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Contains fulltext : 283099.pdf (Publisher’s version ) (Open Access) BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and

Contains fulltext : 282959.pdf (Publisher’s version ) (Open Access) BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to

Persistence of HIV through integration into host DNA in CD4(+) T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8(+) T cells are triggered to kill infected CD4(+) T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial'' HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A*02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8(+) T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4(+) T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing—termed kick and kill regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.

Background While barriers to uptake of antenatal care (ANC) among pregnant women have been explored, much less is known about how integrating prevention of mother-to-child transmission (PMTCT) programmes within ANC services affects uptake. We explored barriers to uptake of integrated ANC services in a poor Zimbabwean community. Methods A cross-sectional survey was conducted among post-natal women at Mbare Clinic, Harare, between September 2010 and February 2011. Collected data included participant characteristics and ANC uptake. Logistic regression was conducted to determine factors associated with ANC registration. In-depth interviews were held with the first 21 survey participants who either did not register or registered after twenty-four weeks gestation to explore barriers. Interviews were analysed thematically. Results Two hundred and ninety-nine participants (mean age 26.1 years) were surveyed. They came from ultra-poor households, with mean household income of US$181. Only 229 (76.6%) had registered for ANC, at a mean gestation of 29.5 weeks. In multivariable analysis, household income was positively associated with ANC registration, odds ratio (OR) for a $10-increase in household income 1.02 (95% confidence interval, CI, 1.0–1.04), as was education which interacted with having planned the pregnancy (OR for planned pregnancy with completed ordinary level education 3.27 (95%CI 1.55–6.70). Divorced women were less likely to register than married women, OR 0.20 (95%CI 0.07–0.58). In the qualitative study, barriers to either ANC or PMTCT services limited uptake of integrated services. Women understood the importance of integrated services for PMTCT purposes and theirs and the babies’ health and appeared unable to admit to barriers which they deemed “stupid/irresponsible”, namely fear of HIV testing and disrespectful treatment by nurses. They represented these commonly recurring barriers as challenges that “other women” faced. The major proffered personal barrier was unaffordability of user fees, which was sometimes compounded by unsupportive husbands who were the breadwinners. Conclusion Women who delayed/did not register were aware of the importance of ANC and PMTCT but were either unable to afford or afraid to register. Addressing the identified challenges will not only be important for integrated PMTCT/ANC services but will also provide a model for dealing with challenges as countries scale up ‘treat all’ approaches. Electronic supplementary material The online version of this article (10.1186/s12884-018-1898-7) contains supplementary material, which is available to authorized users.

Antibody titres against Kaposi's sarcoma associated herpesvirus (KSHV or human herpesvirus 8 (HHV-8)) and Epstein-Barr virus (EBV) were examined in people who subsequently developed Kaposi's sarcoma and non-Hodgkin's lymphoma, within randomised controlled trials of antiretroviral therapy in adults infected with the human immunodeficiency virus-1 (HIV). For each case of Kaposi's sarcoma (n=189) and each case of non-Hodgkin's lymphoma (n=67), which developed after randomisation, one control was randomly selected from other trial participants, after matching for age, sex, ethnicity, mode of HIV transmission, type of treatment received and period of follow-up. Using sera taken an average of two and a half years before the diagnosis of cancer, titres of antibodies against KSHV latent (LANA) and lytic (K8.1) antigens and against EBV (VCA) antigens were investigated in relation to subsequent risks of cancer by calculating odds ratios (OR) using conditional logistic regression. Latent antibodies against KSHV were detectable among 38% (72 out of 189) of Kaposi's sarcoma cases and 12% (23 out of 189) of their controls (OR=4.4, 95% confidence intervals (CI) 2.3-8.3, P

We demonstrate that peptides (16 amino acids long) covering the sequence of the HIV-1 core protein p24 induce significant proliferation in peripheral blood mononuclear cells (PBMC) of several (greater than 50%) healthy seronegative volunteers as well as seronegative homosexual men. The nature of this response was characterized and compared with those of HIV-infected patients. Several peptides induced responses; however, the most frequent responses in both seropositive and seronegative individuals were noted to the following peptides: 1 and 2 (aa 133-157); 6 and 7 (aa 183-207); 15 (aa 273-287); and 17 and 18 (aa 293-317). The response pattern was related to the disease stage of the patients; seronegative individuals as well as asymptomatic seropositive individuals (CDC II/III) responded to low concentrations of several peptides, but symptomatic patients (CDC IV) only responded to high concentrations of a few peptides. Cell separation studies of PBMC from healthy volunteers showed that the responding cells were CD4+ and expressed the CD45RO differentiation antigen. Furthermore, cord-blood mononuclear cells with less than 5% of CD45RO T cells did not proliferative to any of the peptides. Finally, CD4+ T cell lines specific for both peptides and p24 protein were successfully established from the PBMC of seronegative individuals confirming the data obtained with freshly isolated cells. These studies therefore suggest that the CD4+ cell response to p24 is not strictly disease related, instead, the response may be due to priming of the host with cross-reactive antigens.

Background Lactic acidosis (LA) and severe hyperlactataemia (HL) are infrequent but serious complications of antiretroviral therapy that have been associated with a high fatality rate. Methods In a multinational retrospective cohort study, LA was defined as arterial blood pH5 mmol/l. Logistic regression was used to identify factors associated with fatality. Sensitivity and specificity of different case definitions as predictors of death were compared. Results The overall case-fatality rate was 19/110 (17.3%), but among acidotic patients it was 33% (16/49 cases). There were 10 asymptomatic patients and none of them died as a consequence of the event. The median lactate for fatal, non-fatal and all patients was 8.3 mmol/l (IQR 7.2–13.1), 6.4 mmol/l (IQR 5.4–7.8) and 6.7 mmol/l (IQR 5.5–8.1), respectively. After adjusting for age and current CD4+ T-cell count, lactate >7 mmol/l (OR 6.27, 95% CI 1.13–34.93), blood bicarbonate 18 mmol/l, 95% CI 1.33–75.65) and concurrent opportunistic infections (OR 8.69, 95% CI 1.45–52.22) were independently associated with case fatality. Blood lactate >7 mmol/l showed a sensitivity of 84% for fatality with a specificity of 60%, whereas bicarbonate Conclusions Our data suggest that blood lactate >7 mmol/l and blood bicarbonate

Objective The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir. Methods NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years. Results The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg). Conclusions We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension

BACKGROUND. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. METHODS. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. CONCLUSIONS. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide.

Objective: To examine the effect of early syphilis on blood and semen plasma HIV-1 viral loads and CD4 counts. Methods: In a retrospective case-control study, blood plasma HIV-1 viral loads and CD4 counts in cases during early syphilis (n = 63, 27 receiving antiretroviral therapy) were compared to those before and after syphilis and with controls with non-systemic acute sexually transmitted infections (STI) (n = 104, 39 receiving antiretroviral therapy). In a prospective substudy in those not receiving antiretroviral therapy, semen plasma viral loads during early syphilis (n = 13) were compared with those 1 month, 3 months, and 6 months after treatment for syphilis and with controls with no STIs (n = 20). Results: Retrospective study: CD4 counts were similar in cases (median 410, n = 139 counts) during early syphilis compared to before (485, n = 80) and after (475, n = 88). In a secondary analysis, a drop in CD4 count (21%) among those with early latent syphilis was observed compared with controls. Blood plasma viral loads did not change significantly overall or in those with primary, secondary, or early latent syphilis. Effects were similar on or off antiretroviral therapy. Prospective study: blood and semen viral loads were slightly higher in cases compared with controls but treatment of early syphilis did not reduce either. Conclusions: We detected no association between early syphilis and changes in blood or semen viral load or CD4 count. Increased HIV-1 infectivity associated with early syphilis is unlikely to be associated with increased levels of HIV-1 RNA in blood or semen.

Objective: To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors associated with this complication. Methods: Systematic review of cases reported in the medical literature. Results: 217 published cases were identified, 90 of which fulfilled the study definition and had sufficient individual data on potential risk factors to be included. The 90 patients had a mean age of 40.1 years (range 16–69) and 53% were female. All 90 patients were taking nucleoside reverse transcriptase inhibitors (NRTI) at the time of the episode. Among the 83 patients with details of their antiretroviral therapy (ART) regimen 51 patients were taking stavudine, 29 zidovudine, 27 didanosine, and 25 lamivudine. Around 50% of the patients had abdominal pain, nausea, or vomiting. Hepatic steatosis was consistently reported (53/90) and in 36 (68%) there was histological evidence. The case fatality rate was 48%. Six cases were rechallenged with NRTI and three developed a further LA episode. Using data on the numbers of HIV infected individuals receiving care in the United States, we estimate that the risk of LA could be 2.5 times higher for women than men. Conclusions: NRTI use and female sex appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include duration of NRTI therapy, specific drug use, and genetic predisposition. A case-control study is needed to better define risk factors for severe LA.

In a randomized placebo controlled trial 304 HIV infected patients with CD4 cell counts below 350 cells/microL received therapeutic vaccination with: alum placebo (Group I, n = 102), p24-VLP 500 microg (Group II, n = 101) or p24-VLP 1000 microg (Group III, n = 101) p24-VLP monthly for six months. Over one year the average change in CD4 cell count did not differ significantly between groups (-32, -40 and -52 cells per microL respectively). There was also no difference between groups in progression to CDC category B or C events, or in adverse events. Therapeutic vaccination with p24-VLP does not affect CD4 cell decline in patients with advanced HIV infection.

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.

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.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.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.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.

Kaposi sarcoma-associated herpesvirus (KSHV) is consistently found in biopsy samples from patients with AIDS-related and "classical" Kaposi's sarcoma (KS). Although highly suggestive of a causal role of KSHV in the pathogenesis of KS, this observation does not exclude the possibility that KSHV, like other herpesviruses, is widely distributed and is a mere "passenger" in these lesions. Here we report that KSHV was detectable in peripheral blood mononuclear cells of 24/46 (52%) of KS patients, but in none of 134 blood donors or 26 HIV-uninfected hospital controls. KSHV detection increased with immunosuppression, as shown by a correlation with a reduced number of CD4-positive T-cells. Moreover, KSHV detection in peripheral blood cells of HIV-infected individuals without KS predicted the subsequent appearance of KS lesions. 143 patients who did not have KS at the time of their first (or only) blood sample were followed up for a median of 30 months. Of the 11 who had been KSHV positive 6 developed KS compared with only 12 out of 132 who were KSHV negative. These findings are compatible with a causative role of KSHV in KS. KSHV was rarely detected in sputum and throat swabs of HIV-infected patients, providing a potential explanation for the apparently limited spread of this virus.

As part of the Medical Research Council prospective study of the neurological complications of HIV infection, neurophysiological tests of spinal cord and peripheral nerve function were recorded in a cohort of homosexual or bisexual men. The studies included motor and sensory nerve conduction studies, vibration perception thresholds, somatosensory evoked potentials and motor evoked potentials elicited by magnetic stimulation. The results were compared with markers of immune function. The findings from 114 volunteers were analysed in a cross-sectional study. Fifty-nine were HIV-seropositive but asymptomatic, 26 had progressed to the symptomatic stages of HIV disease and 29 were persistently HIV-seronegative. There was some evidence of a mild sensory axonopathy in the symptomatic HIV-seropositive group. No differences were detected between the asymptomatic HIV-seropositive group and the HIV-seronegative comparison group. There were no consistently significant correlations between the neurophysiological measurements and CD4 counts and beta 2-microglobulin levels. On repeated testing, there was no evidence of a trend towards deterioration over a mean period of approximately 3 years in 36 HIV-seropositive subjects who remained asymptomatic compared with 22 HIV-seronegatives. These findings have failed to demonstrate neurophysiological evidence of spinal cord or peripheral nerve dysfunction in the asymptomatic stages of HIV infection.

Implementation of cotrimoxazole prophylaxis (CTX-p) among HIV-exposed children is poor in southern Africa. We conducted a multi-methods study to investigate the barriers to delivery of CTX-p to HIV exposed infants in Zimbabwe at each step of the care cascade. Here we report findings of the qualitative component designed to investigate issues related to adherence conducted among women identified as HIV positive whose babies were started on CTX-p postnatally. Between Feb-Dec 2011, the first 19 HIV infected mothers identified were invited for in-depth interview 4-5months postnatally. Interviews were recorded, transcribed, translated and analysed thematically. Of note, Zimbabwe also provides nevirapine prophylaxis for HIV-exposed babies, so the majority were giving nevirapine and CTX-p to their babies. All women desired their baby's health above all else, and were determined to do all they could to ensure their wellbeing. They did not report problems remembering to give drugs. The baby's apparent good health was a huge motivator for continued adherence. Testimonies from women whose babies had tested HIV negative strengthened the resolve to adhere. However, most women reported that their husbands were less engaged in HIV care, refusing to be HIV tested and in some cases stealing drugs prescribed for their wives for themselves. In two instances the man stopped the woman from giving CTX-p to the baby either because of fear of side effects or not appreciating its importance: "he said if I kept giving CTX-p he would take the baby away from me and give him to his mother." Stigma continues to be an important issue. Mothers reported being reluctant to disclose their HIV status to other people so found it difficult to collect prescription refills from the HIV clinic for fear of being seen by friends/relatives. Some women reported that it was hard to administer the drugs if there were people around at home. Other challenges faced were stock-outs of CTX-p at the clinic, which occurred four times during the study. The baby would then go without CTX-p if the woman could not afford buying at a private pharmacy. The study highlights that adherence knowledge and desire alone is insufficient to overcome the familial and structural barriers to maintaining CTX-p. Improving adherence to CTX-p among HIV exposed infants will require interventions to improve male involvement, reduce HIV stigma at facilities and ensure adequate supply of drugs. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Sibanda E et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18061 http://www.jiasociety.org/index.php/jias/article/view/18061 | http://dx.doi.org/10.7448/IAS.15.6.18061

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)

Seventy-six homosexual or bisexual men underwent two cranial MRI studies at a mean interval of 13 months; 23 were HIV seronegative, 41 seropositive but asymptomatic (Center for Disease Control (CDC) groups II/III), and 12 had AIDS related complex (ARC)/AIDS (CDC group IV). Agreement between two neuroradiologists was rated as very good for assessment of enlargement of ventricles and good for widening of cerebral sulci and the presence of focal lesions. For assessment of serial studies, the agreement was moderate. The prevalence of cerebral atrophy and focal white matter lesions was no higher in the asymptomatic patients (CDC group II/III) than in appropriate seronegative controls. Some patients with ARC/AIDS showed evidence of developing cerebral atrophy during the study period when serial scans were compared. The imaging evidence supports the other data obtained from this cohort, which suggest that no significant CNS involvement occurs in HIV infection before the development of ARC/AIDS.

A systematic review designed to explore whether cotrimoxazole prophylaxis for HIV increases bacterial resistance to other classes of antibiotics. There is suggestive evidence that cotrimoxazole protects against antibiotic resistance., Background. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis has long been recommended for immunosuppressed HIV-infected adults and children born to HIV-infected women. Despite this, many resource-limited countries have not implemented this recommendation, partly because of fear of widespread antimicrobial resistance not only to TMP-SMX, but also to other antibiotics. We aimed to determine whether TMP-SMX prophylaxis in HIV-infected and/or exposed individuals increases bacterial resistance to antibiotics other than TMP-SMX. Methods. A literature search was conducted in Medline, Global Health, Embase, Web of Science, ELDIS, and ID21. Results. A total of 501 studies were identified, and 17 met the inclusion criteria. Only 8 studies were of high quality, of which only 2 had been specifically designed to answer this question. Studies were classified as (1) studies in which all participants were infected and/or colonized and in which rates of bacterial resistance were compared between those taking or not taking TMP-SMX and (2) studies comparing those who had a resistant infection with those who were not infected. Type 1 studies showed weak evidence that TMP-SMX protects against resistance. Type 2 studies provided more convincing evidence that TMP-SMX protects against infection. Conclusion. There was some evidence that TMP-SMX prophylaxis protects against resistance to other antibiotics. However, more carefully designed studies are needed to answer the question conclusively.

A sample of 26 HIV seronegative, 59 HIV seropositive asymptomatic and 7 HIV seropositive symptomatic homosexual and bisexual men were assessed over two visits, a mean of 11 months apart, using the BDI, STAI, and CIS. Significant differences emerged between the symptomatic group and the other two groups. Past psychiatric history and the somatic items in the assessments accounted for some of these differences. The seropositive asymptomatic and the seronegative groups did not differ on any of the mood or psychiatric assessments, suggesting minimal effect on psychological well-being of seroconversion in the absence of symptoms.

BACKGROUND: The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy. METHODOLOGY: Participants not on continuous ART with > or = 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly. PRINCIPAL FINDINGS: A total of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (p

The causal agent of Kaposi's sarcoma is unknown. That the disorder is ten times more common in homosexual or bisexual men with the acquired immunodeficiency syndrome (AIDS) than in other human immunodeficiency virus (HIV) transmission groups suggests that a certain aspect of their behaviour exposes them to the agent or facilitates its spread. We therefore assessed social and demographic characteristics, including sexual behaviour, of 65 homosexual or bisexual men with AIDS from London. Sexual practices in which there was contact with partner's faeces before AIDS developed were the main determinants of Kaposi's sarcoma risk. Risk increased with frequency of insertive "rimming" (oral-anal contact): Kaposi's sarcoma developed in 18% of the men with AIDS who reported never having practised insertive rimming compared with 50% who practised it less than once a month, 73% between once a week and once a month, and 75% or more once a week (two-sided exact p-value for trend less than 0.001). 45 men had been interviewed about their sexual practices before AIDS developed, and 20 were interviewed at the time the syndrome developed. The findings were similar and statistically significant when each group was analysed separately. The men with Kaposi's sarcoma also tended to be more sexually active and were more likely to engage in other sexual activities that entailed contact with faeces than were the men who had other features of AIDS only. Other behaviours and exposures, including the use of "poppers" (nitrite inhalants), were not related to Kaposi's sarcoma risk, after taking into account whether the subjects had practised insertive rimming. The data suggest that faecal-oral contact is the main route of transmission of the agent of Kaposi's sarcoma in homosexual or bisexual men with AIDS.

One of the most difficult problems in HIV care today is the management of individuals infected with multidrug-resistant viruses. Well-controlled, carefully designed clinical trials have recently resulted in the approval of several new antiviral agents for the treatment of drug-resistant HIV. The design of these trials has come at the cost of the predictable emergence of drug-resistant viruses among individuals randomly assigned to receive a suboptimal revised treatment regimen. We propose here a different approach to the evaluation of drug efficacy in individuals harbouring multidrug-resistant HIV.

Objectives: To examine the effects of urethritis and its treatment on semen plasma HIV-1 RNA load in HIV-1 infected men not receiving antiretroviral therapy (ART), in a developed world setting. Methods: Prospective case-control study. HIV-1 infected homosexual men, not receiving ART for at least 3 months, with (cases) and without (controls) symptomatic urethritis, were recruited. Blood and semen were collected for HIV-1 RNA quantification at presentation, before antibiotic therapy, and at 1 and 2 weeks. Results: 20 cases (13 gonococcal urethritis and/or chlamydial urethritis (GU/CU) and seven non-specific urethritis (NSU)) and 35 controls were recruited. Baseline characteristics and blood plasma viral load were similar in cases and controls. Mean log semen plasma viral loads were higher among those with GU/CU compared with controls (4.27 log versus 3.55 log respectively; p = 0.01) but not in those with NSU (3.48 log; p = 0.82). Following antibiotics, semen plasma viral loads fell by a mean of 0.25 log (95% CI: 0.03 to 0.47) in those with GU/CU. Semen plasma viral loads did not fall in those with NSU. Conclusions: In this study of 55 homosexual men not on ART, semen plasma viral loads were approximately fivefold higher in those with GU/CU, but not NSU, compared with controls. Treatment of GU/CU resulted in reduction in semen plasma viral loads. Although absolute effects were considerably lower when compared to patients from a similar study from sub-Saharan Africa, our data demonstrate the potential for sexually transmitted infections to enhance HIV infectivity of men not receiving ART in the developed world. Abbreviations: ART, antiretroviral therapy; BPVL, blood plasma viral loads; CU, chlamydial urethritis; GEE, generalised estimating equations; GU, gonococcal urethritis; NGU, non-gonococcal urethritis; NSU, non-specific urethritis; PCR, polymerase chain reaction; p/hpf, polymorphs per high power field; SPVL, seminal plasma viral loads.

Sexually transmitted infections may enhance the sexual transmission of HIV-1. It is possible that loss of virological control in patients with such infections receiving antiretroviral therapy (ART) may even facilitate the transmission of drug-resistant HIV. We have recently demonstrated that in those on maximally suppressive ART this effect is reduced. We have examined the virus obtained from the blood plasma and seminal plasma of six HIV-1-infected men receiving poorly suppressive ART with acute urethritis for the presence of drug resistance-associated mutations. In four men with gonorrhoea the blood and seminal plasma HIV-1 had mutations conferring reduced susceptibility to one or more available drugs. In one of these men the viral load of drug-resistant virus in seminal plasma was 20-fold higher during gonorrhoea than following antibiotic treatment, with no change in blood plasma viral load. We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1.

Background: High seminal plasma HIV-1 RNA loads (SVL) have been reported during gonococcal, non-gonococcal and chlamydial urethritis in patients not taking antiretroviral therapy.Objective: To examine if urethritis leads to increased SVLin HIV-positive patients taking antiretroviral therapy. Methods: Men who had been taking therapy for at least 3 months were recruited: 24 had urethitis (PWU) and 16 were without urethritis (controls). At three visits, 1 week apart, blood plasma viral load (BVL) and SVL were assayed by quantitative polymerase chain reaction or the NASBA assay.Results: Most subjects had undetectable SVL (18 PWU, 13 controls). Among those with undetectable BVL prior to first study visit, virus was undetectable in semen in 5/5 episodes of chlamydial urethritis, 6/7 episodes of non-gonococcal urethritis and 4/5 cases of gonococcal urethritis. Two PWU with undetectable BVL just prior to the first study visit had low to moderate SVL, which became undetectable by visit 2 following treatment. Of nine subjects with detectable SVL, eight had detectable BVL (3/3 controls and 5/6 PWU). Of these, 1/3 controls and 4/5 PWU (all with gonococcal urethritis) had poorly controlled BVL just prior to the first study visit. These four PWU had high SVL and one had higher levels in semen than in blood. This patient's SVL was reduced more than 20-fold following treatment for gonococcal urethritis.Conclusions: Effective antiretroviral therapy appeared to limit the effect of urethritis on SVL. When BVL was poorly controlled by antiretroviral therapy, high SVL occurred during gonococcal urethritis, increasing the potential risk of transmitting both wild type and drug resistant strains of HIV-1. (C) 2002 Lippincott Williams Wilkins.

1 London School of Hygiene and Tropical Medicine, London, UK 2 Uganda Virus Research Institute, Entebbe, Uganda 3 Department for International Development, Kampala, Uganda 4 The AIDS Support Organisation, Kampala, Uganda 5 Wakiso District Council, Entebbe, Uganda 6 HIV Division, World Health Organisation, Geneva, Switzerland 7 Centre for Sexual Health & HIV Research, University College London, London, UK

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.

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.

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.

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)

As part of the Medical Research Council prospective study of the neurological and neuropsychological complications of human immunodeficiency virus (HIV) infection, long-latency event-related potentials were recorded in a cohort of homosexual and bisexual men. The latencies and amplitudes of the potentials, recorded from three scalp sites, were compared with the scores from neuropsychological tests of memory, attention, and concentration and with markers of immune function. The findings from 94 men were analyzed in the cross-sectional study of whom 47 were HIV seropositive without symptoms or signs of HIV type 1 (HIV-1) infection, 24 had progressed to the symptomatic stages of the disease, and 23 were persistently HIV seronegative. There were no consistently significant differences between the three subject groups in mean latencies and amplitudes of the P300 and N200 or in the numbers of abnormal P300 latencies. There were no significant correlations between either the neuropsychological tests scores or the immune measures (CD4 lymphocyte count and beta(2) microglobulin level) and the neurophysiological parameters. On repeated testing an average of 2 years later, there was no evidence of a significant trend towards deterioration in 30 HIV-seropositive subjects who remained asymptomatic compared with 22 HIV seronegatives. These findings indicate that there is no neurophysiological evidence of cognitive dysfunction in the asymptomatic stages of HIV-1 infection.

Background: Recent studies have shown some association between specific mitochondrial DNA (mtDNA) polymorphisms and peripheral neuropathy in both white European and black American populations. An association between mtDNA haplogroup H and peripheral lipoatrophy has been reported in white Europeans. Our group has shown a lack of association between mtDNA polymorphisms and the occurrence of HL in white Europeans exposed to dideoxynucleosides, but there have been no studies in black African people. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P96 Cite this article as: Arenas-Pinto et al.: Lack of association between mitochondrial DNA polymorphisms and didexoxynucleoside-induced hyperlactataemia in black-African, HIV-1-infected patients. Journal of the International AIDS Society 2010 13(Suppl 4):P96. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113104/

Cell-free human immunodeficiency virus type-1 (HIV-1) was precipitated from archival serum with polyethylene glycol (PEG), and HIV-1 RNA was detected and quantified by reverse transcription and amplification in a nested polymerase chain reaction (PCR). The assay of end-point dilutions cDNA in nested PCRs allowed an estimation of the minimum RNA copies per unit volume of serum. RNA titres correlated with the classification of HIV-1 infection by CDC disease groups (30 patients). The geometric mean titres of HIV-1 serum RNA from patients grouped by disease stage gave minimum estimates of 340 and 400 virions per millilitre of serum in CDC groups II and III (n = 6 and 10, respectively) and 4,240 virions per millilitre in CDC group IV (n = 14). An overall fall in viral titre measured in this way was observed in 3 patients during zidovudine treatment. HIV-1 titres increased in a further 4 patients when therapy was interrupted, stopped, or complicated by secondary infection.

Thirty one homosexual men with antibody to human immunodeficiency virus (HIV) but without major neurological complaints were assessed in a cross sectional study of neurological and neuropsychological function. Eleven patients had AIDS, 10 had persistent generalised lymphadenopathy (PGL), and 10 had HIV infection without PGL (called "well"). Thirteen age matched homosexual men without antibody to HIV acted as controls. Significant abnormalities were found in six on clinical neurological examination, in eight on nerve conduction studies, in six on electroencephalography, in six on neuropsychological assessment, and in eight on computed tomography of the head. Eighteen patients (nine with AIDS, four with PGL, and five "well") performed abnormally in at least one section of the assessment. The study highlights the incidence of nervous system dysfunction in HIV infection even in people who do not have AIDS. Prospective evaluation using electrophysiological and imaging techniques is necessary to assess the natural history of such manifestations and the effect of antiviral treatment.

Four patients with acquired immunodeficiency syndrome (AIDS) (CDC group IV) were investigated for biliary disease because of the presence of both severe upper abdominal pain and raised levels of serum alkaline phosphatase. None was clinically jaundiced. Upper abdominal ultrasound was abnormal in three. All had endoscopic retrograde cholangiographic evidence of both an intrahepatic sclerosing cholangitis suggestive of primary sclerosing cholangitis and an irregular suprapapillary common bile duct dilation suggestive of papillary stenosis. Three had evidence of gastrointestinal cryptosporidiosis and two of disseminated cytomegalovirus infection. Endoscopic sphincterotomy, performed in two patients, gave good pain relief. We propose the name 'AIDS sclerosing cholangitis' for this form of secondary cholangitis. The cause of this disorder remains unclear. Recent evidence is discussed which suggests that it is not due to HIV itself but to an opportunistic infection. Cryptosporidium appears to be the most likely candidate.

An empirical approach to treating Pneumocystis carinii pneumonia was adopted in a prospective study of 73 men with antibodies to human immunodeficiency virus 1 (HIV-1) presenting with respiratory problems. At presentation 49 patients (group 1) were thought to have a history, findings at clinical examination, chest radiograph, and arterial blood gas tensions typical of pneumocystis pneumonia, and empirical treatment was begun immediately. Twenty four patients (group 2) were thought to have features not typical of pneumocystis pneumonia. All patients were subsequently referred for bronchoscopy to determine the diagnosis. In group 1 four patients were excluded from the analysis because bronchoscopy was not possible. Of the remaining 45, 42 had pneumocystis pneumonia, which was diagnosed at bronchoscopy in 40, and on the basis of the clinical response to co-trimoxazole in two who had negative results from investigations. Of the three patients without pneumocystis pneumonia, one patient with lymphoid interstitial pneumonitis and Branhamella catarrhalis infection would have failed to respond to empirical treatment. The other two had multiple bacterial pathogens at bronchoscopy; one already had Kaposi's sarcoma and the other would have been misdiagnosed as having AIDS. In group 2 a specific diagnosis was made at bronchoscopy in 21 cases, including pneumocystis pneumonia in seven (all had atypical chest radiographs). In three cases no diagnosis was made and spontaneous recovery occurred. Adopting an empirical approach to treatment for typical pneumocystis pneumonia (group 1) led to the correct treatment in 43 of 45 cases (95%) and would have saved 44 of the 45 of bronchoscopies in this group. Adopting an empirical approach would have caused one patient to be misdiagnosed as having AIDS. Overall, 44 out of 69 bronchoscopies (64%) would have been saved; the specificity for the diagnosis of pneumocystis pneumonia was 85% and the sensitivity was 85%. Adopting an "empirical" treatment policy for typical pneumocystis pneumonia will cause a large reduction in the number of "high risk" bronchoscopies performed.