Articles tagged as "Epidemiology"

Botswana within reach of UNAIDS 90-90-90 treatment target

Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey.

Gaolathe T, Wirth KE, Holme MP, Makhema J, Moyo S, Chakalisa U, Yankinda EK, Lei Q, Mmalane M, Novitsky V, Okui L, van Widenfelt E, Powis KM, Khan N, Bennett K, Bussmann H, Dryden-Peterson S, Lebelonyane R, El-Halabi S, Mills LA, Marukutira T, Wang R, Tchetgen EJ, DeGruttola V, Essex M, Lockman S, Botswana Combination Prevention Project study team. Lancet HIV. 2016 May;3(5):e221-30. doi: 10.1016/S2352-3018(16)00037-0. Epub 2016 Mar 24.

Background: HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswana's progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90-90-90).

Methods: A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470.

Findings: 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83.3%, 95% CI 81.4-85.2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87.4%, 95% CI 85.8-89.0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96.5%, 95% CI 96.0-97.0) had viral load of 400 copies per mL or less. Overall, 70.2% (95% CI 67.5-73.0) of HIV-infected people had virological suppression, close to the UNAIDS target of 73%.

Interpretation: UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden.

Abstract access    

Editor’s notes: The UNAIDS treatment target set for 2020 aim for at least 90 percent of all people living with HIV to be diagnosed, at least 90 percent of people diagnosed to receive antiretroviral therapy, and for treatment to be effective and consistent enough in at least 90 percent of those people on treatment to suppress the virus. This would result in about 73% of all HIV-positive people being virally suppressed. 

This study estimated coverage of HIV diagnosis, antiretroviral therapy and viral suppression among 30 communities in Botswana, a country with a high HIV prevalence (~ 25%), to assess the country’s progress towards the UNAIDS treatment target. They found that overall, about 70% of people living with HIV had viral suppression (defined in this analysis as having a viral load of less than HIV RNA 400 copies per mL), close to the UNAIDS target of 73%. However, there is still substantial ongoing transmission (demonstrated by an HIV incidence of 1.4% per year in 2013). The authors attribute this mainly to the 30% of people living with HIV that remain unsuppressed (undiagnosed, or not on treatment, or not virally suppressed because of poor adherence or drug resistance). They also acknowledge that other factors such as the complexities of sexual networks, risk behaviour patterns, and biological factors may play a role.

Interestingly the authors found very high proportions of viral suppression. Nearly 97% of people on ART were virally suppressed. The authors also found that younger age was the strongest predictor of not reaching the ultimate target (diagnosed, on treatment and being virally suppressed). People living with HIV aged 20-29 years old were about 50% less likely to be virally suppressed compared with people 60 years and older. Young people living with HIV aged between 16-19 years old were 60% less likely to be virally suppressed. This emphasizes again the need for focussed programmes for adolescents and young people.

Botswana has reached this level of coverage even when the criterion for initiating antiretroviral therapy was a CD4 cell count below 350 cells per μL, even before moving to providing treatment for everyone diagnosed with HIV. The authors conclude that the high proportions of HIV testing, antiretroviral therapy and viral suppression provide good evidence that the UNAIDS treatment target is achievable.

Africa
Botswana
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Comparing the performance of different community-based measures of viral load as correlates for HIV incidence

Community viral load, antiretroviral therapy coverage, and HIV incidence in India: a cross-sectional, comparative study.

Solomon SS, Mehta SH, McFall AM, Srikrishnan AK, Saravanan S, Laeyendecker O, Balakrishnan P, Celentano DD, Solomon S, Lucas GM. Lancet HIV. 2016 Apr;3(4):e183-90. doi: 10.1016/S2352-3018(16)00019-9. Epub 2016 Mar 11.

Background: HIV incidence is the best measure of treatment-programme effectiveness, but its measurement is difficult and expensive. The concept of community viral load as a modifiable driver of new HIV infections has attracted substantial attention. We set out to compare several measures of community viral load and antiretroviral therapy (ART) coverage as correlates of HIV incidence in high-risk populations.

Methods: We analysed data from a sample of people who inject drugs and men who have sex with men, who were participants of the baseline assessment of a cluster-randomised trial in progress across 22 cities in India (ClinicalTrials.gov number NCT01686750). We recruited the study population by use of respondent-driven sampling and did the baseline assessment at 27 community-based sites (12 for men who have sex with men and 15 for people who inject drugs). We estimated HIV incidence with a multiassay algorithm and calculated five community-based measures of HIV control: mean log10 HIV RNA in participants with HIV in a community either engaged in care (in-care viral load), aware of their status but not necessarily in care (aware viral load), or all HIV-positive individuals whether they were aware, in care, or not (population viral load); participants with HIV in a community with HIV RNA more than 150 copies per mL (prevalence of viraemia); and the proportion of participants with HIV who self-reported ART use in the previous 30 days (population ART coverage). All participants were tested for HIV, with additional testing in HIV-positive individuals. We assessed correlations between the measures and HIV incidence with Spearman correlation coefficients and linear regression analysis.

Findings: Between Oct 1, 2012, and Dec 19, 2013, we recruited 26 503 participants, 12 022 men who have sex with men and 14 481 people who inject drugs. Median incidence of HIV was 0.87% (IQR 0.40-1.17) in men who have sex with men and 1.43% (0.60-4.00) in people who inject drugs. Prevalence of viraemia was more strongly correlated with HIV incidence (correlation 0.81, 95% CI 0.62-0.91; p<0.0001) than all other measures, although correlation was significant with aware viral load (0.59, 0.27-0.79; p=0.001), population viral load (0.51, 0.16-0.74; p=0.007), and population ART coverage (-0.54, -0.76 to -0.20; p=0.004). In-care viral load was not correlated with HIV incidence (0.29, -0.10 to 0.60; p=0.14). With regression analysis, we estimated that to reduce HIV incidence by 1 percentage point in a community, prevalence of viraemia would need to be reduced by 4.34%, and ART use in HIV-positive individuals would need to increase by 19.5%.

Interpretation: Prevalence of viraemia had the strongest correlation with HIV incidence in this sample and might be a useful measure of the effectiveness of a treatment programme.

Abstract access    

Editor’s notes: The ideal metric of impact for a programme looking at the prevention benefits of treatment would be the reduction in HIV incidence in the target population. Incidence is however very difficult to measure. ‘Community viral load’ has been proposed as an alternative. However its estimation using data collected either in a routine clinical setting or from a cohort study can suffer from bias, due to the population included not being representative of the wider population of people living with HIV.

This paper describes a study among gay men and other men who have sex with men and people who inject drugs carried out at 27 sites in India. Participants were recruited using respondent-driven sampling (in which respondents recruit their peers to produce a generally representative sample of hard-to-reach populations). At each site incidence was estimated using a multi-assay algorithm designed to identify seroconversion occurring approximately within the last six months. Five community-based measures of viral load were measured at each site. Of these, the prevalence of HIV viraemia (i.e. the proportion of the population with a viral load greater than 150 copies per mL), was most strongly associated with HIV incidence, while mean viral load among people in-care was not associated. This latter finding is important if a case-based surveillance approach using only data collected at clinics is to be used to estimate incidence. Population ART coverage, a measure of the proportion of the site participants on ART was also strongly correlated with incidence. As this can be measured through a simple questionnaire, rather than lab-based assays, it could be an easily and cheaply obtainable correlate for incidence, albeit one potentially prone to response bias.

Asia
India
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HPV prevalent in a key population in India – potential for vaccination

Prevalence of anal HPV infection among HIV-positive men who have sex with men in India.

Hernandez AL, Karthik R, Sivasubramanian M, Raghavendran A, Gnanamony M, Lensing S, Lee JY, Kannangai R, Abraham P, Mathai D, Palefsky JM. J Acquir Immune Defic Syndr. 2016 Apr 1;71(4):437-43. doi: 10.1097/QAI.0000000000000855.

Background: India has a large population of HIV-positive individuals, including men who have sex with men (MSM), and the incidence of human papillomavirus (HPV)-related cancers is high. In developed countries, HIV-positive MSM exhibit the highest prevalence of anal HPV infection and incidence of anal cancer. Little is known about anal HPV infection in HIV-positive Indian MSM.

Methods: We evaluated 300 HIV-positive MSM from 2 cities in India. Men were tested for anal HPV infection using L1-HPV DNA polymerase chain reaction with probes specific for 29 types and a mixture of 10 additional types. CD4 level and plasma HIV viral load were measured. Participants completed an interviewer-administered questionnaire including a sexual history.

Results: The prevalence of anal HPV was 95% (95% confidence interval: 91% to 97%). The 3 most common types were HPV 35 (20%), HPV 16 (13%), and HPV 6/11 (13%). History of taking antiretroviral medications decreased risk of anal HPV 16 infection [relative risk (RR): 0.6 (0.4-1.0)]. Having an increased number of vaginal sex partners lowered risk of any anal HPV infection. Ever having receptive sex increased risk of any anal HPV [RR: 1.2 (1.1-1.4)] and anal HPV 16 [RR: 6.5 (1.8-107)].

Conclusions: Almost all Indian HIV-positive MSM had anal HPV infection. The prevalence of HPV 16 was lower and the prevalence of other oncogenic HPV types was higher than in similar populations in North America and Europe. Vaccine-based prevention strategies for HPV infection in India should consider potential differences in HPV type distribution among HIV-infected MSM when designing interventions.

Abstract access  

Editor’s notes: This is the first report of anal human papilloma virus (HPV) prevalence and associated risk factors among HIV-positive gay men and other men who have sex with men in India. The incidence of HPV-associated anogenital disease is high in Indian men and women. Given that Indian men who are HIV-positive have an increased risk of anal cancer compared to HIV negative men, data on HPV infection in this population is warranted.

The authors report a high prevalence of any HPV type (95%) and any oncogenic HPV type (49%), similar to reports among other HIV-positive gay men and other men who have sex with men in northern America and Europe. An important distinction within this cohort is that many of these men self-identify as bisexual. Just under half (47%) reported being married and two-thirds (62%) reported having at least one female sex partner in their lifetime. This finding has important implications for HPV transmission between gay men and other men who have sex with men and female partners, given the high HPV prevalence in this population. HPV vaccination of key populations has the potential to reduce this transmission.

HPV vaccination in HIV-negative men and women with evidence of prior infection has been shown to confer protection against infection from other HPV types. Men in this cohort had an average of 1.7 oncogenic HPV infections, and so a broader spectrum vaccine such as the 9-valent vaccine which targets seven of the oncogenic HPV types (16/18/31/33/45/52/58) could still protect against acquisition of other vaccine types. Notably, the most common oncogenic type detected was HPV35 which, although not targeted by any of the currently available vaccines, is implicated in cervical cancer. While HPV16 and 18 are the types most commonly found in anal cancer in the general population and in cervical cancer among HIV-positive and negative women, little is known about the association of HPV types with anal disease in people living with HIV. Additional studies are necessary to firstly determine the incidence of anal cancer among HIV-positive gay men and other men who have sex with men in India, and secondly to evaluate which HPV types are linked to anal disease in order to estimate the fraction of disease that could be prevented through vaccination. Further, HPV vaccination of gay men and other men who have sex with men in India could confer additional protection to their female partners through a reduction in transmission of oncogenic HPV types, resulting in a consequent reduction in cervical disease attributed to these HPV types.   

Comorbidity, Epidemiology
Asia
India
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Profound effect of ART on mortality through reduction of opportunistic infections

Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low and middle income countries: a systematic review and meta-analysis. 

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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High TB mortality among people living with HIV in eastern Europe: a growing concern

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study. 

Podlekareva DN, Efsen AM, Schultze A, Post FA, Skrahina AM, Panteleev A, Furrer H, Miller RF, Losso MH, Toibaro J, Miro JM, Vassilenko A, Girardi E, Bruyand M, Obel N, Lundgren JD, Mocroft A, Kirk O, TB:HIV study group in EuroCoord. Lancet HIV. 2016 Mar;3(3):e120-31. doi: 10.1016/S2352-3018(15)00252-0. Epub 2016 Feb 2.

Background: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study.

Methods: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models.

Findings: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0.0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0.0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0.23 (95% CI 0.16-0.31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3.17; 95% CI 1.83-5.49) as were those who did not have baseline drug-susceptibility tests (2.24; 1.31-3.83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0.0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0.0001).

Interpretation: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe.

Abstract access

Editor’s notes: Eastern Europe is experiencing one of the fastest growing HIV epidemics globally. Within this, the number of HIV-positive people with tuberculosis (TB) is also rising rapidly, posing a significant public health challenge. The authors have previously reported retrospective data illustrating 30% mortality at one year among HIV-positive people with TB in eastern Europe. This was noted to be at least three times higher than mortality among people from western Europe and Argentina. Within this study they go further to provide prospective data with comparison across multiple regions. They also highlight prognostic markers associated with death.

The study spans across eastern Europe, western Europe and Latin America with a cohort of 1406 people. It robustly demonstrates a significant excess of TB-associated mortality in HIV-positive people with TB receiving care in eastern Europe. The cumulative probability of TB-associated death at 12 months in eastern Europe was 23% (95% confidence interval [CI] 20 – 26), versus 1% (95% CI 0 - 3) in western Europe and 4% (95% CI 2-8) in Latin America. Prognostic markers associated with an increased risk of death included multidrug-resistant TB, disseminated TB and modifiable factors such as choice of initial anti-TB regimen and a lack of baseline drug susceptibility tests.

These findings highlight the hugely detrimental impact of the fragmented system of HIV and TB services within eastern Europe. Such inequality in outcomes emphasises the need for urgent strategic change. Co-ordinated care across HIV and TB services, alongside timely and appropriate diagnostics and treatment, is of paramount importance.

Europe, Latin America
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ART reduces fertility differences by HIV status among women living in sub-Saharan Africa

Measuring the impact of antiretroviral therapy roll-out on population level fertility in three African countries. 

Marston M, Nakiyingi-Miiro J, Hosegood V, Lutalo T, Mtenga B, Zaba B, and on behalf of the ALPHA network. PLoS One. 2016 Mar 25;11(3):e0151877. doi: 10.1371/journal.pone.0151877. eCollection 2016.

Background: UNAIDS official estimates of national HIV prevalence are based on trends observed in antenatal clinic surveillance, after adjustment for the reduced fertility of HIV positive women. Uptake of ART may impact on the fertility of HIV positive women, implying a need to re-estimate the adjustment factors used in these calculations. We analyse the effect of antiretroviral therapy (ART) provision on population-level fertility in Southern and East Africa, comparing trends in HIV infected women against the secular trends observed in uninfected women.

Methods: We used fertility data from four community-based demographic and HIV surveillance sites: Kisesa (Tanzania), Masaka and Rakai (Uganda) and uMkhanyakude (South Africa). All births to women aged 15-44 years old were included in the analysis, classified by mother's age and HIV status at time of birth, and ART availability in the community. Calendar time period of data availability relative to ART introduction varied across the sites, from 5 years prior to ART roll-out, to 9 years after. Calendar time was classified according to ART availability, grouped into pre ART, ART introduction (available in at least one health facility serving study site) and ART available (available in all designated health facilities serving study site). We used Poisson regression to calculate age adjusted fertility rate ratios over time by HIV status, and investigated the interaction between ART period and HIV status to ascertain whether trends over time were different for HIV positive and negative women.

Results: Age-adjusted fertility rates declined significantly over time for HIV negative women in all four studies. However HIV positives either had no change in fertility (Masaka, Rakai) or experienced a significant increase over the same period (Kisesa, uMkhanyakude). HIV positive fertility was significantly lower than negative in both the pre ART period (age adjusted fertility rate ratio (FRR) range 0.51 95%CI 0.42-0.61 to 0.73 95%CI 0.64-0.83) and when ART was widely available (FRR range 0.57 95%CI 0.52-0.62 to 0.83 95%CI 0.78-0.87), but the difference has narrowed. The interaction terms describing the difference in trends between HIV positives and negatives are generally significant.

Conclusions: Differences in fertility between HIV positive and HIV negative women are narrowing over time as ART becomes more widely available in these communities. Routine adjustment of ANC data for estimating national HIV prevalence will need to allow for the impact of treatment.

Abstract  Full-text [free] access 

Editor’s notes: Antenatal care (ANC) clinics records on demographic characteristics and HIV status of attenders are a major component of primary data used to estimate HIV prevalence in sub-Saharan Africa. Prior to scale-up of antiretroviral therapy (ART), the fertility of women living with HIV was lower than that for people without HIV. This means that prevalence estimates from ANC data were adjusted to avoid underestimating the true population fertility rates.

This paper analyses the changing fertility patterns in four longitudinal community-based cohorts in eastern and southern Africa. The study finds that differences in fertility rates between women living with HIV and women without HIV are narrowing as ART is scaled-up, although substantial differences still exist. There was considerable variation in the patterns between the sites reflecting the differing local epidemic profiles. The authors explain this variation as being due to various factors including biological (increased fertility associated with viral suppression), or behavioural (increased fertility among women experiencing widowhood and then forming new partnerships). The impact of treatment on fertility needs to be incorporated into models of HIV prevalence estimated from ANC data, to inform national policy makers measuring their progress towards HIV elimination targets.

Africa
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Tenofovir resistance – need for caution but not panic

Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.

TenoRes Study Group. Lancet Infect Dis. 2016 Jan 28. pii: S1473-3099(15)00536-8. doi: 10.1016/S1473-3099(15)00536-8. [Epub ahead of print]

Background: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.

Methods: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.

Findings: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per µL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]).

Interpretation: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.

Abstract  Full-text [free] access 

Editor’s notes: Global surveillance for tenofovir (TDF) resistance is important at a time of expanding use of TDF-containing regimens for treatment and prevention. This collaborative analysis used data collated from several small studies in different settings. Overall, around one in three people who had failed on TDF-containing treatment had evidence of TDF resistance, although this frequency varied between 20% in Europe to almost 60% in Africa. Mutations associated with NNRTIs and lamivudine/emtricitabine resistance were more common overall and were present in most people with TDF resistance.

The regional variation probably reflects differences in clinical practice and study inclusion criteria. All European studies involved cohorts with frequent viral load monitoring, whereas half of the African cohorts had no routine viral load monitoring. All European studies included people with virologic failure but with low-level viraemia (viral load <1000 copies/ml) whereas almost all African studies included only people with viral load >1000 copies/ml.

While these data provide useful estimates of the frequency of drug resistance mutations in people with virologic failure on first-line ART, there should be caution about extrapolating beyond this. Reports from cohort studies with an accurate denominator of all people starting TDF-containing first-line ART would be useful to give more reliable estimates of overall incidence of acquired TDF resistance. Moreover, there remains a need for representative population-based surveillance for acquired and transmitted drug resistance. So far, global surveillance has detected limited evidence of transmitted TDF-associated mutations, but this needs to be monitored closely, especially in high incidence settings.

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HIV and injecting ‘krokodile’

Krokodile Injectors in Ukraine: fueling the HIV Epidemic?

Booth RE, Davis JM, Brewster JT, Lisovska O, Dvoryak S. AIDS Behav. 2016 Feb;20(2):369-76. doi: 10.1007/s10461-015-1008-z.

This study was designed to assess the characteristics of krokodile injectors, a recent phenomenon in Ukraine, and HIV-related risk factors among people who inject drugs (PWID). In three Ukraine cities, Odessa, Donetsk and Nikolayev, 550 PWID were recruited between December 2012 and October 2013 using modified targeted sampling methods. The sample averaged 31 years of age and they had been injecting for over 12 years. Overall, 39% tested positive for HIV, including 45% of krokodile injectors. In the past 30 days, 25% reported injecting krokodile. Those who injected krokodile injected more frequently (p < 0.001) and they injected more often with others (p = 0.005). Despite knowing their HIV status to be positive, krokodile users did not reduce their injection frequency, indeed, they injected as much as 85% (p = 0.016) more frequently than those who did not know their HIV status or thought they were negative. This behavior was not seen in non-krokodile using PWID. Although only a small sample of knowledgeable HIV positive krokodile users was available (N = 12), this suggests that krokodile users may disregard their HIV status more so than non-krokodile users. In spite of widespread knowledge of its harmful physical consequences, a growing number of PWID are turning to injecting krokodile in Ukraine. Given the recency of krokodile use in the country, the associated higher frequency of injecting, a propensity to inject more often with others, and what could be a unique level of disregard of HIV among krokodile users, HIV incidence could increase in future years.

Abstract access

Editor’s notes: This is an important study among a highly vulnerable population of people who inject drugs where HIV prevalence has been consistently high over the last decade. This is one of the first empirical studies to examine the role of krokodile use on HIV risk acquisition. Krokodile is a home produced drug that has become more popular among people who inject drugs in Ukraine and the Russian Federation over the last five years. There is a long history of injection with home-produced opioids and amphetamines in these countries. The key component of krokodile is codeine, an opioid, but severe side effects have been associated with its injection including tissue damage, gangrene and organ failure. This study highlights some of the characteristics and HIV risk behaviours associated with krokodile injection to inform appropriate HIV prevention programming. Findings note that people who inject krokodile are more likely to inject with others. This reflects the home-produced nature of the drug that facilitates more group injecting as people congregate at places where it is produced to buy and inject. Programmes need to focus on strategies to avoid injecting with other people’s used injecting equipment, such as marking equipment, as can happen in group injecting scenarios. This programme would ensure there are sufficient numbers of clean needles/syringes in circulation. Worryingly, a higher prevalence of HIV was observed among people who inject krokodile, most likely associated with their older age and more frequent injecting. Targeted harm reduction information is urgently needed for krokodile users to prevent further HIV transmission and prevent soft tissue damage. There is already a large network of needle-syringe programmes and opioid substitution therapy available for people who inject drugs in Ukraine. However, access is often reduced since people who inject drugs are concerned about being arrested. Registration as a person who injects drugs causes problems with employment, families and police. Collaboration with the police is necessary to increase access to opioid substitution and needle and syringe programmes. Programmes are also required to reduce the stigma associated with injection in order to address the health needs of this population. 

Europe
Ukraine
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Novel specimens feasible and sensitive for Xpert® MTB/RIF diagnosis in children

Performance of Xpert® MTB/RIF and alternative specimen collection methods for the diagnosis of tuberculosis in HIV-infected children.

Marcy O, Ung V, Goyet S, Borand L, Msellati P, Tejiokem M, Nguyen Thi NL, Nacro B, Cheng S, Eyangoh S, Pham TH, Ouedraogo AS, Tarantola A, Godreuil S, Blanche S, Delacourt C, PAANTHER study group. Clin Infect Dis. 2016 Feb 7. pii: ciw036. [Epub ahead of print]

Methods: HIV-infected children aged 13 years with suspected intrathoracic tuberculosis were enrolled in 8 hospitals in Burkina Faso, Cambodia, Cameroon, and Vietnam. Gastric aspirates were taken for children aged <10 years and expectorated sputum samples were taken for children aged 10 years (standard samples); nasopharyngeal aspirate and stool were taken for all children, and a string test was performed if the child was aged 4 years (alternative samples). All samples were tested with Xpert®. The diagnostic accuracy of Xpert® for culture-confirmed tuberculosis was analyzed in intention-to-diagnose and per-protocol approaches.

Results: Of 281 children enrolled, 272 (96.8%) had ≥1 specimen tested with Xpert® (intention-to-diagnose population), and 179 (63.5%) had all samples tested with Xpert® (per-protocol population). Tuberculosis was culture-confirmed in 29/272 (10.7%) children. Intention-to-diagnose sensitivities of Xpert® performed on all, standard, and alternative samples were 79.3% (95% confidence interval [CI], 60.3-92.0), 72.4% (95% CI, 52.8-87.3), and 75.9% (95% CI, 56.5-89.7), respectively. Specificities were 97.5%. Xpert® combined on nasopharyngeal aspirate and stool had intention-to-diagnose and per-protocol sensitivities of 75.9% (95% CI, 56.5-89.7) and 75.0% (95% CI, 47.6-92.7), respectively.

Conclusions: The combination of nasopharyngeal aspirate and stool sample is a promising alternative to methods usually recommended by national programs. Xpert® performed on respiratory and stools samples enables rapid confirmation of tuberculosis diagnosis in HIV-infected children.

Abstract access  

Editor’s notes: This article reports on a prospective cohort study of HIV-positive children (≤ 13 years) with suspected intrathoracic tuberculosis in eight hospitals in Burkina Faso, Cambodia, Cameroon, and Viet Nam. Diagnosis of tuberculosis among children is challenging because it is more difficult to obtain sputum, and their sputum often has fewer bacilli, requiring more sensitive tests. In 2014, WHO recommended scaling-up the use of Xpert® MTB/RIF among children. However, any test which is dependent on obtaining a sputum specimen will be suboptimal for diagnosis of tuberculosis in children.

In this study the investigators examined the feasibility of using alternative specimens with Xpert® MTB/ RIF for the diagnosis of tuberculosis in HIV-positive children. Using an intention-to-diagnose and a per-protocol analysis, they also assessed the diagnostic accuracy of Xpert® on nasopharyngeal aspirate and stool samples, using culture-confirmed tuberculosis as the reference standard.

The authors found that the performance of Xpert® in alternative samples was comparable to that of standard samples. They found excellent feasibility of obtaining samples of nasopharyngeal aspirates and stool, and a good sensitivity of Xpert® (~76%) when using that combination of samples. The authors suggested more research to simplify the processing of the stool samples for Xpert®, which would make the combination of both samples an attractive collection method for children unable to produce sputum.

Although Xpert® produces results relatively rapidly, some testing was done retrospectively, and only half of the Xpert® results were immediately available. As many children in this study had features of severe disease, it is not surprising that clinicians often started TB treatment immediately without waiting for results. Thus in practice the Xpert® result often provided bacteriological confirmation of a clinical diagnosis for children who had already started TB treatment, although it did also lead to some TB treatment initiations.

Despite conducting this study over more than two years in eight hospitals, the final number of enrolled children with culture-confirmed tuberculosis was only 29. It would be interesting to know whether using Xpert® on alternative specimens from children had an impact on patient-important outcomes, particularly mortality, though this would have required a much larger study. Studies of Xpert® implementation among adults have found increased yield in terms of bacteriological diagnoses. However, most have not found an impact on patient-important outcomes. Several children died before all the protocol-required specimens could be obtained, emphasizing the importance of rapid and more sensitive TB diagnostic tests for severely-ill children.

Africa, Asia
Burkina Faso, Cambodia, Cameroon, Viet Nam
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Spatial analysis methods to improve localised estimates of HIV prevalence

Evaluation of geospatial methods to generate subnational HIV prevalence estimates for local level planning.

Anderson SJ, Subnational Estimates Working Group of the HIVMC. AIDS. 2016 Feb 25. [Epub ahead of print]

Objective: There is evidence of substantial subnational variation in the HIV epidemic. However, robust spatial HIV data are often only available at high levels of geographic aggregation and not at the finer resolution needed for decision making. Therefore, spatial analysis methods that leverage available data to provide local estimates of HIV prevalence may be useful. Such methods exist but have not been formally compared when applied to HIV.

Design/methods: Six candidate methods - including those used by UNAIDS to generate maps and a Bayesian geostatistical approach applied to other diseases- were used to generate maps and subnational estimates of HIV prevalence across three countries using cluster level data from household surveys. Two approaches were used to assess the accuracy of predictions: (1) internal validation, whereby a proportion of input data is held back (test dataset) to challenge predictions, (2) comparison with location specific data from household surveys in earlier years.

Results: Each of the methods can generate usefully accurate predictions of prevalence at unsampled locations, with the magnitude of the error in predictions similar across approaches. However, the Bayesian geostatistical approach consistently gave marginally the strongest statistical performance across countries and validation procedures.

Conclusions: Available methods may be able to furnish estimates of HIV prevalence at finer spatial scales than the data currently allow. The subnational variation revealed can be integrated into planning to ensure responsiveness to the spatial features of the epidemic. The Bayesian geostatistical approach is a promising strategy for integrating HIV data to generate robust local estimates.

Abstract access  

Editor’s notes: Data from intensively monitored populations indicates that large differences in HIV prevalence can be seen across small geographic spaces. Understanding these localised spatial variations within a generalised epidemic can enable HIV programme resources to be used most effectively. However the data required for such localised estimation are often lacking. As a result modelling strategies must be used to predict local variation based on the best available data.

This study compares six different geospatial methods of estimating local HIV prevalence. The methods can be categorised by whether or not they use ancillary information such as road networks to improve their predictions and also whether they generated continuously changing prevalence surfaces (like map contours) or gave discrete estimates for geographic sub-regions e.g. districts.

While all methods produced reasonable overall levels of performance, those using a Bayesian geostatistical approach illustrated marginally better predictive accuracies. The levels of accuracy appeared more dependent on the national prevalence than the choice of model used.

The authors conclude by setting out a strategy for improvement of the models, principally through integrating additional data from sources such as antiretroviral therapy and prevention of mother-to-child transmission programmes, antenatal clinic surveys and case based reporting. 

Africa
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