Articles tagged as "Avoid TB deaths"

Following TB diagnostic algorithms: could do better

What happens after a negative test for tuberculosis? Evaluating adherence to TB diagnostic algorithms in South African primary health clinics.

McCarthy K, Grant AD, Chihota V, Ginindza S, Mvusi L, Churchyard G, Fielding K. J Acquir Immune Defic Syndr. 2015 Nov 25. [Epub ahead of print]

Introduction and background: Diagnostic tests for tuberculosis (TB) using sputum have suboptimal sensitivity among HIV-positive persons. We assessed health care worker adherence to TB diagnostic algorithms after negative sputum test result/s.

Methods: The XTEND trial compared outcomes among people tested for TB in primary care clinics using Xpert® MTB/RIF vs. smear microscopy as the initial test. We analysed data from XTEND participants who were HIV-positive or HIV status unknown, whose initial sputum Xpert® MTB/RIF or microscopy result was negative. If chest radiography, sputum culture or hospital referral took place, the algorithm for TB diagnosis was considered followed. Analysis of intervention (Xpert® MTB/RIF) effect on algorithm adherence used methods for cluster-randomised trials with small number of clusters.

Results: Amongst 4037 XTEND participants with initial negative test results, 2155 (53%) reported being or testing HIV positive and 540 (14%) had unknown HIV status. Amongst 2155 HIV-positive participants (684 [32%] male, mean age 37 years [range 18-79 years]), there was evidence of algorithm adherence amongst 515 (24%). Adherence was less likely among persons tested initially with Xpert® MTB/RIF vs. smear (14% [142/1031] vs 32% [364/1122], adjusted risk ratio 0.34 [95% CI 0.17-0.65]) and for participants with unknown vs. positive HIV status (59/540 [11%] vs. 507/2155 [24%]).

Conclusions: We observed poorer adherence to TB diagnostic algorithms amongst HIV-positive persons tested initially with Xpert® MTB/RIF vs. microscopy. Poor adherence to TB diagnostic algorithms and incomplete coverage of HIV testing represents a missed opportunity to diagnose TB and HIV, and may contribute to TB mortality.

Abstract access

Editor’s notes: Despite advances in the TB diagnostic field in recent years, molecular tests such as Xpert® MTB/RIF will still miss a substantial proportion of HIV-positive people with active TB disease. For that reason, diagnostic algorithms have been developed to guide further evaluation of people with symptoms suggestive of TB who test negative with Xpert®. This paper presents findings from South Africa that, in the context of a cluster-randomised trial, few people received further investigation according to the algorithm.

Only one in seven of the HIV-positive people with a negative Xpert® MTB/RIF had any further investigations recorded. Sputum culture was the most common investigation in this group but was done for only around one in ten. It should be noted that the outcome of having further investigations was largely based on review of clinic and laboratory records. As a result, it is possible that additional investigations were performed but remained undocumented. Although considerable between-clinic variation in performance was noted, the reasons underlying this were not explored in this analysis. The algorithm for people living with HIV was not overly complex and was broadly similar to the algorithm in place previously for investigation of people with a negative sputum smear. The observation that algorithm adherence was lower than for people with a negative smear suggests that health care workers might have had false confidence in the negative Xpert® result. In the broader context, this study took place at a time when there was much hype around Xpert® as a tool that would revolutionise the diagnosis of TB. It would not be surprising if this resulted in health care workers being over-confident in their interpretation of negative test results.

There are other possible explanations for the low numbers having additional investigations:

  • People may not have returned for their initial test result so further investigation was not possible (this is not quantified here)
  • People did return but symptoms had fully resolved or they were unable to produce sputum for further investigation
  • Health care workers used clinical judgement to decide on the need for further investigation rather than adhering strictly to the algorithm. This is supported at least partly by the fact that people with more TB symptoms were more likely to receive additional investigations. The yield of culture is not reported here – that might have given a further clue as to whether the people selected to have further investigations were individuals with a high likelihood of TB.  

These issues and others may need to be explored in future analyses to determine whether modifications to the algorithm are required or whether strengthened training and support of health care workers would improve adherence to the algorithm.

Avoid TB deaths
Africa
South Africa
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ART for people living with TB and HIV: practice still lags behind policy

The impact of HIV status and antiretroviral treatment on TB treatment outcomes of new tuberculosis patients attending co-located TB and ART services in South Africa: a retrospective cohort study.

Nglazi MD, Bekker LG, Wood R, Kaplan R. BMC Infect Dis. 2015 Nov 19;15(1):536. doi: 10.1186/s12879-015-1275-3.

Background: The implementation of collaborative TB-HIV services is challenging. We, therefore, assessed TB treatment outcomes in relation to HIV infection and antiretroviral therapy (ART) among TB patients attending a primary care service with co-located ART and TB clinics in Cape Town, South Africa.

Methods: In this retrospective cohort study, all new TB patients aged ≥ 15 years who registered and initiated TB treatment between 1 October 2009 and 30 June 2011 were identified from an electronic database. The effects of HIV-infection and ART on TB treatment outcomes were analysed using a multinomial logistic regression model, in which treatment success was the reference outcome.

Results: The 797 new TB patients included in the analysis were categorized as follows: HIV- negative, in 325 patients (40.8 %); HIV-positive on ART, in 339 patients (42.5 %) and HIV-positive not on ART, in 133 patients (16.7 %). Overall, bivariate analyses showed no significant difference in death and default rates between HIV-positive TB patients on ART and HIV-negative patients. Statistically significant higher mortality rates were found among HIV-positive patients not on ART compared to HIV-negative patients (unadjusted odds ratio (OR) 3.25; 95 % confidence interval (CI) 1.53-6.91). When multivariate analyses were conducted, the only significant difference between the patient categories on TB treatment outcomes was that HIV-positive TB patients not on ART had significantly higher mortality rates than HIV-negative patients (adjusted OR 4.12; 95 % CI 1.76-9.66). Among HIV-positive TB patients (n = 472), 28.2 % deemed eligible did not initiate ART in spite of the co-location of TB and ART services. When multivariate analyses were restricted to HIV-positive patients in the cohort, we found that being HIV-positive not on ART was associated with higher mortality (adjusted OR 7.12; 95 % CI 2.95-18.47) and higher default rates (adjusted OR 2.27; 95 % CI 1.15-4.47).

Conclusions: There was no significant difference in death and default rates between HIV-positive TB patients on ART and HIV negative TB patients. Despite the co-location of services 28.2% of 472 HIV-positive TB patients deemed eligible did not initiate ART. These patients had a significantly higher death and default rates.

Abstract Full-text [free] access

Editor’s notes: There is clear evidence that for people with TB and HIV, particularly individuals with low CD4+ cell counts (<350 cells/µL), being on antiretroviral therapy (ART) during TB treatment reduces the risk of mortality. However, practice still lags far behind policy in this area, as in 2013, globally, only around a third of known HIV-positive people with TB were treated with ART. This paper from a single health centre in South Africa highlights the impact of this treatment gap, and emphasizes the fact that co-location of TB and HIV services does not always translate to integrated patient-centred care.

The people included in this analysis were treated for TB between 2009 and 2011, which was before South Africa adopted guidelines recommending ART for all people with TB testing positive for HIV. Nevertheless, the majority of the people living with HIV had CD4+ cell counts that would have made them eligible for ART at the time of the study. Although overall outcomes were relatively good, one in six people starting TB treatment died or were lost to follow-up. Mortality among HIV-positive people not on ART was substantially higher than individuals on ART and people who were HIV-negative. One in four people who were ART-eligible did not start ART. It was not clear whether some did not start ART because they had already died or had been lost to follow-up. In this analysis, there was no differentiation between people already on ART at the time of starting TB treatment and people who started ART during TB treatment.

This study illustrates that co-location of HIV and TB services does not necessarily meet peoples’ needs if care remains fragmented. Care was provided by different people, and the HIV and TB programmes had separate organizational structures, as is still common. Workable models of integrated, patient-centred care for HIV and TB are necessary. Furthermore, to achieve targets of ending TB deaths, we still need a deeper understanding of why people die after starting TB treatment.  

Avoid TB deaths
Africa
South Africa
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Can cryptococcal antigen screening and treatment improve outcomes?

Cryptococcal antigen screening in patients initiating ART in South Africa: a prospective cohort study.

Longley N, Jarvis JN, Meintjes G, Boulle A, Cross A, Kelly N, Govender NP, Bekker LG, Wood R, Harrison TS. Clin Infect Dis. 2015 Nov 12. pii: civ936. [Epub ahead of print]

Background: Retrospective data suggest that cryptococcal antigen (CrAg) screening in patients with late-stage HIV initiating antiretrovirals may reduce cryptococcal disease and deaths. Prospective data are limited.

Methods: CrAg was measured using lateral flow assays (LFA) and latex agglutination (LA) tests in 645 HIV-positive, ART-naive patients with CD4 counts ≤100 cells/µL in Cape Town, South Africa. CrAg-positive patients were offered lumbar puncture (LP) and treated with antifungals. Patients were started on ART between 2-4 weeks and followed up for 1 year.

Results: 4.3% (28/645) of patients were CrAg-positive in serum and plasma with LFA. These included 16 also positive by urine LFA (2.5% of total screened) and 7 by serum LA (1.1% of total). In 4 of 10 LFA-positive cases agreeing to LP, the cerebrospinal fluid (CSF) CrAg-LFA was positive. A positive CSF CrAg was associated with higher screening plasma/serum LFA titres. Among the 28 CrAg-positive patients, mortality was 14.3% at 10 weeks and 25% at 12 months. Only one CrAg-positive patient, who defaulted from care, died from cryptococcal meningitis (CM). Mortality in CrAg-negative patients was 11.5% at 1 year. Only 2 possible CM cases were identified in CrAg-negative patients.

Conclusions: Cryptococcal antigen screening of individuals initiating ART and pre-emptive fluconazole treatment of CrAg-positive patients resulted in markedly fewer cases of cryptococcal meningitis compared to historic unscreened cohorts. Studies are needed to refine management of CrAg positive patients, who have high mortality that does not appear to be wholly attributable to cryptococcal disease.

Abstract   Full-text [free] access

Editor’s notes: In sub-Saharan Africa, cryptococcal meningitis is the leading cause of adult meningitis. Even with current antifungal therapies, mortality remains high. Asymptomatic cryptococcal antigenemia precedes cryptococcal meningitis and independently predicts mortality in people initiating antiretroviral therapy (ART). Therefore, preventing disease in people found to be cryptococcal antigen (CrAg) positive at ART initiation has potential to reduce morbidity and mortality.

In this prospective study in Cape Town, South Africa, people initiating ART with low CD4 counts (≤100 cells/ μL) underwent CrAg screening. People without proven cryptocococcal meningitis but with a positive cryptococcal antigen test were pre-emptively treated with oral fluconazole, and were started on ART within two to four weeks. They were followed up for a year. This approach did not lead to delays in ART initiation, and resulted in fewer cryptococcal meningitis cases. However, despite pre-emptive antifungal therapy, mortality remained twice as high among people who were CrAg positive, even after adjustment for CD4 cell count. This high mortality appears not completely attributable to cryptococcal disease, and the authors hypothesize that cryptococcal antigen positivity in itself is a marker for severe immunosuppression.

Interestingly, the authors found a lower prevalence of asymptomatic antigenaemia than expected: about 4% in this study (2011-2014) compared to 6% in a similar population in 2002 to 2005. The authors suggest that earlier HIV diagnosis and improved access to care may be the main reasons for this, proposing that reducing the duration of severe immunosuppression may reduce the risk of cryptococcal disease, either due to reactivation or rapid progression of new infection.

The authors conclude that the optimal strategies for implementing screening and the optimal pre-emptive antifungal regimen remain to be defined. Screening may best be delivered as part of a combined opportunistic infection screening and treatment package for people presenting with low CD4 counts. 

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
South Africa
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AIDS and bacterial disease remain leading causes of hospital admission

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

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

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

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

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

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

Abstract access 

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

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

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

Avoid TB deaths
Comorbidity, Epidemiology
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Some success in improving infant-feeding practices in South Africa

Effect of an integrated community-based package for maternal and newborn care on feeding patterns during the first 12 weeks of life: a cluster-randomized trial in a South African township.

Ijumba P, Doherty T, Jackson D, Tomlinson M, Sanders D, Swanevelder S, Persson LA. Public Health Nutr. 2015 Oct;18(14):2660-8. doi: 10.1017/S1368980015000099. Epub 2015 Feb 9.

Objective: To analyse the effect of community-based counselling on feeding patterns during the first 12 weeks after birth, and to study whether the effect differs by maternal HIV status, educational level or household wealth.

Design: Cluster-randomized trial with fifteen clusters in each arm to evaluate an integrated package providing two pregnancy and five postnatal home visits delivered by community health workers. Infant feeding data were collected using 24 h recall of nineteen food and fluid items.

Setting: A township near Durban, South Africa.

Subjects: Pregnant women (1894 intervention and 2243 control) aged 17 years or more.

Results: Twelve weeks after birth, 1629 (intervention) and 1865 (control) mother-infant pairs were available for analysis. Socio-economic conditions differed slightly across intervention groups, which were considered in the analyses. There was no effect on early initiation of breast-feeding. At 12 weeks of age the intervention doubled exclusive breast-feeding (OR=2.29; 95 % CI 1.80, 2.92), increased exclusive formula-feeding (OR=1.70; 95 % CI 1.28, 2.27), increased predominant breast-feeding (OR=1.71; 95 % CI 1.34, 2.19), decreased mixed formula-feeding (OR=0.68; 95 % CI 0.55, 0.83) and decreased mixed breast-feeding (OR=0.54; 95 % CI 0.44, 0.67). The effect on exclusive breast-feeding at 12 weeks was stronger among HIV-negative mothers than HIV-positive mothers (P=0.01), while the effect on mixed formula-feeding was significant only among HIV-positive mothers (P=0.03). The effect on exclusive feeding was not different by household wealth or maternal education levels.

Conclusions: A perinatal intervention package delivered by community health workers was effective in increasing exclusive breast-feeding, exclusive formula-feeding and decreasing mixed feeding.

Abstract access 

Editor’s notes: This trial assesses the provision of an integrated package of motivational interviewing-based counselling during home visits by systematically supervised, remunerated full-time community health workers on breastfeeding practices. It found stronger effects among HIV negative mothers than mothers living with HIV. This is particularly important in the context of a setting where exclusive breast feeding is practised by only 8% of mothers and where messages have been mixed about the safety of breastfeeding among mothers living with HIV. The smaller effect among mothers living with HIV may be a legacy of the free provision of formula to these mothers from 2002 to 2011, and cultural feeding practices. Exit interviews with the community health workers revealed that no mothers had exclusively breast-fed their babies, and this may have influenced their delivery of the programme. Further work is necessary to communicate messages on the need for exclusive breast feeding among mothers living with HIV.

Avoid TB deaths
Africa
South Africa
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Tracing the origins of extensively drug-resistant TB

Evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of mycobacterium tuberculosis isolates from Kwazulu-Natal.

Cohen KA, Abeel T, Manson McGuire A, Desjardins CA, Munsamy V, Shea TP, Walker BJ, Bantubani N, Almeida DV, Alvarado L, Chapman SB, Mvelase NR, Duffy EY, Fitzgerald MG, Govender P, Gujja S, Hamilton S, Howarth C, Larimer JD, Maharaj K, Pearson MD, Priest ME, Zeng Q, Padayatchi N, Grosset J, Young SK, Wortman J, Mlisana KP, O'Donnell MR, Birren BW, Bishai WR, Pym AS, Earl AM. PLoS Med. 2015 Sep 29;12(9):e1001880. doi: 10.1371/journal.pmed.1001880. eCollection 2015.

Background: The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents.

Methods and findings: We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of Mycobacterium tuberculosis collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR M. tuberculosis that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (katG S315T [isoniazid]; gidB 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937-1971]), with the subsequent emergence of MDR and XDR occurring 20 y (rpoB L452P [rifampicin]; pncA 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974-1992]) and 10 y (rpoB D435G [rifampicin]; rrs 1400 [kanamycin]; gyrA A90V [ofloxacin]; 1995 [95% HPD: 1988-1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe.

Conclusions: In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.

Abstract  Full-text [free] access

Editor’s notes: Drug-resistant TB is estimated to be responsible for over 500 deaths globally every day, many of which are in people living with HIV. Improved understanding of how drug-resistant TB emerges and spreads in certain populations could help to inform the development of effective population-level programmes to eliminate TB. This study was conducted in KwaZulu-Natal, South Africa, an area with the highest population rates of drug-resistant TB in the world and the location of the largest ever outbreak of extensively drug-resistant TB (XDR-TB) in 2005-6. This study was not a population-based survey but rather 337 Mycobacterium tuberculosis isolates collated from different studies over a five year period (2008-2013), 20% of which were XDR-TB. Genetic analysis demonstrated that multidrug-resistant TB (MDR-TB) may have first emerged around 30 years ago and XDR-TB around 20 years ago in this region. The analysis highlighted that the current burden of drug resistance in this province is driven both by the transmission of drug-resistant strains and the emergence of new resistant strains. Unfortunately, although there were some data on HIV status of individual cases, the study design did not allow for an assessment of the impact of HIV on the emergence and spread of TB drug resistance. These data suggest that, in settings like KwaZulu-Natal, population-level strategies to interrupt drug-resistant TB transmission and to prevent the emergence of drug resistance will need to be combined effectively in order to eliminate TB.         

Avoid TB deaths
Basic science, Comorbidity
Africa
South Africa
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Invasive cervical cancer and HIV – young women need access to screening

Implementation and operational research: age distribution and determinants of invasive cervical cancer in a "screen-and-treat" program integrated with HIV/AIDS care in Zambia.

Kapambwe S, Sahasrabuddhe VV, Blevins M, Mwanahamuntu MH, Mudenda V, Shepherd BE, Chibwesha CJ, Pfaendler KS, Hicks ML, Vermund SH, Stringer JS, Parham GP. J Acquir Immune Defic Syndr. 2015 Sep 1;70(1):e20-6. doi: 10.1097/QAI.0000000000000685.

Background: Cervical cancer screening efforts linked to HIV/AIDS care programs are being expanded across sub-Saharan Africa. Evidence on the age distribution and determinants of invasive cervical cancer (ICC) cases detected in such programs is limited.

Methods: We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia, the largest public sector programs of its kind in sub-Saharan Africa. We examined age distribution patterns by HIV serostatus of histologically confirmed ICC cases and used multivariable logistic regression to evaluate independent risk factors for ICC among younger (≤35 years) and older (>35 years) women.

Results: Between January 2006 and April 2010, of 48 626 women undergoing screening, 571 (1.2%) were diagnosed with ICC, including 262 (46%) HIV seropositive (median age: 35 years), 131 (23%) HIV seronegative (median age: 40 years), and 178 (31%) of unknown HIV serostatus (median age: 38 years). Among younger (≤35 years) women, being HIV seropositive was associated with a 4-fold higher risk of ICC [adjusted odds ratio = 4.1 (95% confidence interval: 2.8, 5.9)] than being HIV seronegative. The risk of ICC increased with increasing age among HIV-seronegative women and women with unknown HIV serostatus, but among HIV-seropositive women, the risk peaked around age 35 and nonsignificantly declined with increasing ages. Other factors related to ICC included being married (vs. being unmarried/widowed) in both younger and older women, and with having 2+ (vs. ≤1) lifetime sexual partners among younger women.

Conclusions: HIV infection seems to have increased the risk of cervical cancer among younger women in Zambia, pointing to the urgent need for expanding targeted screening interventions.

Abstract access 

Editor’s notes: Increasingly, HIV care services (includes AIDS) are providing platforms for introduction of cervical cancer screening programmes in sub-Saharan Africa. Screening is often also available for HIV-negative women. This analysis of data from a large routine programme gives a useful indication of the rates of identification of invasive cervical cancer (ICC), and describes the burden and distribution of disease; information relevant to future service provision. The association described of ICC with HIV and sexual behaviour is well-known. The findings highlight the importance of ensuring that younger women (especially if known to be HIV-positive) have access to routine screening. A significant part of the burden is borne by older women. HIV status may not always be known or revealed. Important questions remain concerning the cost-benefit of providing screening services and the effect of ART on risk of ICC. In addition, the potential role of human papilloma virus vaccine, which GAVI is currently implementing in demonstration projects in the region, in influencing the risk of ICC in younger women remains to be determined. 

Avoid TB deaths
Cancers, HIV
Africa
Zambia
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Understanding delays in TB diagnosis: where do people go before accessing TB services?

Four degrees of separation: social contacts and health providers influence the steps to final diagnosis of active tuberculosis patients in urban Uganda.

Sekandi JN, Zalwango S, Martinez L, Handel A, Kakaire R, Nkwata AK, Ezeamama AE, Kiwanuka N, Whalen CC. BMC Infect Dis. 2015 Aug 21;15:361. doi: 10.1186/s12879-015-1084-8.

Background: Delay in tuberculosis (TB) diagnosis adversely affects patients' outcomes and prolongs transmission in the community. The influence of social contacts on steps taken by active pulmonary TB patients to seek a diagnosis has not been well examined.

Methods: A retrospective study design was use to enroll TB patients on treatment for 3 months or less and aged ≥18 years from 3 public clinics in Kampala, Uganda, from March to July 2014. Social network analysis was used to collect information about social contacts and health providers visited by patients to measure the number of steps and time between onset of symptoms and final diagnosis of TB.

Results: Of 294 TB patients, 58% were male and median age was 30 (IQR: 24-38) years. The median number of steps was 4 (IQR: 3, 7) corresponding to 70 (IQR: 28,140) days to diagnosis. New patients had more steps and time to diagnosis compared retreatment patients (5 vs. 3, P < 0.0001; 84 vs. 46 days P < 0.0001). Fifty-eight percent of patients first contacted persons in their social network. The first step to initiate seeking care accounted for 41 % of the patients' time to diagnosis while visits to non-TB providers and TB providers (without a TB diagnosis) accounted for 34 % and 11 % respectively. New TB patients vs. retreatment (HR: 0.66, 95 % CI; 1.11, 1.99), those who first contacted a non-TB health provider vs. contacting social network (HR: 0.72 95 % CI; 0.55, 0.95) and HIV seronegative vs. seropositive patients (HR: 0.70, 95 % CI; 0.53, 0.92) had a significantly lower likelihood of a timely final diagnosis.

Conclusions: There were four degrees of separation between the onset of symptoms in a TB patient and a final diagnosis. Both social and provider networks of patients influenced the diagnostic pathways. Most delays occurred in the first step which represents decisions to seek help, and through interactions with non-TB health providers. TB control programs should strengthen education and active screening in the community and in health care settings to ensure timely diagnosis of TB.

Abstract  Full-text [free] access

Editor’s notes: Delays in tuberculosis diagnosis are well documented in the literature and barriers to diagnosis exist in the community and the health system. This study, in an urban setting in Uganda, included a more in-depth exploration of the steps people take when symptomatic before receiving a TB diagnosis. The median time from onset of symptoms to diagnosis was over two months and the majority of people sought help from relatives and friends and non-TB providers (e.g. private clinics or pharmacies) before accessing public health facilities. There was evidence that having been treated for TB previously reduced the delay, suggesting that existing knowledge of TB in these cases may have influenced their health-seeking behaviour. It was also of interest that delays to diagnosis were greater in HIV-negative people, although it was not possible to establish whether that related to different access to care or to different patterns or severity of symptoms. This is of particular interest because it is thought that in communities with high HIV prevalence, most TB transmission may be attributable to HIV-negative people with active TB.

This study highlights the potential risk of TB transmission in the community during the pre-diagnostic phase. It seems clear that to interrupt TB transmission we need to develop programmes that go beyond public health facilities and this underlines the need for broad community engagement and education as well as more focused programmes to facilitate links between other health care providers and TB services. It is also important to remember that to interrupt transmission we must ensure that TB services and programmes are accessible to HIV-negative people as well as people living with HIV. 

Avoid TB deaths
Africa
Uganda
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HIV-related cancer risk declines with ART in Botswana and Uganda, but population burden a major concern

Cancer incidence following expansion of HIV treatment in Botswana

Dryden-Peterson S, Medhin H, Kebabonye-Pusoentsi M, Seage GR, 3rd, Suneja G, Kayembe MK, Mmalane M, Rebbeck T, Rider JR, Essex M, Lockman S. PLoS One. 2015 Aug 12;10(8):e0135602. doi: 10.1371/journal.pone.0135602. eCollection 2015.

Background: The expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa.

Methods: We included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003-2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage.

Findings: During this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi's sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%).

Interpretation: Expansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.

Abstract  Full-text [free] access


 

A population-level evaluation of the effect of antiretroviral therapy on cancer incidence in Kyadondo county, Uganda, 1999-2008.

Mutyaba I, Phipps W, Krantz EM, Goldman JD, Nambooze S, Orem J, Wabinga HR, Casper C. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):481-6. doi: 10.1097/QAI.0000000000000620.

Background: The introduction of antiretroviral therapy (ART) in the United States and Europe has led to changes in the incidence of cancers among HIV-infected persons, including dramatic decreases in Kaposi sarcoma and non-Hodgkin lymphoma, and increases in Hodgkin lymphoma, liver, and anogenital malignancies. We sought to evaluate whether increasing availability of ART is associated with changing cancer incidence in Uganda.

Methods: Incident cases of 10 malignancies were identified from Kampala Cancer Registry from 1999 to 2008. ART coverage rates for Uganda were abstracted from the Joint United Nations Program on HIV/AIDS reports. Negative binomial and Poisson regression modeled the association between ART coverage and age-adjusted cancer incidence.

Results: ART coverage in Uganda increased from 0% to 43% from 1999 to 2008. With each 10% increase in ART coverage, incidence of Kaposi sarcoma decreased by 5% [incidence rate ratio (IRR) = 0.95, 95% confidence interval: 0.91 to 0.99, P = 0.02] and stomach cancer decreased by 13% [IRR = 0.87 (95% CI: 0.80 to 0.95), P = 0.002]. Conversely, incidence of non-Hodgkin lymphoma increased by 6% [IRR = 1.06 (95% CI: 1 to 1.12), P = 0.05], liver cancer by 12% [IRR = 1.12 (95% CI: 1.04 to 1.21), P = 0.002], prostate cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.10), P = 0.05], and breast cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.11), P = 0.05]. ART coverage was not associated with incidence of invasive cervical cancer, lung, colon, and Hodgkin disease. These findings were similar when restricted to histologically confirmed cases.

Conclusions: Our findings suggest that AIDS-defining malignancies and other malignancies are likely to remain significant public health burdens in sub-Saharan Africa even as ART availability increases.

Abstract access 

Editor’s notes: There is increasing concern about non-communicable diseases, including cancers, in sub-Saharan Africa. The increasing population of people on antiretroviral therapy (ART) may result in increased absolute numbers of people diagnosed with cancer, presenting a major challenge to often under-resourced cancer diagnosis and treatment services. Few African countries have functional cancer registries. This month, we highlight data reported from both Botswanan and Ugandan cancer registries.

The article by Dryden-Petersen et al. presents data from the Botswanan registry from 2003-2008, a time of rapid ART roll-out. Age-adjusted rates of cancer were estimated using population survey denominators which include HIV status. The analysis distinguishes cancers occurring in HIV-positive individuals from those attributable to HIV (includes Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer). Kaposi’s sarcoma, cervix and breast cancer were the most commonly-reported cancers. Overall, against a background of increasing age-adjusted incidence of cancers, the age-adjusted incidence in the HIV-positive population decreased compared to an early peak prior to ART implementation. However, given this expanding population of survivors, the absolute numbers of reported cases remained constant. Different cancers had different trends. Cervical cancer, which affects younger women and which increased over the period studied, may be a particular focus as it is common and relatively easy to identify in the early stages.

The article by Mutyaba et al. presents data from the Ugandan cancer registry for Kyadondo county from 1999-2008, similarly a time of rapid ART roll-out. The analysis uses population denominators, and an ecologic analysis to estimate change in cancer incidence by ART coverage for 10 selected cancers, including Kaposi’s sarcoma, invasive cervical cancer and non-Hodgkin’s lymphoma. Although significant differences in the incidence rate of about half of the cancers were observed over this period, the differences per increase of ART coverage (by 10%) were modest.

These data are now somewhat out of date, but despite the limitations of use of routine data (incomplete and biased ascertainment of cancers, HIV status etc) it is clear that the burden of cancers in these two settings is unlikely to decrease and there are major implications for service provision including screening programmes. 

The findings from the two studies are consistent in showing an important decrease in Kaposi’s sarcoma with ART, but an increase in non-Hodgkin’s lymphoma. However the trends for other cancers (cervical, breast, prostate, liver and lung) are in different directions, which may reflect different ascertainment abilities, ART programmatic differences or different methods of data analysis. Overall both studies highlight that cancer is not declining as ART programmes have been rolled out.

Avoid TB deaths
Africa
Botswana, Uganda
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TEMPRANO: more evidence for early ART

A trial of early antiretrovirals and isoniazid preventive therapy in Africa.

TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015 Jul 20. [Epub ahead of print]

Background: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast.

Methods: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficieny syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies.

Results: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies.

Conclusions: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter.

Abstract  Full-text [free] access

Editor’s notes: Recommendations and guidelines on the optimal time to start antiretroviral therapy (ART) are evolving rapidly. These are driven by improved ART regimens with better safety profiles, the desire to improve further the survival and health of people living with HIV, and the need to halt HIV transmission. The TEMPRANO study in Côte d’Ivoire is among several randomised trials reporting significant benefits in severe morbidity and mortality from early ART initiation, before serious decline in CD4 count or presentation with clinical disease. Findings are consistent with the multi-site START trial (also discussed in this edition of HIV This Month) and long-term follow-up from HPTN 052 (a trial of early ART among HIV serodiscordant couples), despite the different CD4 count cut-offs, outcome definitions etc. Collectively these findings were a major focus of discussion at the International AIDS Society conference in Vancouver, Canada in July 2015, and they will shape ongoing revision of the WHO treatment guidelines. 

The TEMPRANO study looked at immediate ART (usually tenofovir-emtricitabine + efavirenz) plus or minus six months of isoniazid prophylaxis in people who did not meet the (evolving) WHO criteria for eligibility, in a rigorous, controlled trial with a 2x2 factorial design. The results illustrate significant reductions in risk of a serious event (TB or HIV-associated illness) or death attributable to both programmes over 30 months. Tuberculosis represented 42% of all primary endpoints. It should be noted that the absolute risk of serious events (TB or severe illness or death) was low in the group with higher baseline CD4 counts.

Early ART initiation will be required to meet the UNAIDS target of 90-90-90 (90% of HIV positive individuals knowing their status, 90% of people being on ART and 90% of people on ART being virally suppressed), but may only have an impact on the second of these targets. Observers recognise that the challenge of earlier diagnosis, and retention and adherence on treatment, remain barriers to maximising public health impact of the very promising results of early treatment trials.

In the TEMPRANO study a significant proportion of people screened for this study declined to participate and there was a further loss to follow-up during the study, proportions which may increase in an operational setting. There was a higher rate of short term adverse events in the earlier treatment group, relating to the toxicity of the drugs themselves.

The evidence for earlier ART in terms of individual benefit and reduction of transmission is increasing, particularly in settings with high burdens of tuberculosis and bacterial disease. The challenge will be engaging populations of healthy people and designing treatment systems and strategies to optimise that engagement. Long term follow-up of the cohorts in these trials will be informative as will trials of treatment delivery strategies.   

Avoid TB deaths
Africa
Côte d'Ivoire
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