidence of AIDS diagnoses and mortality rate decreased by 18% and 22%, respectively, in the first 9 months of use of PIs compared with the preceding 9 months, and by 47% and 56%, respectively, in the following 9 months (p<.001). The number of hospitalizations and the proportion of patients with a CD4 cell count <200/mm3 decreased. AIDS cases diagnosed after introduction of PIs had rarely been treated with PIs. CONCLUSION: Over this 3-year period, physicians prescribed antiretroviral treatments more and more frequently, and triple combination therapy with PI is now common practice in France. Patients clinical and biological patterns have improved 18 months after the introduction of PIs.

Acquired Immunodeficiency Syndrome↗

Guidelines for using antiretroviral agents among HIV-infected adults and adolescents.

The availability of an increasing number of antiretroviral agents and the rapid evolution of new information have introduced substantial complexity into treatment regimens for persons infected with human immunodeficiency virus (HIV). In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for clinical management of HIV-infected adults and adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV Infection and Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR. 1998;47[RR-5]:1-41). This report, which updates the 1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid levels (i.e., viral load) and CD4+ T cell count; 2) using testing for antiretroviral drug resistance; 3) considerations for when to initiate therapy; 4) adherence to antiretroviral therapy; 5) considerations for therapy among patients with advanced disease; 6) therapy-related adverse events; 7) interruption of therapy; 8) considerations for changing therapy and available therapeutic options; 9) treatment for acute HIV infection; 10) considerations for antiretroviral therapy among adolescents; 11) considerations for antiretroviral therapy among pregnant women; and 12) concerns related to transmission of HIV to others. Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions are critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. In general, treatment should be offered to persons who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4+ T cell count; the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replicatioing a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates at the HIV/AIDS Treatment Information Service website ( http://www.hivatis.org ).

Adolescent↗

[EEG in HIV infection].

Since 1985, early changes in the EES have been demonstrated in the course of HIV infection. This method can be considered one of the accurate tests for the assessment of evolution of the disease. Abnormal anterior changes are present in about 30% of HIV+subjects with at least stage II disease. EEG abnormalities during the disease form a spectrum ranging from minor changes to slow diffuse activity, usually found in cortical lesions. These are associated in some cases with a periodic or pseudo-periodic activity as often found in white matter lesions.

AIDS-Related Opportunistic Infections↗

[Stevens-Johnson syndrome and toxic epidermal necrolysis in Lomé (Togo). Evolutional and etiological profiles of 40 cases].

INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous drug reactions, the prognosis of which largely depends on the quality of their treatment. The purpose of this study was to determine the evolutional and etiological profiles of SJS/TEN in a teaching hospital in Lome (Togo). METHODS: The medical records of patients hospitalized in the departments of dermatology and intensive care of the university hospital center of Lome for SJS/TEN from 1992 to 2001 were reviewed retrospectively. The records of patients retained corresponded to the international classification criteria of SJS/TEN. RESULTS: We collected 40 cases of SJS/TEN (27 cases of SJS, 12 cases of TEN and one overlap SJS/TEN). Patients' mean age was of 30 +/- 7 years. The sex ratio (male/female) was of 1.5 and the mean follow-up after hospitalization was of 2 months (range: 4 weeks to 8 months). The HIV serology was known in 20 cases (13 cases of SJS and 7 cases of TEN). It was positive in 10 cases (5 during TEN and 5 during SJS). Five of the 12 patients (41.7 p.cent) exhibiting NET died (all were HIV-infected) versus 2 of the 27 patients (7.4 p.cent) exhibiting SJS (2 patients were also HIV-infected). The principle drugs incriminated were: antibacterial sulphonamides (16 cases; 40 p.cent), rifampicin-isoniazid combination (7 cases; 17.9 p.cent), anti-epileptics (5 cases; 12.5 p.cent); amino-penicillin (4 cases; 10 p.cent) and non-steroidal anti-inflammatories (2 cases; 5 p.cent). Chinese drugs of undetermined nature were incriminated in 3 cases of SJS. No drug was formally identified in 3 cases of SJS. DISCUSSION: This study confirms the rareness of SJS/NET. These affections are of poor prognosis, particularly in developing countries. The results of this study suggest that the concomitance of an opportunist infection due to HIV-immunodepression is of poor prognosis in the evolution of SJS/NET. Antibacterial sulphonamides and the rifampicin-isoniazid combination are frequently incriminated in Togo.

Adult↗

[Non-Hodgkin's lymphoma in Dakar: study of 107 cases diagnosed between 1986 and 1998].

Non-Hodgkin's Lymphomas (NHL) are the most prevalent malignant hemopathies in Senegal. In this study we have investigated the epidemiological aspects considering the HIV infection pandemic, and evaluated the diagnosis means and evolutive features of this disease in Dakar. Between 1986 and 1998 (13 years), we collected 107 cases of NHL, all histologically confirmed. Average age of patients was 31.4 years (2-85 years) and sex ratio was 21. HIV infection was found in three out of 62 patients tested (4.8%). At moment of diagnosis, 72% of patients were in stage III or IV according to the Ann Arbor Staging System. Large cell lymphomas were predominant (67.2%), followed by small lymphocyte lymphomas (24.2%) and follicular lymphoma with 8.4% of cases. Localization of lymphomas was exclusively nodal (30.8%) or extra nodal (31.7%) or mixed (37.3%). In therapeutical field, 21.5% of patients were treated with only symptomatical means. Chemotherapy was used in 54 patients (78.2% of treated patients), surgery was performed in 6 patients (8.6%), association of radiotherapy and chemotherapy in 5 patients (7.2%) and 4 patients (5.7%) were treated with surgery + chemotherapy. The average survival time was 344 days. Four patients (3.7%) were alive 3 years after diagnosis and only 2 patients (1.8%) after 5 years.

Adolescent↗

Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy.

In human immunodeficiency virus (HIV)-infected patients treated with potent antiretroviral therapy, the persistence of latently infected cells may reflect the long decay half-life of this cellular reservoir or ongoing viral replication at low levels with continuous replenishment of the population or both. To address these possibilities, sequences encompassing the C2 and V3 domains of HIV-1 env were analyzed from virus present in baseline plasma and from viral isolates obtained after 2 years of suppressive therapy in six patients. The presence of sequence changes consistent with evolution was demonstrated for three subjects and correlated with less complete suppression of viral replication, as indicated by the rapidity of the initial virus load decline or the intermittent reappearance of even low levels of detectable viremia. Together, these results provide evidence for ongoing replication. In the remaining three patients, virus recovered after 2 years of therapy was either genotypically contemporary with or ancestral to virus present in plasma 2 years before, indicating that virus recovery had indeed resulted from activation of latently infected cells.

Amino Acid Sequence↗

Selection and evolution of high-affinity human anti-viral antibodies.

High-affinity human anti-viral antibodies [e.g. for human immunodeficiency virus type 1 (HIV-1), respiratory syncytial virus (RSV) and herpes simplex virus (HSV)] can be selected from immune phage-display libraries using a variety of strategies. A small subset of these antibodies show potent neutralization in vitro and anti-viral efficacy in vivo in animal models. The affinities of such antibodies arising from secondary or higher order immune responses can be improved using "CDR walking'. Sequential and parallel optimization variants of this strategy have been used to improve the affinity of a prototype anti-HIV-1 antibody 420-fold. Ultra-high-affinity human antibodies could constitute a new class of useful anti-viral reagents.

Animals↗

The reverse transcriptase sequence of human immunodeficiency virus type 1 is under positive evolutionary selection within the central nervous system.

The human immunodeficiency virus type 1 (HIV-1) enters the central nervous system (CNS) during the acute phase of infection and causes AIDS-related encephalitis and dementia in 30% of individuals. Previous studies show that HIV-1 sequences derived from the CNS of infected patients, including the sequence encoding reverse transcriptase (RT), are genetically distinct from sequences in other tissues. The hypothesis of the current study is that the RT sequence of HIV-1 is under positive selection within the CNS. Multiple alignments of non-CNS-derived and CNS-derived HIV-1 RT sequences were constructed using the ClustalW 1.8 program. The multiple alignments were analyzed with the Synonymous/Nonsynonymous Analysis Program. Codon positions 122-125, 135-149, and 166-212 of the CNS-derived RT sequences underwent a greater accumulation of nonsynonymous than synonymous substitutions, which was markedly different from the analysis results of the non-CNS-derived RT sequences. These residues are located in the finger and palm subdomains of the RT protein structure, which encodes the polymerase active site. The analysis of CNS-derived partial-length RT sequences that encompass these regions yielded similar results. A comparison of CNS-derived RT sequences to a non-CNS-derived RT consensus sequence revealed that a majority of the nonsynonymous substitutions resulted in a specific amino acid replacement. These results indicate that reverse transcriptase is under positive selection within the CNS. The amino acid replacements were visualized on a three-dimensional structure of HIV-1 RT using the Sybyl software suite. The protein structure analysis revealed that the amino acid replacements observed among the CNS-derived sequences occurred in areas of known structural and functional significance.

Amino Acid Sequence↗

The population biology of the interaction between HIV-1 and HIV-2: coexistence or competitive exclusion?

BACKGROUND: The emergence and rapid world-wide spread of HIV provides an unusual opportunity for the study of the evolution and maintenance of virulence in a major human pathogen. OBJECTIVE: To analyse the available biological and epidemiological data on the pathogenicity, transmissibility and antigenic similarity of HIV-1 and HIV-2, and use simple mathematical models of competition between the two viral types within a defined host community. RESULTS AND CONCLUSIONS: Analysis revealed a positive association between pathogenicity and reproductive success. A mathematical model of the concomitant transmission of the two viruses suggests that HIV-1 will competitively displace HIV-2 in the longer term in areas where both viruses are being transmitted within the same sexually active population.

Female↗

In vivo characteristics of human immunodeficiency virus type 1 intersubtype recombination: determination of hot spots and correlation with sequence similarity.

Recombination plays a pivotal role in the evolutionary process of many different virus species, including retroviruses. Analysis of all human immunodeficiency virus type 1 (HIV-1) intersubtype recombinants revealed that they are more complex than described initially. Recombination frequency is higher within certain genomic regions, such as partial reverse transcriptase (RT), vif/vpr, the first exons of tat/rev, vpu and gp41. A direct correlation was observed between recombination frequency and sequence similarity across the HIV-1 genome, indicating that sufficient sequence similarity is required upstream of the recombination breakpoint. This finding suggests that recombination in vivo may occur preferentially during reverse transcription through the strand displacement-assimilation model rather than the copy-choice model.

Evolution, Molecular↗

[Virological diagnosis of HIV infection in children].

The laboratory diagnosis of HIV-1 infection in newborns should be carried out using virological methods, viral isolation or molecular methods for the detection of proviral DNA by PCR. Serological methods have poor sensitivity in the first months of life because the IgG of the seropositive mother crosses the placenta. Once HIV-1 infection is diagnosed, other assays are available which indicate the clinical progression of the infection, the genetic variability of the virus, its biological behavior and sensitivity to different antiretroviral medications. These studies can be used independently of the clinical manifestations in order to assess disease progression. Different immunological markers and virological markers of disease progression have been described, but the CD4+ T lymphocyte count is used routinely as an immunological marker and as a virological marker of the virus load. In HIV-1 newborns and children, the largest decrease in the number of CD4+ T lymphocytes is due to the combined effect of infection progression and a natural decrease in CD4+ T lymphocytes with age. In newborns, low viral load levels suggest that the infection was acquired shortly before birth or that maternal and/or placental factors inhibited viral replication before birth, or that the child was infected at birth. In children, viral loads are greater than in adult patients during the primary infection and throughout their evolution. Because of advances in the treatment of HIV-1 infection, the study of resistance to antiretroviral agents by phenotypical and genotypical methods is important. Increased viral load suggests the loss of effectiveness of a treatment and should be monitored.

AIDS Serodiagnosis↗

Establishment of new transmissible and drug-sensitive human immunodeficiency virus type 1 wild types due to transmission of nucleoside analogue-resistant virus.

Sequence analysis of human immunodeficiency virus type 1 (HIV-1) from 74 persons with acute infections identified eight strains with mutations in the reverse transcriptase (RT) gene at positions 41, 67, 68, 70, 215, and 219 associated with resistance to the nucleoside analogue zidovudine (AZT). Follow-up of the fate of these resistant HIV-1 strains in four newly infected individuals revealed that they were readily replaced by sensitive strains. The RT of the resistant viruses changed at amino acid 215 from tyrosine (Y) to aspartic acid (D) or serine (S), with asparagine (N) as a transient intermediate, indicating the establishment of new wild types. When we introduced these mutations and the original threonine (T)-containing wild type into infectious molecular clones and assessed their competitive advantage in vitro, the order of fitness was in accord with the in vivo observations: 215Y < 215D = 215S = 215T. As detected by real-time nucleic acid sequence-based amplification with two molecular beacons, the addition of AZT or stavudine (d4T) to the viral cultures favored the 215Y mutant in a dose-dependent manner. Our results illustrate that infection with nucleoside analogue-resistant HIV leads in newly infected individuals to mutants that are sensitive to nucleoside analogues, but only a single mutation removed from drug-resistant HIV. Such mutants were shown to be transmissible, stable, and prone to rapid selection for resistance to AZT or d4T as soon as antiretroviral therapy was administered. Monitoring of patients for the presence of new HIV-1 wild types with D, S, or N residues at position 215 may be warranted in order to estimate the threat to long-term efficacy of regimens including nucleoside analogues.

Drug Resistance, Microbial↗

Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation.

We examined consecutive protease (PR) and reverse transcriptase (RT) sequences from human immunodeficiency virus (HIV) type 1-infected individuals, to distinguish changes resulting from sequence evolution due to possible superinfection. Between July 1997 and December 2001, >/=2 PR and RT samples from 718 persons were sequenced at Stanford University Hospital. Thirty-seven persons had highly divergent sequence pairs characterized by a nucleotide distance of >4.5% in PR or >3.0% in RT. In 16 of 37 sequence pairs, divergence resulted from the loss of mutations during a treatment interruption or from the gain of mutations with reinstitution of treatment. tat and/or gag sequencing of HIV-1 from cryopreserved plasma samples could be performed on 15 of the 21 divergent isolate pairs from persons without a treatment interruption. The sequences of these genes, unaffected by selective drug pressure, were monophyletic. Although HIV-1 PR and RT genes from treated persons may become highly divergent, these changes usually are the result of sequence evolution, rather than superinfection.

California↗

Codon volatility does not reflect selective pressure on the HIV-1 genome.

Codon volatility is defined as the proportion of a codon's point-mutation neighbors that encode different amino acids. The cumulative volatility of a gene in relation to its associated genome was recently reported to be an indicator of selection pressure. We used this approach to measure selection on all available full-length HIV-1 subtype B genomes in the Los Alamos HIV Sequence Database, and compared these estimates against those obtained via established likelihood- and distance-based comparative methods. Volatility failed to correlate with the results of any of the comparative methods demonstrating that it is not a reliable indicator of selection pressure.

Biological Evolution↗

Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1).

CD4 is the primary cellular receptor for human immunodeficiency virus type 1 (HIV-1), but is not sufficient for entry of HIV-1 into cells. After a decade-long search, the cellular coreceptors that HIV-1 requires in conjunction with CD4 have been identified as members of the chemokine receptor family of seven-transmembrane G-protein coupled receptors. The discovery of distinct chemokine receptors that support entry of T-cell tropic (CXCR-4) and macrophage tropic HIV-1 strains (CCR-5) explains the differences in cell tropism between viral strains, the inability of HIV-1 to infect most nonprimate cells, and the resistance of a small percentage of the population to HIV-1 infection. Further understanding of the role of chemokine receptors in viral entry may also help explain the evolution of more pathogenic forms of the virus, viral transmission, and HIV-induced pathogenesis. These recent discoveries will aid the development of strategies for combating HIV-1 transmission and spread, the understanding of HIV-1 fusion mechanisms, and the possible development of small animal models for HIV-1 drug and vaccine testing.

CD4 Antigens↗

High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS.

OBJECTIVE: To determine the serum levels of the soluble form of the CD30 (sCD30) activation molecule in the early phase of HIV-1 infection, and to investigate the possible correlation with evolution to AIDS. METHODS: sCD30 values were determined by an enzyme-linked immunosorbent assay (ELISA) on serum samples collected at the time of the first evidence of HIV-1 infection in 110 individuals with a median follow-up of 56 months (range, 12-88 months), at the A1 (74 cases) or A2 (36 cases) stages of the 1993 revised Centers for Disease Control and Prevention classification. The data were evaluated using established clinical and immunological parameters, including circulating CD4+ T-cell count. The controls were 110 blood donors and 51 HIV-1-negative subjects belonging to groups at risk for HIV-1 infection. RESULTS: Elevated sCD30 levels (> 20 U/ml) were found in 83.6% of HIV-1-infected cases and in 47% of at-risk seronegatives. Data analysis revealed that HIV-1-infected patients with higher sCD30 levels (> 35 U/ml) experienced faster disease progression (P = 0.0002). This was also the case in patients at the earliest stage (A1) of HIV infection (P = 0.0027). In these latter cases the predictive value of sCD30 was independent of the initial absolute number of circulating CD4+ lymphocytes. CONCLUSIONS: Serum levels of sCD30 are increased in the large majority of patients in the early phase of HIV-1 infection and represent an indicator of progression to AIDS independent of other prognostic parameters.

Acquired Immunodeficiency Syndrome↗

RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase.

High-affinity ligands of the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) were isolated by the SELEX procedure (systematic evolution of ligands by exponential enrichment) from RNA populations randomized at 32 positions. Analysis of these ligands revealed a pseudoknot consensus with primary sequence bias at some positions. We demonstrated that at least one of the ligands inhibits cDNA synthesis by HIV reverse transcriptase but fails to inhibit other reverse transcriptases. These experiments highlight the power of SELEX to yield highly specific ligands that reduce the activity of target proteins. Such ligands may provide therapeutic reagents for viral and other diseases.

Antiviral Agents↗

The origin of acquired immune deficiency syndrome: Darwinian or Lamarckian?

The subtypes of human immunodeficiency virus type 1 (HIV-1) group M exhibit a remarkable similarity in their between-subtype distances, which we refer to as high synchrony. The shape of the phylogenetic tree of these subtypes is referred to as a sunburst to distinguish it from a simple star phylogeny. Neither a sunburst pattern nor a comparable degree of symmetry is seen in a natural process such as in feline immunodeficiency virus evolution. We therefore have undertaken forward-process simulation studies employing coalescent theory to investigate whether such highly synchronized subtypes could be readily produced by natural Darwinian evolution. The forward model includes both classical (macro) and molecular (micro) epidemiological components. HIV-1 group M subtype synchrony is quantified using the standard deviation of the between-subtype distances and the average of the within-subtype distances. Highly synchronized subtypes and a sunburst phylogeny are not observed in our simulated data, leading to the conclusion that a quasi-Lamarckian, punctuated event occurred. The natural transfer theory for the origin of human acquired immune deficiency syndrome (AIDS) cannot easily be reconciled with these findings and it is as if a recent non-Darwinian process took place coincident with the rise of AIDS in Africa.

Acquired Immunodeficiency Syndrome↗