The role of HIV-proteinase inhibitors.
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Anti-HIV Agents↗
Biomedical subjects
B Gazzard
Publications and source records attributed to B Gazzard.
Current knowledge and future prospects for the use of HIV protease inhibitors.
The HIV protease (or proteinase) enzyme is an essential component of the replicative cycle of HIV, performing the post-transitional processing of the gag and gag-pol gene products into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to production of immature noninfectious viral progeny, and hence prevention of further rounds of infection. Structurally, the enzyme is a homodimer consisting of two identical 99 amino acid chains. HIV protease is a member of the aspartic protease family but is structurally dissimilar to human aspartic proteases such as renin, gastricsin and cathepsin D and E, suggesting the possibility of creating inhibitors with a wide therapeutic index. At least 6 inhibitors of HIV protease are currently in clinical development: saquinavir, indinavir, ritonavir, nelfinavir (AG-1343), KNI-272 and VX-478, the first four of which have shown antiretroviral activity and acceptable tolerability in initial phase I/II clinical trials. Resistance or reduced sensitivity to the leading protease inhibitors has been reported in vivo and appears to be associated with loss of therapeutic effect. However, resistance patterns appear to be distinct. Treatment for 1 year with indinavir has been reported to lead to selection of virus in 4 patients, which was cross-resistant to all other leading protease inhibitors. On the other hand, a larger series of clinical isolates from patients receiving saquinavir alone or in combination with zidovudine for up to 3 years did not lead to virus cross-resistant to either indinavir or ritonavir. This suggests that care should be exercised in designing the sequence of protease usage. Additionally, differing resistance patterns may be used to select combinations of protease inhibitors in future trials. Data from studies combining protease inhibitors with nucleoside analogues suggest value in terms of larger and more prolonged virological and immunological marker responses than are observed with single agent therapy, and this is likely to be the primary role for protease inhibitors; both in initial combinations for patients commencing therapy and as add-in therapies for patients previously treated with antiretrovirals. However, in vitro and animal pharmacokinetic studies also give evidence of the possibility of combining protease inhibitors, potentially leading to improved bioavailability, antiviral synergy and delay in emergence of viral resistance.
Anti-HIV Agents↗
Anti-herpesvirus treatment and risk of Kaposi's sarcoma in HIV infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group.
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.
Acyclovir↗
What we know so far.
AIM: To review current knowledge of anti-HIV therapy and the implications for patient management. WHAT IS KNOWN: In three large clinical studies, combination therapy with zidovudine plus didanosine or zalcitabine improved survival and delayed clinical events in comparison with zidovudine alone, with greater benefits in zidovudine-naive than zidovudine-experienced patients. Initial studies suggest addition of an HIV protease inhibitor to combination therapy with two nucleoside analogues may result in greater reduction in viral loads, raising hopes about eradication therapy. Two clinical endpoint studies involving protease inhibitors are available. In one of these, saquinavir/zalcitabine combination therapy offered significant clinical benefits over monotherapy with either drug and in the other ritonavir improved survival in individuals with late HIV infection. IMPLICATIONS AND REMAINING QUESTIONS: It remains unclear at what stage therapy should be started. Evidence from clinical studies suggests initial therapy should be a combination regimen, probably two nucleoside inhibitors. Data from surrogate marker studies suggest that even greater reductions in viral load and increments in CD4+ count can be seen using triple therapy, either with two nucleosides and a non-nucleoside reverse transcriptase inhibitor, or two nucleoside analogues and a protease inhibitor. It remains unclear whether there is a qualitative difference between reducing viral load below detectable levels and more modest reductions in viral load, and whether immune destruction caused by HIV can be reversed and if sustained suppression of HIV replication can be achieved. CONCLUSIONS: It is now possible to offer real hope of improvements in survival to HIV-infected patients, through the use of combinations of antiretroviral agents, but more evidence from ongoing and further studies is still needed.
Anti-HIV Agents↗
Testing patients for HIV before surgery: the views of doctors performing surgery.
The aim of this study was to investigate the attitudes of doctors performing surgery to the HIV antibody testing of surgical patients. Fifty of eighty (62.5%) doctors performing surgery who are working in two London teaching hospitals returned completed anonymous postal questionnaires. Sixty-six per cent of the sample would like some form of compulsory testing of pre-operative patients, although most of them feel that this is only necessary for patients considered to be in 'high-risk groups'. Eighty-four per cent believe that this would ensure their safety from infection during surgery. Forty-eight per cent agreed with testing patients without their consent. Results suggest that most of the doctors performing surgery in this study agree with compulsory HIV antibody testing of pre-operative patients in the belief that this would protect them from infection during surgery. The problems associated with compulsory testing and relying on such testing in order to protect doctors from infection during surgery are discussed.
AIDS Serodiagnosis↗
The treatment of microsporidial diarrhoea with thalidomide.
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AIDS-Related Opportunistic Infections↗
HIV-1 p17 synthetic peptide vaccine HGP-30: induction of immune response in human subjects and preliminary evidence of protection against HIV challenge in SCID mice.
An HIV-1 p17 subunit vaccine, HGP-30, was evaluated in 38 HIV-1 seronegative individuals in phase I clinical trials in U.K. and U.S.A. The vaccine preparation induced cytotoxic T-cell (CTL) (11/25) and lymphocyte proliferation responses to KLH (19/20) and HGP-30/p17 (24/29) as well as antibody responses to HGP-30 (29/38) and KLH (38/38). The CTL activity was observed in a higher number of vaccine recipients (9/18) in the lower dose groups (10 and 25 micrograms/kg) than the vaccine recipients (2/7) in the 50 and 100 micrograms/kg dose group. These observations suggest that the 10-25 micrograms/kg vaccine dose may preferentially induce TH1 cell responses. TH1 cell responses have been suggested as important in inducing protective cell mediated immunity. The CTL response has been shown to be CD8+. In a pilot study in SCID mice, HIV-1 virus challenge studies in mice reconstituted with cells from an HGP-30 immunized individual showed protection against virus challenge as compared to SCID mice reconstituted with cells from a non-immunized subject. These studies suggest that HGP-30 is capable of inducing protective cellular immunity.
AIDS Vaccines↗
How should a positive HIV result be given? The patients' view.
The study aimed at obtaining information about the experience of how the diagnosis of HIV infection was given. Thirty asymptomatic HIV seropositive subjects completed a self-report questionnaire enquiring about their views of the process of communication of a positive test result. Subjects' current mood was assessed with the Hospital Anxiety and Depression Scale (HAD). Only about one-third of subjects were definitely satisfied with the way they were told the diagnosis. Satisfaction was associated with perceived reassurance and sympathy, and with the quality of the information given. The views of patients, as reported in this study, should be taken into account when training staff in the notification of HIV test results.
AIDS Serodiagnosis↗
Whose health is it? Views about decision-making and information-seeking from people with HIV infection and their professional carers.
The views of people with HIV and their professional carers about patients' views on involvement in decision-making and information-seeking were studied, using a standardized self-report instrument. Patients and staff reported high levels of desire for patients' involvement in their care, but there were important differences between groups. Staff had higher preference for patients' involvement in decision-making than the patients themselves, while the opposite was the case for information-seeking. There were differences between professional groups and symptomatic and asymptomatic patients, social workers generally reporting higher preference for patients' autonomy, while doctors reported lower levels. Symptomatic patients tended to have lower preference for autonomy than asymptomatic ones. The significance and practical implications of the findings are discussed.
Adult↗
Characterization of HIV-1 strains isolated from patients treated with TIBO R82913.
The drug sensitivities of human immunodeficiency virus type 1 (HIV-1) isolates from a group of four untreated and seven TIBO R82913-treated patients were determined in a reverse transcriptase (RT) assay. Five of the treated patients harbored HIV-1 isolates with R82913 sensitivity comparable to that of the isolates of untreated patients, ranging from almost 2-fold higher sensitivity to 13-fold lower sensitivity than that of recombinant p66 RT. From one of the seven treated patients, an HIV-1 strain with a 20-fold reduced sensitivity to R82913 could be isolated; and from another patient, a strain with 100-fold reduced sensitivity (resistance) was isolated. The drug-resistant strain in this patient emerged after 3 weeks of treatment and was due to the Y188L mutation in its RT. On passaging the virus in cord blood lymphocytes, but not in CEM cells, the resistant virus was lost in favor of a different HIV-1 strain harboring the wild-type Y188 with a sensitivity to R82913 comparable to that of wild-type p66 RT. In several HIV-1 isolates (from treated and untreated patients), some HIV-2- and CIVgab-specific amino acids were found. One of these substitutions, that is, I/V179D (from an untreated patient), conferred a sevenfold reduced RT sensitivity to R82913.
Acquired Immunodeficiency Syndrome↗
Emerging patterns of heart disease in HIV infected homosexual subjects with and without opportunistic infections; a prospective colour flow Doppler echocardiographic study.
We studied 124 homosexual men aged 36.7 +/- 7.6 years (range 23-57) using Doppler echocardiography. One hundred and one patients (Group A) had had acquired immunodeficiency syndrome for 1.6 +/- 1.0 years and 23 patients (Group B) had had HIV infection without opportunistic infections for 3.2 +/- 2.3 years. Doppler echocardiography was normal in 31% of Group A patients and in 61% of Group B. Pericardial effusion was found in 44 Group A patients (44%) and two Group B patients (9%). In Group A, left ventricular dilatation and/or dysfunction were found in 20 patients (20%), aortic root dilatation and regurgitation in eight patients (8%) and an intracardiac echogenic mass in seven patients (7%); in Group B one patient (4%) had an intracardiac mass. Forty-four (44%) Group A patients had cardiac presentations, and of these 22 had cardiomegaly with clinical signs of heart failure; 10 patients had tachyarrhythmias compared to only two in Group B. Although the CD4 lymphocyte count (%) was significantly lower in Group A than in Group B (5.4 +/- 6.1 vs 13.3 +/- 7.3, P < 0.001), the presence of pericardial effusion, left ventricular dysfunction, right-sided cardiac enlargement or the duration of HIV infection, did not relate to the CD4 level in either group. Although often not diagnosed clinically, cardiac involvement in patients with AIDS is a clinical reality, with pericardial effusion, cardiomyopathy and left ventricular dysfunction appearing to have a high prevalence in male homosexual patients with AIDS. These clinical and echocardiographic findings are associated with clinically apparent intercurrent opportunistic infections, rather than the HIV virus per se, or the severity of infection as reflected by the CD4 count.
AIDS-Related Opportunistic Infections↗
Cutaneous manifestations of mycobacterial infection in patients with AIDS.
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AIDS-Related Opportunistic Infections↗
Methemoglobinemia caused by the accidental contamination of drinking water with sodium nitrite.
Sodium nitrite is used commercially as a coloring agent, a food preservative and a corrosion inhibitor. Accidental poisoning usually results from the ingestion of contaminated food and water and causes gastrointestinal irritation, vasodilatation and methemoglobinemia with subsequent tissue hypoxia. We describe an unusual case of sodium nitrite-induced methemoglobinemia following the ingestion of drinking water contaminated with a corrosion inhibitor. To our knowledge this is the first report of such a case.
Adult↗
HIV antibody testing in the antenatal clinic.
With the increase in human immunodeficiency virus (HIV) seroprevalence amongst women attending the antenatal clinic in the UK it is essential that women are adequately prepared to make an informed decision about being tested for HIV and to receive the result of such testing. This paper discusses the purpose of testing, the necessity of pre-test counselling, its content and the practical implications of providing it. Guidelines for the content of a pre-test counselling session are outlined with particular reference to issues pertinent to the pregnant woman: vertical transmission, the effect of pregnancy on disease progression, the effect of HIV on pregnancy, the prognosis for an infected child and so on.
AIDS Serodiagnosis↗
HIV antibody testing in the antenatal clinic: the views of the consumers.
OBJECTIVE: to investigate the attitudes of parturient women to HIV antibody testing in the antenatal clinic. DESIGN; anonymous self completion questionnaire. SUBJECTS: 318 women attending antenatal clinic for their first booking appointment. SETTINGS: a central London hospital, UK. RESULTS: 58% of the women felt that testing should not be compulsory, 33% that it should. Sixty per cent felt that results of the test should be given as routine but 38% felt that they should only be given if requested. Fifty five per cent felt the HIV test was as important as all the other routine tests and 60% felt that they personally did not need to be tested. Only 44% wanted to speak to a midwife about the test, with 23% saying that they did not want to speak to anyone at all. The main reason given for accepting testing was concern about passing the virus on to the baby, which was also the main concern if the test was found positive. Few women (23%) felt that those identified as positive should be encouraged to terminate their pregnancy. CONCLUSIONS: policy decisions around HIV testing should take into account the diversity of the needs and wants of this multicultural and multiracial group of consumers.
AIDS Serodiagnosis↗
Diarrhoea in AIDS and other immunodeficiency states.
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AIDS-Related Opportunistic Infections↗
"I plan to have the HIV test"--predictors of testing intention in women attending a London antenatal clinic.
In order to identify which factors predict a parturient womans intention to take up voluntary HIV testing in the antenatal clinic, 318 women were surveyed by anonymous self-completion questionnaire. The strongest predictors of intention to be tested were the perceived benefit of the test to the woman herself, her partner, and the midwife, perceived risk of HIV infection, younger age and being single and having a poor knowledge of the sexual routes of HIV transmission. Health education strategies should therefore concentrate on: (a) increasing the parturient woman's knowledge of HIV transmission which will increase accuracy of perception of risk; and (b) stressing the potential benefits of HIV testing to all antenatal attenders, particularly to those who are older and in long term relationships.
AIDS Serodiagnosis↗
The reliability and validity of two HIV-specific health-related Quality-of-Life measures: a preliminary analysis.
OBJECTIVE: To evaluate the reliability and validity of two HIV-specific Quality-of-Life (QoL) questionnaires in a UK sample. METHOD: Subjects were 99 HIV-seropositive gay men (23 were asymptomatic, 41 were asymptomatic, 35 had AIDS). QoL was measured using two HIV-specific QoL questionnaires. MEASURES: An adaptation of the Medical Outcomes Study questionnaire and a self-completion version of the Health-Related Quality-of-Life Questions. Affect was measured using the Hospital Anxiety and Depression (HAD) Scale. Disease measures included Centers for Disease Control and Prevention (CDC) stage, and CD4 and CD8 cell count. RESULTS: Both QoL instruments showed good internal reliability on all scales used. Many of the scales, particularly those related to physical health and functional performance, showed significant correlations with CD4 cell count and other measures of disease progression. Measures of physical health showed a deterioration in QoL as disease progressed from asymptomatic disease to AIDS. In contrast, most subscales purporting to measure psychological aspects of QoL did not correlate significantly with measures of disease progression, nor was there any difference between CDC stages. Subjects' global ratings of QoL were most strongly correlated with the HAD depression scale, although there were also significant correlations with most other QoL scales. CONCLUSION: This study provides further evidence for the reliability and validity of two HIV-specific QoL questionnaires in a wider range of disease stages than hitherto reported and raises issues relevant to the practical use of QoL scales in HIV disease.
CD4 Antigens↗