Articles tagged as "Comorbidity"

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
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A new drug for cryptococcal meningitis?

Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR, Team A-CS. Lancet Infect Dis. 2016 Mar 9. pii: S1473-3099(16)00074-8. doi: 10.1016/S1473-3099(16)00074-8. [Epub ahead of print]

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.

Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with, number NCT01802385. 

Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0.37 colony forming units per mL per day (95% CI -0.41 to -0.33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1.27, 95% CI 0.69-2.32; p=0.45).

Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy.

Editor’s notes: Mortality from cryptococcal meningitis remains unacceptably high, especially in low-income settings. This is partly due to high cost and limited availability of effective antifungal agents.  Even when antifungal drugs are available, toxic side effects and suboptimal clearance of cryptococcus from the cerebrospinal fluid (CSF) result in continued morbidity and mortality.  There is an urgent need for new effective antifungal drugs in the treatment of cryptococcal meningitis which improve the rate of CSF sterilisation, have low toxicity, and are readily available.

Sertraline, a commonly used selective serotonin reuptake inhibitor antidepressant with excellent brain parenchymal penetration, has been shown to have potent in vitro and in vivo fungicidal activity against cryptococcus in mice. This is the first clinical study in humans to assess the efficacy of adjunctive sertraline for cryptococcal meningitis, when added to standard amphotericin B and high-dose fluconazole antifungal treatment. Faster cryptococcal CSF clearance and lower incidence of immune reconstitution inflammatory syndrome and relapse were seen in people receiving oral sertraline compared to a historical cohort. Repurposing of sertraline, a drug which is widely available, non-toxic and affordable, as an effective novel adjunctive fungicidal agent shows early promise. It is yet to be seen if improved cryptococcal CSF clearance will translate into better survival.  We will have to wait until 2018 to see the outcome of the Adjunctive Sertraline for the Treatment of Cryptococcal Meningitis (ASTRO-CM) randomised clinical trial.

Comorbidity, HIV Treatment
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Substantial drop in opportunistic infections in children with ART

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

B-Lajoie MR, Drouin O, Bartlett G, Nguyen Q, Low A, Gavriilidis G, Easterbrook P, Muhe L. Clin Infect Dis. 2016 Mar 21. pii: ciw139. [Epub ahead of print]

Background: We conducted a systematic review and meta-analysis to evaluate the incidence and prevalence of 14 opportunistic infections (OIs) and other infections as well as the impact of antiretroviral therapy (ART) among HIV-infected children (<18 years) in low and middle-income countries (LMIC), to understand regional burden of disease, and inform delivery of HIV services.

Methods: Eligible studies described the incidence of OIs and other infections in ART-naive and exposed children from January 1990 to November 2013, using Medline, Global Health, Embase, Cinahl, Web of Knowledge and Lilacs databases. Summary incident risk and prevalent risk for each OI in ART-naive and ART-exposed children were calculated, and unadjusted odds ratios calculated for impact of ART. The number of OI cases and associated costs averted were estimated using the AIM model.

Results: We identified 4542 citations, and 88 studies were included, comprising 55 679 HIV-infected children. Bacterial pneumonia and tuberculosis were the most common incident and prevalent infections in both ART-naive and ART-exposed children. There was a significant reduction in incident risk with ART for the majority of OIs. There was a smaller impact on bacterial sepsis and pneumonia, and an increase observed for varicella zoster. ART initiation based on 2010 WHO guidelines criteria for ART initiation in children was estimated to potentially avert more than 161 000 OIs (2013 UNAIDS data) with estimated cost savings of at least USD $17 million per year.

Conclusion: There is a substantial decrease in the risk of most OIs with ART use in HIV-infected children in LMIC, and estimated large potential cost savings in OIs averted with ART use, although there are greater limitations in paediatric data compared to adults.

Abstract  Full-text [free] access

Editor’s notes: The scale-up of programmes to prevent mother-to-child HIV transmission has resulted in a 60% decline in paediatric HIV infections. The scale-up of antiretroviral therapy (ART), however, has been less successful in children, with only a third of eligible children aged under 15 years receiving ART as of 2014. In high-income countries, there has been a substantial decrease in the incidence of most opportunistic infections (OIs) following the introduction of ART. The impact of ART on burden of OIs in low and middle income countries (LMICs) is much less well-understood.

This meta-analysis estimated the incidence and prevalence of 14 key OIs and other infections in children (aged 0-18 years) before and after the introduction of ART across three geographical regions, namely sub-Saharan Africa, Latin America and the Caribbean, and Asia.

The use of ART has resulted in a decline in incidence of all but three infections, namely tuberculosis, pneumonia and candidiasis. These remain the most common incident and prevalent infections in ART-naïve and ART-exposed children. It is important to note that there is a high incidence of lower respiratory infections in children in LMIC regardless of HIV status.

There is a paucity of well-described or large studies in children compared to in adults. There was significant heterogeneity in the studies included in the review, and few studies reported important confounding factors such as use of co-trimoxazole prophylaxis, age at ART initiation and CD4 count. Also, regional differences could not be examined due to a limited number of studies in Latin America and Asia.

Notwithstanding these limitations, ART has resulted in a substantial cost-saving due to the numbers of OIs averted by use of ART. The 2015 WHO guidelines now recommend ART initiation in all children and this is likely to have an even larger impact on the incidence of OIs and mortality. Along with this, strategies to reduce the burden of TB and pneumonia in children are urgently needed.

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Near-patient TB test reduces hospital deaths in HIV-positive adults

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. 

Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, Mehta N, Calligaro G, Lombard CJ, Kadzirange G, Bandason T, Chansa A, Liusha N, Mangu C, Mtafya B, Msila H, Rachow A, Hoelscher M, Mwaba P, Theron G, Dheda K. Lancet. 2016 Mar 19;387(10024):1187-97. doi: 10.1016/S0140-6736(15)01092-2. Epub 2016 Mar 10.

Background: HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.

Methods: We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weight loss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with, number NCT01770730.

Findings: Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0.83 (95% CI 0.73-0.96), p=0.012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0.82 [95% CI 0.70-0.96], p=0.015). No adverse events were associated with LAM testing.

Interpretation: Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital in-patients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum.

Abstract access  

Editor’s notes: TB is a leading cause of hospitalization and in-hospital death among people living with HIV worldwide. This randomised controlled trial in southern Africa provides strong evidence of the impact of a simple, urine-based test in HIV-positive adults admitted to hospital with symptoms of TB. Use of the lateral flow lipoarabinomannan (LAM) test, in addition to a package of routine TB diagnostic tests, led to a modest reduction in all-cause mortality. This reduction in mortality occurred despite only a small increase in the proportion starting TB treatment, suggesting that LAM testing might have enabled more precision in the identification of people with TB.

Half of all deaths occurred in people with CD4 cell count ≤50 cells/µL and the impact of the urinary LAM test was greatest in this group, as suggested by previous studies. This may lead to strengthening of WHO policy recommendations to use the lateral flow LAM test to assist with TB diagnosis in people admitted to hospital with advanced HIV and with symptoms and signs of TB. There is still no strong evidence to suggest a role for LAM testing at more peripheral levels of the health system or in people who are not seriously ill.

The heterogeneity in effect between countries is notable, although the trial was not powered to detect mortality differences at each site. The availability and use of other diagnostics (which could include sputum smear microscopy, Xpert®, chest X-ray, ultrasound and computed tomography), and the level of physician input in clinical management, differed substantially across sites and could have modified the effect of LAM testing. Additional exploration of data from this trial and from other ongoing studies should help to further define the role of urine LAM in the TB diagnostic bundle in different health care settings.

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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. 

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, Adult ACTGAST. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert® MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Abstract access

Editor’s notes: Tuberculosis (TB) remains the leading cause of death among HIV-positive people worldwide. Existing diagnostic tests for TB lack sensitivity, particularly among HIV-positive people, and autopsy studies consistently illustrate that TB is common at death, but often not identified prior to death. This has led to questions about whether empirical TB treatment, meaning treatment for TB in the absence of bacteriological confirmation, should be more widely used among HIV-positive people.

This trial compared empirical TB treatment to isoniazid preventive therapy among adult outpatients with very low CD4 counts starting antiretroviral therapy (ART). People could be enrolled in the study if they did not have confirmed or suspected TB based on symptoms, locally-accessible diagnostic tests (including chest radiography and sputum smear) and, when available, testing with Xpert® MTB/RIF. There was no difference in mortality at six months between participants given empirical TB treatment compared to isoniazid preventive therapy. Mortality was remarkably low overall, particularly considering that participants had very low CD4 counts. It seems likely that the enrolment criteria excluded people at highest risk of death from participating in the study.

Screening for TB at the time of starting ART could reduce mortality if the tests are sufficiently sensitive, and if people identified to have TB receive effective treatment. However, this study was not designed to address how best to do this in resource-limited settings, where chest radiography and Xpert® MTB/RIF are often not accessible. This study does suggest that isoniazid preventive therapy can be given at the time of ART initiation among people who have been effectively screened for TB. The results of other studies of empirical TB treatment, with different designs in different populations, are awaited. Data from all these studies together may provide evidence to guide the optimal package of care for people presenting with advanced HIV disease. 

Comorbidity, HIV Treatment
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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Shorter treatment for latent TB infection?

Three months of weekly rifapentine plus isoniazid for treatment of M. tuberculosis infection in HIV co-infected persons. 

Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, Chen MP, Benator DA, Gordin F, Benson CA, Chaisson RE, Villarino ME, Tuberculosis Trials Consortium, the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26 ACTG 5259). AIDS. 2016 Mar 17. [Epub ahead of print]

Objective: Compare the effectiveness, tolerability, and safety of three months of weekly rifapentine plus isoniazid under direct observation (3HP) vs. 9 months of daily isoniazid (9H) in HIV-infected persons.

Design: prospective, randomized, open-label non-inferiority trial.

Setting: U.S., Brazil, Spain, Peru, Canada, and Hong Kong.

Participants: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.

Intervention: 3HP vs. 9H.

Main outcome measures: The effectiveness endpoint was tuberculosis; the non-inferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation due to adverse drug reaction.

Results: Median baseline CD4+ counts were 495 (IQR: 389-675) and 538 (IQR: 418-729) cells/mm3 in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention to treat analysis, there were two tuberculosis cases among 206 persons (517 person-years (p-y) of follow-up) in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01% vs. 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval (CI) of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation due to an adverse drug reaction was similar (3% vs. 4%; P = 0.79) in 3HP and 9H, respectively.

Conclusions: Among HIV-infected persons with median CD4+ count of approximately 500 cells/mm3, 3HP was as effective and safe for treatment of latent M. tuberculosis infection as 9H, and better tolerated.

Abstract access 

Editor’s notes: People with HIV are at higher risk of reactivation of latent tuberculosis (TB). The standard treatment for latent TB, with six to nine months of daily isoniazid, is effective, but treatment completion rates are typically low, and implementation has been poor. Shorter, effective regimens to treat latent TB are therefore necessary, and rifapentine and isoniazid, given weekly for 12 weeks, is one such candidate regimen. The analysis reported in this paper is a sub-study of a larger trial which was reported in 2011 (Sterling et al, NEJM 2011;365:2155). The main trial was open to people regardless of HIV status, but few HIV-positive people were enrolled. Trial enrolment was therefore continued for HIV-positive people, and this paper reports outcomes among this group.

Although the number of tuberculosis events was very small in this sub-study (two versus six people developed tuberculosis in the rifapentine-isoniazid versus isoniazid only arms), the rifapentine-isoniazid regimen, given directly-observed, was non-inferior to self-administered isoniazid, similar to the results of the main trial. Treatment completion was substantially better with the rifapentine-isoniazid regimen, as expected for a shorter regimen given under direct observation. The rifapentine-isoniazid regimen was equally well-tolerated to the isoniazid-only regimen.

This study provides evidence that rifapentine-isoniazid has potential as an alternative to isoniazid for the treatment of latent tuberculosis among HIV-positive people. Several questions remain. Weekly directly-observed therapy could be difficult to implement in resource-limited settings, especially if people are required to travel to health centres to receive their weekly dose, and the effectiveness of this regimen is uncertain when self-administered. The weekly dose represents a substantial pill burden unless combination tablets are available, and there are potential drug interactions between rifapentine and some antiretroviral agents. Further research is necessary to establish whether, in settings where the risk of tuberculosis reinfection is high, a single 12-week course of rifapentine-isoniazid has a long-lasting effect.

Comorbidity, HIV Treatment
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Routine use of steroids harmful in cryptococcal meningitis

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN, CryptoDex Investigations. N Engl J Med. 2016 Feb 11;374(6):542-54. doi: 10.1056/NEJMoa1509024.

Background: Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600 000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis.

Methods: In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole.

Results: The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.

Conclusions: Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Abstract  Full-text [free] access 

Editor’s notes: Outcomes from cryptococcal meningitis in people living with HIV are very poor. This was highlighted here. Three out of five people overall had died or were severely disabled ten weeks after enrolment. This clinical trial provides strong evidence that steroids cause more harm than good and therefore routine use should not be recommended. Dexamethasone was not only associated with higher risk of death or disability but also with higher risk of significant adverse events, particularly bacterial sepsis.

The majority of deaths occurred early, in the first three weeks. Most participants were ART naïve and severely immunosuppressed (CD4+ cell count <50 cells/µL) and most deaths look to have occurred prior to the scheduled start of antiretroviral therapy. This may also partly explain the low frequency of immune reconstitution inflammatory syndrome (IRIS) and the lack of any observed benefit of dexamethasone in reducing IRIS.

Although dexamethasone was associated with greater decline in intracranial pressure, this did not translate into improved neurological outcomes. All participants had regular lumbar punctures for pressure monitoring. This might have limited the potential to observe a benefit from dexamethasone. Some explanation for the adverse outcomes might come from the impaired fungal clearance in cerebrospinal fluid – a marker of poor outcomes in previous studies. It should be noted that antifungal treatment in this trial was suboptimal. The combination of amphotericin and flucytosine was not used, despite evidence of improved outcomes and more rapid fungal clearance with this regimen.

While the search should go on for better treatment strategies, the findings in this study emphasise the importance of prevention, focused firmly, on earlier HIV diagnosis and treatment.  

Comorbidity, HIV Treatment
Indonesia, Laos, Malawi, Thailand, Uganda, Viet Nam
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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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CrAg screening needs strengthened implementation in South Africa

Evaluation of a public-sector, provider-initiated cryptococcal antigen screening and treatment program, western Cape, South Africa.

Vallabhaneni S, Longley N, Smith M, Smith R, Osler M, Kelly N, Cross A, Boulle A, Meintjes G, Govender NP. J Acquir Immune Defic Syndr. 2016 Feb 29. [Epub ahead of print]

Background: Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and pre-emptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012-August 31, 2013.

Methods: We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened.

Results: Of 4395 eligible patients, 26.6% (n=1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg-positive patients; nine of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (p=0.07).

Conclusions: Relatively few eligible patients were screened under the WC provider-initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible.

Abstract access  

Editor’s notes: Cryptococcus, a ubiquitous soil fungus, can cause cryptococcal meningitis (CM) or disseminated cryptococcal disease (DCD), which is often fatal among people with advanced HIV disease.  Despite antiretroviral therapy availability, CM is now the leading cause of adult meningitis in sub-Saharan Africa with a mortality of up to 70% at 12 weeks in low-income settings. Asymptomatic individuals with a positive serum cryptococcal antigen (CrAg) and low CD4 counts are at a high risk of progression to disease. Identifying these individuals and initiating pre-emptive treatment to reduce morbidity and mortality forms the rationale for the inclusion of CrAg screening in the South African national guidelines.

This evaluation of the public sector provider-initiated CrAg screening and treatment programme in the western Cape revealed disappointing coverage during the first year of implementation. A laboratory-based reflex testing strategy, where the CrAg test is performed in the laboratory on any blood sample with CD4<100 may improve screening coverage. But, this requires adequate laboratory infrastructure and needs to be paired with optimal uptake of pre-emptive fluconazole among people with a positive CrAg result. In this study, uptake of fluconazole was lower than desired with about a third of eligible patients, for whom records were available, lacking any evidence of receiving fluconazole. In addition, a significantly higher proportion of people screened started ART compared with people who were not screened. This might partly explain the reduced incidence of cryptococcal disease in the screened group. 

A stepped-wedge randomised trial evaluating CrAg screening in Uganda, presented at CROI 2016, found that one-third of persons with baseline CrAg titre of ≥1:160 died, despite receiving recommended pre-emptive fluconazole therapy. This suggests that semi-quantitative CrAg screening may be required to identify people at risk of death in whom more potent antifungal therapy may be necessary. The very high mortality in CrAg-positive patients despite antifungal therapy suggests that, for people at highest risk, CrAg screening should be implemented as part of a combined opportunistic infection screening and intervention package, including more intensive follow-up.

South Africa
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