ABSTRACT
Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.
Subject(s)
Anthozoa/virology , Ecosystem , Host-Pathogen Interactions , Viruses/pathogenicity , Animals , Anthozoa/physiology , Bacteriophages/pathogenicity , Bacteriophages/physiology , Coral Reefs , Genes, Viral/genetics , Lysogeny , Models, Biological , Virulence/genetics , Viruses/genetics , Viruses/isolation & purificationABSTRACT
OBJECTIVES: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. METHODS: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12 ± 3 months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL < 200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4 count > 750 cells/µL or a 33% increase where the baseline CD4 count was ≥ 500 cells/µL. Poisson regression compared clinical failures (AIDS/death ≥ 14 days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. RESULTS: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged > 50 years, 2539 (49.4%) had CD4 counts < 350 cells/µL and 1891 (36.8%) had VL > 100 000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40-50 and > 50 years), CD4 count categories (≤ 350 vs. > 350 cells/µL) and VL categories at ART initiation (≤ 100 000 vs. > 100 000 copies/mL), with all investigated interactions being nonsignificant (P > 0.05). CONCLUSIONS: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.
Subject(s)
HIV Infections/drug therapy , HIV Integrase Inhibitors/therapeutic use , HIV-1/genetics , Protease Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Adult , CD4 Lymphocyte Count , Cohort Studies , Female , HIV Infections/immunology , HIV Infections/virology , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Humans , International Cooperation , Logistic Models , Male , Middle Aged , Protease Inhibitors/pharmacology , RNA, Viral/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Treatment Outcome , Viral LoadABSTRACT
OBJECTIVES: The objective of this paper is to summarize the outcomes of the Euroguidelines in Central and Eastern Europe (ECEE) conference held in Warsaw in February 2016. The main aim of this conference was to facilitate a discussion on European AIDS Clinical Society (EACS) guidelines implementation across the region and neighbouring countries and to present the current obstacles in benchmarking HIV care in Europe. METHODS: During a 2-day meeting, there were country-based presentations using a predefined template so as to make the data comparable and focus the discussion. Areas covered were country epidemiology, surveillance, national strategy for treatment and prevention, standards of care, access to care and treatment availability. Each participant filled in a questionnaire investigating HIV guidelines usage per country. RESULTS: In total, 16 Central and Eastern Europe (CEE) and neighbouring countries were represented at the conference: Albania, Armenia, Belarus, Croatia, Czech Republic, Estonia, Georgia, Hungary, Lithuania, Moldova, Poland, Romania, Russia, Serbia, Slovakia and Turkey. EACS guidelines version 7.1 were used in 14 (87%) countries. In 11 (69%) countries, national guidelines were available, of which eight had been recently updated. Half of the countries declared that they use World Health Organization (WHO) and Department of Health and Human Services (DHHS) guidelines, over one-third the European Centre for Disease Prevention and Control (ECDC) HIV testing guidelines and one in five the International Antiviral Society-USA (IAS-USA) Panel guidelines from 2012. CONCLUSIONS: Participants declared their will to promote the widespread use of EACS guidelines for HIV infection in the CEE region and neighbouring countries by signing the Warsaw Declaration. They also emphasized the need to increase publishing of data from national cohorts in that region.
Subject(s)
HIV Infections/diagnosis , HIV Infections/drug therapy , Practice Guidelines as Topic , Standard of Care , Europe , HIV Infections/epidemiology , HIV Infections/prevention & control , Humans , Surveys and QuestionnairesABSTRACT
OBJECTIVES: The aim of the study was to characterize the impact of the cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP3A5 and ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms on nevirapine plasma concentrations. METHODS: A total of 104 patients (82% male; 26% non-Caucasian) were genotyped for eight single nucleotide polymorphisms at four loci (CYP2B6, CYP3A4, CYP3A5 and MDR1). Nevirapine plasma concentrations were determined using high-performance liquid chromatography. RESULTS: Non-Caucasian ethnicity [5609 ng/mL (n=27) for non-Caucasians vs. 3771 ng/mL (n=77) for Caucasians; P<0.0001] and CYP2B6 516G-->T [GG, 3574 ng/mL (n=50); GT, 4634 ng/mL (n=50); TT, 8170 ng/mL (n=4); P(analysis of variance (anova))=0.001] were significantly associated with a higher nevirapine trough concentration (C(trough)). The latter association was maintained with both 200 mg twice daily (bid) and 400 mg once daily (qd) dosing [GG, 3527 ng/mL (n=30); GT, 4525 ng/mL (n=32); TT, 7020 ng/mL (n=2); P(anova)=0.05 and GG, 3645 ng/mL (n=20); GT, 4861 ng/mL (n=17); TT, 9508 ng/mL (n=2); P(anova)=0.01, respectively]. In a multivariable analysis, CYP2B6 516G-->T and non-Caucasian ethnicity remained significant predictors of nevirapine C(trough) but CYP2B6 516G-->T homozygosity had the greatest effect (108% higher, 46% higher). No associations were found between nevirapine C(trough) and the remaining polymorphisms. CONCLUSION: In this population, both non-Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G-->T were significant predictors of nevirapine C(trough). The association between CYP2B6 516G-->T and higher plasma nevirapine exposure was maintained at both bid and qd dosing.
Subject(s)
Cytochrome P-450 Enzyme System/genetics , HIV Infections/drug therapy , Nevirapine/blood , Reverse Transcriptase Inhibitors/blood , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adult , Aged , Alleles , Analysis of Variance , Black People/genetics , Chromatography, High Pressure Liquid , Cohort Studies , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP3A/genetics , Female , Genotype , HIV Infections/blood , Humans , Male , Middle Aged , Nevirapine/administration & dosage , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Reverse Transcriptase Inhibitors/administration & dosage , White People/geneticsABSTRACT
OBJECTIVE: More and more highly treatment-experienced patients are achieving viral suppression. However, the durability of suppression remains unclear. METHODS: Patients from Royal Free Hospital (London, UK) and JW Goethe University Hospital (Frankfurt, Germany) who had failed > or = 1 antiretroviral (ARV) regimen in all three main drug classes and > or = 3 previous ARV regimens and subsequently achieved viral load < 50 HIV-1 RNA copies/mL were included. They were followed until stopping pre-combination antiretroviral therapy, end of follow-up or viral rebound (two viral loads >400 copies/mL). RESULTS: Two hundred and forty-seven patients contributed 723 person-years and 114 viral rebounds [rate=15.8 per 100 person-years; 95% confidence interval (CI) 12.9-18.7]. More recent calendar years of viral suppression [relative risk (RR)=0.90 per year later; 95% CI 0.81-1.00; P=0.05] and greater number of ARVs in the regimen not previously failed (RR=0.78 per 1 ARV more; 95% CI 0.65-0.95; P=0.01) were associated with lower viral rebound rates. At 0-1, 1-2, 2-3 and > 3 years after achieving suppression, the rebound rates were 30.9, 9.2, 4.3 and 3.5 per 100 person-years, respectively. Compared to 0-1 years, the adjusted RRs (95% CIs) after 1-2, 2-3 and > 3 years were 0.33 (0.18-0.58), 0.21 (0.09-0.48) and 0.14 (0.06-0.33), respectively (P<0.0001). CONCLUSIONS: Although rebound rates are high, especially in the first year after viral suppression, this risk reduces substantially if highly treatment-experienced patients can maintain viral suppression.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , HIV-1 , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Drug Administration Schedule , Female , Germany , HIV Infections/virology , Humans , London , Male , Recurrence , Time Factors , Treatment Failure , Viral LoadABSTRACT
BACKGROUND: Use of dideoxynucleoside reverse transcriptase inhibitors (dNRTIs) may lead to increased mitochondrial toxicity. We compared nucleoside reverse transcriptase inhibitor (NRTI) use as part of antiretroviral therapy (ART) in two HIV clinics: one in a low-middle income (HIV Centre Belgrade [HCB], Serbia) and one a high income (ICDC, Royal Free Hospital, London, UK) country. METHODS: Antiretroviral naïve patients starting ART from 2003 to 2005 were included. Specific NRTIs were compared between centers, focusing on dNRTI use. Kaplan-Meier estimates of the percentage of patients making changes to their NRTI backbone (a) for any reason or (b) for mitochondrial toxicity (peripheral neuropathy, pancreatitis, lactic acidosis) were calculated. RESULTS: Of 287 HCB patients, 89 (31.0%) received didanosine (ddI)-containing, 39 (13.6%) stavudine (d4T)-containing, and 39 (13.6%) ddI+d4T-containing regimens; for 539 ICDC patients, these were 18 (3.3%), 66 (12.2%), and 0 (0.0%), respectively (p < .0001). After 12 months, 57.5% and 52.6% at HCB and ICDC had switched their NRTI backbone. This was reduced to 34.5% at HCB after excluding changes due to drug supply interruption and to 11.2% and 1.3% at HCB and ICDC after changes were made for mitochondrial-related reasons. At 6 months, 73/80 (91.3%) and 385/488 (78.9%) had viral load below 50 copies/mL at HCB and ICDC, respectively. CONCLUSION: Patients treated at HCB faced higher levels of mitochondrial-related toxicity, likely due to greater dNRTI use.
Subject(s)
HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/administration & dosage , Adult , Didanosine/administration & dosage , Didanosine/adverse effects , Drug Administration Schedule , Female , Hospitals , Humans , Male , Mitochondria/drug effects , Reverse Transcriptase Inhibitors/adverse effects , Serbia , Socioeconomic Factors , Stavudine/administration & dosage , Stavudine/adverse effects , Treatment Outcome , United KingdomABSTRACT
OBJECTIVES: Subcutaneous administration of interleukin-2 (IL-2) has been shown to increase CD4 counts in HIV-infected patients. It remains unclear whether this effect is associated with a clinical benefit. PATIENTS AND METHODS: We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm(3) received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively. RESULTS: Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non-significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely. CONCLUSIONS: We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV Infections/immunology , Immunologic Factors/administration & dosage , Immunologic Factors/therapeutic use , Interleukin-2/administration & dosage , Interleukin-2/therapeutic use , Anti-Retroviral Agents/therapeutic use , Area Under Curve , Biomarkers , CD4 Lymphocyte Count , Cohort Studies , Follow-Up Studies , Humans , Immunologic Factors/adverse effects , Injections, Subcutaneous , Interleukin-2/adverse effects , RNA, Viral/blood , Viral LoadABSTRACT
The aim of this study was to estimate the outcome and cost-effectiveness per life-year-gained (LYG) of first-, second- and third-line non-nucleoside reverse transcriptase inhibitors (NNRTI) versus protease inhibitor (PI) containing highly active antiretroviral therapy regimens. Hospital care costs (2002 US dollars discounted 3.5% per annum) were linked to treatment failure times. Results show that the median time-to-treatment failure for first-line (nucleoside reverse transcriptase inhibitors) 2NRTIs + NNRTI was substantially longer than that for 2NRTIs + PI(boosted), 2NRTIs + PI and 2NRTIs + 2PIs, whereas for second- and third-line they were similar. Comparing first-line 2NRTIs + NNRTI with 2NRTIs + PI(boosted) cost per LYG was US$ 12,375; US$ 12,139 per LYG when compared with 2NRTIs + PI and US$ 2948 per LYG when compared with 2NRTIs + 2PIs. For second-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PI(boosted) was US$ 19,501; US$ 18,364 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. For third-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PI(boosted) was US$ 2708; US$ 11,559 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. In conclusion, first-line 2NRTIs + NNRTI was cost-effective or cost-saving when compared with PI-containing regimens for all lines of therapy. Such information is required by clinicians and managers of HIV services to make appropriate treatment decisions based on clinical and financial grounds, and given the increasing number of people living with HIV, such information will become more important over time.
Subject(s)
Antiretroviral Therapy, Highly Active/economics , HIV Infections/drug therapy , HIV Infections/economics , Reverse Transcriptase Inhibitors/therapeutic use , Treatment Outcome , Adult , Anti-HIV Agents/economics , Anti-HIV Agents/therapeutic use , Cost-Benefit Analysis , England/epidemiology , Female , HIV Infections/blood , HIV Infections/virology , Humans , Male , Middle Aged , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effectsABSTRACT
BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-defining illnesses are known to occur at different levels of immunosuppression, and the incidence of diagnoses may also vary according to the CD4 lymphocyte count strata. Information about the incidence of disease at different levels of immunosuppression would help clinicians monitoring patients and would allow prophylaxis to be targeted at the most appropriate population. METHODS: Between 1982 and July 1995, 4883 patients testing positive for the human immunodeficiency virus were seen at either the Royal Free or Chelsea and Westminster Hospitals in London, England. The incidence of each diagnosis, both overall and stratified by CD4 lymphocyte count, was calculated using a person-years analysis. Patients who had no CD4 lymphocyte counts measured during follow-up were excluded from the analysis. RESULTS: During a median follow-up period of 27.6 months, 3875 AIDS-defining illnesses were reported in 1713 patients. The incidence of AIDS-defining illnesses ranged from 6.22 per 100 person-years of follow-up for Pneumocystis carinii pneumonia (95% confidence interval, 5.74-6.70) to 0.37 for extrapulmonary tuberculosis (95% confidence interval, 0.26-0.48). The incidence of each AIDS-defining illness increased as the CD4 lymphocyte count declined; diagnoses such as cytomegalovirus and Mycobacterium avium-intracellulare complex infection had a low incidence at CD4 lymphocyte counts above 0.05x10(9)/L (50/mm3), while Kaposi sarcoma, P carinii pneumonia, and esophageal candidiasis had a high incidence throughout all CD4 lymphocyte count strata. CONCLUSIONS: This study provides important information about the risk of AIDS-defining illnesses at lower CD4 lymphocyte counts, enabling disease-specific prophylaxis to be targeted at the most appropriate population. In the future, as more prophylactic therapies are developed, this study will provide historical data of the incidence of diseases before specific prophylaxis was introduced.
Subject(s)
AIDS-Related Opportunistic Infections/epidemiology , AIDS-Related Opportunistic Infections/immunology , Acquired Immunodeficiency Syndrome/diagnosis , Acquired Immunodeficiency Syndrome/immunology , CD4 Lymphocyte Count , Adult , Female , Follow-Up Studies , Humans , Incidence , London/epidemiology , Male , Middle Aged , Sex FactorsABSTRACT
Addition of varying concentrations of HIV-1-seropositive plasma to purified virus particles and soluble viral antigen preparation inhibited the detection of HIV-1-antigen by ELISA. The degree of inhibition on p24 antigen ELISA depended on the relative concentrations of viral antigen and anti-p24 antibodies in the mixtures. The relevance of these observations to clinical specimens was demonstrated when serial plasma samples from nine AIDS-related complex (ARC) patients in a clinical trial of foscarnet therapy were assayed for p24 antigen. Six (66.6%) out of nine patients were negative on screening. However, when their plasma was centrifuged through a sucrose solution, virus particles were pelleted that were depleted of anti-p24 and virus-specific p24 antigen was detected in resuspended pellets obtained from samples from all six patients. Eight serial samples collected from a male homosexual over 50 weeks following seroconversion were also subjected to the separation procedure. HIV-1-antigen was detected in all eight samples. In the light of these observations, the application of the separation technique in monitoring the efficacy of zidovudine or other anti-retroviral therapy should reveal more precise antigen levels in patients who otherwise appear to be antigen-negative in HIV-antigen assays. We propose that the natural history of HIV infections follows a pattern of chronic viral infection with continuous shedding of virus particles circulating as immune complexes.
Subject(s)
Antigens, Viral/analysis , Enzyme-Linked Immunosorbent Assay , HIV/immunology , AIDS-Related Complex/etiology , AIDS-Related Complex/immunology , Antibodies, Viral/immunology , HIV Antibodies , HIV Antigens , Humans , Retroviridae Proteins/immunology , Time Factors , Viral Core Proteins/immunologyABSTRACT
OBJECTIVE: To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns. METHODS: We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells. RESULTS: Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence. CONCLUSIONS: This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.
Subject(s)
Anti-HIV Agents/administration & dosage , Computer Simulation , Drug Resistance, Multiple, Viral , HIV Infections/drug therapy , HIV-1/drug effects , Models, Statistical , Stochastic Processes , Anti-HIV Agents/therapeutic use , Drug Resistance, Viral , HIV-1/genetics , Humans , MutationABSTRACT
OBJECTIVE: To investigate the rate of decline of drug resistant viruses after stopping therapy. DESIGN: Twenty-five patients receiving multiple combination therapies (mean five; range three to nine drugs) for more than 3 months were tested for HIV-1 resistance on therapy and off therapy. The sample off therapy was tested 6-175 days after stopping therapy. METHODS: Patients were tested for genotypic changes associated with drug resistance using an in-house automated DNA sequencing assay to detect resistance in the protease and reverse transcriptase genes. RESULTS: All samples tested when patients were on therapy showed evidence of drug resistance (range 1-9 mutations). The patients were divided into three groups: <2 weeks after stopping therapy, median 1.1 weeks (n = 8, group A); 2 weeks-2 months, median 6.4 weeks (n = 7, group B) and 2 months-6 months, median 12.9 weeks (n = 10, group C). Of primary mutations (protease: 30N, 461/L, 82A, 90M; reverse transcriptase: 70R, 184I/V, 215 Y/F) detected on therapy 100% remained after stopping therapy in group A; 68% remained in group B and 15% remained in group C. For secondary mutations 98% remained in group A; 99% remained in group B and 57% in group C. CONCLUSIONS: This study showed a rapid decline in detectability of the majority of primary mutations within 13 weeks of stopping combination therapy. From this data, HIV-1 resistance testing to direct patients' therapy should only be carried out when on existing therapy, or < 2 weeks off therapy, if reliable decisions are to be made relating to future combinations.
Subject(s)
Acquired Immunodeficiency Syndrome/virology , Drug Resistance, Multiple/genetics , HIV Protease/genetics , HIV-1/genetics , RNA-Directed DNA Polymerase/genetics , Acquired Immunodeficiency Syndrome/drug therapy , Adult , Anti-HIV Agents/therapeutic use , DNA Mutational Analysis , Drug Resistance, Microbial , Drug Therapy, Combination , HIV-1/drug effects , HIV-1/enzymology , Humans , Male , Middle Aged , Mutation , Salvage Therapy , Statistics, NonparametricABSTRACT
Patients with epidemic Kaposi's sarcoma, who are often taking zidovudine, may be treated with cytotoxic chemotherapeutic agents. Both cytotoxic chemotherapy and zidovudine are myelotoxic and we have treated 16 patients with this combination. We report an acceptable rate of anaemia, leucopaenia, thrombocytopaenia and non-haematological side effects. This combination can be safely administered to this group of patients, although much of our experience is with the relatively non-myelotoxic chemotherapeutic agents, bleomycin and vincristine.
Subject(s)
Antineoplastic Agents/administration & dosage , Sarcoma, Kaposi/drug therapy , Zidovudine/administration & dosage , Antineoplastic Agents/adverse effects , Bleomycin/administration & dosage , Drug Therapy, Combination , Humans , Injections, Intravenous , Male , Vincristine/administration & dosage , Zidovudine/adverse effectsABSTRACT
The cell-surface antigen CD4 is the major receptor for HIV. Anti-CD4 autoantibodies and anti-idiotypic antibodies to murine monoclonal anti-CD4 antibodies have been described in HIV-infected people. Ninety-seven sera from HIV-infected people at all stages of disease were examined for the presence of anti-idiotypic antibodies to three anti-CD4 monoclonal antibodies. None were found. The same sera were screened for antibodies reactive with soluble CD4, and five (5.2%) were positive. These antibodies did not recognize native CD4, and it is thought unlikely that they arise as anti-idiotypes to anti-gp120 antibodies.
Subject(s)
Antibodies, Anti-Idiotypic/isolation & purification , Autoantibodies/isolation & purification , CD4 Antigens/immunology , HIV Antibodies/isolation & purification , HIV Seropositivity/immunology , Antibodies, Monoclonal , Cell Line , Enzyme-Linked Immunosorbent Assay , HIV Envelope Protein gp120/immunology , HIV-1/immunology , HumansABSTRACT
Eflornithine (DFMO) was used to treat 31 AIDS patients with confirmed Pneumocystis carinii pneumonia who had clinically failed treatment with pentamidine, sulphamethoxazole-trimethoprim or both agents as their first-line therapy. Twenty-one of 31 (68%) responded to second-line treatment with 400mg/kg per day of eflornithine. Five patients discontinued treatment because of bone marrow toxicity. Eflornithine appears to be a useful salvage therapy in patients failing first-line treatments.
Subject(s)
Acquired Immunodeficiency Syndrome/complications , Eflornithine/therapeutic use , Pneumonia, Pneumocystis/drug therapy , Eflornithine/administration & dosage , Female , Homosexuality , Humans , Male , Pentamidine/therapeutic use , Pneumonia, Pneumocystis/complications , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic useABSTRACT
OBJECTIVE: With the recent identification of a new herpesvirus in patients with Kaposi's sarcoma (human herpesvirus-8 or Kaposi's sarcoma-associated herpesvirus), there have been several reports on the use of anti-herpesvirus therapy (foscarnet, ganciclovir and aciclovir) and risk of developing Kaposi's sarcoma. We therefore investigated the association between use of anti-herpesvirus drugs and Kaposi's sarcoma in a large unselected group of patients with AIDS. PATIENTS AND METHODS: We studied a group of HIV-positive patients at the Chelsea and Westminster Hospital, for whom details on all AIDS-defining diagnoses made during follow-up, treatment and regular CD4 counts were available. Cox proportional hazards models with time-dependant covariates were used to assess the association between treatment with aciclovir, foscarnet and ganciclovir and risk of Kaposi's sarcoma. RESULTS: A total of 3688 patients have been followed up for a median period of 4.2 years, during which time 598 patients (16.2%) developed Kaposi's sarcoma. After adjustments for sex, exposure category, age, treatment with antiretrovirals or Pneumocystis carinii pneumonia prophylaxis, the development of AIDS-defining conditions (including separate adjustment for the development of cytomegalovirus and herpes simplex virus) and CD4 count, there was a decreased risk of developing Kaposi's sarcoma with foscarnet [relative hazard (RH), 0.38; 95% confidence interval (CI), 0.15-0.95; P = 0.038] and with ganciclovir (RH, 0.39; 95% CI, 0.19-0.84; P = 0.015), but not with aciclovir (RH, 1.10; 95% CI, 0.88-1.38; P = 0.40). CONCLUSIONS: These results suggest that both foscarnet and ganciclovir may have some activity in preventing the occurrence of Kaposi's sarcoma, but that aciclovir has no benefit. Further studies of the effect of these drugs on the risk of Kaposi's sarcoma is warranted.
Subject(s)
Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Foscarnet/therapeutic use , Ganciclovir/therapeutic use , HIV Infections/complications , Sarcoma, Kaposi/prevention & control , Adolescent , Adult , Aged , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Proportional Hazards Models , Sarcoma, Kaposi/complicationsABSTRACT
We performed a retrospective study on 112 patients with AIDS-related pneumonias who underwent bronchoscopy and in whom Pneumocystis carinii pneumonia (PCP) and/or cytomegalovirus (CMV) were identified in bronchoalveolar fluid (BAL). CMV was identified by detection of early antigen fluorescent foci (DEAFF) testing in cell cultures of BAL fluid. The short- and long-term survival of all patients was similar regardless of whether PCP, CMV or both were detected at bronchoscopy. Ten out of 14 patients with CMV alone and 13 out of 26 with both CMV and PCP were treated with anti-CMV therapy, but the short- and long-term mortality was similar to that in patients who had no specific antiviral therapy. Extrapulmonary recurrence of CMV (retinitis or gastrointestinal disease) occurred in 22% of patients with evidence of CMV in BAL compared with 16% of those with PCP alone, but this difference was not statistically significant and this recurrence rate was independent of anti-CMV therapy. Detection of CMV shedding from more than one site (BAL, urine, throat or blood) was associated with a worse prognosis at 3 months than in patients in whom CMV was detected in BAL alone. It does not appear that finding CMV shedding is a guide to the cause of pneumonia or an indication for treatment in AIDS patients.
Subject(s)
Acquired Immunodeficiency Syndrome/diagnosis , Antibodies, Viral/analysis , Bronchoalveolar Lavage Fluid/microbiology , Cytomegalovirus Infections/diagnosis , Cytomegalovirus/immunology , Pneumonia, Pneumocystis/diagnosis , Acquired Immunodeficiency Syndrome/complications , Acquired Immunodeficiency Syndrome/mortality , Antiviral Agents/therapeutic use , Bronchoscopy , Colitis/complications , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/mortality , Esophagitis/complications , Fluorescent Antibody Technique , Humans , Pneumonia, Pneumocystis/complications , Pneumonia, Pneumocystis/mortality , Recurrence , Retinitis/complications , Retrospective StudiesABSTRACT
BACKGROUND: A high proportion of individuals receiving highly active antiretroviral treatment (HAART) complain of sexual dysfunction (SD), encompassing a lack of desire or erectile dysfunction. OBJECTIVE: To determine whether SD was associated with particular components of the HAART regimens and to identify risk factors for the development of SD in patients on HAART. METHODS: A survey among patients with HIV infection using an anonymous questionnaire was conducted in 10 European countries between December 1998 and December 1999. A total of 904 individuals currently receiving antiretroviral agents were included in the analyses. RESULTS: A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI) (308/766, 40%), compared with PI-naive patients (22/138, 16%; OR 3.55; 95% CI 2.15--5.89). In addition, a significantly larger number of PI-experienced men reported a decrease in sexual potency (216/628, 34%) compared with PI-naive men (12/99, 12%; OR 2.56; 95% CI 1.33--5.03). In multivariate analyses the following factors were associated with a decrease in sexual interest: a current PI-containing regimen, a history of a PI regimen, symptomatic HIV infection, age and homosexual contact as HIV transmission mode. Factors associated with a decrease in sexual potency were: current use of a PI-containing regimen, symptomatic HIV disease, age and the use of tranquillisers. CONCLUSION: SD appears to be a common side-effect of HAART regimens containing a PI. The potential association between SD and other side-effects of HAART, such as lipodystrophy syndrome and neuropathy, should be investigated further.
Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/adverse effects , Sexual Dysfunctions, Psychological/chemically induced , Adult , Antiretroviral Therapy, Highly Active/adverse effects , Erectile Dysfunction/chemically induced , Female , HIV Infections/transmission , HIV Protease Inhibitors/therapeutic use , Humans , Indinavir/adverse effects , Indinavir/therapeutic use , Male , Multivariate Analysis , Nelfinavir/adverse effects , Nelfinavir/therapeutic use , Prevalence , Risk Factors , Ritonavir/adverse effects , Ritonavir/therapeutic use , Sexual Dysfunctions, Psychological/epidemiology , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed. METHODS: We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen. RESULTS: Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002). CONCLUSION: Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption.