Does an HIV clinical trial information booklet improve patient knowledge and understanding of HIV clinical trials?

Objectives To evaluate the impact of an information booklet on HIV clinical trials, Clinical Trials in HIV and AIDS: Information For People Who Are Thinking About Joining a Trial, in addition to the standard trial information (SI) on patients' knowledge; understanding and attitudes about clinical trials; and to investigate patients' motivations and reasons for enrolling or not enrolling in a clinical trial. Methods Fifty HIV‐1 positive patients who attended the HIV clinic at a west London hospital were randomized to receive either SI alone (n = 27) or SI and a 16 page information booklet explaining the principles and procedures of HIV clinical trials (n = 23). A self‐administered questionnaire was used at baseline to assess past experience and attitudes to clinical trials (10 questions), knowledge and understanding of HIV treatments (8 questions) and clinical trials (11 questions). At 2–6 months after randomization, a second interviewer‐administered questionnaire addressed the patient's assessment of the usefulness and comprehensiveness of the information provided by the SI and information booklet, whether or not the patient had enrolled in a clinical trial and reasons for enrolling/not enrolling, knowledge of specific aspects of the trial protocol the patient was eligible to join (13 questions) and general knowledge of clinical trial procedures (repeat of 11 baseline questions). Changes in the attitudes and scores on knowledge and understanding of clinical trials were compared for the two groups. Results In both groups, patient knowledge of clinical trial procedures improved significantly over the study period. The median score increased from 30 at baseline to 35/44 at follow‐up (SI only) vs. 24–31/44 (SI plus booklet), but this did not differ significantly between the two groups. However, knowledge of the specific trial protocol was poor [median score 13/25, interquartile range (IQR) 8–14], and there was no difference in the scores for the two groups. The prime motivations for joining a clinical trial were to benefit personal health and to gain access to new treatments. Potential side‐effects were the main concern of prospective trial participants. Conclusions This small trial shows that, while the patients' general knowledge and understanding of clinical trials improved over time, this was not improved by the information booklet and recollection of the details of the relevant trial protocol remained poor.     

Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes

Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection without clear understanding of its immunological effects. Here, we demonstrate that early use of HAART during primary infection preserves HIV-specific CD8(+) T cells physically and functionally while HIV-specific T cell help is sustained. We also show that even transient administration of HAART at seroconversion can preserve HIV-specific immunity. In contrast, delayed initiation of HAART is associated with a progressive loss of HIV-specific CD8(+) T cells and absent HIV-specific T cell help. These results imply that HIV-specific T help is damaged during primary HIV-1 infection. Early drug treatment, which preserves this immunity, also preserves HIV-specific CD8(+) T cells. These results have implications for understanding the early pathogenesis of HIV-1 infection and suggest that acute HIV infection should be treated aggressively and as early as possible.     

Epidemiological risk factors for hypersensitivity reactions to abacavir

We investigated risk factors for hypersensitivity reactions (HSR) to abacavir in a case-control study. In a multivariate analysis, white race [odds ratio (OR), 5.16; 95% confidence interval (CI), 1.16-22.97] and a higher CD8 cell count at initiation of abacavir (>850 vs. < or =850 cells: OR, 3.74; 95% CI, 1.19-11.77) were found to be significantly associated with the development of HSR. Age, gender, stage of disease, prior antiretroviral exposure and type of concurrent antiretroviral therapy were not associated with HSR. Differences in predisposition to HSR according to ethnicity and baseline CD8 cell count may be explained by the reported MHC genetic associations with HSR.     

Herpesvirus saimiri-immortalized human lymphocytes: novel hosts for analyzing HIV type 1 in vitro neutralization

Herpesvirus saimiri-immortalized CD4(+) T lymphocytes (HVS T cells) are activated memory cells that support efficient replication of primary R5 strains of HIV-1, which predominate in virus transmission. Being continuous, they are phenotypically more stable and technically less demanding than peripheral blood mononuclear cells (PBMCs). Here we present the first report using HVS T cells to assay HIV-1 neutralization in vitro. Neutralization sensitivities of paired viruses isolated from individuals in both HVS T cells (CN-2 cells) and PBMCs were similar, with homologous and heterologous plasma/sera in both CN-2- and PBMC-based assays. Analysis of V3 loop and CD4-binding site (CD4-BS) sequences showed that changes present in CN-2 isolates were neither more numerous nor more significant than those selected in their PBMC counterparts. Neutralization profiles of CN-2/PBMC virus pairs were similar again when V3- and CD4-binding site (BS)-specific monoclonal antibodies, whose mapped epitopes were conserved or of similar sequence in the virus pairs, were tested. Unlike other T cell line isolates, CN-2 isolates were not more sensitive to neutralization than their PBMC counterparts. We also show that HVS T cells do not appear to exert significant biological selection pressures on primary isolates. Paired viruses have a similar phenotype with respect to syncytium formation, cell tropism, and coreceptor usage. Thus CN-2 cells are suitable hosts for assaying neutralization and could be useful in standardizing neutralization assays performed in different laboratories.     

Prevalence of hepatitis C in an ethnically diverse HIV-1-infected cohort in south London

OBJECTIVES: There is limited information on the prevalence of and risk factors for hepatitis C virus (HCV) infection among HIV-1-infected patients in the UK. Our objective was to determine the prevalence of HCV infection among an ethnically diverse cohort of HIV-infected patients in south London, and to extrapolate from these data the number of co-infected patients in the UK. METHODS: A total of 1017 HIV-1-infected patients who had attended King's College Hospital HIV clinic between September 2000 and August 2002 were screened for HCV antibody using a commercial enzyme-linked immunosorbent assay (ELISA). Positive results were confirmed by polymerase chain reaction (PCR) or recombinant immunoblot assay. Demographic, clinical and laboratory data were obtained from the local computerized database and medical records. We applied our HCV prevalence rates in the different HIV transmission groups to the estimated number of HIV-infected persons in these groups in the UK, to obtain a national estimate of the level of HIV-HCV co-infection. RESULTS: Of the 1017 HIV-1-infected patients, 407 (40%) were white men, 158 (15.5%) were black African men, 268 (26.3%) were black African women, and 61 (6%) and 26 (2.6%) were black Caribbean men and women, respectively. Heterosexual exposure was the most common route of HIV acquisition (53.5%), followed by men having sex with men (36.9%), and current or previous injecting drug use (IDU) (7.2%). The overall prevalence of HCV co-infection was 90/1017 (8.9%), but this varied substantially according to route of transmission, from 82.2% among those with a history of IDU (which accounted for 67% of all HCV infections), to 31.8% in those who had received blood products, to 3.5% and 1.8% in those with homosexually and heterosexually acquired infection, respectively. Multivariate logistic regression analysis identified several independent risk factors for HCV infection: a history of IDU [odds ratio (OR) = 107.2; 95% confidence interval (CI) = 38.5-298.4], having received blood products (OR = 16.5; 95% CI = 5.1-53.7), and either being from a white ethnic group (OR = 4.3; 95% CI = 1.5-12.0) or being born in Southern Europe (OR = 6.7; 95% CI = 1.5-30.7). Based on the 35,473 known HIV-1-infected persons in the UK and the 10 997 estimated to be unaware of their status, we projected that there are at least 4136 HIV-HCV co-infected individuals in the UK and 979 who are unaware of their status. CONCLUSIONS: Overall, 9% of our cohort was HIV-HCV co-infected. The prevalence was highest among intravenous drug users (82%), who accounted for most of our HCV cases, and lowest among heterosexual men and women from sub-Saharan Africa and the Caribbean [< 2%]. Our estimate that a significant number of co-infected persons may be unaware of their HIV and HCV status, highlights an urgent need to increase the uptake of HCV and HIV testing, particularly among injecting drug users, to reduce the risk of onward transmission.     

Economic evaluations of HBV testing and treatment strategies and applicability to low and middle-income countries

Background

Many people living with chronic HBV infection remain undiagnosed until later stages of disease. Increasing testing and treatment rates form part of the strategy to respond to the WHO goal of eliminating viral hepatitis as a public health threat by 2030. However, achieving these ambitious targets is dependent on finding effective and cost-effective methods of scale up strategies. The aim of this study was to undertake a narrative review of the literature on economic evaluations of testing and treatment for HBV infection, to help inform the development of the 2017 WHO Hepatitis Testing Guidelines.

Methods

We undertook a focussed literature review for economic evaluations on testing for HBV accompanied by antiviral treatment. The search was carried out in Pubmed and included only articles published after 2000 and written in English. We narratively synthesise the results and discuss the key drivers of cost-effectiveness and their applicability to low and middle-income countries (LMICs).

Results

Nine published studies were included in this review, only one of which was performed in a low or middle-income setting in West Africa. Eight studies were performed in high-income settings, seven among high risk groups and one among the general population. The studies were heterogeneous in many respects including the population and testing strategy under consideration, model structure and baselines parameters, willingness to pay thresholds and outcome measures used. However, most studies found HBV testing and treatment to be cost-effective, even at low HBsAg prevalence levels.

Conclusions

Currently economic evaluations of HBV testing and treatment strategies in LMICs is lacking, therefore limiting the ability to provide formal recommendations on the basis of cost-effectiveness alone. Further implementation research is needed in order to help guide national policy planning.

     

Economic evaluation of HCV testing approaches in low and middle income countries

Background

Hepatitis C virus (HCV) infection represents a major public health burden with diverse epidemics worldwide, but at present, only a minority of infected persons have been tested and are aware of their diagnosis. The advent of highly effective direct acting antiviral (DAA) therapy, which is becoming available at increasingly lower costs in low and middle income countries (LMICs), represents a major opportunity to expand access to testing and treatment. However, there is uncertainty as to the optimal testing approaches and who to prioritize for testing. We undertook a narrative review of the cost-effectiveness literature on different testing approaches for chronic hepatitis C infection to inform decision-making and formulation of recommendations in the 2017 World Health Organization (WHO) viral hepatitis testing guidelines.

Methods

We undertook a focused search and narrative review of the literature for cost effectiveness studies of testing approaches in three main groups:- 1) focused testing of specific high-risk groups (defined as those who are part of a population with higher seroprevalence or who have a history of exposure or high-risk behaviours); 2) “birth cohort” testing among easily identified age groups (i.e. specific birth cohorts) known to have a high prevalence of HCV infection; and 3) routine testing in the general population. Articles included were those published in PubMed, written in English and published after 2000.

Results

We identified 26 eligible studies. Twenty-four of them were from Europe (n = 14) or the United States (n = 10). There was only one study from a LMIC (Egypt) and this evaluated general population testing. Thirteen studies evaluated focused testing among specific groups at high risk for HCV infection, including nine in persons who inject drugs (PWID); five among people in prison, and one among HIV-infected men who have sex with men (MSM). Eight studies evaluated birth cohort testing, and five evaluated testing in the general population. Most studies were based on a one-time testing intervention, but in one study testing was undertaken every 5 years and in another among HIV-infected MSM there was more frequent testing. Comparators were generally either: 1) no testing, 2) the status quo, or 3) multiple different strategies. Overall, we found broad agreement that focused testing of high risk groups such as persons who inject drugs and men who have sex with men was cost-effective, as was birth cohort testing. Key drivers of cost-effectiveness were the prevalence of HCV infection in these groups, efficacy and cost of treatment, stage of disease and linkage to care. The evidence for routine population testing was mixed, and the cost-effectiveness depends largely on the prevalence of HCV.

Conclusions

The evidence base for different HCV testing approaches in LMICs is limited, minimizing the contribution of cost-effectiveness data alone to decision-making and recommendations on testing approaches in the 2017 WHO viral hepatitis testing guidelines. Overall, the guidelines recommended focused testing in high risk-groups, particularly PWID, prisoners, and men who have sex with men; with consideration of two other approaches:- birth cohort testing in those countries with epidemiological evidence of a significant birth cohort effect; and routine access to testing across the general population in those countries with a high HCV seroprevalence above 2% - 5% in the general population. Further implementation research on different testing approaches is needed in order to help guide national policy planning.

     

Prevalence and burden of HBV co‐infection among people living with HIV: A global systematic review and meta‐analysis

Globally, in 2017 35 million people were living with HIV (PLHIV) and 257 million had chronic HBV infection (HBsAg positive). The extent of HIV‐HBsAg co‐infection is unknown. We undertook a systematic review to estimate the global burden of HBsAg co‐infection in PLHIV. We searched MEDLINE, Embase and other databases for published studies (2002‐2018) measuring prevalence of HBsAg among PLHIV. The review was registered with PROSPERO (#CRD42019123388). Populations were categorized by HIV‐exposure category. The global burden of co‐infection was estimated by applying regional co‐infection prevalence estimates to UNAIDS estimates of PLHIV. We conducted a meta‐analysis to estimate the odds of HBsAg among PLHIV compared to HIV‐negative individuals. We identified 506 estimates (475 studies) of HIV‐HBsAg co‐infection prevalence from 80/195 (41.0%) countries. Globally, the prevalence of HIV‐HBsAg co‐infection is 7.6% (IQR 5.6%‐12.1%) in PLHIV, or 2.7 million HIV‐HBsAg co‐infections (IQR 2.0‐4.2). The greatest burden (69% of cases; 1.9 million) is in sub‐Saharan Africa. Globally, there was little difference in prevalence of HIV‐HBsAg co‐infection by population group (approximately 6%‐7%), but it was slightly higher among people who inject drugs (11.8% IQR 6.0%‐16.9%). Odds of HBsAg infection were 1.4 times higher among PLHIV compared to HIV‐negative individuals. There is therefore, a high global burden of HIV‐HBsAg co‐infection, especially in sub‐Saharan Africa. Key prevention strategies include infant HBV vaccination, including a timely birth‐dose. Findings also highlight the importance of targeting PLHIV, especially high‐risk groups for testing, catch‐up HBV vaccination and other preventative interventions. The global scale‐up of antiretroviral therapy (ART) for PLHIV using a tenofovir‐based ART regimen provides an opportunity to simultaneously treat those with HBV co‐infection, and in pregnant women to also reduce mother‐to‐child transmission of HBV alongside HIV.     

The changing pattern of AIDS-defining illnesses with the introduction of highly active antiretroviral therapy (HAART)in a London clinic

OBJECTIVES: To quantify the progressive impact of combination antiretroviral therapy (ART) on the incidence of AIDS-defining illnesses (ADIs) over a 9-year period. METHODS: Retrospective cohort study. Eligible patients were 1538 AIDS-free, HIV-1-positive patients attending a large HIV clinic in west London who were at risk of developing AIDS because their CD4 count had declined to < or =350 x 10(6)/l cells during the period 1 January 1990 and 31 December 1998. Incidence rates for the 12 most frequent ADIs were compared for two time periods, 1990-1995 (pre-HAART) and 1996-1998 (post-HAART), using Poisson regression methods. Multivariate Poisson regression models were used to examine the contribution of ART and HAART to any observed temporal trends in incidence rates. RESULTS: After a median follow-up of 35 months, 450 (29%) patients had developed AIDS. Between the two time periods there was a significant decrease in the incidence of Pneumocystis carinii pneumonia (PCP) by 35% (4.11 per 100 person-years in 1990-1995 vs. 2.67 in 1996-1998;P= 0.007), Kaposi's sarcoma by 34% (3.27 vs. 2.17;P= 0.022) and cryptosporidiosis by 60% (0.76 vs. 0.31;P= 0.029). A non-significant reduction in incidence was observed for cryptococcosis by 45% (0.81 vs. 0.45;P= 0.11), oesophageal candidiasis by 29% (3.34 vs. 2.39;P= 0.053) and mycobacterium avium complex by 18% (1.58 vs. 1.29;P= 0.4), and a non-significant increase was observed for tuberculosis by 17% (0.62 vs. 0.73;P= 0.66) and non-Hodgkins lymphoma (NHL) by 51% (0.43 vs. 0.65;P= 0.31). The incidence of cerebral toxoplasmosis, cytomegalovirus, recurrent bacterial chest infections and dementia remained stable. There was a clear stepwise reduction in the incidence of PCP, Kaposi's sarcoma and cryptosporidiosis with the use of non-H AART and HAART regimens relative to no ART. In a multivariate analysis, the use of ART and HAART explained the progressive decrease in incidence of PCP and Kaposi's sarcoma. CONCLUSIONS: The incidence of most ADIs has decreased over the last 9 years. The striking reduction in the inci-dence of PCP and Kaposi's sarcoma since 1996 can be attributed to the use of combination ART and particularly HAART. The non-significant increase in the incidence of NHL and tuberculosis needs confirmation in other patient cohorts.