ABC of AIDS. Antiretroviral drugs.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
I V Weller
Publications and source records attributed to I V Weller.
ABC of AIDS: Treatment of infections.
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AIDS-Related Opportunistic Infections↗
Lipodystrophy in patients naive to HIV protease inhibitors.
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Adult↗
A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection.
Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.
Adenine↗
Comparison of culture- and non-culture-based methods for quantification of viral load and resistance to antiretroviral drugs in patients given zidovudine monotherapy.
Virological assays for human immunodeficiency virus type 1 load and drug resistance can broadly be divided into culture-based and molecular biology-based methods. Culture-based methods give a direct measure of infectious virus load and phenotypic drug resistance, whereas molecular biology-based methods are indirect, assaying nucleic acid levels to determine virus load and point mutations associated with drug resistance. We have compared culture-based and non-culture-based methods for patients enrolled in a placebo-controlled trial of zidovudine (the Concorde Trial). Virus loads were assayed by culture of peripheral blood mononuclear cells (PBMCs) or quantitative PCR, and drug resistance was assayed in culture or in a quantitative, PCR-based point mutation assay. The rates of detection of viremia and drug resistance were higher by PCR than by culture for this population of subjects. Comparison of the virus loads by the two measures showed a good correlation for virus loads in PBMCs but a poor correlation for virus loads in plasma. The latter result probably reflected the inaccuracies of culture in assaying plasma with the low infectious virus titers seen in the study population. The concordance of phenotypic and genotypic drug resistance methods was high, with all phenotypically resistant isolates having at least one resistance-associated mutation and with no mutations being found in a drug-sensitive isolate. Genomic resistance scores (weighted sums of levels of resistance mutations) showed good correlations with the levels of phenotypic resistance, and both resistance measures were observed to increase as the duration of exposure to drug increased. Overall, non-culture-based methods were shown to correlate well with culture-based methods and offer a low-cost, high-throughput alternative. However, culture-based methods remain the final arbiters of infectious virus load and phenotypic drug resistance and are unlikely to be superseded entirely.
Acquired Immunodeficiency Syndrome↗
Hepatitis B virus infection in patients attending a genitourinary medicine clinic: risk factors and vaccine coverage.
BACKGROUND: The hepatitis B virus (HBV) immunisation policy in the United Kingdom includes offering vaccines selectively to those at risk by sexual contact. Among genitourinary medicine (GUM) clinic attenders, homosexual men are offered vaccine, but estimates of the vaccine uptake are required to monitor policy and estimate the possible impact on transmission; heterosexuals are not routinely offered vaccine, but this policy might change if the prevalence was found to be high. OBJECTIVE: To determine the prevalence of HBV infection and vaccine uptake among patients attending a GUM clinic. METHODS: HBV seroprevalence determined by unlinked anonymous testing of consecutive blood samples sent for syphilis serology. Demographic and risk factor data and history of HBV immunization extracted from clinic notes before unlinking. Prevalence data were compared with a population of first time blood donors from the same area. SETTING: Open access GUM clinic in central London. RESULTS: Samples were obtained and tested from 441 homosexual and 527 heterosexual men and from 821 women over a 4 month period in 1990. After exclusion of injecting drug users and their sexual partners (n = 30) and HBV carriers attending for follow up (n = 12), the prevalence of antibody to HBV core (anti-HBc) was 38.7% in homosexual men, 5.9% in heterosexual men, and 3.5% in women (50.0%, 6.0%, 3.7% respectively if previous vaccinees were also excluded). The prevalence of HBV surface antigen positivity was 4.2%, 0.60%, and 0.39% respectively after exclusion of vaccinees (chi(2) p < 0.001 for homosexual men versus others). The prevalence of the anti-HBc in first time blood donors was 1.1% (8/749). Among male GUM clinic attenders, the prevalence of anti-HBc was higher in those of non-UK origin or place of birth and/or non-white ethnicity (odds ratios 2.87, 95% CI 1.57-5.24 and 8.06, CI 3.39-19.1, in homosexuals and heterosexuals respectively). In homosexual men anti-HBc prevalence increased with age (OR 1.05, CI 1.02-1.07 for each year) and lifetime number of STDs (OR 6.36, CI 3.77-10.8 for > or = 2 versus < 2) and in clinic reattenders compared with new patients (OR 5.42, 95% CI 3.32-9.16). Among heterosexuals, age was associated with anti-HBc prevalence in women (OR 1.09, CI 1.04-1.12) but not men (OR 0.99, 95% CI 0.95-1.02). There were no other associations in heterosexuals. A history of HBV immunisation in homosexual men was recorded in 13/131 (9.9%) of new patients and 103/305 (33.8%; OR 4.63, CI 2.49-8.60) clinic reattenders. CONCLUSIONS: Although higher than a sample of blood donors, the prevalence of serological markers of HBV infection among heterosexuals was low, providing little support for extending HBV immunisation to all heterosexuals attending GUM clinics as a targeted strategy for control of HBV infection. Homosexual men remain at high risk of infection, but many are now being immunised. Efforts to improve compliance with existing vaccine policies in GUM clinics should be encouraged.
Adult↗
Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors.
OBJECTIVE: To ascertain the prevalence of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, and cytomegalovirus (CMV) DNA in semen was investigated. METHODS: Amplification by nested polymerase chain reaction was used to detect viral DNA sequences in samples from 24 HIV-infected gay men, 15 of them with Kaposi's sarcoma (KS), and 115 healthy donors. RESULTS: Six of the 24 HIV-infected patients had detectable HHV-8 DNA in their semen: three of the 15 patients with KS and three of the nine patients without KS. CMV DNA was detected in 20 semen samples from HIV-infected patients. None of the semen samples from healthy donors had detectable HHV-8 DNA and rates of CMV DNA detection were low (3%). CONCLUSIONS: The study demonstrates the presence of HHV-8 in semen from HIV-infected individuals with, or at risk, of developing KS and the potential for sexual transmission of the virus. We found no evidence of HHV-8 in the semen of HIV-uninfected donors.
Cytomegalovirus↗
Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection.
OBJECTIVES: Hepatitis B virus (HBV) and HIV infections share risk-factors; therefore coinfection is common. Interactions have been reported but controlled studies have been limited. Our objective was to study the effect of HIV infection on the natural history of chronic HBV infection and the reverse effect of the HBV carrier state on HIV infection. DESIGN: Prospective observational cohort study. SETTING: Open-access outpatient HIV/genitourinary medicine clinic at a Central London hospital. PATIENTS: Total of 152 untreated homosexual male HBV carriers and 212 HBV surface antigen-negative controls (41.4 and 70.3% HIV-seropositive, respectively). OUTCOME MEASURES: The rate of loss of serum HBV e antigen (HBeAg) and its reappearance in HIV-infected and HIV-uninfected HBV carriers; serum HBV DNA levels measured by dot-blot hybridization assay), HBV DNA polymerase activity and liver transaminase activities, the progression of HIV infection to symptomatic disease or AIDS in HIV-infected compared with HBV-HIV coinfected patients. RESULTS: In HIV-infected HBV carriers, serum HBV DNA polymerase activity was higher, alanine aminotransferase was lower and loss of serum HBeAg (mean follow-up, 2.8 years) occurred at a lower rate when compared with HIV-uninfected HBV carriers (estimated relative hazard, 0.39; 95% confidence interval, 0.161-0.942) Concomitant chronic HBV infection had no detectable effect on the rate of progression of HIV disease after correction for lead-time bias. CONCLUSION: This study strengthens the evidence for a significant effect of HIV infection on the natural history of chronic HBV infection, which by prolonging the period of infectivity could have an important impact on the epidemiology of HBV infection in regions, or patient groups, with high HIV seroprevalence. There was no evidence of an important effect of HBV carriage on HIV disease progression.
AIDS-Related Opportunistic Infections↗
HIV infection alters the production of both type 1 and 2 cytokines but does not induce a polarized type 1 or 2 state.
OBJECTIVE: To test the T-helper (TH)1/TH2 cytokine paradigm in HIV infection. DESIGN AND METHODS: Cytokine profiles in two separate studies of HIV patients and controls are presented: (i) a longitudinal study of HIV patients with CD4 counts > 500 x 10(6)/l tested at three timepoints compared with controls; (ii) a blinded cross-sectional study of controls and patients with high (> 500 x 10(6)/l) and low (< 500 x 10(6)/l) CD4 counts. Peripheral blood mononuclear cells (PBMC) from patients and controls were tested for the production of two type 1 [interleukin (IL)-2, interferon (IFN)-gamma] and two type 2 (IL-4, IL-10) cytokines by enzyme-linked immunosorbent assay. Both spontaneous and mitogen-induced cytokine production was measured. RESULTS: HIV infection was noted to have the following effects on cytokine production: (i) it led to the in vivo activation of type 2 cytokines in a small group of individuals with high CD4 numbers characterized by the spontaneous release of IL-4 and IL-10. Longitudinal data showed high spontaneous IL-4 and IL-10 to be a consistent feature of the patient group (at each timepoint some patients were high producers) but to be variable in a given individual; (ii) HIV infection impaired the ability of PBMC to respond to stimuli (selected for their ability to optimally induce each cytokine) in terms of IL-2, IL-4 and IL-10 production in patients with both high and low CD4 cell counts; and (iii) conversely, HIV infection led to an overproduction of IFN-gamma in patients with high CD4 counts; patients with low CD4 produced normal levels of IFN-gamma. CONCLUSIONS: Our observations did not suggest polarization of the type 1/type 2 cytokine profile in HIV patients. Instead, the data suggested more complex changes to type 1/type 2 cytokine patterns in HIV infection than originally proposed by the TH1/TH2 dichotomy.
CD4 Lymphocyte Count↗
Proton Spectroscopy in a Cross-Section of HIV-Positive Asymptomatic Patients Receiving Immediate Compared with Deferred Zidovudine (Concorde Study).
The purpose of this study was to examine by proton spectroscopy for any difference in cerebral metabolites in patients taking part in the Concorde study (comparing the efficacy of immediate versus deferred treatment with zidovudine on asymptomatic HIV infected individuals). Forty seven HIV positive male patients [29 immediate, 18 deferred zidovudine] were examined in the last 9 months of the therapeutic trial. Magnetic resonance imaging and proton spectroscopy were performed at 1.5 Tesla using a single voxel placed in the parieto-occipital white matter. No significant difference was found in metabolite ratios comparing immediate versus deferred zidovudine (NA/NA+Cho+Cr 0.52 vs. 0.52). High quality spectra were acquired in relatively large numbers of patients and logistically spectroscopy may be applied to clinical therapeutic studies.
HIV Infections↗
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex. METHODS: We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay. FINDINGS: 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays. INTERPRETATION: The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.
Adult↗
Immunization with recombinant p17/p24:Ty virus-like particles in human immunodeficiency virus-infected persons.
In studies of the natural history of human immunodeficiency virus type 1 (HIV-1) infection, it has been repeatedly shown that higher-titer antibody responses to the HIV gag p24 protein correlate with less rapid disease progression. In HIV-negative persons, immunization with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) induced humoral and cellular immune responses to p24. This construct was therefore studied as a potential immunotherapeutic agent with the objective of augmenting the immune response to p24 in a double-blind placebo-controlled trial involving 74 p24 antibody-positive, asymptomatic HIV-1-infected subjects with CD4 cell counts > 350/mm3. Immunization with p24-VLP was generally well tolerated. Immunization with p24-VLP did not increase p24 antibody levels and had no effect on CD4 cell counts or virus load. The failure to increase p24 antibody titers cannot entirely be explained by the subjects' immunodeficiency because most generated an antibody response to Ty, a yeast component of the immunogen.
AIDS Vaccines↗
Safety, tolerance, and efficacy of atevirdine in asymptomatic human immunodeficiency virus-infected individuals.
Atevirdine is a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). In this study we investigated the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3. Patients were randomized to receive 600 mg of atevirdine (n = 15) or a placebo (n = 15) three times a day for 12 weeks. There was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data do not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients.
Adult↗
Ups and downs--and ups in the antiviral therapy of HIV infection.
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AIDS-Related Complex↗
Reference ranges and sources of variability of CD4 counts in HIV-seronegative women and men.
BACKGROUND: CD4 lymphocyte counts are used to monitor immune status in HIV disease. An understanding of the variability of CD4 counts which occurs in the absence of HIV infection is essential to their interpretation. The sources and degree of such variability have not been extensively studied. OBJECTIVES: To establish reference ranges for CD4 counts in HIV-seronegative women and heterosexual men attending a genitourinary medicine (GUM) clinic, and to identify possible differences according to gender and cigarette smoking and, in women, any effect of the menstrual cycle, oral contraceptive use and cigarette smoking. DESIGN: Female and heterosexual male patients attending a GUM clinic and requesting an HIV-antibody test were recruited prospectively. Results from an earlier study of CD4 counts in homosexual men were available for comparison. METHODS: Lymphocyte subpopulation analysis on whole blood by flow cytometry. RESULTS: The absolute CD4 count and percentage of CD4 cells (CD4%) were significantly higher in women (n = 195) than heterosexual men (n = 91) [difference between the means 111 x 106/1 (95% CI 41, 180) and 3.1% (1.30, 4.88)]. The absolute CD4 count and CD4% were also significantly higher in smokers (n = 143) than non-smokers (n = 140) [difference 143 (79, 207) and 2.1% (0.43, 3.81)]. Reference ranges for absolute CD4 counts (geometric mean +/- 2SD) were calculated on log transformed data as follows; female smokers 490-1610, female non-smokers 430-1350, heterosexual male smokers 380-1600, heterosexual male non-smokers 330-1280. Among other variables examined, combined oral contraceptive pill use was associated with a trend towards a lower absolute CD4 count. Changes were seen in CD4% with the menstrual cycle. CD4 counts and CD4% did not differ significantly between heterosexual men and homosexual men (n = 45). CONCLUSION: There is a significant gender and smoking effect on CD4 counts. The effects of oral contraceptive use and the menstrual cycle warrant further investigation.
Adolescent↗
HIV-1 RNA serum-load and resistant viral genotypes during early zidovudine therapy.
The response of HIV-1 to initial zidovudine (ZDV) treatment was assessed in 11 patients with severe HIV disease. We quantified serum HIV-1 concentrations and mutations associated with ZDV resistance by culture-independent methods. There was a prompt fall in serum HIV-1 RNA within 1-2 days of treatment with maximum suppression by seven days, which was paralleled by changes in serum p24 antigen (p24 Ag). Serum RNA started to return to pretreatment levels within weeks. The HIV reverse transcriptase (RT) gene in most patients developed mutations associated with drug resistance within months and as early as 25 days on therapy in one patient. The codon changes were not sufficient to explain the early return of serum HIV-1 RNA levels and their patterns continued to evolve after patients stopped taking ZDV. The significance of these findings is discussed in relation to the limited long-term efficacy of ZDV. The dynamic time course of viral load and RT responses to ZDV is of particular importance in short-term interventions such as pregnancy.
Adult↗
Conservation of precore and core sequences of hepatitis B virus in chronic viral carriers.
Mutations in the precore region of hepatitis B virus (HBV) have been associated with failure of expression of HBV e-antigen (HBeAg), however, the prevalence of these and other mutations in HBV carriers without overt chronic liver disease remains uncertain. Homosexual or bisexual males (n = 65) with chronic HBV infection attending The Middlesex Hospital, London were studied, of whom two had clinical evidence of chronic liver disease. HBV DNA was amplified from 62 of 65 serum samples using nested and double nested polymerase chain reaction (PCR) assays. Direct sequencing of the PCR products was employed to investigate sequence variation. HBV-DNA from all available HBeAg-negative (n = 9) and selected HBeAg-positive (n = 33) sera were sequenced in the entire precore gene, the 3' terminal portion of the X gene (aa128-154), and the 5' terminus of the core gene (aa18-73). Sequences were highly conserved in all regions studied. Samples from two anti-HBe-seropositive patients contained mutations in the precore region. In one, a single mutation in the first amino acid resulted in a change to leucine, which would prevent translation of this region and therefore HBeAg expression. Wild type sequences were also detected in this sample. In the other sample from a patient with overt chronic liver disease, a mutation of precore amino acid 28 changed a tryptophan residue to a stop codon which would also prevent HBeAg expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Novel application of a point mutation assay: evidence for transmission of hepatitis B viruses with precore mutations and their detection in infants with fulminant hepatitis B.
Mutations of the precore region of hepatitis B virus (HBV) genome have been associated with fulminant and severe chronic hepatitis. However uncertainty remains about the clinical significance and transmissibility of these mutant strains. A point mutation assay (PMA) was developed to identify qualitatively and quantitatively mutations affecting precore amino acids 1 and 28. We have analysed serum samples from six mother-infant pairs where perinatal transmission of HBV has occurred and where the mothers were HBV carriers without detectable serum HBeAg. In three cases fulminant hepatitis developed in the infant, in two cases acute hepatitis resolved, and in one case the infant was immunised and did not become infected. We also examined serum from a healthcare worker, an anti-HBe-seropositive HBV carrier, believed to have transmitted HBV infection to a patient. The PMA results were confirmed in all cases by direct sequencing of polymerase chain reaction (PCR) products using nested and double-nested PCR with primers to the precore and X region. Precore aa28 mutant-type virus was detected in the serum of one mother at the time of delivery of three of her children, two of whom developed fulminant hepatitis. Another mother of an infant with fulminant hepatitis had no precore mutations. In one mother-infant pair a mixed viral population was found; the acute hepatitis B in the infant resolved. The HBV sequence from the healthcare worker was also of aa28 mutant type. No mutations of aa1 were detected in any of the specimens. The study supports the association of precore mutations with some cases of transmission of HBV infection from HBeAg-negative mothers to their infants.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗