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Delayed-type hypersensitivity (DTH) responses to intradermal recombinant HIV envelope glycoprotein (rgp160) may assess cell-mediated immune responses to HIV envelope. In three studies, DTH and lymphocyte proliferation responses to rgp160 were obtained in a total of 106 HIV-seropositive subjects with CD4+ counts >400 cells/mm3. Several subjects participated in more than one study. Before immunization, DTH responses were seen in 5 of 56 (9%) of HIV-infected study subjects. After immunization with an alum-adjuvanted experimental rgp160 vaccine, DTH responses were seen in 46 of 52 (89%). Using in vitro lymphocyte proliferation activity (LPA) to rgp160 as an indication of cellular immune response, skin testing has a sensitivity of 0.75 (95% confidence Interval [CI], 0.59-0.88) and a specificity of 0.84 (95% CI, 0.72-0.92). Biopsy samples of skin that had tested positive confirmed the presence of a DTH reaction with a predominance of CD4+ T cells in the perivascular, inflammatory infiltrate. Skin testing before and after immunization with candidate AIDS vaccines could provide a simple method in the field to assess new cell mediated immune responses.
An anti-HIV strategy combining chemotherapy and therapeutic vaccination.
Rosenwirth-B; Bogers-WM; Nieuwenhuis-IG; Haaft-PT; Niphuis-H; Kuhn-EM; Bischofberger-N; Erfle-V; Sutter-G; Berglund-P; Liljestrom-P; Uberla-K; Heeney-JL
J-Med-Primatol. 1999 Aug-Oct; 28(4-5): 195-205
Combination chemotherapy using potent anti-retroviral agents has led to significant advances in the clinical management of human immunodeficiency virus (HIV) disease. However, the emergence of multiple drug-resistant mutants, the high need for compliance to adhere to demanding drug-dosing schemes, and the remaining toxic side-effects of drugs make the perspective of life-long treatment unattractive and possibly unrealistic. Therefore, means must be sought to shorten the time span during which treatment is necessary. Such means could be to stimulate an efficient immune response during the period of low virus load and restored CD4 + cell levels, which might be capable of keeping the virus under long-lasting control after treatment is stopped. Here we tested this concept of combined chemotherapy/ therapeutic vaccination in a non-human primate model. Rhesus macaques chronically infected with the chimeric simian/human immunodeficiency virus (SHIV) containing the HIV type 1 (HIV-1) HXBc2 gene for reverse transcriptase (RT) in the genomic background of simian immunodeficiency virus (SIV)(mac239) (RT-SHIV) were treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a potent anti-HIV drug. When virus load had decreased significantly, we immunized with SIV genes env, gag/pol, rev, tat, and nef inserted in two different expression vector systems. Four weeks after the second immunization, drug treatment was stopped. Animals were monitored to determine if virus load stayed low or if it increased again to the original levels and if CD4+ T-cell levels remained stable. Humoral and cellular immune responses were also measured. This combined chemotherapy/ therapeutic vaccination regimen induced a significant reduction in the steady-state level of viremia in one out of two chronically infected rhesus macaques. Chemotherapeutic treatment alone did not achieve reduction of viremia in two chronically infected animals. The nature of the immune responses assumed to have been induced by vaccination in one out of the two monkeys remains to be elucidated.
In vitro immune function after vaccination with an inactivated, gp120-depleted HIV-1 antigen with, immunostimulatory oligodeoxynucleotides.
Moss RB, Diveley J, Jensen F, Carlo DJ
Vaccine. 2000 Jan 6; 18(11-12): 1081-7
We examined the effect of a synthetic oligodeoxynucleotide containing unmethylated CpG immunostimulatory sequences (ISS) as an adjuvant for an HIV-1 immunogen (inactivated, gp120-depleted HIV-1 virus particles). The addition of the ISS to HIV-1 in incomplete Freund's adjuvant (IFA) was the optimal combination for the production of HIV-1-specific immune responses as measured by IFN-gamma (p=0.002) and IgG antibody production. Furthermore, the group that was immunized with HIV/IFA/ISS, as well as the group that received HIV-1 in complete Freund's adjuvant (CFA), stimulated significantly more RANTES (a beta-chemokine) (p=0.002) production from lymph node cells. These results suggest that the addition of CpG immunostimulatory sequences to HIV antigens in IFA may optimize HIV-1-specific immune responses and provides further rationale for the testing of ISS in combination with gp120-depleted whole-killed HIV-1 in IFA as a potential preventive or therapeutic HIV-1 vaccine.
Vaccination and HIV: a review of the literature
Rousseau MC, Moreau J, Delmont J
: Vaccine. 1999 Dec 10; 18(9-10): 825-31
People with HIV are at risk for a variety of infections both at home and abroad. Recent studies have reported conflicting data concerning potential harmful effects following several inactivated vaccines. Antigenic stimulation by vaccines designed to prevent secondary infections may promote HIV-1 replication in certain patients. In HIV-positive subjects, immune response worsens with progression of the HIV infection. When vaccination is considered, administration of the vaccine must be performed as early as possible in the course of HIV infection because an HIV-infected patient's response to inactivated vaccines is closely related to HIV infection stage. A minority of subjects have a protective antibody response to vaccination. Consequently, specific antibody titers should be measured after vaccination to ensure immune protection. Immune response is improved by highly active antiretroviral therapy.Some live attenuated vaccines are considered as beneficial in some specific indications and if administered in the early stages of AIDS. However, viral load variations following administration of live attenuated vaccines have not been studied yet.
Belief of vaccine receipt in HIV vaccine trials: further cautions
Johnson MO
J Acquir Immune Defic Syndr 1999 Aug 15;21(5):413-6
The purpose of this cross-sectional study was to examine relationships between belief in vaccine receipt, motivations for trial participation, and side effects in phase 1 vaccine trials. Anonymous questionnaires were completed by 125 active vaccine volunteers at two vaccine evaluation sites. Participants believing they had received the vaccine reported more side effects (p < .01), were less likely to report knowing someone with HIV/AIDS as a motivation for trial participation (p < .01), and endorsed greater concern about becoming HIV-infected as motivation for participation (p < .05). Results indicate that inferences made by trial participants in vaccine trials should be identified and addressed, and that greater efforts for maintaining the blinded nature of vaccine trials and educating trial participants about the meaning of side effects are warranted. Clinical trial
Estimation of the direct and indirect effects of vaccination
Haber M
Stat-Med. 1999 Aug 30; 18(16): 2101-9
Indirect effects play a major role in the protection afforded by a vaccination programme. In this work we define new measures of direct, indirect and total (direct + indirect) effects of a vaccination programme in terms of the protection they provide to unvaccinated and vaccinated individuals, and to the entire population. We show how these measures can be estimated using data from a vaccine trial or an observational study. The bias and standard errors of these estimates can be evaluated via stochastic simulations. Examples from a mumps outbreak and a (hypothetical) HIV vaccine trial are used to illustrate the estimation of these new measures of vaccination effectiveness.
MN and IIIB recombinant glycoprotein 120 vaccine-induced binding antibodies to native envelope glycoprotein of human immunodeficiency virus type 1 primary isolates..
Gorse GJ, Patel GB, Mandava M, Berman PW, Belshe
AIDS-Res-Hum-Retroviruses. 1999 Jul 1; 15(10): 921-30
The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human immunodeficiency virus type 1 (HIV-1) vaccines to bind to oligomeric native HIV-1 envelope glycoproteins of primary isolates of HIV-1 was measured by flow cytometric indirect immunofluorescence assay (FIFA) in 25 uninfected, healthy adults. After three immunizations, MN rgp120 HIV-1 vaccine given alone and coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody that bound to cells infected with each of a panel of six subtype B strains of HIV-1. Lower levels of vaccine-induced binding antibody were detected against envelope subtype A, D, and (EA) strains of HIV-1 than against subtype B strains. Priming immunization with IIIB rgp120 HIV-1 vaccine alone induced low levels of antibody capable of binding to envelope glycoprotein of primary isolate strains of HIV-1, and booster immunizations with MN rgp120 HIV-1 vaccine resulted in much higher antibody levels. We conclude that MN rgp120 HIV-1 vaccine was an effective inducer of antibody to native envelope glycoproteins of antigenically diverse primary isolates of HIV-1.
Rapid loss of specific antibodies after pneumococcal vaccination in patients with human immunodeficiency virus-1 infection.
Nielsen H, Kvinesdal B, Benfield TL, Lundgren JD, Konradsen HB
Scand-J-Infect-Dis. 1998; 30(6): 597-601
Pneumococcal infections are frequently observed in patients with human immunodeficiency virus (HIV) infection and active immunization has been recommended as prophylaxis in this patient group. We studied 103 out-patients with asymptomatic or mildly symptomatic HIV infection with respect to specific IgG and IgG2 pneumococcal antibodies before and after vaccination with a 23-valent pneumococcal polysaccharide vaccine. A significant increase ( > 2-fold) in IgG and IgG2 antibody levels was observed after 1 month in 69/103 patients (67%) with no correlation with the CD4 cell count at the time of vaccination. The response rate was not influenced by concurrent treatment with anti-retroviral monotherapy, or by age or gender. After immunization a strong correlation between IgG and IgG2 anti-pneumococcal antibodies was demonstrated. Nevertheless, 12 months after vaccination the specific antibody titres were not significantly different from pre-vaccination values. In conclusion, antibodies induced by pneumococcal vaccination in patients with HIV infection have a short duration. This raises the question as to whether vaccination will have any impact on clinical end-point in this group of patients.
Tumor necrosis factor alpha and human immunodeficiency virus-specific functional immune responses after immunization with Gp120-depleted, inactivated HIV-1 in incomplete Freund's adjuvant (REMUNE) in HIV-1-seropositive subjects.
Moss RB, Li L, Giermakowska WK, Lanza P, Turner JL, Wallace MR, Jensen FC, Richieri SP, Daigle AE, Theofan G, Carlo DJ
J-Hum-Virol. 1998 Jan-Feb; 1(2): 77-81
OBJECTIVE:
We examined the relation between tumor necrosis factor-alpha (TNF-alpha) levels and human immunodeficiency virus type 1 (HIV-1)-specific functional immune responses, as measured by HIV-1 antigen-stimulated lymphocyte proliferation and beta-chemokine production after immunization with gp120-depleted, inactivated HIV-1 in incomplete Freund's adjuvant (i.e., HIV-1 Immunogen; REMUNE, The Immune Response Corporation, Carlsbad, CA, U.S.A.).STUDY DESIGN/METHODS:
CONCLUSIONS:
HIV-1-seropositive subjects who enrolled in an open-label study were immunized with REMUNE every 12 weeks and monitored for 60 weeks. HIV-1 antigen-stimulated lymphocyte proliferation and RANTES production were measured in peripheral blood mononuclear cells (PBMCs). TNF-alpha levels were measured in serum. RESULTS: TNF-alpha (P = 0.0003) significantly decreased and HIV-1 antigen-stimulated RANTES production (P = 0.002) and lymphocyte proliferation (P = 0.07) increased after immunization with REMUNE. TNF-alpha levels negatively correlated with HIV-1 antigen-stimulated RANTES production (r = -0.71; P = 0.0002) and lymphocyte proliferation (r = -0.37; P = 0.09).
This study demonstrated decreased TNF-alpha levels with a concomitant augmentation of HIV-specific functional immunity in subjects immunized with REMUNE. Because TNF-alpha has been implicated in the induction of anergy in HIV-1 infection, the ability to decrease TNF-alpha may allow the immune system to respond to HIV and non-HIV antigens. Larger studies are being conducted to confirm the clinical utility of REMUNE in combination with potent antiviral drugs.
Detection of intracellular antigen-specific cytokines in human T cell population
Kallas EG, Gibbons DC, Soucier H, Fitzgerald T, Treanor JJ, Evans TG
J-Infect-Dis. 1999 May; 179(5): 1124-31
Determination of antigen-specific cytokine responses of T lymphocytes after vaccination is made difficult by the low frequency of responder cells. In order to detect these responses, the profile of intracellular cytokines was analyzed using flow cytometry after antigenic expansion. Peripheral blood mononuclear cells were stimulated with antigens for 5 days, further expanded with interleukin (IL)-2, and then restimulated on day 10. Cytokine production was detected by intracellular staining with monoclonal antibodies after saponin-based permeabilization. Influenza expansion resulted in specific interferon-gamma (IFN-gamma) production of 6%-20%, with less IL-4 production (0%-2%). Tetanus toxoid resulted in even greater production. IL-4 and IFN-gamma were produced mainly by memory cells of the CD45RO+ phenotype. IFN-gamma production was contributed by both CD4 and CD8 populations. These methods were then applied to a clinical trial of a candidate human immunodeficiency virus type 1 vaccine. Antigen-specific increases in IFN-gamma were measured, which corresponded to antibody production, lymphoproliferation, and skin testing.
Mucosal vaccination strategies for women
Kozlowski PA, Cu-Uvin S, Neutra MR, Flanigan TP
J-Infect-Dis. 1999 May; 179 Suppl 3: S493-8
Women were immunized orally, rectally, or vaginally with a recombinant cholera toxin B-containing vaccine to determine which of these mucosal immunization routes generate the greatest levels of antibody in the female genital tract and rectum. ELISA was used to measure concentrations of cholera toxin B-specific IgA and IgG antibody in serum and secretions before and after three immunizations. Each immunization route similarly increased specific IgG in serum and specific IgA in saliva. Only the vaginal route increased IgA antibodies in genital tract secretions and could be shown to induce a local IgG response. However, vaginal immunization failed to produce antibody in the rectum. In a similar fashion, rectal immunization elicited highest concentrations of locally derived IgA and IgG antibody in the rectum but was ineffective for generating antibody in the genital tract. The data suggest that local immunization may induce the greatest immune responses in the female genital tract and rectum of humans.
Comparison of the antibody repertoire generated in healthy volunteers following immunization with a monomeric recombinant gp120 construct derived from a CCR5/CXCR4-using human immunodeficiency virus type 1 isolate with sera from naturally infected individuals.
Beddows S, Lister S, Cheingsong R, Bruck C, Weber J
J-Virol. 1999 Feb; 73(2): 1740-5
Department of GU Medicine and Communicable Diseases, Imperial College School of Medicine at St. Mary's, London W2 1PG, United Kingdom. We have characterized sera from healthy volunteers immunized with a monomeric recombinant gp120 (rgp120) derived from a CCR5/CXCR4 (R5X4)-using subtype B isolate of human immunodeficiency virus type (HIV-1), HIV-1W61D, in comparison to sera from long-term HIV-1-infected individuals, using homologous reagents. Sera from vaccinees and HIV-1 positive subjects had similar binding titers to native monomeric rgp120W61D and showed a similar titer of antibodies inhibiting the binding of soluble CD4 (sCD4) to rgp120W61D. However, extensive peptide binding studies showed that the overall pattern of recognition of vaccinee and HIV-1-positive sera is different, with vaccinee sera displaying a wider and more potent recognition of linear V1/V2 and V3 domain epitopes. Neutralization of homologous HIV-1W61D or heterologous HIV-1M2424/4 peripheral blood mononuclear cell (PBMC)-derived virus lines by vaccinee sera could be achieved, but only after adaptation of the viruses to T-cell lines and was quickly lost on readaptation to growth in PBMC. Sera from HIV-positive individuals were able to neutralize both PBMC-grown and T-cell line-adapted viruses. Interestingly, rgp120W61D was recognized by monoclonal antibodies previously shown to neutralize primary HIV-1 isolates. The use of very potent adjuvants and R5X4 rgp120 led to an antibody response equivalent in binding activity and inhibition of binding of sCD4 to gp120 to that of HIV-positive individuals but did not lead to the induction of antibodies capable of neutralizing PBMC-grown virus.
Genetic vaccination-induced immune responses to the human immunodeficiency virus protein Rev: emergence of the interleukin 2-producing helper T lymphocyte
Chan SY, Louie MC, Piccotti JR, Iyer G, Ling X, Yang ZY, Nabel GJ, Bishop DK.
Hum-Gene-Ther. 1998 Oct 10; 9(15): 2187-96
Rev M10 is a trans-dominant negative inhibitor of HIV replication. Hence, stable transduction of CD4+ T cells with Rev M10 represents a novel gene therapy aimed at inhibiting HIV replication within these cells, thereby slowing the progression of AIDS. However, the immune system may recognize Rev M10 as foreign and target transduced cells for elimination. In the current study, mice were genetically immunized with a plasmid encoding Rev M10, to (1) identify immune parameters that may be induced by Rev M10 gene transfer, (2) determine the impact of repeated introduction of the Rev M10-encoding plasmid on the immune response to the transgene product, and (3) determine if cotransfection with a plasmid encoding TGFbeta1 would suppress the response. Kinetic studies revealed that Rev-specific IL-2-producing helper T lymphocytes (HTLs) appeared following the second genetic immunization, peaked after the third, and persisted at peak levels for at least 6 weeks. Rev-specific HTLs were CD4+, and the development of these cells was ablated by cotransfection with TGFbeta1. Other cytokines were not readily detectable when immune splenocytes were restimulated with Rev in vitro, and Rev-specific IgG antibodies were not present in the sera of these mice. To our knowledge, this represents the first report that genetic immunization with Rev M10 induces an immune response that is dominated by IL-2-producing HTLs. Further, this study demonstrates the potential utility of introducing immunosuppressive genes as a means to control the immune response to foreign transgene products.
[Which are the vaccines that human immunodeficiency virus infected patients must receive] [Article in Spanish]
Valencia Ortega ME, Gonzalez Lahoz J
An Med Interna 1998 Aug;15(8):439-42
Servicio de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid.Patients with aids are at increased risk of opportunistic and non opportunistic infections. It is now known that the incidence can be reduced by prophylactic measures and/or the use of vaccines. HIV infection produces an elevated frequency of severe pneumococcal disease with a rate of bacteriemia caused by Streptococcus pneumoniae 150-300 fold greater than rates reported in non-HIV infected people. For this reason, pneumococcal vaccine should be administered as early as possible in the course of the infection. Besides, the antibody response may be significantly higher for asymptomatic persons. Acute hepatitis caused by hepatitis B virus is milder than in non HIV infected patients but chronic disease is more frequent. The prognosis is worse and there is higher risk for infecting another persons. Hepatitis B vaccine is indicated for all the patients with HIV and negative serology for hepatitis B virus. Influenza vaccine is of limited effectiveness due to the high variability of the virus. Besides, influenza incidence is low among approximately young adults, HIV related immunodeficiency increased influenza risk only minimally, the vaccine is administered yearly and HIV-replication can increase in temporal association with vaccination. For all these reasons, fewer hospitalizations and deaths are prevented making it a far less cost-effective prevention strategy than pneumococcal vaccination. The risk of Haemophilus influenzae infections is elevated, but the vaccine is not routinely recommended because the more frequent serotype in HIV infected patients is b. For these subjects, passive immunization with immunoglobulin may also be necessary to provide protection. In conclusion, pneumococcal and hepatitis B vaccination is a reasonable prevention strategy for HIV infected patients at all stages of immunodeficiency. Influenza and H. influenzae vaccination are not recommended and alternative prevention strategies may be done.
Immunization of persons with HIV infection and other secondary immunodeficie
Castello-Branco LR, Ortigao-de-Sampaio MB
Mem Inst Oswaldo Cruz 1998 May-Jun;93(3):387-90
Patients with secondary immunodeficiencies are at a high risk of infection. Currently some of these infections are preventable through specific immunization. Prevention of these diseases can diminish morbidity and mortality amongst these patients. In this review we describe the use of vaccines in persons with secondary immunodeficiencies.
In vitro p24 antigen-stimulated lymphocyte proliferation and beta-chemokine production in human immunodeficiency virus type 1 (HIV-1)-seropositive subjects after immunization with an inactivated gp120-depleted HIV-1 immunogen (Remune).
Moss RB, Wallace MR, Lanza P, Giermakowska W, Jensen FC, Theofan G, Chamberlin C, Richieri SP, Carlo DJ
Clin-Diagn-Lab-Immunol. 1998 May; 5(3): 308-12
We examined the effect of immune stimulation by a human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) compared to a non-HIV vaccine (influenza) on HIV-1-specific immune responses in HIV-1-seropositive subjects. HIV-1 p24 antigen-stimulated lymphocyte proliferation was not augmented after immunization with the influenza vaccine. In contrast, subjects increased their lymphocyte proliferative responses to p24 antigen after one immunization with HIV-1 immunogen (Remune) (gp120-depleted inactivated HIV-1 in incomplete Freund's adjuvant). Furthermore, p24 antigen-stimulated beta-chemokine production (RANTES, MIP-1alpha, MIP-1beta) was also augmented after immunization with the HIV-1 immunogen but not influenza vaccine. Taken together, these results suggest that in this cohort, HIV-specific immune responses to p24 antigen can be augmented after immunization with an HIV-1 immunogen. The ability to upregulate immune responses to the more conserved core proteins may have important implications in the development of immunotherapeutic interventions for HIV-1 in
An experimental prime-boost regimen leading to HIV type 1-specific mucosal and systemic immunity in BALB/c mice.
Bruhl P, Kerschbaum A, Eibl MM, Mannhalter J
AIDS-Res-Hum-Retroviruses. 1998 Mar 20; 14(5): 401-7
Induction of mucosal as well as systemic immunity to HIV-1 is considered to have high priority in current concepts of future AIDS vaccines. Here we show that the desired immune responses can be elicited by an experimental prime-boost regimen consisting of mucosal (intragastric) application of a recombinant vaccinia virus carrying the HIV-1 env gene (vSC25), followed by parenteral (intradermal) immunization with the recombinant HIV-1 glycoprotein 160 (rgp160). Following intragastric immunization of mice with vSC25 in combination with the mucosal adjuvant cholera toxin (CT), HIV-1 env-specific IgA was secreted by B cells of Peyer's patches and the lamina propria. Moreover, mucosal (intragastric and intranasal) application of vSC25 (both in presence or absence of CT) induced a long-lasting, HIV-1 env-specific systemic cytotoxic T cell response. Subsequent intradermal boosters with rgp160 led to HIV-1-specific T cell memory and serum antibodies.
A clinically relevant HIV-1 subunit vaccine protects rhesus macaques from in vivo passaged simian-human immunodeficiency virus infection.
Mooij P, van der Kolk M, Bogers WM, ten Haaft PJ, Van Der Meide P, Almond N, Stott J, Deschamps M, Labbe D, Momin P, Voss G, Von Hoegen P, Bruck C, Heeney JL
AIDS. 1998 Mar 26; 12(5): F15-22
OJECTIVES:
To investigate whether immunization with recombinant HIV-1 envelope protein derived from a clinical isolate could protect macaques from infection with an in vivo passaged chimeric simian-human immunodeficiency virus (SHIV). DESIGN AND METHODS:
A total of 16 animals were studied from which three groups of four animals were immunized with vaccine formulations of the CC-chemokine receptor-5-binding recombinant gp120 of HIV-1W6.1D. Four weeks after the last immunization, all 16 animals were intravenously challenged with in vivo passaged SHIV derived from the same HIV-1 group B clinical isolate (W6.1D) as the vaccines. RESULTS:
Vaccine protection from infection was demonstrated in 10 out of 12 macaques immunized with recombinant gp120. Complete protection from infection was achieved with all of the animals that received the SBAS2-W6.1D formulation, a potent inducer of both T-cell and humoral immune responses. Partial protection was achieved with SBAS1-W6.1D, a formulation based on immunomodulators known to induce T-cell responses in humans. In vaccinated animals that were infected, virus load was reduced and infection was delayed. CONCLUSIONS:
In a relatively large number of primates, vaccine efficacy was demonstrated with a clinically relevant HIV-1 vaccine. These results reveal that it is possible to induce sterilizing immunity sufficient to protect from infection with SHIV which was passaged multiple times in vivo. Our findings have implications for current HIV-1 clinical vaccine trials and ongoing efforts to develop safe prophylactic AIDS vaccines.
Pneumococcal vaccination and HIV infection in Africa.
Moore D, Nelson M, Henderson D, Gilks CF
Int-J-STD-AIDS. 1998 Jan; 9(1): 1-7
The pneumococcus (Streptococcus pneumoniae) is a leading cause of morbidity and mortality in tropical and temperate climes. Despite being well recognized as an important pathogen associated with human immunodeficiency virus (HIV) infection in industrialized countries, this interaction has received little attention in Africa. Work on this subject carried out in Nairobi (Kenya) over a period of 5 years (1989-1993) is reviewed. Among epidemiological aspects, nasopharyngeal carriage is discussed and the increased risks for invasive disease and pneumococcal pneumonia, recorded in cross-sectional and prospective studies, are highlighted. Clinical aspects include the wider spectrum of HIV-related invasive pneumococcal disease that is seen in adults, emphasizing that, even with high rates of penicillin resistance, standard benzylpenicillin therapy is effective if started early in disease. Many patients, however, present late in the course of illness and mortality rates for pneumococcal pneumonia are higher in HIV-infected adults. Pneumococcal disease is preventable in immunocompetent adults and, although no efficacy data are available, vaccination is recommended for all HIV-infected adults in industrialized countries. Current research investigating the efficacy of pneumococcal vaccination in HIV-infected adults living in Entebbe (Uganda) and clients of The AIDS [acquired immune deficiency syndrome] Support Organization (TASO) is summarized. The results of this 'double-blind' placebo-controlled trial will be known in July 1998.
[The natural history of tuberculosis infection and skin tuberculin reaction]. [Article in French]
Flament-Saillour M, Perronne C
Rev-Mal-Respir. 1997 Dec; 14 Suppl 5: S27-32
Though most often asymptomatic, tuberculous infection induces a delayed hypersensitivity reaction in the host by activating cellular immunity thus rendering the host refractory, "a priori", to a new infection; at least provided that the infecting dose is not massive or that the immune system of the host is not compromised. Less that ten per cent of immuno-competent individuals infected by Mycobacterium tuberculosis will develop tuberculous disease during their life. The intradermal reaction (IDR to tuberculin) in revealing delayed hypersensitivity to Mycobacterial antigens is in the absence of obvious signs, the only means of diagnosing a tuberculous infection in an individual. It is performed in France by an intradermal injection of 0.1 mls (10 U) of Merieux tuberculin. The response is read at 72 hours. In those who have not had BCG vaccination, an area of induration with a diameter of greater than or equal to 10 mm gives a positive result and is evidence of a tuberculous infection. The test is negative if the diameter is less than 5 mm and indeterminate between 5 and 9 mm. These indeterminate reactions may be the consequence of previous BCG vaccination or of a contact with atypical Mycobacteria in the environment. An IDR of greater than or equal to 10 mm less than ten years after BCG vaccination would not permit any discrimination between a reaction to the vaccine or an authentic tuberculous infection. On the other hand, an IDR of greater than 10 mm ten years after BCG vaccination is evidence of renewed contact with wild tubercle bacilli in 88 per cent of cases. In individuals whose immune defence is altered in particular in patients infected with HIV the threshold of positivity for IDR is lowered to 5 mm.
Nucleic acid-based vaccines as an approach to immunization against human immunodeficiency virus type-1.
Bagarazzi ML, Boyer JD, Ayyavoo V, Weiner DB
Curr Top Microbiol Immunol 1998;226:107-43
Cross-clade immune responses after immunization with a whole-killed gp120-depleted human immunodeficiency virus type-1 immunogen in incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE) in human immunodeficiency virus type-1 seropositive subjects
Moss RB, Giermakowska W, Lanza P, Turner JL, Wallace MR, Jensen FC, Theofan G, Richieri SP, Carlo DJ
Viral-Immunol. 1997; 10(4): 221-8
Lymphocyte proliferation responses to gp120-depleted HZ321 virus (clade A) antigen were compared to BAL human immunodeficiency virus (HIV) virus antigen (clade B) responses, clade E HIV virus antigen responses, and purified native p24 antigen responses in 15 human immunodeficiency virus type-1 (HIV-1) seropositive subjects immunized with a whole-killed inactivated gp120-depleted HIV-1 antigen in Incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE). A significant increase in lymphocyte proliferation to HZ321 antigen was observed after immunization with the HIV-1 immunogen (p = 0.02). A strong association was demonstrated between the HIV-1 immunizing antigen, HZ321, and native p24 antigen responses (r = 0.80, p < 0.0001). Furthermore, a strong association in terms of proliferative responses was demonstrated between HZ321 virus (clade A) responses and BAL virus (clade B) (r = 0.95, p < 0.0001) and clade E virus antigen (r = 0.92, p < 0.0001). Proliferative responses to HIV antigens also correlated with baseline CD4 counts. Taken together, these results support the specificity of immune responses induced by REMUNE (HIV-1 immunogen). The development of cross-reactive immune responses between clades and to the more conserved epitopes of the virus have implications in the development of therapeutic and prophylactic HIV vaccines.
Safety and immunogenicity of a candidate therapeutic vaccine, p24 virus-like particle, combined with zidovudine, in asymptomatic subjects.
Kelleher AD, Roggensack M, Jaramillo AB, Smith DE, Walker A, Gow I, McMurchie M, Harris J, Patou G, Cooper DA
AIDS. 1998 Jan 22; 12(2): 175-82
OBJECTIVES:
To evaluate the impact of therapeutic immunization with p24 virus-like particle (VLP) and zidovudine (ZDV) on p24 antibody titre (primary endpoint), CD4+ cell counts, cellular responses to the immunogen and recall antigens, and viral load (secondary endpoints) in subjects with asymptomatic HIV infection and CD4+ counts greater than 400 x 10(6) cells/l. DESIGN:
A double dummy, double-blind randomized placebo-controlled Phase II trial of the therapeutic vaccine p24-VLP, with or without ZDV. METHODS:
ZDV-naive subjects were randomized to one of three groups for 6 months: group A, ZDV 200 mg three times daily plus intramuscular administration of alum adjuvant monthly; group B, ZDV 200 mg three times daily plus p24-VLP (500 microg) in intramuscular alum monthly; group C, placebo capsules plus p24-VLP (500 microg) in intramuscular alum monthly. Subjects were followed for a further 6 months. RESULTS:
Sixty-one patients received vaccinations. The mean CD4+ cell counts pretherapy for groups A, B, and C were 605 +/- 25, 668 +/- 43, and 583 +/- 30 x 10(6) cells/l, respectively. Treatment was well tolerated. At both 24 and 52 weeks there were no significant differences between the treatment groups in terms of antibody responses to p24, CD4+ or CD8+ cell counts, viral load, T-cell responses to p24, p17, recall antigen or mitogen, or markers of immune activation, despite induction of antibody and proliferative responses to the carrier protein of the vaccine. CONCLUSION:
Vaccination with p24-VLP was well tolerated. p24-VLP either alone or in combination with ZDV did not significantly alter either antibody or proliferative responses to p24, or CD4+ cell number, immune activation or viral load over 12 months.
Comparison of neutralizing and hemagglutination-inhibiting antibody responses to influenza A virus vaccination of human immunodeficiency virus-infected individuals.
Benne CA, Kroon FP, Harmsen M, Tavares L, Kraaijeveld CA, De Jong JC.Eijkman-Winkler
Clin-Diagn-Lab-Immunol. 1998 Jan; 5(1): 114-7
A neutralization enzyme immunoassay (N-EIA) was used to determine the neutralizing serum antibody titers to influenza A/Taiwan/1/86 (H1N1) and Beijing/353/89 (H3N2) viruses after vaccination of 51 human immunodeficiency virus (HIV) type 1-infected individuals and 10 healthy noninfected controls against influenza virus infection. Overall, the N-EIA titers correlated well with the hemagglutination-inhibition (HAI) titers that were observed in the same samples in a previous study (F. P. Kroon, J. T. van Dissel, J. C. de Jong, and R. van Furth, AIDS 8:469-476,1994).The N-EIA appeared to be more sensitive than the HAI test. Significantly more fourfold or higher rises in N-EIA titer and higher mean N-EIA titers occurred in HIV-infected individuals with > or =200 CD4+ cells per microl than in those with <200 CD4+ cells per microl.
| Drug names* | Studied most in combination | How given | Special features and comments*** | Side effects |
| Nucleoside analog reverse trancriptase inhibitors | ||||
| Retrovir (zidovudine [ZDV], AZT) | DdI, ddC, 3TC, sauquinavir, ritonavir, indinavir, nelfinavir, nevirapine | Two or three times daily | Reaches HIV in spinal cord and brain; often combined with 3TC; probably should not be given with d4T; works best in cells actively producing new HIV | Anemia (low number of red blood cells), granulocytopenia (low number of white blood cells), muscle weakness |
| Videx (didanosine ddI) | AZT, d4T, indinavir, nevirapine | Twice daily, 1 hour before or 2 hours before eating | Effectiveness in combination with AZT demonstrated in large studies; recent smaller study shows good results in combination with d4T; combination with ddC should probably be avoided; most active in "resting" infected cells | Pancreatitis (inflammation of the pancreas), periperal neuropathy (numbness or pain starting in the feet or hands), diarrhea |
| Hivid (azlcitabine ddC) | AZT, saquinavir | Three times daily, 1 hour before or 2 hours after eating | Effectiveness in combination with AZT demonstrated in large studies; recent smaller study shows good results in combination with d4T; combination with ddC should probably be avoided; most active in "resting" infected cells | Periperhal neuropathy (numbness or pain starting in the feet r hands), periperal neuropathy (numbness or pain starting in the feet or hands), diarrhea |
| Zerit (stavudine ,3TC) | DdI, 3TC, nelfinavir | Twice daily | Reaches HIV in spinal cord and brain; effectiveness in combination with ddI or 3TC indicated in recent studies; probably should not be given with AZT; works best in cells in actively producing HIV | Periperhal neuropathy (numbness or pain starting in the feet or hands) |
| Epivir(Lamivudine 3TC) | AZT; d4T; AZT =3TC is well studied with all protease inhibitors | Twice daily | Combination with AZT well studied and popular with doctors; effectiveness in combination with d4T indicated by recent studies; most active in "resting" infected cells | In adults, side effects mostly mild: headache, nausea, fatigue; children who have had pancreatitis (inflammation of the pancreas) should use AZT + 3TC only if they cannot take other anti-HIV drugs |
| Protease inhibitors | ||||
| Invirase (Saquinavir) | AZT, ddC, AZT+ddC; saquinavir*** , | Twice Daily | As it is made now, saquinavir appears to be the weakest protease inhibitor, but its activity increases greatly when it is combine with ritonavir; can be given twice a day with ritonavir but the best dose for the combination is still unknown. A new version of saquinavir now being studies looks stronger that the first versionMostly mild side effects; nausea, diarrhea | |
| Norvir (ritonavir) | AZT + 3TC, AZT + ddC; saquinavir*** | Twice daily, with meals if possible | First protease inhibitor shown to prolong survival in people with advanced disease; being studies with AZT + 3TC in people soon after they are infected with HIV Nausea | numbness around mouth, diarrhea common, especially in first weeks of therapy; doctors advised to start 300 mg twice a day, then build up the full dose, 600 mg twice a day within 2 weeks Crixivan (indinavir) AZT, AZT + 3TC, AZT + ddI Three times daily, 1 hour before or 2 hours after eating, or with a light low-fat meal Study in combination with AZT + 3TC demonstrating long control of HIV in large majority of people; being studied with AZT + 3TC in people soon after they infected with HIV Painful kidney stones (drinking lots of water, especially in summer, lowers chance of this side effect) |
| Viracept (Neflinavir) | D4T, AZT + ddI | Three times daily with food | If taken with ddI, take more than 2 hours before or 1 hour after ddI | Diarrhea usually goes away by itself or can be controlled by taking Imodium |
| Viramune (nevirapine) | AZT, AZT + ddI | Once daily for first 2 weeks, then twice daily with or without food | Reaches Hive in spinal cord and brain; most effective when combined with AZT + ddI in people who have never taken these drugs; this triple combination being studied in children lowers levels of protease of inhibitors indinavir and saquinavir I blood | Rash usually goes away by itself; report sever rash to doctor immediately |
| Rescriptor (delavirdine) | AZT, ddI, AZT + ddI | Three times daily | Raises levels of indinavir and saquinavir in blood | Rash usually goes away by itself; report sever rash to doctor immediately |
4. What drug combinations work well together?
§ Nucleoside-nucleoside combinations. Because nucleosides were the first anti-HIV drugs available, combinations of two nucleosides are the best-studied double therapies for HIV infection. Large studies in the United States, Europe, and Australia showed that AZT + ddI or AZT + ddC work better than AZT alone. These studies showed this difference both by counting clinically significant signs of HIV disease and by measuring CD4 counts and amounts of virus in the blood. Another large study in Canada, Europe, Australia, and South Africa showed that adding 3TC to AZT, to AZT + ddI, or to AZT + ddC lowered the chance that HIV disease would get worse. Smaller studies showed that AZT + 3TC, ddI + d4T, and d4T + 3TC are effective in lowering amounts of virus in the blood and helping raise CD4 counts. It's likely that double-nucleoside combinations will be a part of anti-HIV therapy for a long time.
©1999, International Association of Physicians in AIDS Care
Research has been done in Chingola, Mansa, Magoye and Mazabuka. Snail prevalence studies have also been undertaken in Kafue and Siavonga. It has been shown that bilharzia is still prevalent in these areas because of inadequate control of the vector (snail). Studies conducted in 1998 in Mansa (4 schools), Kafue (3 villages), Magoye (4 villages) the parasite prevalence rate of 31.7% for Mansa, 22.9% for Kafue and 29% for Magoye. The severity and spread of the disease is mainly attributed to the snail-borne infections, in the man-made irrigation project, dams, streams, and rivers. In children, it is reported that the disease affects both growth and school performance while in adults it affects economic productivity. Schistosomiasis causes significant morbidity and mortality to those infected if not timely treated.
The studies conducted in the 1970's showed that incidence of bilharziasis in Northern and Luapula Provinces were about 7% attributed to S. mansoni and 15% in the case of S. haematobium. The studies done during the same period in Siavonga showed the prevalence was highest in the ages 5-14 for these two types of parasites. The widespread of the disease is recognised by the World Health Organisation's World health Report of 1998 which indicate that schistosomiasis is a significant problem in Far East Asia, Africa, South America and the Caribbean region. The disease was reported to be endemic in 74 developing countries with about 200 million people infected. The disease was estimated to result in about 20,000 deaths per year.
It is hoped that results of the research done by NISIR using (Endod) phytolacca dodecandra, in the control of bilharzia carrier snails, will go a long way to improve the incidence of bilharziasis which affect mostly the rural areas and in particular school children in Zambia. This research the disease continues to be of importance to the improvement of health and productivity of the populations. The results obtained so far show that the natural product Endod plays a significant role in the control of schistosomiasis. The merit of using endod is that it can be grown in Zambia and is biologically degradable leaving no residues when it is applied in water bodies. NISIR at its Tree Improvement Research Centre, in Kitwe, is currently growing about 2 hectares of phytolacca plantation which may be a source of planting material.
Editorial Comment from SCI_TECH Newsletter Mar-Dec 1999
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Schistosomiasis is a major public health problem in rural Zambia. It affects over one million Zambians. Agricultural development is contributing to the severity and spread of this snail-borne infection and yet inadequate attention is being paid to the health problem. A recommended control strategy which relies on chemotherapy and chemical molluscicides are very expensive for a developing country like Zambia. Therefore, the use of phytolacca dodecandra commonly known as Endod as an indigenous plant molluscicide to Zambia is the most promising and practical method to control the disease.
MATERIALS AND METHODS:
Muchinshi, where the study was carried out between 1993 and 1995, is a village in Chingola, Copperbelt Province. Muchinshi stream flows through the village and is used for domestic and recreational activities. The site selected for the trials is a stretch of 1.2 km of Muchinshi stream.
Unripe Endod berries harvested from Ichimpe plantation, in Kitwe were used. The stream was treated with Endod at each trial. The 1.2 km stretch of the stream was divided equally into 12 stations. 100 meters. The control was the first station up-stream of experimental section.
Snail surveillance was performed in Muchinshi stream monthly for one year for each trial in order to observe the long-term effect on the snail population.
RESULTS:
When water extract of Endod was applied at concentrations of 150 ppm and 75 ppm for 8 hours, 98% of the snail population was eliminated by 24 hours after the application. However, concentration of 37.5 ppm eliminated only 65% of the snail population. This result showed that snails were not brought under control at low concentration. In the third month, the population for both snail species returned to its initial density. This is attributed to the new hatches of snail egg masses since Endod is not ovicidal. Therefore, at the fourth trial, Endod was applied twice at the rate of 75 ppm interspaced by one month. The data obtained from the first application has confirmed the high molluscicidal activity of Endod. Furthermore, snails were brought under control for a period of six months by the second application of Endod.
This study demonstrated that Zambian Endod can successfully control transmission of schistosomiasis. Therefore, health authorities must be aware of all the benefits that would accrue from the use of Endod in the control of schistosomiasis.
Dr Mohammed Shehata, SCI_TECH Newsletter Mar-Dec 1999
Facts and figures:
Modes of transmission The AIDS epidemic in women is overwhelmingly heterosexual - almost entirely so in Africa and South and South East Asia. In other areas, a proportion of women are infected through:
Why are women more vulnerable to HIV infection?
Economically:
Socially and culturally:
Why must the response be gender-based?
Three main reasons:
What will make a difference? Physical and material independence and
security for women which is independent of the "protection" of a man or men?
Women must be empowered so that they are able to control their own lives and in particular their sexual relations. This implies a profound shift in social and economic power relations between men and women. It cannot be achieved tomorrow but action must start today, through:
Treatment and prevention of sexually transmissible infections:
Safe blood Women and children are the chief recipients of transfusions; women - during and after delivery. The following action is required:
Education for prevention including the use of condoms Condoms, male and female, are currently the only protection methods available. They need to be more widely accepted, available and used plus education to promote their use and increasing access through free distribution, subsidies, or social marketing so that they are really affordable.
It has been shown that even in the most favourable circumstances, condom use (male and female) is low. The acceptability of these methods remains problematic. The female condom is if anything more cumbersome than the male condom and considerably more expensive. Furthermore, women cannot control their use. Impact will continue to be low if people's preferences and therefore their actual use of methods, are not given due attention.
Women as careers:
Making men more responsible:
A posting from: health-l@hivnet.ch
Treatments to prevent the development of an infection are known as prophylaxis, from the Greek word meaning `to guard against'. Primary prophylaxis simply means trying to prevent even a first occurrence of an opportunistic infection in someone who is likely to be vulnerable to it. It is quite well established that particular opportunistic infections usually only occur after a particular degree of immune damage has taken place, as measured by the CD4 cell count. This makes it possible to start particular prophylactic drugs when the CD4 count falls below certain levels. Secondary prophylaxis means trying to prevent a subsequent episode of an opportunistic infection after one episode has occurred. It is standard medical practice to provide `maintenance therapy' to people who have already experienced certain opportunistic infections, such as tuberculosis, CMV of the eye or brain, toxoplasmosis or cryptococcal infection, to prevent a recurrence. Maintenance therapy usually consists of lower doses of similar drugs to those used to treat the active infection.
Making a choice on primary or secondary prophylaxis is an individual decision made between people with HIV and their doctor. Targeting prophylaxis is also important. No-one who feels entirely healthy will want to start taking prophylactic drugs until he or she is genuinely at risk. There is also a chance of resistance to drugs occurring if pathogens are exposed to those drugs over long periods. The choice of drug is also clearly important: some treatments for active opportunistic infections are too toxic to be given over the long periods needed for prophylaxis.
Does prophylaxis work?
There is good evidence that prophylaxis works. For example, the incidence of PCP as a first AIDS diagnosis decreased in the mid 1990s, before the widespread uptake of antiretroviral therapy, due to primary prophylaxis. Studies have shown that prophylaxis and antiretroviral therapy has increased survival among people with HIV. See the entry "Survival, AIDS and mortality" in the section "Effectiveness of HIV therapy" for more details.
In the 2000s, people with HIV who develop AIDS tend to do so only when their CD4 count has fallen to a much lower level than in the past. This is presumably because antiviral treatment and the use of prophylaxis are delaying the opportunistic diseases that might otherwise occur earlier. Unfortunately prophylaxis is not always as effective once the CD4 count becomes very low, although it remains of value.
For further discussion of prophylaxis see: Immune restoration illnesses" and "Prophylaxis and immune restoration"