Articles tagged as "Europe"

AIDS and bacterial disease remain leading causes of hospital admission

Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis.

Ford N, Shubber Z, Meintjes G, Grinsztejn B, Eholie S, Mills EJ, Davies MA, Vitoria M, Penazzato M, Nsanzimana S, Frigati L, O'Brien D, Ellman T, Ajose O, Calmy A, Doherty M. Lancet HIV. 2015 Oct;2(10):e438-44. doi: 10.1016/S2352-3018(15)00137-X. Epub 2015 Aug 11.

Background: Morbidity associated with HIV infection is poorly characterised, so we aimed to investigate the contribution of different comorbidities to hospital admission and in-hospital mortality in adults and children living with HIV worldwide.

Methods: Using a broad search strategy combining terms for hospital admission and HIV infection, we searched MEDLINE via PubMed, Embase, Web of Science, LILACS, AIM, IMEMR and WPIMR from inception to Jan 31, 2015, to identify studies reporting cause of hospital admission in people living with HIV. We focused on data reported after 2007, the period in which access to antiretroviral therapy started to become widespread. We estimated pooled proportions of hospital admissions and deaths per disease category by use of random-effects models. We stratified data by geographical region and age.

Findings: We obtained data from 106 cohorts, with reported causes of hospital admission for  313 006 adults and 6182 children living with HIV. For adults, AIDS-related illnesses (25 119 patients, 46%, 95% CI 40-53) and bacterial infections (14 034 patients, 31%, 20-42) were the leading causes of hospital admission. These two categories were the most common causes of hospital admission for adults in all geographical regions and the most common causes of mortality. Common region-specific causes of hospital admission included malnutrition and wasting, parasitic infections, and haematological disorders in the Africa region; respiratory disease, psychiatric disorders, renal disorders, cardiovascular disorders, and liver disease in Europe; haematological disorders in North America; and respiratory, neurological, digestive and liver-related conditions, viral infections, and drug toxicity in South and Central America. For children, AIDS-related illnesses (783 patients, 27%, 95% CI 19-34) and bacterial infections (1190 patients, 41%, 26-56) were the leading causes of hospital admission, followed by malnutrition and wasting, haematological disorders, and, in the African region, malaria. Mortality in individuals admitted to hospital was 20% (95% CI 18-23, 12 902 deaths) for adults and 14% (10-19, 643 deaths) for children.

Interpretation: This review shows the importance of prompt HIV diagnosis and treatment, and the need to reinforce existing recommendations to provide chemoprophylaxis and vaccination against major preventable infectious diseases to people living with HIV to reduce serious AIDS and non-AIDS morbidity.

Abstract access 

Editor’s notes: Despite the widening availability of antiretroviral therapy (ART), HIV-associated disease remains an important cause of illness and death. In this systematic review the authors summarise published data concerning causes of hospital admission among HIV-positive people since 2007. This date was selected on the basis that access to ART was limited prior to 2007.

Overall the most common causes of admission among adults, across all geographical regions, were AIDS-associated illness and bacterial infections. Tuberculosis was the most common cause among adults, accounting for 18% of all admissions, followed by bacterial pneumonia (15%). Among children, similarly AIDS-associated illnesses (particularly tuberculosis and Pneumocystis pneumonia) and bacterial infections were the most common causes of admission. Among the 20% of adults who died during their admission, the most common causes of death were tuberculosis, bacterial infections, cerebral toxoplasmosis and cryptococcal meningitis. Among children the most common causes of death were tuberculosis, bacterial infections and Pneumocystis pneumonia. Tuberculosis is likely to have been underestimated in these studies. Autopsy studies consistently illustrate that around half of HIV-positive people who have tuberculosis identified at autopsy had not been diagnosed prior to death.

The review highlights that the majority of severe HIV-associated disease remains attributable to advanced immunosuppression. This is reflected by a median CD4 count at admission among adults of 168 cells per µl. Some 30% of people first tested HIV positive at the time of the admission. The review underlines the need to promote HIV testing so that HIV-positive people can access ART, and prevent the complications of advanced HIV disease. It also underscores the need for better coverage of screening for tuberculosis and preventive therapy for people without active disease.  

Avoid TB deaths
Comorbidity, Epidemiology
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PrEP is effective in a real world setting

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.

McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, Sullivan AK, Clarke A, Reeves I, Schembri G, Mackie N, Bowman C, Lacey CJ, Apea V, Brady M, Fox J, Taylor S, Antonucci S, Khoo SH, Rooney J, Nardone A, Fisher M, McOwan A, Phillips AN, Johnson AM, Gazzard B, Gill ON. Lancet. 2015 Sep 9. pii: S0140-6736(15)00056-2. doi: 10.1016/S0140-6736(15)00056-2. [Epub ahead of print]

Background: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect.

Methods: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and (NCT02065986).

Findings: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1.2/100 person-years) versus 20 in the deferred group (9.0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0.0001; absolute difference 7.8/100 person-years, 90% CI 4.3-11.3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEP. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients.

Interpretation: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection.

Abstract  Full-text [free] access

Editor’s notes: The PROUD study was an open label pragmatic randomised controlled trial designed to assess the effectiveness of pre-exposure prophylaxis (PrEP) in gay men and other men who have sex with men and whether the benefits are counteracted by risk compensation in users of PrEP. During the pilot phase of the study to test the feasibility of a large-scale trial the investigators found an unexpectedly high incidence of HIV infections. It was seven times higher than the national estimate reported for gay men and other men who have sex with men in the UK. The incidence of HIV infection was significantly lower in the group assigned to receive PrEP immediately, compared with the group assigned to receive it after a deferral period of one year. Moreover the reduction in HIV incidence was greater than has been observed in placebo-controlled trials. As a result the trial was stopped early on the recommendation of the trial steering committee. The high incidence of HIV suggests that, despite the broad eligibility criteria, the study population was highly selective and that the offer of PrEP attracted men who were at high risk of HIV and most likely to benefit from it. Despite some limitations, for example, lack of data on adherence and sexual behaviour, the results of this study are encouraging and have important implication for HIV prevention. They indicate that PrEP is effective in a real world setting, particularly in a population that is aware of its risk of HIV infection. Furthermore, there was no evidence of risk compensation among PrEP recipients. 

United Kingdom
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When to switch to second-line ART in children?

HIV-1 drug resistance and second-line treatment in children randomized to switch at low versus higher RNA thresholds.

Harrison L, Melvin A, Fiscus S, Saidi Y, Nastouli E, Harper L, Compagnucci A, Babiker A, McKinney R, Gibb D, Tudor-Williams G; PENPACT-1 (PENTA 9PACTG 390) Study Team. J Acquir Immune Defic Syndr. 2015 Sep 1;70(1):42-53. doi: 10.1097/QAI.0000000000000671.

Background: The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold.

Methods: PENPACT-1 had a 2 x 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30 000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end.

Results: Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30 000 copies/mL (PI-30 000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30 000 copies/mL (NNRTI-30 000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30 000 copies/mL threshold arms, median time from 1000 to 30 000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30 000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30 000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30 000, 64% NNRTI-1000, and 100% NNRTI-30 000 were <400 copies/mL 24 weeks later.

Conclusions: Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

Abstract access 

Editor’s notes: Paediatric guidelines recommend that children living with HIV initiate ART early in life. Therefore duration of treatment is likely to be for several decades in children. Children have tended to be maintained on failing therapies longer than adults due to limited treatment options, particularly in resource-limited settings.

The PENPACT-1 trial compared two HIV viral load thresholds, <1000 and <30 000 copies/ml, for switching to second-line ART among children taking non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)-based first-line regimens. As expected, children starting NNRTIs as their first-line regimen developed more NRTI mutations than children starting on boosted PIs. Importantly, children switching to second line ART at the higher viral load threshold were much more likely to develop resistance if they were taking NNRTI as their first line regimen than if they were taking boosted PIs. The study highlights the more “forgiving” nature of the PI drug class in terms of development of drug resistance. The main implication of this finding is that delayed switching on PI-based ART is a safe option in settings where future drug options are limited, as the risk of development of clinically significant PI or NRTI mutations is low. Interestingly, use of an abacavir + lamivudine nucleoside backbone resulted in fewer thymidine analogue mutations (TAMs) than use of lamivudine + zidovudine or stavudine backbone. This finding was based on analysis of non-randomised data, but supports the current WHO recommendations to use abacavir as the first-line drug of choice in the NRTI backbone.

HIV Treatment
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Better integration of programmes against alcohol use necessary at every step of the HIV treatment cascade

The impact of alcohol use and related disorders on the HIV continuum of care: a systematic review: alcohol and the HIV continuum of care.

Vagenas P, Azar MM, Copenhaver MM, Springer SA, Molina PE, Altice FL. Curr HIV/AIDS Rep. 2015 Sep 28. [Epub ahead of print]

Alcohol use is highly prevalent globally with numerous negative consequences to human health, including HIV progression, in people living with HIV (PLH). The HIV continuum of care, or treatment cascade, represents a sequence of targets for intervention that can result in viral suppression, which ultimately benefits individuals and society. The extent to which alcohol impacts each step in the cascade, however, has not been systematically examined. International targets for HIV treatment as prevention aim for 90% of PLH to be diagnosed, 90% of them to be prescribed with antiretroviral therapy (ART), and 90% to achieve viral suppression; currently, only 20% of PLH are virally suppressed. This systematic review, from 2010 through May 2015, found 53 clinical research papers examining the impact of alcohol use on each step of the HIV treatment cascade. These studies were mostly cross-sectional or cohort studies and from all income settings. Most (77 %) found a negative association between alcohol consumption on one or more stages of the treatment cascade. Lack of consistency in measurement, however, reduced the ability to draw consistent conclusions. Nonetheless, the strong negative correlations suggest that problematic alcohol consumption should be targeted, preferably using evidence-based behavioral and pharmacological interventions, to indirectly increase the proportion of PLH achieving viral suppression, to achieve treatment as prevention mandates, and to reduce HIV transmission.

Abstract access 

Editor’s notes: This systematic review examined the impact of alcohol consumption on each step of the HIV treatment cascade. This covered HIV diagnosis, linkage to care, retention in care, ART initiation and adherence, and sustained virologic suppression. Overall, there was an association between alcohol consumption and negative consequences on various steps of the treatment cascade. The majority of studies focused on the effect of alcohol use disorders and ART adherence, and on viral suppression. There was fairly consistent evidence of reduced adherence among people with alcohol use disorders. Key findings of this review include the lack of consistency in studies of alcohol consumption. Many studies are not using standardised, validated, measures such as the AUDIT, and there is the lack of studies on the association of alcohol use with earlier stages of the cascade, including testing uptake and linkage to care. Further studies in this area would be useful, to identify whether programmes focused on problematic alcohol use are necessary at HIV testing centres.

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HIV-associated stigma may impede HIV medication adherence among people living with HIV

The association of HIV-related stigma to HIV medication adherence: a systematic review and synthesis of the literature.

Sweeney SM, Vanable PA. AIDS Behav. 2015 Aug 25. [Epub ahead of print]

This paper provides a review of the quantitative literature on HIV-related stigma and medication adherence, including: (1) synthesis of the empirical evidence linking stigma to adherence, (2) examination of proposed causal mechanisms of the stigma and adherence relationship, and (3) methodological critique and guidance for future research. We reviewed 38 studies reporting either cross-sectional or prospective analyses of the association of HIV-related stigma to medication adherence since the introduction of antiretroviral therapies (ART). Although there is substantial empirical evidence linking stigma to adherence difficulties, few studies provided data on psychosocial mechanisms that may account for this relationship. Proposed mechanisms include: (a) enhanced vulnerability to mental health difficulties, (b) reduction in self-efficacy, and (c) concerns about inadvertent disclosure of HIV status. Future research should strive to assess the multiple domains of stigma, use standardized measures of adherence, and include prospective analyses to test mediating variables.

Abstract access 

Editor’s notes: People living with HIV often experience stigma and discrimination including social isolation and negative stereotyping. Recent evidence suggests that stigma may influence adherence to HIV medication among people living with HIV. This paper presents findings from a systematic review of the evidence on the impact of HIV-associated stigma on HIV medication adherence. The authors identified 38 studies which quantitatively assessed the association between stigma and medication adherence. All studies found evidence indicating that stigma contributed to adherence difficulties among people living with HIV. Included studies looked at diverse patient populations sampled from different countries and contexts. While stigma is heavily influenced by the socio-cultural context, the association between stigma and adherence across diverse contexts indicates that there may be commonalities in what causes stigma and how this relates to adherence.

The authors of this review suggest three possible causal mechanisms of HIV-associated stigma and medication adherence: (1) There may be links between stigma and depressive symptoms, and between depressive symptoms and adherence. Internalized stigma may enhance vulnerability to depressive symptoms, and this may influence adherence to HIV medication. (2) Stigma may cause reductions in self-efficacy – a person’s judgment of his or her ability to organize and execute behaviours - which may influence medication adherence. (3) People may fear HIV status disclosure by being seen taking HIV medication. Fear of status disclosure, and associated stigma, may cause people to avoid taking HIV medication.

The studies included in this review indicate a clear link between HIV-associated stigma and HIV medication adherence. There may be commonalities in what causes stigma across multiple populations. Future research should assess the influence of multiple forms of stigma on adherence, and on testing causal mechanisms between stigma and adherence. 

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START trial illustrates benefit of ART start with CD4>500

Initiation of antiretroviral therapy in early asymptomatic HIV infection.

Lundgren J, Babiker A,  Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper D, Fätkenheuer G, Llibre J, Molina J, Munderi P, Schechter M, Wood R, Klingman K, Collins S, Lane H, Phillips A,  Neaton J. INSIGHT START Study Group. N Engl J Med. 2015 Jul 20. [Epub ahead of print]

Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12 759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.

Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.

Abstract  Full-text [free] access

Editor’s notes: Guidelines on when to start antiretroviral therapy (ART) are rapidly evolving. The major point of uncertainty, and disagreement between guidelines, has been whether the benefits to individuals of starting ART outweigh the risks for people with high CD4 counts, where the absolute risk of morbidity and mortality is relatively low.

The START study addressed this question among people with CD4 counts greater than 500 cells per µl. Study participants were recruited across the global regions, with the largest number from Europe (33%) followed by Latin America (25%) and Africa (21%). Some 55% were gay men and other men who have sex with men. Retention in the study was very good, and virologic outcomes among people who started ART were excellent (98% and 97% had virologic suppression by 12 months in the immediate versus deferred study arms). There was a 57% reduction in the hazard of the primary outcome, a composite of serious AIDS-associated events, serious non-AIDS associated events or death from any cause. The most common AIDS-associated events were tuberculosis (mostly seen in African participants), malignant lymphoma and Kaposi’s sarcoma. Among the serious non-AIDS events, cancers unrelated to AIDS were reduced by 50%, but interestingly there was no change in cardiovascular events. There was no increase in risk of serious adverse events. Interestingly the magnitude of risk reduction for the primary outcome was similar in high- and low-income countries.

These results will be very important as ART guidelines are reviewed and are likely to lead to recommendations for ART initiation, regardless of CD4 count in most settings. The authors note that, with a relatively low absolute risk of serious events, some people with high CD4 counts may opt to defer treatment, and this trial has produced very useful data to inform this discussion. Benefits from earlier ART initiation are dependent on earlier testing.  With an estimated 50% of people with HIV globally unaware of their status, the uptake of testing by asymptomatic people will need to be increased. In addition, retention in care will need to be optimised if the potential benefits of ART demonstrated by this study are to be realised.

HIV Treatment
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Multiple harms faced by Azerbaijani prisoners

Burden of substance use disorders, mental illness, and correlates of infectious diseases among soon-to-be released prisoners in Azerbaijan.

Azbel L, Wickersham JA, Wegman MP, Polonsky M, Suleymanov M, Ismayilov R, Dvoryak S, Rotberga S, Altice FL. Drug Alcohol Depend. 2015 Mar 19. pii: S0376-8716(15)00136-2. doi: 10.1016/j.drugalcdep.2015.02.034. [Epub ahead of print]

Background: Despite low HIV prevalence in the South Caucasus region, transmission is volatile. Little data are available from this region about addiction and infectious diseases among prisoners who transition back to communities.

Methods: A nation-wide randomly sampled biobehavioral health survey was conducted in 13 non-specialty Azerbaijani prisons among soon-to-be-released prisoners. After informed consent, participants underwent standardized health assessment surveys and testing for HIV, hepatitis B and C, and syphilis.

Results: Of the 510 participants (mean age=38.2 years), 11.4% were female, and 31.9% reported pre-incarceration drug injection, primarily of heroin. Prevalence of HCV (38.2%), HIV (3.7%), syphilis (3.7%), and HBV (2.7%) was high. Among the 19 HIV-infected inmates, 14 (73.7%) were aware of their HIV status, 12 (63.2%) were receiving antiretroviral therapy (ART), and 5 (26.3%) had CD4<350cells/mL (4 of these were on ART). While drug injection was the most significant independent correlate of HCV (AOR=12.9; p=0.001) and a significant correlate of HIV (AOR=8.2; p=0.001), both unprotected sex (AOR=3.31; p=0.049) and working in Russia/Ukraine (AOR=4.58; p=0.008) were also correlated with HIV.

Conclusion: HIV and HCV epidemics are concentrated among people who inject drugs (PWIDs) in Azerbaijan, and magnified among prisoners. A transitioning HIV epidemic is emerging from migration from high endemic countries and heterosexual risk. The high diagnostic rate and ART coverage among Azerbaijani prisoners provides new evidence that HIV treatment as prevention in former Soviet Union (FSU) countries is attainable, and provides new insights for HCV diagnosis and treatment as new medications become available. Within prison evidence-based addiction treatments with linkage to community care are urgently needed.

Abstract access 

Editor’s notes: This is an important study describing prevalence of HIV, hepatitis B and hepatitis C among a prison population in Azerbaijan. The importance of the study stems from the need to monitor infections among a highly vulnerable population of prisoners. While the study does not report on current injecting drug use among the population, a third of the sample reported injecting drugs prior to their detention and will need support with their injecting drug use while in prison. This will include the provision of opioid substitution therapy and needle-syringe programmes.  This study highlights the vulnerability of prisoners to HIV, hepatitis B and hepatitis C and the need for harm reduction in prisons. At the same time, the study also highlights other adverse health outcomes relating to drug use or being in prison in terms of poor mental health outcomes among the sample. It illustrates an association between a measure of anxiety disorder and HIV infection. The strengths of this study lie in the large sample that were recruited from a broad range of prison facilities across the country, increasing the representativeness of the findings to all people living in prisons. Findings suggest an association between HIV infection and condomless sex, as well as a history of working in Russia and Ukraine. This suggests the potential for transmission of HIV across the region and points to the potential for sexual transmission of HIV in a region where transmission has been historically driven by injecting drug use. Findings contribute to the growing evidence for the urgent need for hepatitis C virus (HCV) treatment and increased access to needle-syringe programmes and opioid substitution therapy within prisons and communities in the region.  The high adherence among prisoners to HIV treatment demonstrates the provision of HCV treatment to the population is entirely feasible. Previous evidence from Russia has illustrated the difficulties for people living in prisons in maintaining HIV treatment post-release and this study underscores the need for support to facilitate the integration of individuals into harm reduction programmes including HIV treatment in community settings post-release. 

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Combination harm reduction may be more effective and cost-effective than partial approaches alone

The cost-effectiveness of harm reduction.

Wilson DP, Donald B, Shattock AJ, Wilson D, Fraser-Hurt N. Int J Drug Policy. 2015 Feb;26 Suppl 1:S5-11. doi: 10.1016/j.drugpo.2014.11.007. Epub 2014 Dec 1.

HIV prevalence worldwide among people who inject drugs (PWID) is around 19%. Harm reduction for PWID includes needle-syringe programs (NSPs) and opioid substitution therapy (OST) but often coupled with antiretroviral therapy (ART) for people living with HIV. Numerous studies have examined the effectiveness of each harm reduction strategy. This commentary discusses the evidence of effectiveness of the packages of harm reduction services and their cost-effectiveness with respect to HIV-related outcomes as well as estimate resources required to meet global and regional coverage targets. NSPs have been shown to be safe and very effective in reducing HIV transmission in diverse settings; there are many historical and very recent examples in diverse settings where the absence of, or reduction in, NSPs have resulted in exploding HIV epidemics compared to controlled epidemics with NSP implementation. NSPs are relatively inexpensive to implement and highly cost-effective according to commonly used willingness-to-pay thresholds. There is strong evidence that substitution therapy is effective, reducing the risk of HIV acquisition by 54% on average among PWID. OST is relatively expensive to implement when only HIV outcomes are considered; other societal benefits substantially improve the cost-effectiveness ratios to be highly favourable. Many studies have shown that ART is cost-effective for keeping people alive but there is only weak supportive, but growing evidence, of the additional effectiveness and cost-effectiveness of ART as prevention among PWID. Packages of combined harm reduction approaches are highly likely to be more effective and cost-effective than partial approaches. The coverage of harm reduction programs remains extremely low across the world. The total annual costs of scaling up each of the harm reduction strategies from current coverage levels, by region, to meet WHO guideline coverage targets are high with ART greatest, followed by OST and then NSPs. But scale-up of all three approaches is essential. These interventions can be cost-effective by most thresholds in the short-term and cost-saving in the long-term.

Abstract   Full-text [free] access

Editor’s notes: The spread of HIV among people who inject drugs has driven epidemics throughout regions of eastern Europe, and central and South-East Asia. In eastern Europe and central Asia, the majority of HIV infections have been attributed to injecting drug use. Some countries in the Middle East and North Africa region have also been experiencing rapidly emerging HIV epidemics among people who inject drugs. Harm reduction refers to methods of reducing health risks when eliminating them may not be possible. This paper provides a comprehensive review of evidence on the effectiveness and cost-effectiveness of different harm reduction approaches. These include needle- syringe programmes, opioid substitution therapy (OST), and antiretroviral therapy (ART), when implemented in different settings. Importantly, alongside considering the potential benefits of each approach separately, it makes the case that combination  prevention strategies are synergistic, and may achieve multiple impacts. Sadly still however, the coverage of harm reduction remains very low across the world. An estimated 90% of people who inject drugs worldwide are not accessing needle-syringe programmes, despite this being a highly effective and cost-effective programme. Along with the need for a greater investment in harm reduction, there are socio-political and legislative reasons for poor coverage of harm reduction. This cannot be improved without first addressing the stigma, discrimination and intolerance that restricts the expansion of harm reduction programmes in many settings. Addressing these barriers remains of paramount importance for facilitating effective harm reduction programmes. Encouragingly however, high OST coverage has been reported in Iran, Czech Republic and western Europe, and several countries in Asia and the Middle East have begun to scale-up their programmes. China has recently had the largest OST scale-up programme in the world. Uptake of ART by people living with HIV who inject drugs illustrates the largest disparities with what is required or deemed to be appropriate access. Only 14% of people living with HIV who inject drugs globally, have access to ART, with the largest gaps in ART provision in eastern Europe and central Asia. The further expansion of harm reduction is urgently needed, both to meet WHO targets, and to achieve the UNAIDS 90-90-90 target.

Asia, Europe, Oceania
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Can a simple risk score predict chronic kidney disease among people living with HIV?

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O, Smith C, Wentworth D, Neuhaus J, Fux CA, Moranne O, Morlat P, Johnson MA, Ryom L, D:A:D study group, the Royal Free Hospital Clinic Cohort, and the INSIGHT, SMART, and ESPRIT study groups. PLoS Med. 2015 Mar 31;12(3):e1001809. doi: 10.1371/journal.pmed.1001809. eCollection 2015.

Background: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.

Methods and findings: A total of 17 954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR >60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103 185 person-years of follow-up (PYFU; incidence 6.2/1000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score <0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1702 (95% CI 1166-3367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2548 individuals, of whom 94 individuals developed CKD (3.7%) during 18 376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria.

Conclusions: Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

Abstract  Full-text [free] access

Editor’s notes: The nephrotoxicity of antiretroviral drugs, particularly tenofovir, is of concern, particularly where there is limited access to laboratory monitoring of kidney function. The development of kidney impairment among people with HIV is associated with poor outcomes, and in low resource settings where dialysis is not available this can be catastrophic.

This study, like previous work, attempts to address this problem by developing a risk score for the development of chronic kidney disease (CKD). The strength of this study is the availability of data for over 17 000 men and women living with HIV enrolled in cohort studies for many years, and in over 40 countries globally. The resulting risk score uses nine simple clinical variables which predict CKD both overall, and after starting potentially nephrotoxic antiretrovirals. A short risk score, not including cardiovascular risk factors, which may be more suitable for low resource settings, shows almost as good a prediction of CKD.

So will this risk score become widely used in clinical decision making? For high income countries this tool may be useful to identify people where strategies to prevent cardiovascular and renal disease are best focussed. It may also be useful to identify people at high risk of developing CKD for whom use of tenofovir may be unacceptable, especially when monitoring of kidney function is limited. However, few of the enrolled people were from low and middle income countries, and there was limited information on the race of participants. Therefore, the risk score may need to be validated in low resource settings before it can be widely used. Whether the use of the tool would help to improve clinical outcomes where kidney function is frequently monitored is unclear.

Meanwhile, a new drug formulation, tenofovir alafenamide (TAF), is currently in clinical trials. This appears to be associated with less renal toxicity, and to be safe and well tolerated among adults with decreased kidney function. If future trial results support this evidence, and tenofovir alafenamide becomes widely available, concern about drug nephrotoxicity may become a less pressing clinical issue.

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Adolescent adherence to antiretroviral therapy: what matters?

Factors associated with adherence to antiretroviral therapy among adolescents living with HIV/AIDS in low- and middle-income countries: a systematic review.

Hudelson C, Cluver L. AIDS Care. 2015 Feb 23:1-12. [Epub ahead of print]

Adolescents living in low- and middle-income countries (LMICs) are disproportionately burdened by the global HIV/AIDS pandemic. Maintaining medication adherence is vital to ensuring that adolescents living with HIV/AIDS receive the benefits of antiretroviral therapy (ART), although this group faces unique challenges to adherence. Knowledge of the factors influencing adherence among people during this unique developmental period is needed to develop more targeted and effective adherence-promoting strategies. This systematic review summarizes the literature on quantitative observational studies examining correlates, including risk and resilience-promoting factors, of ART adherence among adolescents living with HIV/AIDS in LMICs. A systematic search of major electronic databases, conference-specific databases, gray literature, and reference lists of relevant reviews and documents was conducted in May 2014. Included studies examined relationships between at least one factor and ART adherence as an outcome and were conducted in primarily an adolescent population (age 10-19) in LMICs. The search identified 7948 unique citations from which 15 studies fit the inclusion criteria. These 15 studies identified 35 factors significantly associated with ART adherence representing a total of 4363 participants across nine different LMICs. Relevant studies revealed few consistent relationships between measured factors and adherence while highlighting potentially important themes for ART adherence including the impact of (1) adolescent factors such as gender and knowledge of serostatus, (2) family structure, (3) the burdensome ART regimens, route of administration, and attitudes about medication, and (4) health care and environmental factors, such as rural versus urban location and missed clinic appointments. Rates of adherence across studies ranged from 16% to 99%. This review identifies unique factors significantly related to ART adherence among adolescents living in LMICs. More research using longitudinal designs and rigorous measures of adherence is required in order to identify the range of factors influencing ART adherence as adolescents living with HIV/AIDS in LMICs grow into adulthood.

Abstract access 

Editor’s notes: Expanded access to antiretroviral therapy (ART) and scale-up of programmes to prevent mother-to-child HIV transmission has resulted in the burden of paediatric HIV infection shifting onto adolescents, in low- and middle-income countries. Adolescents and young adults account for 41% of incident infections globally and are the only age group for which AIDS-associated deaths have risen in the past decade.

As the number of adolescents on ART increases, sustaining optimal adherence has emerged as the key challenge. While there are limited adolescent-specific data available, estimates of ART adherence suggest that adolescents have much poorer adherence than adults. This leads to increased risk of disease progression, transmission to sexual partners and antiretroviral drug resistance.

There is a growing body of literature that has examined factors affecting adherence, but to date the focus has been on adults and young children. Therefore, this systematic review of factors associated with good and suboptimal adherence specifically among adolescents aged 10 to 19 years, is timely.

There were a diverse range of factors associated with adherence across the fifteen studies considered. These include knowledge of serostatus, the influence of family structure, burdensome regimens, route of administration (caregiver giving medication versus adolescent self-medicating), and attitudes about medication and missed appointments. These factors likely interact with the complexities faced during adolescence to increase the risk of suboptimal adherence.   

The studies considered in this review had significant weaknesses. Firstly, most studies were cross-sectional. Therefore the extent to which causality between the considered factors and adherence can be inferred is limited. Secondly, not all studies reported on the strengths of the relationship between the factors and adherence or accounted for confounding. Thirdly, the method of measuring adherence varied between studies. Only one study in the review used a gold standard, objective treatment outcome measure, HIV viral load.

Notwithstanding these limitations, this is the first study to examine correlates of adherence to ART in adolescence. Although there were few consistent relationships between these factors and adherence, the study does suggest potential activities to improve adherence.

Given the central role of adolescents in determining the trajectory of the HIV epidemic, there is a need for more rigorous research to define factors affecting adherence behaviours among adolescents. Programmes addressing important risk- and resilience-promoting factors such as caregiver support and less burdensome regimens have potential to improve adherence. 

Africa, Asia, Europe, Latin America
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