Articles tagged as "Greece"

Technology for tuberculosis, but why can’t we simply prevent it with proven tools that save lives?

Editor’s notes: Advances in diagnostic test technology have transformed the management of HIV and related infections.  For HIV, we have seen the introduction of self-administered test kits as well as new approaches to HIV viral load testing and nucleic acid based infant diagnosis.  Cryptococcal antigen screening can make prophylaxis and treatment more focused and potentially cost-effective.  For tuberculosis the biggest revolution has been the widespread introduction of the geneXpert® system.  The newest version, the Xpert® Ultra, is more sensitive than the original cartridge and is now being scaled up in countries including South Africa.  Agizew and colleagues conducted a study in Botswana to compare how the Xpert® MTB/RIF cartridge performed when used in centralized or peripheral health facilities.  Encouragingly there were few differences between the two levels, suggesting that the systems can be used close to the point of care.  However, the authors did note a surprisingly high level of unsuccessful tests (15%) both at the central lab and at the peripheral clinic.  Many of these test failures seem to have been because the sample was not processed correctly, and so should be amenable to better training for the health care workers performing the test.  The yield of testing varied greatly between the 13 sites. Between 1% and 23% of samples were positive for tuberculosis, with an average of 14%.  This may be because some sites were receiving specialized referrals.  Of the 447 positive samples, 8% were shown to be rifampicin resistant.  This figure is hard to interpret without more detail of the sample of patients in whom the test was performed.  Resistance is always higher among those who have been treated previously and may be higher in those referred to specialized centres.  Nonetheless, it demonstrates that there are a significant number of people with tuberculosis in Botswana who are very likely to have multi-drug resistant disease and need effective second line treatment.  Technology comes with a price tag.  In this study, the team bought test kits for $18 each, which makes it an expensive choice.  However, if it leads to prompt treatment of multi-drug resistant disease and more accurate diagnosis of tuberculosis, including among those living with HIV, this might still be cost-effective.

A small implementation research study from a single provincial referral centre in Zambia also examined the use and results of geneXpert® screening.  Masenga and colleagues found that 6.6% of 2374 samples tested by geneXpert® over the course of a year were positive for tuberculosis.  An additional 1301 samples were tested by sputum microscopy.  Their results suggest that geneXpert® was used mainly on people who were living with HIV, given that more than 90% of the positive samples came from people living with HIV.  5.9% of the 152 positive samples that were tested in the system were resistant to rifampicin, with no difference by gender.  This study leaves many questions unanswered, such as the sampling strategy, the history of previous treatment and the outcomes of the diagnosis in terms of treatment regimen and success.  However, it shines a light on the ways that new technology is now routine in some settings.  We need more research from diverse settings to paint the full picture of implementation outside traditional research centres.

Zenner and colleagues revisit the question of the risks and benefits of treatment for latent tuberculosis infection.  In a systematic review and network meta-analysis, they demonstrate once more that we have several effective ways to prevent tuberculosis among people living with HIV and that the harms are much smaller than the risks.  The question remains why we have failed so badly to scale up preventive therapy for tuberculosis alongside the success in scale up of antiretrovirals.

 

Peripheral clinic versus centralized laboratory-based XPERT® MTB/RIF performance: experience gained from a pragmatic, stepped-wedge trial in Botswana

Agizew T, Boyd R, Ndwapi N, Auld A, Basotli J, Nyirenda S, Tedla Z, Mathoma A, Mathebula U, Lesedi C, Pals S, Date A, Alexander H, Kuebrich T, Finlay A. PLoS One. 2017 Aug 17;12(8):e0183237. doi: 10.1371/journal.pone.0183237. eCollection 2017.

Background: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert® MTB/RIF (Xpert®) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert® scale-up.

Methods: Xpert® was implemented from August 2012 through November 2014 with 13 GeneXpert® instruments (GeneXpert®) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert® testing. We documented our experience with staff training and GeneXpert® performance. Test results were extracted from GeneXpert® software; unsuccessful tests were analysed in relation to testing sites and trends over time.

Results: During 276 instrument-months of operation a total of 3630 tests were performed, of which 3102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3630 Xpert® tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert® instruments (14%, 95% CI: 11-17%; p = 0.140).

Conclusions: Xpert® introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert® location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert® testing staff is essential to minimize errors.

Abstract  Full-text [free] access

Rifampicin resistance in mycobacterium tuberculosis patients using GeneXpert® at Livingstone Central Hospital for the year 2015: a cross sectional explorative study

Masenga SK, Mubila H, Hamooya BM. BMC Infect Dis. 2017 Sep 22;17(1):640. doi: 10.1186/s12879-017-2750-9

Background: Since the recent introduction of GeneXpert® for the detection of Tuberculosis (TB) drug resistance mutations in both primary resistance and acquired resistance in Zambia, little has been documented in literature on the issue of rifampicin resistance especially in the face of a high National TB burden. The study aimed to determine the prevalence of rifampicin resistance in tuberculosis patients at Livingstone Central Hospital for the year 2015.

Methods: This was a cross sectional study conducted at Livingstone Central Hospital where we reviewed 152 records (from January 1, 2015 to 31st December 2015) involving patients who presented with clinically suspected TB or documented TB, whose samples were sent to the laboratory for GeneXpert® Mycobacterium tuberculosis/rifampicin testing. Statistical evaluations used a one-sample test of proportion and Fisher's exact test.

Results: The age of participants ranged from 8 months to 73 years old (median = 34). Of the participants with complete data on gender, 99 (66%) and 52 (34%) were males and females respectively. The TB co-infection with HIV prevalence was 98.3% (p < 0.001). Prevalence of rifampicin resistance was 5.9% and there was no statistical significant difference between being male or female (p = 0.721).

Conclusion: We were able to show from our study, evidence of rifampicin resistance at Livingstone Central Hospital. Hence, there was need for further in-depth research and appropriate interventions (i.e. close follow-up and patient care for drug resistance positive patients).

Abstract  Full-text [free] access

Treatment of latent tuberculosis infection: an updated network meta-analysis

Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ.  Ann Intern Med. 2017 Aug 15;167(4):248-255. doi: 10.7326/M17-0609. Epub 2017 Aug 1.

Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.

Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.

Data sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.

Study selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).

Data extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.

Data synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.

Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.

Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.

Abstract  Full-text [free] access

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How do we know which activities make a difference to HIV prevention?

Editor’s notes: In order to be fairly certain that an intervention is responsible for changes in HIV or HIV-related behaviours, the gold standard is randomization. This allows for fair comparisons between groups, since factors that might alter the outcomes will be more or less equally balanced between the study groups.  This is true whether such confounding factors are expected, but also importantly, even those factors that are unknown, unexpected and unmeasured will also be balanced between the arms. 

A second key determinant of high quality research is to use an approach that maximizes full engagement and follow-up of participants in the study.  One such approach that is widely recognized is to use Good Participatory Practice.  

Rhodes and colleagues study condom promotion and HIV testing among the Hispanic/Latino community of gay men and other men who have sex with men in North Carolina, USA.  Although gay men and other men who have sex with men represent approximately 4% of the adult male population in the United States of America, they account for more than 80% of new HIV infections among men.  Around one quarter of gay men and other men who have sex with men are Hispanic or Latino.  The authors therefore wanted to use research to make a difference to the HIV burden of the Hispanic/Latino gay men and other men who have sex with men community in North Carolina, USA.  They found that despite the impact of HIV on Hispanic/ Latino gay men and other men who have sex with men, they were only able to identify one evidence-based behavioural HIV prevention programme focussed on this population.

The authors used an extensive community based participatory research partnership, whose members represented the Hispanic/ Latino gay men and other men who have sex with men community, AIDS service organizations, Hispanic/Latino-serving community organizations, and universities to develop, implement, and evaluate a Spanish-language, small group intervention designed to increase condom use and HIV testing among Hispanic/Latino gay men and other men who have sex with men (HOLA en Grupos).

304 participants were randomly allocated to the HOLA en Grupos intervention, or to a general health education comparison intervention having the same number of sessions (4) and duration (16 hours in total) that focussed on prostate, lung, and colorectal cancers; diabetes; high cholesterol; cardiovascular disease; and alcohol misuse. These topics for the control group were identified on the basis of identified needs and priorities of Hispanic/Latino gay men and other men who have sex with men.

HOLA en Grupos is grounded on social cognitive theory, empowerment education, and traditional Hispanic/Latino cultural values and includes four interactive modules of four hours each delivered in groups.  Participants in both intervention and control arms received reimbursement for their time, certificates of completion and meals and a celebration at the completion of the course.  In other words this was an intensive intervention that might be hard to replicate in most settings, but it follows very high standards both for developing and conducting the research and also for determining the impact of the intervention.

The intervention was associated with a large effect on both condom usage (four-fold higher in the intervention arm than the control) and HIV test uptake (an astonishing 14-fold higher, reflecting the relatively low testing rate in the control group).

A major limitation in many HIV prevention studies, including this one, is that the outcome is based on reported behaviour.  The challenge is that the real outcome of interest, which is new HIV infections, is relatively rare in almost all communities so that studies have to be huge and expensive, and the large majority of participants in both intervention and control arms do not in fact acquire HIV.  This is in contrast to most studies of treatment, where there are clearly defined biological, standardized measures which many or all participants are likely to reach.  Nonetheless, there are many examples of studies that find changes in reported behaviour that are not associated with biological markers of such change (such as incidence of HIV or other sexually transmitted infections, or pregnancy). 

There are also many observational or ecological studies that report changes in new HIV infections but that cannot truly say why the number of infections fell and whether the interventions used in the study were responsible for the changes.  For example Nwokolo and colleagues report in a short research letter on the dramatic decline in new HIV diagnoses in the large London clinic where they work.  New infections in that clinic, and in fact in other large clinics in London, have dropped by a remarkable 40% from 2015 to 2016, as originally reported in the popular science press before any scientific publication or presentation. The authors of the research letter are suitably cautious about how to account for the impressive decline.  Various systems have been improved over the past few years in this clinic to make it easier to have an HIV test and start treatment immediately.  However, most of the clinic team (and many other commentators) assume that it is also due to the rapid rise in the use of PrEP.  Although it is still not available through the UK National Health Service, the clinic has been at the forefront of encouraging gay men and other men who have sex with men who might benefit from PrEP to purchase it from on-line pharmacies.  The clinic then provides the appropriate monitoring and follow up to ensure that their clients get the best possible PrEP service given the current constraints.  Whatever the cause, we should be celebrating the rapid fall in new HIV infections across London, which is home to a substantial proportion of the new HIV infections in the UK.

The challenges of demonstrating evidence of effectiveness for HIV prevention is also felt among black women in the USA.  Although they have the highest burden of HIV among women in the USA, the incidence rates are such that a traditional randomized trial design would need to be huge, and consequently hugely expensive.  Adimora and colleagues consider whether an alternative trial design might be to use data from high HIV incidence settings and then to develop proxies of protection, such as the concentration of a PrEP medicine to infer whether black women are protected.  An alternative that has been proposed for men who have sex with men would be to look for other markers of high risk, such as sexually transmitted infections, reported partners, age, and substance use and estimate the likely risk of HIV acquisition in the absence of PrEP from these parameters.  Then the observed incidence could be compared to this modelled counterfactual, much as was done in the open label extension of the Partners PrEP study in Kenyan and Ugandan sero-different couples.  However, translating risk factors for infection across populations, and even continents when there is such heterogeneity in risk of infection is not at all straightforward.  So there is still plenty to think about and no clear answers yet!

A useful addition to the tool box for designing studies and assessing the effectiveness of interventions, would be better tools for measuring recent infection.  There are several assays all with differing characteristics but increasingly these differences and how they interact with different clades of HIV are becoming clear.  Key determinants for each assay are the mean duration of recent infection (MDRI) estimate (which does seem to vary by clade) and the false recency rate (FRR) which needs to be less than 2% to be considered useful.  Hargrove and colleagues used three different assays to test samples from 101 women who seroconverted during the ZVITAMBO trial.  The MDRI measured using standard cut-off points, were considerably shorter than those published for the general population.  The authors point out that changes in antibody properties among women who have recently given birth or other unspecified physiological states, mean that incidence assays may give different results from those published and expected.  Yet more caution when comparing incidence estimates between studies.  As an endpoint in a comparison between two groups in the same population, the assays are still attractive. Although, given typical MDRIs of around six to nine months, these assays will still need to be embedded in very large samples to give reliable estimates of incidence and statistically significant differences between groups.

This month saw the production of a useful supplement on many aspects of how data from different sources, including incidence assays are used to inform the sophisticated models on which so much HIV planning, programming and financing is based.  An example is Mahiane and colleagues’ paper on the development of a new tool to fit existing programme data into the spectrum suite of models in order to estimate incidence.

Finally in this section, for those who are keen on laboratory studies, Richardson-Harman and colleagues describe the current state of ex-vivo challenge models for assessing potential candidates as microbicides.  In these models, biopsies of rectal, cervical or vaginal tissue, taken during other procedures, or from volunteers, are kept alive in the laboratory.  The tissues can then be challenged with HIV in the presence or absence of potential microbicide products.  The current model works best for rectal tissues, in which infection occurs promptly and consistently, so that the effect of a microbicide can clearly be seen by a reduction in the production of HIV p24 antigen.  However, for cervical and vaginal tissues, the infection (in the absence of any microbicide) was less consistent, slower and lasted longer making it less easy to determine statistical differences between those tissues with microbicide and those without.  Further work of this sort may help to streamline the choice of microbicide or PrEP products that can most sensibly be taken out of the laboratory and into the (almost) real world of clinical trials.

Small-group randomized controlled trial to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Rhodes SD, Alonzo J, Mann L, Song EY, Tanner AE, Arellano JE, Rodriguez-Celedon R, Garcia M, Freeman A, Reboussin BA, Painter TM. Am J Public Health. 2017 Jun;107(6):969-976. doi: 10.2105/AJPH.2017.303814. Epub 2017 Apr 20.

Objectives: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Methods: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%.

Results: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001).

Conclusions: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

Abstract access 

Not just PrEP: other reasons for London's HIV decline.

Nwokolo N, Whitlock G, McOwan A. Lancet HIV. 2017 Apr;4(4):e153. doi: 10.1016/S2352-3018(17)30044-9.

The reduction in HIV diagnoses in London in 2016 is attributed to pre-exposure prophylaxis (PrEP). We believe that the causes of the 42% decline seen at our clinic are likely to be multifactorial. 56 Dean Street diagnoses one in four of London's HIV cases, 50% of whom have incident infection (ie, within 4 months of infection). Because of this, and following the results of the START study, we actively recommend treatment at, or close to, diagnosis, reducing the risk of transmission in people who would otherwise be highly infectious.

Abstract access 

US black women and HIV prevention: time for new approaches to clinical trials.

Adimora AA, Cole SR, Eron JJ Clin Infect Dis. 2017 Apr 5. doi: 10.1093/cid/cix313. [Epub ahead of print]. 

Black women bear the highest burden of HIV infection among US women. Tenofovir/ emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV pre-exposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high incidence settings - and then applying these observations to drug concentrations measured among at risk individuals in lower incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates.

Abstract access 

Heightened HIV antibody responses in postpartum women as exemplified by recent infection assays: implications for incidence estimates.

Hargrove JW, van Schalkwyk C, Humphrey JH, Mutasa K, Ntozini R, Owen SM, Masciotra S, Parekh BS, Duong YT, Dobbs T, Kilmarx PH, Gonese E. AIDS Res Hum Retroviruses. 2017 May 24. doi: 10.1089/AID.2016.0319. [Epub ahead of print].

Laboratory assays that identify recent HIV infections are important for assessing impacts of interventions aimed at reducing HIV incidence. Kinetics of HIV humoral responses can vary with inherent assay properties, and between HIV subtypes, populations, and physiological states. They are important in determining mean duration of recent infection (MDRI) for antibody-based assays for detecting recent HIV infections. We determined MDRIs for multi-subtype peptide representing subtypes B, E and D (BED)-capture enzyme immunoassay, limiting antigen (LAg), and Bio-Rad Avidity Incidence (BRAI) assays for 101 seroconverting postpartum women, recruited in Harare from 1997 to 2000 during the Zimbabwe Vitamin A for Mothers and Babies trial, comparing them against published MDRIs estimated from seroconverting cases in the general population. We also compared MDRIs for women who seroconverted either during the first 9 months, or at later stages, postpartum. At cutoffs (C) of 0.8 for BED, 1.5 for LAg, and 40% for BRAI, estimated MDRIs for postpartum mothers were 192, 104, and 144 days, 33%, 32%, and 52% lower than published estimates of 287, 152 and 298 days, respectively, for clade C samples from general populations. Point estimates of MDRI values were 7%-19% shorter for women who seroconverted in the first 9 months postpartum than for those seroconverting later. MDRI values for three HIV incidence biomarkers are longer in the general population than among postpartum women, particularly those who recently gave birth, consistent with heightened immunological activation soon after birth. Our results provide a caution that MDRI may vary significantly between subjects in different physiological states.

Abstract access 

Improvements in Spectrum's fit to program data tool.

Mahiane SG, Marsh K, Grantham K, Crichlow S, Caceres K, Stover J.  AIDS. 2017 Apr;31 Suppl 1:S23-S30. doi: 10.1097/QAD.0000000000001359.

Objective: The Joint United Nations Program on HIV/AIDS-supported Spectrum software package (Glastonbury, Connecticut, USA) is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15-49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with program and vital registration data, such as historical trends in the number of newly diagnosed infections or people living with HIV and AIDS related deaths. This article describes development and application of the fit to program data (FPD) tool in Joint United Nations Program on HIV/AIDS' 2016 estimates round.

Methods: In the FPD tool, HIV incidence trends are described as a simple or double logistic function. Function parameters are estimated from historical program data on newly reported HIV cases, people living with HIV or AIDS-related deaths. Inputs can be adjusted for proportions undiagnosed or misclassified deaths. Maximum likelihood estimation or minimum chi-squared distance methods are used to identify the best fitting curve. Asymptotic properties of the estimators from these fits are used to estimate uncertainty.

Results: The FPD tool was used to fit incidence for 62 countries in 2016. Maximum likelihood and minimum chi-squared distance methods gave similar results. A double logistic curve adequately described observed trends in all but four countries where a simple logistic curve performed better.

Conclusion: Robust HIV-related program and vital registration data are routinely available in many middle-income and high-income countries, whereas HIV seroprevalence surveillance and survey data may be scarce. In these countries, the FPD tool offers a simpler, improved approach to estimating HIV incidence trends.

Abstract access 

Analytical advances in the ex vivo challenge efficacy assay.

Richardson-Harman N, Parody R, Anton P, McGowan I, Doncel G, Thurman AR, Herrera C, Kordy K, Fox J, Tanner K, Swartz G, Dezzutti CS. AIDS Res Hum Retroviruses. 2017 Apr;33(4):395-403. doi: 10.1089/AID.2016.0073. Epub 2016 Dec 16.

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.

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Community-based HIV testing for MSM: available at an acceptable cost in Europe

Economic evaluation of HIV testing for men who have sex with men in community-based organizations - results from six European cities.

Perelman J, Rosado R, Amri O, Morel S, Rojas Castro D, Chanos S, Cigan B, Lobnik M, Fuertes R, Pichon F, Slaaen Kaye P, Agusti C, Fernandez-Lopez L, Lorente N, Casabona J. AIDS Care. 2016 Dec 27:1-5. doi: 10.1080/09540121.2016.1271392. [Epub ahead of print]

The non-decreasing incidence of HIV among men who have sex with men (MSM) has motivated the emergence of Community Based Voluntary Counselling and Testing (CBVCT) services specifically addressed to MSM. The CBVCT services are characterized by facilitated access and linkage to care, a staff largely constituted by voluntary peers, and private not-for-profit structures outside the formal health system institutions. Encouraging results have been measured about their effectiveness, but these favourable results may have been obtained at high costs, questioning the opportunity to expand the experience. We performed an economic evaluation of HIV testing for MSM at CBVCT services, and compared them across six European cities. We collected retrospective data for six CBVCT services from six cities (Copenhagen, Paris, Lyon, Athens, Lisbon, and Ljubljana), for the year 2014, on the number of HIV tests and HIV reactive tests, and on all expenditures to perform the testing activities. The total costs of CBVCTs varied from 54 390€ per year (Ljubljana) to 245 803€ per year (Athens). The cost per HIV test varied from to 41€ (Athens) to 113€ (Ljubljana). The cost per HIV reactive test varied from 1966€ (Athens) to 9065€ (Ljubljana). Our results show that the benefits of CBVCT services are obtained at an acceptable cost, in comparison with the literature (values, mostly from the USA, range from 1600$ to 16 985$ per HIV reactive test in clinical and non-clinical settings). This result was transversal to several European cities, highlighting that there is a common CBVCT model, the cost of which is comparable regardless of the epidemiological context and prices. The CBVCT services represent an effective and "worth it" experience, to be continued and expanded in future public health strategies towards HIV.

Abstract access

Editor’s notes: Although HIV incidence among some key populations in Europe has declined in recent years, new cases among gay men and other men who have sex with men have steadily increased over the last decade. Among those new cases, over a third are reported late, leading to worse health outcomes for the person, as well as an increased risk of onward transmission. As a result, community-based voluntary counselling and testing has been rolled out in European cities to encouraging results in terms of effectiveness.

In that context, the authors of this paper have carried out an economic evaluation of community-based voluntary counselling and testing programmes in six cities across Europe (Athens, Copenhagen, Lisbon, Lyon, Paris and Ljubljana). They collected total annual costs of running the programmes. They found that the cost per HIV test ranged from €41 in Athens to €113 in Ljubljana and the cost per reactive HIV test ranged from €1966 to €9065 in the same two cities. The authors found that these costs are acceptable compared to those found in the literature.

Oddly, one of the more interesting results found in the article, but not discussed within the text, is the cost per reactive HIV test link to care. This varied in absolute terms (€2297- €20 215) likely due to different linkages to care rates, from 100% in Copenhagen to under 40% in Paris. Given the ultimate aims of testing (which ought to be to improve health outcomes and reduce onward transmission) this is a more important figure than the cost per test. Further research therefore should explore the unit costs further down the treatment cascade resulting from these programmes. These would be, for example, cost per person on treatment and cost per person with a suppressed viral load. 

Europe
Denmark, France, Greece, Portugal, Slovenia
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TB still responsible for large proportion of admissions and in-patient deaths among people living with HIV

TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis.

Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, Waldrop G, Kranzer K, Doherty M, Getahun H. J Int AIDS Soc. 2016 Jan 12;19(1):20714. doi: 10.7448/IAS.19.1.20714. eCollection 2016.

Introduction: Despite significant progress in improving access to antiretroviral therapy over the past decade, substantial numbers of people living with HIV (PLHIV) in all regions continue to experience severe illness and require hospitalization. We undertook a global review assessing the proportion of hospitalizations and in-hospital deaths because of tuberculosis (TB) in PLHIV.

Methods: Seven databases were searched to identify studies reporting causes of hospitalizations among PLHIV from 1 January 2007 to 31 January 2015 irrespective of age, geographical region or language. The proportion of hospitalizations and in-hospital mortality attributable to TB was estimated using random effects meta-analysis.

Results: From an initial screen of 9049 records, 66 studies were identified, providing data on 35 845 adults and 2792 children across 42 countries. Overall, 17.7% (95% CI 16.0 to 20.2%) of all adult hospitalizations were because of TB, making it the leading cause of hospitalization overall; the proportion of adult hospitalizations because of TB exceeded 10% in all regions except the European region. Of all paediatric hospitalizations, 10.8% (95% CI 7.6 to 13.9%) were because of TB. There was insufficient data among children for analysis by region. In-hospital mortality attributable to TB was 24.9% (95% CI 19.0 to 30.8%) among adults and 30.1% (95% CI 11.2 to 48.9%) among children.

Discussion: TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV worldwide.

Abstract  Full-text [free] access

Editor’s notes: The last 30 years have seen radical improvements in outcomes for many people living with HIV. This study reminds us that in some parts of the world HIV-associated infections, tuberculosis (TB) in particular, still have a devastating effect on thousands of lives.

The importance of TB is widely recognised. WHO aim to reduce deaths due to TB by 75% over the next 10 years.  The question remains: do we really know how many people die due to TB?  Death certification has repeatedly been shown to be unreliable, particularly in the parts of the world where TB is most prevalent. Verbal autopsy is used to estimate cause of death in areas with poor notification systems, but poorly differentiates deaths due to TB and other HIV-associated conditions. Similar challenges are faced when counting and classifying morbidity and hospitalisations. Data are sparse, and determining the cause of an admission is not straightforward, even with access to well-maintained hospital records.  

This review, a sub-analysis of data from a broader study of HIV-associated hospital admissions, is by far the largest of its kind. The authors have been rigorous, given the heterogeneity of the studies included, and their findings are sobering. Among adults living with HIV, in all areas except Europe and South America, TB was the cause of 20-33% of admissions, and some 30% of adults and 45% of children who were admitted with TB were thought to have died from it. These findings are limited by the fact that not all reviewed studies reported on mortality and very few stated how causes of death were assigned.

This paper raises more questions than it answers, but they are important questions.  We are left in no doubt that TB is a major contributor to global morbidity and mortality in HIV-positive people, but we need to look closely at how we count and classify ‘TB deaths’ and ‘TB-associated admissions’. The recent systematic review of autopsy studies cited by the authors also found that almost half the TB seen at autopsy was not diagnosed before death. Global autopsy rates are in decline. Without access to more accurate data, how will we know if we’re winning or losing in our efforts to end TB deaths?

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Large multi-centre study finds few differences between mortality in migrant and native populations in western Europe

Mortality in migrants living with HIV in western Europe (1997-2013): a collaborative cohort study.

Migrants Working Group on behalf of COHERE in EuroCoord. Lancet HIV. 2015 Dec;2(12):e540-9. doi: 10.1016/S2352-3018(15)00203-9. Epub 2015 Nov 18.

Background: Many migrants face adverse socioeconomic conditions and barriers to health services that can impair timely HIV diagnosis and access to life-saving treatments. We aimed to assess the differences in overall mortality by geographical origin in HIV-positive men and women using data from COHERE, a large European collaboration of HIV cohorts from 1997 to 2013.

Methods: In this observational cohort study, we included HIV-positive, antiretroviral-naive people accessing care in western Europe from COHERE. Individuals were eligible if enrolled in a cohort that collected information on geographical origin or ethnic origin from Jan 1, 1997, to March 19, 2013, aged 18-75 years, they had available information about sex, they were not infected perinatally or after the receipt of clotting factor concentrates, and were naive to combination antiretroviral therapy at cohort entry. Migrants' origins were grouped into seven regions: western Europe and similar countries (Australia, Canada, New Zealand, and the USA); eastern Europe; North Africa and the Middle East; sub-Saharan Africa; Latin America; the Caribbean; and Asia and the rest of Oceania (excluding Australia and New Zealand). Crude and adjusted mortality rate ratios were calculated by use of Poisson regression stratified by sex, comparing each group with the native population. Multiple imputation with chained equations was used to account for missing values.

Findings: Between Oct 25, 1979, and March 19, 2013, we recruited 279 659 individuals to the COHERE collaboration in EuroCoord. Of these 123 344 men and 45 877 women met the inclusion criteria. Our data suggested effect modification by transmission route (pinteraction=0.12 for men; pinteraction=0.002 for women). No significant difference in mortality was identified by geographical origin in men who have sex with men. In heterosexual populations, most migrant men had mortality lower than or equal to that of native men, whereas no group of migrant women had mortality lower than that in native women. High mortality was identified in heterosexual men from Latin America (rate ratio [RR] 1.46, 95% CI 1.00-2.12, p=0.049) and heterosexual women from the Caribbean (1.48, 1.29-1.70, p<0.0001). Compared with that in the native population, mortality in injecting drug users was similar or low for all migrant groups.

Interpretation: Characteristics of and risks faced by migrant populations with HIV differ for men and women and for populations infected heterosexually, by sex between men, or by injecting drug use. Further research is needed to understand how inequalities are generated and maintained for the groups with higher mortality identified in this study.

Abstract access 

Editor’s notes: This topical analysis on migrant health from the large COHERE collaboration examined mortality in people living with HIV who are treatment-naïve and enrolling for care in 11 western European countries. Routinely collected data were analysed to explore differences in mortality by region of origin. Overall, few differences in mortality were seen between migrant and native populations, with a general trend of similar or lower mortality among migrants than native populations.  However, diversity within migrant groups even from the same region makes it challenging to interpret summary data. The authors provide interesting insights into these difficulties. For example, the reasons for migration are likely to result in different socio-economic conditions in the host country, but heterogeneity in mortality between sub-groups may be masked when looking at overall mortality in migrants compared with the native population. The authors discuss both the “healthy migrant effect” (the fact that it is often healthier, younger populations who are able to migrate), and the “salmon bias” (the fact people who are ill often return to their place of origin). Both of these effects can lead to an observed lower disease burden in migrants than native populations. At a time when immigration is a hotly debated issue in western Europe this study highlights the challenges in assessing migrant health and the need for further empirical and methodological research in this area.

Europe
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Violence experience of women living with HIV: a global study

Violence. Enough already: findings from a global participatory survey among women living with HIV.

Orza L, Bewley S, Chung C, Crone ET, Nagadya H, Vazquez M, Welbourn A. J Int AIDS Soc. 2015 Dec 1;18(6 Suppl 5):20285. doi: 10.7448/IAS.18.6.20285. eCollection 2015.

Introduction: Women living with HIV are vulnerable to gender-based violence (GBV) before and after diagnosis, in multiple settings. This study's aim was to explore how GBV is experienced by women living with HIV, how this affects women's sexual and reproductive health (SRH) and human rights (HR), and the implications for policymakers.

Methods: A community-based, participatory, user-led, mixed-methods study was conducted, with women living with HIV from key affected populations. Simple descriptive frequencies were used for quantitative data. Thematic coding of open qualitative responses was performed and validated with key respondents.

Results: In total, 945 women living with HIV from 94 countries participated in the study. Eighty-nine percent of 480 respondents to an optional section on GBV reported having experienced or feared violence, either before, since and/or because of their HIV diagnosis. GBV reporting was higher after HIV diagnosis (intimate partner, family/neighbours, community and health settings). Women described a complex and iterative relationship between GBV and HIV occurring throughout their lives, including breaches of confidentiality and lack of SRH choice in healthcare settings, forced/coerced treatments, HR abuses, moralistic and judgemental attitudes (including towards women from key populations), and fear of losing child custody. Respondents recommended healthcare practitioners and policymakers address stigma and discrimination, training, awareness-raising, and HR abuses in healthcare settings.

Conclusions: Respondents reported increased GBV with partners and in families, communities and healthcare settings after their HIV diagnosis and across the life-cycle. Measures of GBV must be sought and monitored, particularly within healthcare settings that should be safe. Respondents offered policymakers a comprehensive range of recommendations to achieve their SRH and HR goals. Global guidance documents and policies are more likely to succeed for the end-users if lived experiences are used.

Abstract  Full-text [free] access

Editor’s notes: Violence against women who are living with HIV is common globally. This paper reports on a study of 832 women living with HIV from 94 countries who participated in an online survey, recruited through a non-random snowball sampling model. The survey comprised quantitative and qualitative (free text) components. Participants included women who had ever or were currently using injection drugs (14%), who had ever or were currently selling sex (14%), and who had ever or were currently homeless (14%). Lifetime experience of violence among respondents was high (86%). Perpetrators included: intimate partner (59%), family member / neighbour (45%), community member (53%), health care workers (53%) and police, military, prison or detention services (17%). Findings suggest that violence is not a one off occurrence and cannot easily be packaged as a cause or a consequence of HIV. Instead violence occurs throughout women’s lives, takes multiple forms, and has a complex and iterative relationship with HIV.

The study population did not represent all women living with HIV, and was biased towards women with internet access who have an activist interest. Nonetheless, the study provides further evidence of the breadth and frequency of gender based violence experienced by women living with HIV. Key recommendations for policy makers include training of health care workers working in sexual and reproductive services to offer non-discriminatory services to women living with HIV and to effectively respond to disclosures of gender based violence (such as intimate partner violence) as part of the package of care.

Algeria, Angola, Argentina, Armenia, Australia, Austria, Azerbaijan, Belarus, Belgium, Belize, Bolivarian Republic of Venezuela, Bolivia, Botswana, Burkina Faso, Burundi, Cambodia, Cameroon, Canada, Chile, China, Colombia, Costa Rica, Côte d'Ivoire, Czech Republic, Democratic Republic of the Congo, Denmark, Dominican Republic, Ecuador, El Salvador, Estonia, Ethiopia, France, Gabon, Germany, Ghana, Greece, Guatemala, Honduras, Hungary, India, Indonesia, Ireland, Italy, Jamaica, Kazakhstan, Kenya, Kyrgyzstan, Lesotho, Malawi, Mali, Mexico, Moldova, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, New Zealand, Nicaragua, Nigeria, Norway, Panama, Paraguay, Peru, Poland, Republic of the Congo, Romania, Russian Federation, Rwanda, Serbia, South Africa, Spain, Sri Lanka, Sudan, Swaziland, Switzerland, Tajikistan, Togo, Transdniestria, Turkey, Uganda, Ukraine, United Kingdom, United Republic of Tanzania, United States of America, Uruguay, Uzbekistan, Viet Nam, Zambia, Zimbabwe
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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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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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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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Increasing transmitted resistance to antiretroviral therapy in low/middle-income countries - highest prevalence in MSM

Global burden of transmitted HIV drug resistance and HIV-exposure categories: a systematic review and meta-analysis.

Pham QD, Wilson DP, Law MG, Kelleher AD, Zhang L. AIDS. 2014 Nov 28;28(18):2751-62. doi: 10.1097/QAD.0000000000000494.

Objectives: Our aim was to review the global disparities of transmitted HIV drug resistance (TDR) in antiretroviral-naive MSM, people who inject drugs (PWID) and heterosexual populations in both high-income and low/middle-income countries.

Design/methods: We undertook a systematic review of the peer-reviewed English literature on TDR (1999-2013). Random-effects meta-analyses were performed to pool TDR prevalence and compare the odds of TDR across at-risk groups.

Results: A total of 212 studies were included in this review. Areas with greatest TDR prevalence were North America (MSM: 13.7%, PWID: 9.1%, heterosexuals: 10.5%); followed by western Europe (MSM: 11.0%, PWID: 5.7%, heterosexuals: 6.9%) and South America (MSM: 8.3%, PWID: 13.5%, heterosexuals: 7.5%). Our data indicated disproportionately high TDR burdens in MSM in Oceania (Australia 15.5%), eastern Europe/central Asia (10.2%) and east Asia (7.8%). TDR epidemics have stabilized in high-income countries, with a higher prevalence (range 10.9-12.6%) in MSM than in PWID (5.2-8.3%) and heterosexuals (6.4-9.0%) over 1999-2013. In low/middle-income countries, TDR prevalence in all at-risk groups in 2009-2013 almost doubled than that in 2004-2008 (MSM: 7.8 vs. 4.2%, P = 0.011; heterosexuals: 4.1 vs. 2.6%, P < 0.001; PWID: 4.8 vs. 2.4%, P = 0.265, respectively). The risk of TDR infection was significantly greater in MSM than that in heterosexuals and PWID. We observed increasing trends of resistance to non-nucleoside reverse transcriptase and protease inhibitors among MSM.

Conclusion: TDR prevalence is stabilizing in high-income countries, but increasing in low/middle-income countries. This is likely due to the low, but increasing, coverage of antiretroviral therapy in these settings. Transmission of TDR is most prevalent among MSM worldwide.

Abstract access 

Editor’s notes: HIV mutates very rapidly, and many early antiretroviral agents had a low genetic barrier to the development of resistance. Thus the emergence of virus resistant to antiretroviral agents, particularly to early drug classes, was inevitable. Surveillance for drug-resistant virus among people with no prior history of taking antiretroviral drugs (transmitted drug resistance) is essential to monitor the spread of drug resistance at population level.

This systematic review aimed to compare transmitted drug resistance in different geographical regions and between subpopulations of HIV-positive people by likely route of transmission. Transmitted resistance was most prevalent in high income settings. This is not surprising given wide use of suboptimal drug regimens before effective triple therapy was available. Reassuringly, the prevalence of transmitted resistance seems to have stabilised in high-income settings. The increase in transmitted resistance in low and middle income countries is of more concern. It is not surprising, given that first-line regimens comprising two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor are vulnerable to the development of resistance if the drug supply is interrupted or adherence is suboptimal. In addition, if viral load monitoring is not available, people remain on failing drug regimens for longer, and thus have more risk of transmitting resistant virus.

Within the subpopulations examined in this review, transmitted resistance was consistently higher in men who have sex with men, suggesting that resistance testing prior to treatment is particularly valuable for this population.

Limitations of the review include exclusion of studies that did not compare transmitted resistance between the specified subpopulations, and small sample size in many subgroups.

Continued surveillance for transmitted drug resistance is critical. This is most important in settings where individualised resistance testing is not available. This will ensure that people starting antiretroviral therapy receive treatment that will suppress their viral load effectively. Wider use of viral load monitoring, combined with access to effective second and third line regimens, will also help limit spread of drug resistance.

HIV Treatment
Angola, Argentina, Australia, Austria, Belgium, Benin, Botswana, Brazil, Burkina Faso, Cambodia, Cameroon, Canada, Central African Republic, Chad, China, Côte d'Ivoire, Croatia, Cuba, Cyprus, Denmark, Dominican Republic, El Salvador, Estonia, Ethiopia, France, Gabon, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong Special Administrative Region of China, Hungary, India, Indonesia, Ireland, Israel, Italy, Japan, Kazakhstan, Kenya, Latvia, Malawi, Malaysia, Moldova, Mozambique, Netherlands, Peru, Philippines, Poland, Portugal, Republic of Korea, Romania, Russia, Rwanda, Slovenia, South Africa, Spain, Swaziland, Sweden, Switzerland, Taiwan, Thailand, Uganda, United Kingdom of Great Britain and Northern Ireland, United Republic of Tanzania, United States of America, Viet Nam, Zambia, Zimbabwe
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